cincinnati convention center hyatt regency cincinnati cincinnati, ohio

1138 PHARMACOTHERAPY Volume 18, Number 5 , 1998

American College of Clinical Pharmacy

1998 Annual Meeting November 8-1 1,1998

Cincinnati Convention Center Hyatt Regency Cincinnati

Cincinnati, Ohio

Encore Presentations: Abstracts marked with a n “ E ” are Encore Presentations. Encore Presentations undergo the same peer review process as d o Original Presentations, but may have been presented elsewhere or published in abstract form only prior to the 1998 Annual Meeting. For Encore Presentations, the abstract title, authors, and original citation (if provided) are published in Pharmacotherapy. The full abstract will be published in the meeting program book.

Administration 1. Rational pharmacotherapy: formulary agreements and treatment guidelines in Dutch hospitals. Roe1 Fijn, BCPS, Lolkje T.W. de Jong-van den Berg, Pharm.D., Jacobus R.B.J. Brouwers, Pharm.D.; State University Groningen, Groningen; Hospital de Tjongerschans, Heerenveen, The Netherlands.

PURPOSE: To determine the presence and activities of drug and therapeutics (D&T) committees, their management tools, and future perspectives regarding rational pharmacotherapy in Dutch hospitals. METHODS: A survey was held among clinical pharmacists in 121 Dutch Hospitals i n January 1998. Results were categorized by hospital characteristics (size, type and region) and pharmacy characteristics (number of pharmacists, status). RESULTS: The response was 99% (n=120). Ninety-eight percent of all hospitals have a D&T committee. In 89% of hospitals, the D&T committee has a statute with written regulations. In 93% of the hospitals formulary agreements were available. From these hospitals 60% had a restrictive formulary and only 11% had access to an electronic formulary. Only 67 (56%) of the clinical pharmacists had a positive opinion on formulary agreements. Most of the clinical pharmacists had a positive attitude toward antibiotic policy (98%) and treatment guidelines (92%). Large hospitals and those served by hospital pharmacists more often tended to have restrictive agreements compared to small hospitals and those served by a community pharmacist. Pharmacists’ involvement in the development of guidelines was high. Furthermore i t appeared that regional agreements concerning pharmacotherapy were scarce and various. There was a great variation in impact of the formularies; some served as stocklists, where others looked like pharmacological reference booklets. CONCLUSION: Surprisingly, i t appears that only a small majority of pharmacists evaluate formularies positively as management tools. Many principal and practical drawbacks appear to be present. Pharmacists appear more restrictive in antibiotic policies than other drugs. Concerning the pharmacists’ perspectives, this study indicates that in the future the use of treatment guidelines (e.g. as in disease management) will be favored over the use of limitative drug lists (drug management). Information technology and electronic prescriptions will make the management process more comfortable.

Adverse Drug ReactionsDrug Interactions 2. Interaction of nitrofurantoin and cimetidine active transport into rat milk. Phillip M. Gerk, Pharm.D., Earl W. Paxton, B.S., Cheah Y. 00, Pharm.D., Ph.D., Patrick J. McNamara, Ph.D.; University of Kentucky, Lexington, KY.

Inadvertent transfer of medications from nursing mothers to their suckling infants continues to be a cause for concern. Milk to serum ratios (WS) may be predicted for many substances passively transferred into milk. However, cimetidine and nitrofurantoin are actively transported into rat and human milk. PURPOSE: To examine the interaction between the active transport mechanisms for cimetidine and nitrofurantoin excretion into rat milk. METHODS: In three randomized crossover studies, six lactating female rats received intravenous infusions of 1) nitrofurantoin 0.5 m f l r with and

without cimetidine 15 mghr; 2) nitrofurantoin 0.5 mghr with and without cimetidine 30 mg/hr; or 3) cimetidine 0 .5 mg/hr with and wi thout nitrofurantoin 3.75 mg/hr. Rats within each group were crossed over to receive both treatments. Steady-state milk and serum concentrations were measured by HPLC. RESULTS: The lower cimetidine infusion did not significantly change the systemic clearance (Cls) or M/S of nitrofurantoin. However, the higher cimetidine infusion significantly decreased the CIS of nitrofurantoin (2.56 * 0.39 uhr/kg vs 1.42 * 0.41 Uhr/kg, control vs cimetidine-treated; p<0.05), but did not alter its WS (21.6 * 8.8 vs 19.7 t 6.1, control vs cimetidine- treated). Nitrofurantoin significantly decreased both the CIS (2.0 * 0.3 Uhr/kg vs 1.65 + 0.2 Uhr/kg, control vs nitrofurantoin-treated; p<0.05) and the WS of cimetidine (26.6 * 4.9 vs 17.7 + 5.6, control vs nitrofurantoin- treated; p<0.05). CONCLUSION: At the concentrations achieved in these studies, cimetidine did not interact with the nitrofurantoin mammary active transport mechanism. However, nitrofurantoin did inhibit the cimetidine mammary active transport mechanism, suggesting competit ion for a common transporter.

3. Lack of pharmacokinetic and pbarmacodynamic interaction between erythromycin and argatroban. Jonathan Q. Tran, Phann.D., Lisa J. Benincosa, Ph.D., Sunita B. Sheth, M.D., Marcella Tucci, B.S., Diane K. Jorkasky, M.D., Marcie J. Hunting, Ph.D., Robert A. DiCicco, Pharm.D.; SmithKline Beecham Pharmaceuticals; Presbyterian Medical Center, University of Pennsylvania Health System, Philadelphia, PA; Texas Biotechnology Corporation, Houston, TX. 1 PURPOSE: Argatroban, a reversible thrombin inhibitor, is metabolized in vitro by CYP3A4/5. This studrevaluated the effect of erythromycin, a potent CYP3A4/5 inhibitor, on the pharmacokinetics and pharmacodynamics of argatroban during coadministration. METHODS: Fourteen healthy male volunteels were enrolled in an open- label, crossover study with a 5-day washout between regimens. Argatroban 1 mg/kg/min was infused alone for 5 hours (regimen A) and again after the fifth day of a 7-day regimen of 500 mg PO erythromycin four times daily (regimen B). Blood samples for determination of activated partial thromboplastin time (aPTTland plasma argatroban concentrations were collected for up to 48 hours post dosing. Point estimates (B:A) or (B - A) and 95% confidence intervals (CI) were computed using an analysis of variance. RESULTS: Ten subjects completed the study. Data are presented as mean * SD. Argatroban area under the concentration-time curves for regimens A and B were 1015 i 234 ng.h/ml and 1018 i 193 ng.h/ml, respectively (ratio 1.01; 95% C1: 0.92, 1.11). The elimination half-life was 54.5 * 13.2 minutes for regimen A and 60.2 + 18.4 minutes for regimen B (mean difference 5.64 minutes; 95% CI: -4.59, 15.87). Baseline-adjusted aPTT was increased 1.57 * 0.11 and 1.52 * 0.12 fold for regimens A and B, respectively (mean difference -0.06; 95% C1: -0.16, 0.05). No serious adverse events or bleeding episodes occurred during the study. CONCLUSION: Erythromycin, a potent CYP3A4/5 inhibitor, had no effects on the pharmacokinetics and pharmacodynamics of argatroban in healthy volunteers. These data suggest that CYP3A4/5 is unlikely an important in vivo elimination pathway for argatroban.

4. Variability in amphotericin B formulations. John D. Cleary, Phann.D., P. David Rogers, Pharm.D., Stanley W. Chapman, M.D.; University of Mississippi, Jackson, MS.

PURPOSE Variability in toxicity was observed with amphotericin B (AMB) formulations. We evaluated each formulation for AMB quantity, toxicity to human cells, and endotoxin contamination. METHODS: We evaluated AMB formulated by Sigma, Apothecon, VHA, Pharma Tek, Pharmacia, Gensia and lipid formulations by Sequus, Liposome, and Nexstar Pharmaceuticals. The amount of AMB in each vial was quantitated by ELlSA of a 5 mg aliquot. Toxicity to human mononuclear cells (THP-1:ATCC) maintained in culture was evaluated by diluting cells to 5x106 cells/ml and placing 1.0 ml in Coster 24 well culture plates. Cells were incubated at 37°C in 5% C 0 2 for 20 hours in serum enriched media and AmB 2.5 or 5 pg/ml. Supernatants were assayed for interleukin-lp (IL-1) by ELISA as a marker for toxicity. Endotoxin was measured by LAL assay. RESULTS: Apothecon AMB was the standard of comparison. VHA contained equal amounts of AMB compared to Apothecon. However, Pharma Tek, Pharmacia, and Gensia AMB contained significantly more amphotericin, 111% to 268%. Lipid formulations were measured at 23.8-43.9% of AMB controls. THP-1 cells exposed to VHA AMB expressed equal amounts of 1L-1 compared to Apothecon 2.5 pg/ml (IL-1 = 103.8 * 11.7 pg/ml) and 5 pg/ml (IL-1 = 367.8 * 31.6 pg/ml). However, Pharma Tek and Pharmacia brands expressed 38 to 65% more IL-1. Gensia and the lipid formulations expressed less cytokine. No samples tested were positive for endotoxin a t concentrations used. CONCLUSION: AMB formulations appear to differ in their amphotericin content and toxicity. Further investigation of these products will be required to elucidate this observation and identify the toxic components.

ACCP 1998 ANNUAL MEETING ABSTRACTS 1139

5. Response time measurement via the Internet. RolfJ. Martin, Ph.D.; H.R. Herbs, Sherman, CT.

PURPOSE: Concerns about sedative side-effects of pharmaceutical agents fJ Am Geriatr Soc 1998;46:8-13) can be addressed in part by inexpensive, readily accessible software for psychometric measurement. Such software is now available over the Internet at http~/members.uipod.com/-ResponseTimelMeasurement.htm (capitals required). Comments and recommendauons are invited so that thii site can develop into a useful resource for the medical research and health care communities. METHODS: Simple visual response time is measured when site visitors click on a button after a visual stimulus has been presented. A delay of 2 to 10 seconds between each presentation ensures that no response rhythm develops when measurements are repeated. Software at this site performs calibration tests before, during, and after each response to evaluate the precision of time measurements in each computer administering the test. RESULTS: To date, reaction time data have been collected from 52 individuals ranging in age from 7 to 73 years. Participants have measured their reaction times daily, weekly, or bi-weekly and completed a daily questionnaire for as long as 10 weeks so that the effects of age, sex, education, income level, diet, sleep, caffeine and alcohol intake, and physical and psychological factors can he measured. Data collection continues. CONCLUSION: A website that enables individuals to measure response times before, during, and after different courses of treatment can help measure short- and long-term effects of a variety of medicines and other factors that influence cognitive performance.

Analgesia 6. A prospective study of pain control in the emergency department of a university, tertiary care center. Jefirq F. Barletta, Pharm.D., Brian L. Erstad, Pharm.D., Michael Loew, M.D., Samuel M. Keim, M.D.; University of Arizona, Tucson, AZ.

PURPOSE: Pain i s the most common complaint in the emergency department (ED), but its management has not been well studied. This prospective study was designed to assess pain intensity and relief along with satisfaction of patients in the ED. METHODS: Adult patients with a primary complaint of acute pain were asked to complete a 2-part questionnaire by an independent researcher. The first part was completed upon arrival and the second part upon discharge from the ED. Patients were not permitted to view the first part of the questionnaire while filling out the second. The questionnaire utilized a visual analog scale (VAS) for measurement of pain, relief, and satisfaction, along with short answer questions. Choice of drug therapy was decided by the physician according to usual treatment methods. Statistical analysis was performed using a paired, two-sided, Student’s t-test based on VAS scores. Statistical significance was defined as p<0.05. RESULTS: Fifty-seven patients presented with pain. Of these, 30 (53%) were treated with medication. The mean VAS score of pain on admission for treated patients was 6.64 compared to discharge of 4.02 (p=O.OOOl). Untreated patients had a mean admission VAS score of 4.19. When compared to treated patients, this difference was statistically significant (p=O.OOl). A VAS score of 5.43 was reported measuring the mean amount of pain relief among treated patients. Treated patients also reported a VAS score of 6.46 measuring overall satisfaction with pain management, CONCLUSION: There was a statistical and clinical difference in levels of pain and satisfaction hetween admission and discharge in these ED patients.

Cardiology 7. In vitro metformin reverses endothelial dysfunction associated with insulin resistance. Allison Winecoff Miller, Pharm.D., Prasad V.G. Katakam, M.D., Michael R. Ujhelyi, Pharm.D.; University of Georgia; Augusta VA Medical Center, Augusta, GA.

PURPOSE: Insulin resistance (IR) impairs endothelial-mediated relaxation in both humans and animal models. To date, it is not known if treatment with insulin sensitizing agents, such as metformin (M), can reverse this defect. Prior to assessing the effect of in vivo M treatment in a rat model of IR, we sought to determine if M affects vascular function independent of its effects on insulin sensitivity, blood pressure, or lipids. Thus, the purpose of the current study was to determine the in vitro effect of M on endothelial mediated relaxation. METHODS: Sprague Dawley rats were randomized to control (C; n=7) or 1R (n=7). 1R was induced by a fructose rich diet. Mesentery arteries (-250 mM diameter) were isolated and suspended in a vessel chamber. After equilibration, M (100 mmol) or volume equivalent Krebs solution was added to the bath for 30 minutes. Arteries were then preconstricted to 40% of their resting diameter with phenylephrine. Subsequently, endothelium mediated relaxation to acetylcholine (ACh) to 10-5M) was determined by measuring changes in intraluminal diameter.

RESULTS: The dose response curve for 1R arteries was shifted down from the C curve, with a maximal relaxation (Emax) of 44 * 4% (vs 89 + 5% for C, p<O.Ol). Incubation with M reversed the impaired response to ACh in 1R arteries to normal levels (Em,, = 84 * 5%). while having no effect on ACh mLdiated relaxation in C arteries (Em,, = 89 * 3%). CONCLUSION: These data suggest that metformin directly enhances the production of one or more endothelial-derived relaxing factors in arteries from IR rats such that endothelial mediated relaxation is restored. Metformin may have promise in the treatment of vascular dysfunction associated with 1R.

8. Effect of fluoxetine on CYP2D6 expression in heart failure patients on carvedilol. Donald W. Graff. Pharm.D., Kristin M. Williamson, Pharm.D., John A. Pieper, Pharm.D., FCCP, Kirkwood F. Adams, Jr.. M.D., Stanley Carson, Pharm.D., FCCP, J. Herbert Patterson, Pharm.D., FCCP; University of North Carolina, Chapel Hill, NC.

PURPOSE. Carvedilol (C), the first beta-blocker approved for heart failure (HF), is metabolized predominantly by cytochrome P450 2D6 (CYP2D6). Fluoxetine (F) and its major metabolite, norfluoxetine, are potent inhibitors of CYP2D6. Since SSRIs are commonly administered to patients with HF, concomitant therapy may result in metabolic inhibition and enhancement of the pharmacodynamic effects of C. METHODS: Ten extensive metabolizers (EMS) of CYP2D6 with mild to moderate HF (NYHA class 1-111) each received a 30 mg dose of dextromethorphan (DM) before and after 28 days of treatment with F in a randomized, crossover study. Urine was collected for 24 hours and DM and dextrorphan (DX) molar concentrations were measured by HPLC. EM and poor metabolizer (PM) phenotype were defined as DM:DX ratios of < 0.3 and 2 0.3, respectively. RESULTS: Six males (5 receiving 50 mg C BID, one receiving 25 mg C BID) and four females (all receiving 25 mg C BID) were included, age 54.9 i 9.7 years (mean + SD). All were receiving an ACE1 and a diuretic, and 9 of 10 were receiving digoxin. The mean metabolic ratio for patients on C alone was 0.016 * 0.038 versus 0.085 * 0.102 for patients on C and F (p<O.Ol). One patient converted to a CYP2D6 PM. No adverse events or deterioration of cardiac function were observed in any of the patients. CONCLUSION: Concomitant administration of F to HF patients receiving C significantly inhibits CYP2D6 activity and may alter the pharmacokinetics of C. However, the interaction appears to be of little clinical significance.

9. The effect of amiodarone on cardiovascular morbidity and mortality in patients undergoing heart transplantation. Judy Cheng, Pharm.D., BCPS, Alan Gass, M.D., Steven Lansman, M.D., Ph.D., Davendra Mehta, M.D., Ph.D.; Arnold &I Marie Schwartz College of Pharmacy and Health Sciences, Brooklyn, NY; Mount Sinai Medical Center, New York, NY.

PURPOSE To evaluate the effect of amiodarone therapy on cardiovascular morbidity and mortality in patients undergoing cardiac transplantation. METHODS: This was a retrospective cohort study. Patients over 18 years old who underwent first cardiac transplantation between January 1995 and December 1997 were evaluated. Demographic and clinical data, pre- and post-operative hemodynamics, surgical parameters, post-operative inotropes and vasopressors used, and perioperative cardiovascular events (ischemia, heart failure, arrhythmias, organ rejection, and mortality) were compared in patients receiving amiodarone versus those not receiving amiodarone prior to transplant. RESULTS: Forty-five consecutive patients were included in the analysis (12 amiodarone, 33 non-amiodarone). The two groups were similar in age, weight, pre-operative left ventricular ejection fraction, and hemodynamics. Average cumulative dose of amiodarone received was 64.4 g (range 3200 mg to 587.6 g). Amiodarone patients had longer cross-clamp time (mean 116 vs 95 minutes, p=0.004) and bypass time (mean 177 vs 140 minutes, p=O.Ol) during transplant. Post-operatively, amiodarone patients required higher doses of norepinephrine (total 9.2 vs 7.9 mg, p=0.02) and milrinone (total 118.5 vs 37.8 mg, p=0.02) therapy. While incidences of other complications were similar, immediate cardiac mortality (within 14 days post-transplant) was significantly higher in amiodarone patients (3 vs 1, p=0.02; relative risk: 8; 95% CI = 1 to 89). Cumulative doses of amiodarone received pre- transplant correlated with incidences of post-operative cardiac complications (r=0.43, p<O.Ol). CONCLUSION: Use of amiodarone is associated with hemodynamic compromise requiring higher doses of vasopressors and results in higher cardiac mortality during heart transplantation. When feasible, amiodarone therapy should he avoided in patients being considered for cardiac transplantation.

10. Physician prescribing patterns of angiotensin-converting enzyme inhibitors in secondary prevention after acute myocardial infarction. Aileen Bown Luzier, Pharm.D., Anjana Navsarikar, Pharm.D., Khalid Ashai, M.D., Michael F. Wilson, M.D.; Millard Fillmore Health System, State University of New York at Buffalo, Buffalo, NY.

PURPOSE: We evaluated physician prescribing patterns of angiotensin- converting enzyme inhibitors (ACEI), including doses prescribed, for


secondary prevention in post-acute myocardial infarction (AMI) patients, stratified by left ventricular function. In addition, utilization of aspirin and beta-blockers were also assessed. METHODS: Patients discharged from our institution post-AM1 from June 1996 to June 1997 were assessed for frequency of use and dose prescribed of aspirin, ACEI, and beta-blockers. Assessment of dose of each agent was based on doses recommended in the American Heart Association and American College of Cardiology guidelines. Left ventricular ejection fraction (EF) was obtained via echocardiogram, radionuclide study or angiogram during their admission, or stated in the admitting medical history. RESULTS A total of 535 patients were identified; age (mean i SD) was 66 + 14 years, 61% were males, and 25% had an EF of 5 40%. Percent of patients treated with each agent (Tx) and the percentage treated with the recommended dose of each agent (Tx-Rec) were:

Aspirin ACEl Beta-Blockers n= Tx Tx-Rec Tx Tx-Rec Tx Tx-Rec

Allpatients 534 87% 79% 34% 11% 57% 8% EF;40% 378 79% 65% 54% 15% 37% 4% EF540% 125 90% 84% 28% 9% 63% 10%

CONCLUSION: Medical therapy, especially ACEl therapy, is underutilized for secondary prevention in post AM1 patients. In addition, few patients receive the recommended dose of ACEI, illustrating the need for programs to ensure optimal medical management in this population.

11. The treatment of essential hypertension by internal medicine residents. Michael J. Dacey, M.D., David A. Bookstaver, Phann.D., Kimberly Humulock, D.O., Timothy Manown, M.D.; Eisenhower Army Medical Center, Fort Gordon, GA.

PURPOSE: The purpose of the study was to assess the medication choices of internal medicine residents and the thought processes underlying those decisions for the treatment of essential hypertension. METHODS: A data collection instrument documenting the medication, dosage, and rationale for selection was completed by the resident if a new antihypertensive agent was considered during a patient visit. A staff internist reviewed the form and the medical record, rendered an opinion on the choice, and formulated a treatment plan. A clinical pharmacist then repeated the process, blinded to the internist's opinion. RESULTS: One hundred and six cases were reviewed from January through July 1997. Addition of a medication (60%) was more frequent than substitution of one drug for another (40%). Calcium channel antagonists (CA; 35%) and angiotensin converting enzyme inhibitors (32%) were chosen most frequently. The most common reasons were renal protective effect in diabetes (16%), effectiveness at lowering blood pressure (14%), and favorable adverse effect profile (10%). Proven mortality benefit in the treatment of hypertension was the rationale for 8% of the choices. Forty percent of CA were chosen due to perceived effectiveness at lowering blood pressure. The pharmacist was more likely than the staff internist to recommend dosage changes (22% vs lo%, p=0.025) and to suggest discontinuation of another agent (13% vs 3%, p=0.005). The resident's treatment plan was significantly more expensive than either reviewer's (p<O.Ol). CONCLUSION: Despite controversy regarding their safety, the residents showed a strong preference for the heavily marketed CA over beta-blockers and diuretics. This suggests that an evidence-based approach to the treatment of hypertension needs to he re-emphasized.

12. A prospective, randomized, crossover study of the therapeutic effects of brand name Coumadin" versus generic warfarin. Jennijer M. Sichels, Pharm.D., Jack Ansell, M.D., Karen Betz, B.S., Je Lee, B.S.; Boston Medical Center, Boston, MA.

PURPOSE: A generic warfarin product has recently been approved by the Food and Drug Administration as a bioequivalent alternative to brand name Coumadin". However, concern over therapeutic equivalence still exists. This study was conducted to determine if switching from one brand of warfarin to another would impact patient care as determined by fluctuations in international normalized ratio (INR). METHODS Twenty-one stable patients on chronic warfarin therapy enrolled in the observer-blinded, randomized, crossover trial. Patients were randomly assigned to treatment with Coumadin", made by DuPont, or warfarin sodium, made by Barr, for 6 weeks. Patients then crossed over to receive the alternate treatment for 6 weeks. Weekly INR measurements, compliance, and adverse effects were monitored. Dosage adjustments were made when required by protocol. RESULTS Five patients have completed the study. The mean baseline INR was 2.44. Change in INR from baseline was 0.02 in patients taking Barr and - 0.21 in patients taking DuPont. Variability of INR values was 0.855 during Barr therapy and 0.835 during DuPont therapy. Twelve percent (3 of 26) of INR measurements were outside of the therapeutic range for both DuPont and Barr. Four dosage adjustments were required in three patients, three during DuPont treatment and one during Barr treatment. CONCLUSION: Preliminary results have shown that there is no difference between DuPont Coumadin" and Barr warfarin. This data would suggest that

the two products can he considered therapeutically equivalent and can be safely interchanged without the need for additional monitoring. Data from all 21 patients will he presented.

13. Evaluation of the use of thrombolytic agents in a tertiary care center superspecialized in cardiology. Julie Methot, M.Sc., Bettina Hamelin, Phatm.D., Helene Cote, Pharm.D.; Universlte lava1 and Research Center, Ste- Foy, Quebec, Canada.

PURPOSE: I t is well established that the use of thrombolytic agents decreases mortality after acute myocardial infarction by about 20%. However, use of these agents IS very variable from one hospital to another and important delays in administration have been reported. We undertook the current study to evaluate the use of alteplase and streptoki2ase in our tertiary care center with respect to patient characteristics, justification of use, prescriber, and delay of administration. METHODS: This was a retrospective study of 100 consecutive patients who had received thrombolytic therapy between January 1, 1997 and March 31, 1998. Data were collected by chart review using a validated data sheet. RESULTS: Sixty-three of 100 patients had received alteplase and 37/100 streptokinase. Patient baseline characteristics (age, sex, history of cardiovascular disease, cardiovascular risk factors) were similar in both groups. Ninety-nine percent of thrombolysis was justified according to guidelines of the American College of Cardiology. Choice of thrombolytic agent was independent of the type of prescriber (general physician versus cardiologist). Use of alteplase was justified in 84% of cases (anterior infarction, streptokinase in the past, large infarction, hypotension, o left bundle block). Median time to administration of streptokinase tended to be shorter than time to administration of alteplase (34.8 versus 43.7 minutes; p>0.05). Administration qf either thrombolytic agent was significantly prolonged when two prescribers were involved (58 versus 37 minutes; p<O.OOOl). Furthermore, shorter delays were observed when thrombolysis was initiated in the emergency room compare$ to the coronary care unit (46 versus 65 minutes; p<0.03). Hypotension was two times more prevalent in the streptokinase group compared to the alteplase group (p<0.05); both patients suffering a hemorrhagic stroke had received alteplase and 4/5 deaths occurred in the alteplase group. CONCLUSION: In this population, thrombolytic therapy was initiated consistent with standard guidelines in 99% of the cases; however, the choice of alteplase was questionable in 16% of the cases. The administration of either thrombolytic agent was delayed compared to the guideline goal of 30 minutes but was improved compared to recent GUSTO data suggesting a median delay of 85 minutes in Canada. Delays may in part be due to the number hut not the type of prescribers involved and/or the unit where therapy is initiated.

14. Efficacy and safety of ibutilide for cardioversion of patients with atrial fibrillation or flutter: maintenance of sinus rhythm until hospital discharge. Alisha Dunn, Pham.D., C. Michael White, Pharm.D., Moses 5. S. Chow, Pharm.D., FCCP, Jeffrey Kluger, M.D.; Hartford Hospital, Hartford, CT.

PURPOSE: To evaluate the efficacy and safety of ibutilide in patients with atrial fibrillation (AF) or atrial flutter (AFL) in clinical practice. METHODS: The medical records of all patients who received ibutilide from August 1996 to March 1998 were retrospectively reviewed to determine the efficacy (conversion rate within 60 minutes of infusion and maintenance of sinus rhythm [SR] until discharge) and safety (incidence of torsades de pointes [TdP]) of ibutilide in our institution (n=60). The conversion rates with ibutilide were compared for several patient groups using chi squared analysis. RESULTS: Conversion rates with ibutilide were:

J

SR Maintained Initial Ibutilide Until Discharge

Success Pauents (%I Pauents (%I All patients (11.60) 30 (50) 20 (33) AF (n=37) 15 (41) 12 (32) AFL (n=23) 15 (65) 8 (35) Post cardiac surgery (n=19) 9 (47) 7 (37) History of previous AFIAFL episodes (11.28) 11 (39) 6 (21) No history of previous AFIAFL (n.32) 19 (59) 14 (44) Durauon of AFIAFL >15 days (n=14) 2 (14)* 0 (O)* Duration of AF/AFL <15 days (11.46) 28 (61) 21 (46) No history AFIAFL and duration <15 days (n=29) 14 (48) *p<0.05 vs duration < 15 days

Three of 60 patients (5%) experienced nonsustained TdP with ibutilide; in all patients, the arrhythmias resolved with pharmacologic treatment. CONCLUSION: Although the initial conversion rate with ibutilide was 50%, with 67% of patients remaining in SR until discharge, ibutilide appeared to be most useful in patients with a short duration of arrhythmia.

15. Lidocaine decreases myocardial excitability to low voltage monopbasic shocks, but does not affect biphasic shocks. J. Jason Sims, Pharm.D., Theodore Hsu, B.S., Allison W. Miller, Pharm.D., Michael R. Ujhelyi, Pharm.D.; University of Georgia, Augusta VA Medical Center, Augusta, GA.

PURPOSE: Lidocaine (LIDO) raises pacing and defibrillation thresholds for

19 (66)


point stimuli and monophasic shocks (MS), respectively, but does not affect biphasic shocks (BS). LIDO raises point stimuli pacing thresholds by decreasing myocardial excitability, but it is unclear if LIDO alters MS defibrillation efficacy by a similar mechanism. It may be that LIDO decreases myocardial excitability to MS, especially in low voltage regions where post- shock fibrillation activity originates. This would inhibit the ability of MS to prevent post-shock propagation of fibrillation activity and likely lead to failed defibrillation. Therefore, we postulate that LIDO will decrease myocardial excitability to low energy MS, while not affecting BS. METHODS: Sixteen swine were randomized to either a BS (n=7) or MS (n=9) group. Myocardial excitability to low potential gradient shocks was assessed by determining the lowest current needed to induce ventricular fibrillation during the vulnerable period of repolarization (i.e., VF threshold). This was accomplished by delivering incrementing current shocks (1.25A-12.5A) after the last beat of an 18-beat drive train at coupling intervals between 140 ms and 320 ms. VF threshold to point stimuli was assessed to document LIDOS effects using a train of 20 stimuli (100 Hz) given 50 ms after the last beat of an 18-beat drive train at incrementing current (5 mA-75 mA). W threshold for point and field stimuli was determined at baseline and during LIDO 7.5

RESULTS: W thresholds (mean i SEM) in milliamps (mA) for point stimuli and amps (A) for field stimuli were:

mgfltg/hr.

Baseline Lidocaine Point (mA) 23 i 3 48 i 3* MonoDhasic [A) 1.4 i 0.1 2.6 i 0.3*# r ~ - ~~~ . I iiphasic (A) 1.3 i 0 1.6 i 0.2 *p<O 05 YS baseline; #p<0.05 vs biphasidlD0

As expected, LIDO increased VF threshold for point stimuli by 136% (p<O.OOl). Similarly, LIDO increased VF threshold for MS by 106% (p=0.03), but did not significantly alter VF threshold for BS. CONCLUSION: LIDO decreases myocardial excitability to point stimuli and MS by an equal magnitude, without affecting BS. This may explain why LIDO increases MS defibrillation thresholds, but does not affect BS. However, these conclusions are restricted by the assumption that VF threshold is a surrogate of myocardial excitability in low voltage regions during VF.

16E. Mechanisms of lidocaine-induced changes in defibrillation thresholds: role of spatial dispersion in post-shock refractoriness. J. Jason Sims, Pharm.D., Allison W. Miller, Pharm.D., Michael R. Ujhelyi, Pharm.D.; University of Georgia College of Pharmacy; Augusta VA Medical Center; Medical College of Georgia

Published in Pacing Clin Electrophysiol 1998;21:978.

17E. Creating dispersion in conduction, but not refractoriness, increases defibrillation thresholds. J. Jason Sims, Pharm.D., Theodore Hsu, B.S., Allison W. Miller, Pharm.D., Michael R. Ujhelyi, Pharm.D.; University of Georgia; Augusta VA Medical Center, Augusta, GA.

Published in Pacing Clin Electrophysiol 1998;21:978

ME. Endothelial dysfunction precedes the development of hypertension in diet-induced insulin resistance. Prasad V.G. Katakam, M.D., Michael R. Ujhelyi, Pharm.D., Allison Winecoff Miller, Pharm.D.; University of Georgia, Augusta VA Medical Center, Augusta, GA.

Published in FASEB J 1998;12:A190.

19. Fenfluramine amplifies the release of serotonin and adenosine 5'-triphosphate from activated human platelets. Cesar L. Calderon, Ph.D., Peggy E. Mankin, M.A., Johnna B. Maragos, B.S., Kay L. Saving, M.D.; University of Illinois, Peoria, 11.

PURPOSE: The mechanism by which fenfluramine promotes pulmonary hypertension and valvular heart disease in susceptible patients is not established but is believed to be serotonin mediated. Since serotonin in circulating blood is mainly confined within platelets, we assessed whether fenfluramine modulates platelet activity in vitro, in particular, by altering serotonin release. METHODS: Human blood was collected from healthy volunteers. Platelet aggregation and release of adenosine 5'dphosphate (ATP) were measured simultaneously using a whole blood lumi-aggregometer. Plasma serotonin was quantified by HPLC analysis. Phosphatidylserine translocation or dense granule staining was analyzed by fluorescent flow cytometry. RESULTS Pretreatment of blood with 50 numl fenfluramine for one hour at 37°C exerted the following effects on platelets when compared to an untreated counterpart. There was: 1) a high percentage of phosphatidylserine exposure on the plasma membrane of resting platelets (p=O.OOOl); 2) an elevated serotonin concentration in plasma upon activation with 20 mm adenosine 5'-diphosphate (ADP) or 1 U/ml thrombin (p=0.04 and p=0.006, respectively): and 3) enhanced ATP release following activation with ADP (p=0.004) but not with thrombin (p=0.7). However, there was no statistically significant difference (p>0.05) in: 1) serum levels of serotonin when platelets remained unactivated; and 2) the proportion of extruded dense granules and degree of platelet aggregation upon activation with ADP.

CONCLUSION: Fenfluramine primes platelets and amplifies their release of serotonin and/or ATP depending on the type of platelet activator. This information may be useful to elucidate the role of platelets in the progression of fenfluramine-related vascular and pulmonary diseases.

20. Factors associated with bleeding complications in patients treated with abciximab in community teaching hospitals. Ann E. Wehmeyer, Pharm.D., Todd P. Semla, M.S., Pharm.D., Gail S. Crabbe, B.S.N.. Shahriar Dadkhah, M.D.; St. Francis Hospital, Evanston, IL.

PURPOSE: This study evaluated heparin dosing, "early sheath removal" (ESR), the prevalence of bleeding complications, and factors associated with increased risk of bleeding for patients treated with ahciximab. METHODS: Using a retrospective cohort design, 81 consecutive patients who received abciximab during coronary intervention were reviewed for procedure type, abciximab and heparin administration, and bleeding complications. ESR is defined as the discontinuation of heparin immediately following the procedure and sheath removal within 6 hours. Major and minor bleeding events were defined according to TIMI criteria. RESULTS: ESR occurred in 34 patients (42%) and was associated with a reduction in risk of bleeding (odds ratio 0.16; 95% CI 0.02, 0.82). The prevalence of major and minor bleeds was 3.7% and 14.8%, respectively. The mean heparin dose for patients with and without bleeding was 122.8 and 101.9 units/kg for the bolus (p=0.08), and 11.8 and 9.5 units/kg/hr for the initial infusion (p=0.03). The mean heparin bolus dose for patients with minor bleeds compared to patients without bleeding was 132.9 vs 101.9 units& (p=0.02). Age, weight, emergent procedures, final ACT, and heparin infusions of > 7 units/kg/hr were independent predictors of bleeding. Those patients with bleeding had greater lengths of stay (LOS), 7.1 vs 3.9 days (p=O.Ol), and hospital charges (p=0.07). CONCLUSION: Administration of weight-adjusted heparin and adherence to ESR may reduce bleeding complications associated with the combined use of heparin and abciximab and may result in lower LOS and hospital charges.

21. Changes in utilization patterns of beta-blockers after acute myocardial infarction. Patricia Howard, Pharm.D., Edward Ellerbeck, M.D., M.P.H.; Kansas University Medical Center; Kansas City, KS; Kansas Foundation for Medical Care, Topeka, KS.

PURPOSE: To evaluate changes in the frequency of utilization of beta- blockers after acute myocardial infarction (AM0 and identify patient characteristics influencing that change in utilization. METHODS: Medical records were reviewed for 1747 patients discharged alive from Kansas hospitals after AM1 between April 1994 through May 1995 (baseline period) and 1226 similar patients discharged between October 1996 through June 1997 (remeasurement period). RESULTS: Utilization of beta-blockers in patients discharged after AM1 increased from 28% during the baseline period to 44% in the remeasurement period (OR 2.0 p<O.OOOl). Patient characteristics including age more than 80 years, chronic lung disease (COPD or asthma), congestive heart failure, or a left ventricular ejection fraction less than 50% were all associated with lower rates of beta-blocker utilization during both the baseline and remeasurement phases. The absolute rate of increase in beta-blocker utilization for patients with these characteristics ranged from 15-17%, which was similar to the observed increase in utilization for the overall population. During the baseline phase, use of insulin was associated with lower utilization rates with only 17% of these patients discharged on beta-blockers (OR 0.5; p=0.002) During the remeasurement phase, however, 43% of patients receiving insulin were discharged on beta-blockers (OR 1.0; NS). CONCLUSION: There have been dramatic increases in the use of beta blockers after AM1 in Kansas over the past two years. These increases are not associated with changes in patterns of utilization for patients with particular characteristics except for the large increase in utilization for diabetics receiving insulin.

22E. Comparison of the efficacy and safety of three dihydropyridine calcium antagonists in black hypertensive adults. W. Dallas Hall, M.D., Keith Ferdinand, M.D., John M. Flack, M.D., Carla Yunis, Ph.D., James W. Reed, M.D.; Emory University, Atlanta, GA, Heartbeats Life Center, New Orleans, LA; Wayne State University, Detroit, MI; Wake Forest University, Winston-Salem, NC; Morehouse School of Medicine, Atlanta, GA.

Published in Am Heart J 1998;11(1l):E112.

23. Evaluation of appropriateness of use and therapeutic interchange from losartan to angiotensin converting enzyme inhibitors. Daniel E. Hilleman, Pharm.D.; Creighton University, Omaha, NE.

PURPOSE: At our institution, losartan is recommended for patients with hypertension, heart failure, or both, who are either therapeutic failures on angiotensin converting enzyme inhibitors (ACE) inhibitors or who experience dose limiting side effects on ACE inhibitors. We have evaluated the appropriateness of use and the outcomes and cost-effectiveness of a Lherapeutic interchange from losartan to ACE inhibitors in those patients without an appropriate indication for losartan.

1142

METHODS: A total of 66 patients were identified who were receiving losartan (32 for hypertension, 11 for heart failure, and 23 with both hypertension and heart failure). An appropriate indication for losartan could not be verified in 50 patients. These 50 patients were switched to ACE inhibitors (benazepril = 18, fosinopril = 13, quinapril = 19). RESULTS: At 6 months after the switch, there was no evidence of treatment failure in any patient. Three patients developed a cough, but continued to take ACE inhibitors. Acquisition cost of losartan for one year was $16,790 and $11,498 for ACE inhibitors. Cost savings was estimated to be $5292 for these 50 patients, or approximately $100 per patient per year. CONCLUSION: Our evaluation indicates that the vast majority of patients receiving losartan do not have appropriate indications for its use. In addition, all patients receiving losartan without appropriate indication were successfully switched to less expensive ACE inhibitors.

24. The impact of a glucose-insulin-potassium solution administration on the incidence of atrial fibrillation in post-operative coronary artery bypass graft surgery patients. Michael Shara, Phann.D., Ph.D., Thomas Langdon, M.D., Dewaine Peetz, M.D.; Alegent Health-Immanuel Medical Center; Bergan Mercy Medical Center; Creighton University, Omaha, NE.

PURPOSE This study was carried out to determine the impact of glucose- insulin-potassium (GIK) administration on the incidence post-operative atrial fibrillation in patients undergoing coronary artery bypass (CABG) surgery. METHODS: Patients undergoing CABG surgery received one liter of intravenous solution containing 0.9% sodium chloride, 10% dextrose, 80 mEq of potassium chloride, and 50 units of human regular insulin at a rate of 1 mVkg/hr. The infusion was started in the recovery room in the immediate post-operative phase and was completed in the intensive care unit. A matched cohort group of patients did not receive the GIK solution. The incidence of post-operative atrial fibrillation for the two groups was documented. RESULTS Seventy-two out of 264 (27.3%) patients developed post-operative atrial fibrillation in the group receiving GIK solution compared to 80 out of 235 (34%) in the non-GIK cohort. The 19.7% reduction in the incidence of post-operative atrial fibrillation observed in the group of patients receiving GIK solution was not statistically significant (p=O.lO). CONCLUSIONS Although these findings indicate a decreasing trend in the incidence of post-operative atrial fibrillation in patients receiving GIK, the reduction was not statistically significant in this sample of patients. Further study is warranted to determine the cost-effectiveness of utilizing perioperative GIK therapy.

25. Lack of interaction between aspirin and either enalapril or losartan in hypertensive patients. JamesJ. Nawarskas, Pha7m.D.. Raymond R. Townsend, M.D., Michael D. Cirigliano, M.D., Sarah A. Spider, Pharm.D., FCCP; University of New Mexico, Albuquerque, NM; University of Pennsylvania, Philadelphia, PA.

PURPOSE The combination of aspirin (ASA) and an angiotensin converting enzyme inhibitor (ACEI) may be therapeutically antagonistic due to attenuation of prostaglandin production by ASA. This randomized, double- blinded, placebo-controlled study evaluated the interaction between ASA- ACEI and investigated a potential interaction between ASA and the angiotensin 11 receptor antagonist losartan in patients with hypertension. METHODS Essential hypertensives were maintained on a stable dose of enalapril (n=7) or losartan (n=10) monotherapy for 2 12 weeks prior to and throughout the study. Each patient received placebo, 81 mg/d ASA, and 325 mg/d ASA for 2 weeks. Each treatment was separated by a 2-week washout period. Automated blood pressure (BP) cuff measurements and serum thromboxane BZ (TXBz) samples were obtained at the end of each treatment phase. Differences were compared between ASA and placebo for both groups by repeated-measures ANOVA. RESULTS Mean arterial pressure (MAP) in the enalapril group for placebo, 81 mg/d ASA, and 325 mg/d ASA, respectively, was 92 i 7 (mean i SD), 96 t 5, and 91 * 7 mm Hg (p=O.46, power = 76%). MAP in the losartan group was 96 * 6, 95 * 6, and 95 * 7 mm Hg (p=0.89, power = 80%). No significant changes in systolic and diastolic BP were noted in either group upon addition of ASA. Concentrations of TXBz were suppressed to less than 10% in both groups with ASA and were significantly lower than placebo (pS0.02). CONCLUSION: This study demonstrates that ASA 81 and 325 mud exerts no significant effect on BP in essential hypertensives taking enalapril or losartan.

26. Outcomes in the treatment of hypercholesterolemia with HMG-CoA reductase inhibitors in a Department of Defense population. Michael P. Dutro, Pharm.D., Ronald Grosserode, Pharm. D.; Pfizer, Inc., New York, NY; William Beaumont Army Medical Center, El Paso, TX

PURPOSE: This study was done to determine the frequency of LDL-C monitoring in patients taking lipid lowering agents in a Department of Defense (DOD) population and to identify the incidence of positive outcomes (meeting NCEP LDL-C goals) in a sample who were receiving HMG-CoA reductase inhibitors (HMGs). METHODS Methodology used was a combination of retrospective database and chart review. Computer files were created of all prescription records for

lipid lowering agents and all LDL-C values over a 1-year period. The frequency of LDL-C monitoring was determined by matching unique patient identifiers between database files. Patients were randomly included in the outcomes analysis if they had an LDL-C value measured at least 28 days after the date of the first HMG prescription record. Chart review was performed in this sample to identify NCEP-defined risk factors. RESULTS: Forty-seven percent of patients receiving lipid lowering therapy (1117/2397) had LDL-C values reported during the 1-year time period. Ninety-one eligible patients were randomly chosen for inclusion in the outcomes portion of the study. NCEP goal distribution was observed as follows: c 100 mg/dl, 42%; c 130 mg/dl, 40%; < 160 mg/dl, 13%; and undetermined, 5%. Sixty percent of patients in the sample population were found to achieve positive outcomes (NCEP goals). Subgroup analysis revealed 23/41 (56%) of patients on fluvastatin, 22/39 66%) on pravastatin, and 10/11 (91%) on atorvastatin achieved NCEP goals. CONCLUSION: There is significant opportunity for improvement in the monitoring of patients treated for hypercholesterolemia and in the use of HMGs to achieve better outcomes.

27. Comparison of drug and alanine aminotransferase monitoring compliance for statin therapy with and without pharmacist intervention. Joseph S. Bertino, Jr., Phann.D., Roberta L. Steere, B.B.A., Martha Wilhelm, B.S., Anne Nafziger, M.D., M.H.S.; Bassett Healthcare, Cooperstown, NY.

PURPOSE: To evaluate compliance with statin therapy and ALT monitoring in patients with hypercholesterolemia with ongoing pharmacist intervention versus usual care. METHODS: Patients who obtained their statins at our ambulatory phankacy were randomized to pharmacist ALT monitoring at the time of drug refill vs monitoring left up to the pagents primary caregiver. A pharmacist contacted the patients in the pharmacist intervention group every 6 months to remind them to come to the pharmacy for ALT monitoring at the time of statin refill and to reinforce compliance. For the pharmacist intervention group, ALT assay was performed on site using the Abbot( Vision system. Tablet counts were done for all patients at the time of refill to ascertain compliance. Compliance with ALT monitoring was considered positive if it was done t 1 month on an every 6-month basis. Drug compliance was defined as taking more than 80% of the doses over the 18-month study period. Fisher's exact test was used for analysis with a p value S 0.05 considered significant. RESULTS Forty-two patients (mean age 59 t 12.3 years, 51% males) were randomized, 21 into each group. Eight of 42 (19%) discontinued statins during the study period and an additional three dropped out of the study. At 18 months, the pharmacist intervention group had 16 patients and usual care 15 patients. Compliance with ALT monitoring was: Group 6-Month ALT 12-Month ALT 18-Month ALT

Pharmacist intervention 24% 47% 38% Usual care 16% 17% 13% p value 0.684 0.045 0.219 Medication compliance was 95% in both groups at month 6; however, at month 18, 52% of the usual care, and 71% of the pharmacist intervention patients met the definition for compliance (p=NS). CONCLUSION: A pharmacist intervention program at the time of drug refill resulted in significantly greater compliance with ALT monitoring vs usual care at 12 months, but not at 6 months or 18 months. The reason for this is unknown. In addition, compliance with medication usage dropped dramatically over the 18-month period in both groups suggesting that pharmacist intervention alone did not result in increased compliance with statin therapy.

28. Effect of cigarette smoking on the pharmacokinetics of warfarin. Cynthia A. Sanoski, Pharm.D., Harumi Takahashi, Ph.D., Hirotoshi Echizen, M.D., Ph.D., Larry Brace, Ph.D., Cathy Helgason, M.D., James Schuler, M.D., Jerry L. Bauman, Pharm.D., FCCP, Edith Nutescu, Pharm.D.; University of Illinois at Chicago, Chicago, IL; Meiji College of Pharmacy, Tokyo, Japan.

PURPOSE: Although cigarette smoke has been demonstrated to induce hepatic microsomal enzymes, it has been previously implied that warfarin (W) dosage adjustments are not necessary in patients who are smokers. However, the impact of cigarette smoking on the pharmacokinetics of W enantiomers has not been delineated. METHODS: A total of 53 patients, 18 smokers (mean age 59 t 13 years) and 35 nonsmokers (mean age 61 2 12) received a constant dose of W for at least one month prior to enrollment. A blood sample was obtained at least 12 hours following W administration. Total and unbound plasma concentrations of (S)- and (R)-enantiomers of W were quantified by HPLC and pharmacokinetic parameters were estimated. RESULTS: The mean daily dose of W for smokers and nonsmokers was 4.74 i 1.69 and 5.00 i 2.58 mg/day, respectively (p=NS). The mean INR achieved also did not differ significantly between these two groups. Total body clearance (TBC) of W was 3.49 * 1.74 mVmin in smokers and 3.46 t 1.90 mVmin in nonsmokers (p=NS). No significant differences in TBC of the (5)- and (R)-enantiomers were observed between smokers and nonsmokers

Compliance Compliance Compliance


(smokers: TBC[S] = 4.49 i 2.41 mumin and TBC[R] = 3.10 * 1.91 mumin; nonsmokers: TBC[S] = 4.93 2 2.79 mumin and TBCIR] = 2.80 * 1.62 ml/min). Similarly, there were no significant differences in unbound clearances of the (S)- and (R)-enantiomers of W with regard to smoking status. CONCLUSION: Cigarette smoking does not have an effect on the pharmacokinetics of W enantiomers. These findings may explain why the W dose does not need to be adjusted for smoking.

29E. Cerivastatin, a novel potent HMG-CoA reductase inhibitor: comparative efficacy versus fluvastatin. Evan Stein, M.D., Jonathan Isaacsohn, M.D., Richard Weinstein, M.D., Trevor Orchard, M.D., Charles Huh, M.D., Steven Ripa, M.D.; Metabolic and Atherosclerosis Research Center, Cincinnati, OH; Diablo Clinical Research, Inc., Walnut Creek, CA.

Presented at the 1998 Annual Meeting of the American Society of Health- System Pharmacists, Baltimore, MD, May 30, 1998.

30E. Pharmacodynamic assessment of the 0.8 mg dosage of cerivastatin, a novel HMG-CoA reductase inhibitor. Evan Stein, M.D., Ph.D., Jonathan Isaacsohn, M.D., Randall Stoltz, M.D., Arthur Mazzu Ph.D., Ming-Chung Liu, Ph.D., Cindy Lane, B.S.N., Allen H. Heller, M.D.; Metabolic and Atherosclerosis Research Center, Cincinnati, OH; GFI Pharmaceutical Services, Evansville, IN, Bayer Corporation, West Haven, CT.

Published in J Am Coll Cardiol 1998;31:281A.

31E. The influence of specific and nonspecific potassium current blockade on defibrillation energy requirements. Ali A. Mehdirad, M.D., Cynthia A. Cames, Pharm.D., Ph.D., StevenD. Nebon, M.D.; Ohio StateUniversity, Columbus, OH.

Presented at Cardiostim, Nice, France, June 1998.

32E. Antagonistic effect of acidosis on azimilide-induced reduction in defibrillation energy requirement. Cynthia A. Games, PharmD., Ph.D., Ali A. Mehdirad, M.D.; Ohio State University, Columbus, Ohio.

Presented at Cardiostim, Nice, France, June 1998.

Critical Care 33. Impact of trauma stress ulcer prophylaxis guidelines on drug use and incidence of major gastrointestinal bleeding. John W. Devlin, Pharm.D., BCPS, Karen S. Claire, B.S., BCPS, Nadia B. Karmo, B.S., James Tyburski, M.D., Scott Dulchavsky, M.D.; Detroit Receiving Hospital; Wayne State University, Detroit, MI.

PURPOSE: Trauma patients are routinely prescribed stress ulcer prophylaxis (SUP) therapy in our institution despite evidence suggesting SUP be limited to patients with identifiable risk factors for bleeding. Through surgeon consensus, we developed and implemented trauma SUP guidelines and measured the effect of these guidelines on drug use and incidence of major gastrointestinal bleeding. METHODS: Two groups of 150 consecutive trauma patients (admitted 2 24 hours) were evaluated before and after guideline implementation and stratified by Injury Severity Score (IS9 to minor (1% c 9) or major (ISS 2 9) trauma groups. The number of patients prescribed SUP therapy, the length and cost of this therapy, and the number of patients experiencing major gastrointestinal bleeding (a decrease between consecutive hemoglobin measures 2 2 g/dl in conjunction with coffee ground emesis, hematemesis, melena, or hematochezia) were measured. All pharmacist interventions pertaining to SUP were collected. RESULTS: Fewer patients were prescribed SUP therapy after guideline implementation (105/150 [70%1 vs 39/150 [26%], pcO.0001) leading to a decrease in drug acquisition cost of $4558. Use decreased more in minor (40/54 [74%] vs 9/59 [15%1, pc0.0001) than major (65/96 [68%1 vs 30/91 [33%], pc0.0001) trauma patients. Neither length of therapy nor SUP agent of choice (more than 95% cimetidine) differed between groups. SUP not meeting guideline criteria was identified by pharmacists in 15/39 (38%) cases, with 9/15 (60%) subsequent discontinuation recommendations accepted. The incidence of major gastrointestinal bleeding remained unchanged between groups (1/150 vs 0/150, p=l.O). CONCLUSION: Implementation of trauma SUP guidelines, limiting therapy to patients with risk factors for bleeding, led to a 63% decrease in drug use and did not affect the incidence of major gastrointestinal bleeding.

34. Acid neutralizing capacity of enteral feeding products. Raymond W. Pak, Pharm.D., Donald K. Woodward, Pharm.D.; Rutgers-The State University of New Jersey, Piscataway, NJ.

PURPOSE: Enteral feeding of intensive care unit (ICU) patients may be effective in the prevention of stress ulcers. The exact mechanism of prevention is unclear. To determine the role of acid neutralization in this protective effect, acid neutralizing capacity ( A N 0 was determined for six enteral feeding products and compared to the ANC of Mylanta", a stress ulcer prophylaxis therapy with documented efficacy. METHODS ANC was determined in viuo by the USP acid titration method.

Thirty mEq of 1.0 N HC1 were added to 10 ml of each product. After 15 minutes of mixing, sufficient 0.5 N NaOH was added to maintain the solution pH at 3.5. ANC of the product was calculated as the difference between the mEq of acid added and the mEq of base added to neutralize the excess acid. Products, tested in triplicate, were Mylanta", Nutren" 1.0, Nutren" 1.0 with fiber, Nutren" 2.0, Crucial", Renalcal", and Sustacal Plus". RESULTS: The mean ANC (* SD) and ANOVA p value vs Mylanta" for each product were:

Product ANC (mEq) p value vs Mylanta" Mylanta" 25.82 i 0.17 Nutren" 1.0 1.89 + 0.04 >0.05 Nutren" 1.0 with fiber 1.81 * 0.36 >0.05

>0.05 Nutren" 2.0 Crucial" 3.47 + 0.16 >0.05

>0.05 Renalcal" Sustacal Plus" 1.82 f 0.42 >0.05

2.45 * 0.30

1.26 * 0.37

CONCLUSION: ANC of enteral products were significantly lower when compared to Mylanta". Direct acid neutralization plays only a minor role in the mechanism of prevention of stress ulcers by enteral feeding.

35. Abnormal regulation of the vitamin D-endocrine system in neonatal extracorporeal membrane oxygenation therapy. Emily B. Hak, Pharm.D., Catherine M. Grill, Pharm.D., Jay F. Mouser, Pharm.D., Mark C. Bugnitz, M.D., Scott Wagoner, R.R.T., Richard A. Helms, Pharm.D., Russell W. Chesney, M.D.; University of Tennessee; LeBonheur Children's Medical Center, Memphis, TN.

PURPOSE: With age appropriate nutrient dosing, we observed hypocalcemia followed by persistent hypercalcemia and increased magnesium (Mg) requirements in neonates on extracorporeal membrane oxygenation (ECMO). Consequently, we empirically lower calcium (Ca) dose to between 1-1.5 mEq/kg/day and increase Mg to 0.5-0.6 mEq/kg/day in ECMO patients. We studied Ca metabolism in neonates on ECMO to better understand the pathogenesis of these changes. METHODS: Twelve neonates (39 i 2 weeks gestational age: 3.1 i 0.5 kg birthweight; four black females, three black males, three white males, two white females) eligible for ECMO secondary to congenital diaphragmatic hernia (11-41, meconium aspiration (n=4), persistent pulmonary hypertension (n=3), and sepsis (n=l) were enrolled (3 i 2 days of age) after informed consent was obtained. Plasma for parathyroid hormone (PTH) and calcitriol (1,25[OH]2 D) concentrations was obtained pre-ECMO, ECMO days 2 and 4, pre-decannulation (if available), and post-ECMO days 1 and 3. Plasma for calcitonin was obtained pre-ECMO, once during ECMO, and once post- ECMO. Routine laboratory data included ionized calcium (iCa) and Mg levels. Data are presented as mean i SD. RESULTS: Measurement (normal range) PK ECMO Day 2 Day 4 W a n Day 1 PwI Day 3 Po11

Mg (mEqL) 1.3t0.5 1.3+0.4 1.7t0.5 2.3*0.4 2.1+0.6 2.0+0.6 (2 1-2.9) (n.7) (121 (11) (7) (10) (12) iCa (mmoW 1.0a0.1 1.1+0.1 1.2+0.1 1.4+0.1 1.2+0.3 1.2+0.2 (1.1-1 35) (12) (12) (11) (6) (10) (12) PTH (pdrnl) 36.4*34.3 78.1 +W.O 66.8e46.8 49.7 * 28.9 49.5234.3 49.6r43.5 US541 (12) (12) (11) (7) (12) (12) 1,25(OH)1D(pg/ml) 14.5+8.2 7.1e4.4 14.6k6.8 14.8e9.0 284+19.6 34.2*43.3 (15.9-55 6) (9) (9) (9) (4) (7) (7) Cllcitonin (pdml) 687 1 I 521.4 - 648.9 t 544.2 - - 364.4t434.7 (undetectablc-95) (7) (7) (7)

CONCLUSION: Plasma Mg and Ca increased during ECMO. Despite normal to elevated iCa values, PTH concentrations increased during ECMO therapy. 1,25(OH)2D remained low suggesting increased calcium suppresses 1,25(OH)2D synthesis. Calcitonin concentrations were elevated, but may be normal for critically ill neonates. Whether cannulation of the carotid near the parathyroid circulation or persistently low plasma Mg are responsible for the abnormal regulation of Ca metabolism is unclear.

36. Decreasing sedation costs through a pharmacist-directed monitoring program. Kimberly M. Logan, Pharm.D., Scott D. Hans, Pham.D., DavidA. Kuhl, Pharm.D.; University of TeMessee; Baptist Memorial Hospital, Mempb, TN.

PURPOSE: We developed a sedation monitoring service to promote compliance with established hospital guidelines in intensive care unit (ICU) patients receiving continuous infusion sedation. To validate the service, this study evaluated the effect of pharmacist recommendations and adherence to guidelines on sedation costs and patient outcomes. METHODS: Patients requiring continuous infusion sedation were studied for two months retrospectively (n=51), and for three months prospectively (n=92), to assess pre- and post-intervention sedation practice patterns. Patients were categorized as: 1) following guidelines without pharmacy intervention (GF); 2) not following guidelines (GNF); or 3) accepted pharmacy recommendations (PRA; prospective group of patients not compliant with guidelines). Data collected were: patient demographics, days on scheduled sedation, total sedation costs, sedation cost per day, days on mechanical ventilation, days from discontinuing scheduled sedation to extubation, and ICU length of stay (LOS). Dichotomous and continuous data were analyzed using chi squared and one-way ANOVA with post-hoc


comparison (Dunn's Method), respectively. RESULTS: For GF and GNF groups, there were no statistically significant differences between the retrospective and prospective analysis. As a result, these groups were combined for subsequent analysis. No statistically significant difference in age, gender, Apache 11 score, or mortality was identified between the GF, GNF, and PRA groups. Sedation cost and outcome results by group were:

Sedation Corr Sedation Yenulator Sedation to ICU LOS Group n Cost ( 8 ) perDay ($1 Days Days Entubauan (days1 (days) PRA 35 581r365hr 86+37' 6 9 r 4 Z b ~ t 3 4 t 7 B h 5 4 + 6 2 1 8 1 t 8 7 GF' 39 208 * 12 f 32'' 2.7 T 1 ld 9 3 f 8 4" 4 1 * 6 ld 15 0 * 10 9' GNF' 69 t468*857 i + 1 + 5 4 i i 3 + 6 t 2 2 3 a t 3 8 i n 4 * 1 0 9 ~ 3 8 ~ 1 8 0 M C ~ " * SO. 1 r e t r o ~ p e ~ o ~ e and p r ~ ~ p e ~ t ~ e p a t m ~ . PRA vs GF (p<n 05). PRA VI GNF (p<n 05):

CONCLUSION: These results show that pharmacist interventions as part of a sedation monitoring program reduces the cost of sedation without adversely impacting patient outcomes.

37. Absorption and pharmacokinetics of clarithromycin suspension administered via nasogastric tube in severely ill patients. Douglas N. Fish, Pharm.D., Edward Abraham, M.D.; University of Colorado Health Sciences Center, Denver, CO.

PURPOSE: Clarithromycin (CL) is potentially useful for a variety of infections in severely ill patients. However, lack of a parenteral formulation has limited its use in patients unable to receive oral medications. The purpose of this study was to evaluate the absorption and pharmacokinetics of CL when administered via nasogastric tube (NGT) in severely ill patients. METHODS Eligible patients in a medical intensive care unit (ICU) received 500 mg of CL suspension once via NGT. Blood samples were collected for 24 hours after dosing. Plasma was analyzed for CL and the active metabolite 14- OH-CL using validated HPLC methods. Data were analyzed using a noncompartmental pharmacokinetic model and compared with historical data. RESULTS Sixteen nonfed adult patients (7 males, 9 females; mean * SD age 50 * 11 years; weight: 73 * 10 kg; creatinine clearance 86 * 18 ml/min) completed the study. Pneumonia was the most common reason for hospitalization; hepatic and gastrointestinal function were normal as assessed by medical history, physical exam, and clinical and laboratory data. Mean * SD pharmacokinetic parameters were as follows:

GF vs GNF (pen 051

Cmax Tmax A U C k tlR ( m a ) (hr) (mg.hr/L) (hr)

Clarithromycin 2.13 kO.87 3.5 * 0.8 17.652.8 4.3 * 0.5 14-OH-Clanthromvcin 0.92 * 0.32 4.4 * 0.5 10.6 * 1.5 7.9 * 1.7 CONCLUSION: Compared with previous data in healthy adults, the mean C,,, was slightly decreased and mean T,, delayed in severely ill patients. However, CL suspension was well absorbed after administration by NGT and the pharmacokinetics were not substantially different from those seen in other populations. Administration of CL via NGT is a potentially viable and cost-effective option for the treatment of infections in severely ill patients unable to receive CL tablets by mouth.

38. Critical appraisal of semm concentration monitoring of single-daily dose aminoglycoside therapy in critically ill patients. Marc G. Reichert, Pharm.D., Brien L. Neudeck, Pharm.D., Lynda S. Welage, Pharm.D.; University of Michigan Health Systems, Ann Arbor, MI.

PURPOSE: Single-daily dose aminoglycoside therapy (SDDAG) is often utilized in critically ill (CI) patients. This study was designed to evaluate the appropriateness of using either one or two serum concentrations to monitor SDDAG in the CI. METHODS: All C1 patients receiving SDDAG who had two aminoglycoside ( A t ) serum concentrations obtained were enrolled in this retrospective study. Utilizing AG concentrations, patient specific pharmacokinetic parameters (PtPKP) were determined. The doses were normalized to 7 mgkg and peak, trough, and 8-hour concentrations were simulated utilizing PtPKP. The 8-hour concentrations were used with the Hartford Nomogram to determine if dosage adjustments were needed (one concentration approach [OCAI). The peak (target 18-24 pg/ml) and trough (target < 2.0 pg/ml) were used to evaluate the need for dosage adjustments (two concentration approach [TCAI). RESULTS Of the 205 patients who received SDDAG between July 1997 and June 1998, 20 met study criteria. The average AG dose was 6.01 * 0.97 mgkg. Utilizing the TCA, a modification of the dosage regimen was required in 65% of patients, as compared to 25% of patients with the OCA ( ~ ~ 0 . 0 5 ) . No increases in total daily dose (TDD) were required using the OCA, whereas 45% of patients required an increase in TDD using the TCA. Ninety percent and 40% of patients had concentrations below 2.0 and 0.5 pg/ml for greater than 4 hours, respectively. CONCLUSION: CI patients may have concentrations which are below the MIC of ICU pathogens (MIC 0.5-2.0) for greater than 4 hours, which may be in excess of the post-antibiotic effect. Relying on the OCA to monitor SDDAG in CI patients may result in under dosing of this group.

39. Pharmacist-initiated antimicrobial interventions in critically ill patients. Jill A. Rebuck, Pharm.D., Douglas N. Fish, Pharm.D.; University of Colorado Health Sciences Center, Denver, CO.

PURPOSE: Important considerations related to the appropriate use of antimicrobials in the intensive care unit (ICU) include proper indication, individualized dosing based on severity of organ dysfunction, potential for antimicrobial resistance, and cost of therapy. The purpose of this study was to 1) document pharmacist-initiated interventions in medical ICU patients receiving antimicrobials; and 2 ) demonstrate related cost-savings within our ins ti tu tion. METHODS: Patients admitted to the medical ICU at University Hospital were evaluated for potential antimicrobial interventions during a 6-month period. A critical care pharmacist rounded five times per,week with the medical ICU team and prospectively documented all interventions related to antimicrobial usage. Antimicrobial cost savings were calculated by utilizing hospital acquisition and pharmacy preparation costs only. RESULTS: A total of 195 interventions involving 232 individual drug regimens were successfully initiated. The most common antimicrobials for which interventions were made included fluoroquinolones (20°6), vancomycin (20%). and antipseudomonal cephalosporins (17%). The most frequent interventions involved pharmacokinetic dosing and monitoring (26%), dosage adjustments for patients with organ dysfunction (24%), and selection and/or modification of empiric regimens (16%). The overall antimicrobial cost savings accounted for $32,067 during the 6 months studied. CONCLUSION: By focusing on antimicrobial interventions within our ICU, pharmacists were able to ensure patients were dosed appropriately based n level of organ function, empiric antimicrobials were not unnecessahy continued, antimicrobial regimens were appropriately modified based on culture and susceptibility resuu, and medication costs were decreased.

Education 40E. Joint research summit and required student poster presentations. Therese I. Poirier, Pharm.D., Juan R. Avila, Pharm.D.; Duquesne University, Pittsburgh, PA.

Presented at the 1998 Annual Meeting of the American Association of Colleges of Pharmacy, Snowmass Village at Aspen, CO, July 18-22, 1998.

41E. Practice patterns and job satisfaction of graduates of nontraditional Pharm.D. degree programs. Nancy Fjortoft, Ph.D., Lisa Weigand, Mary Lee, PhamD.; Chicago College of Pharmacy, Chicago, 1L.

Presented at the 1998 Annual Meeting of the American Society of Health- System Pharmacists, Baltimore, MD, June 3, 1998.

42. Familiarity of prescription medication costs among physicians in family medicine residency programs. Michael E. Emst, Pharm.D., Michael W. Kelly, Pharm.D., Bernard A. Sorofman, Ph.D., Richard W. Pretorius, M.D.; University of Iowa, Iowa City, IA.

PURPOSE: To determine the familiarity with, and perceived value of, prescription medication cost information among physicians in family medicine residency programs. METHODS: From a series of $10 price intervals (range $0.01 to $80.001, physicians (n=149) in seven family medicine clinics were asked to select the interval containing the cash price of the medication to an uninsured patient for 50 commonly prescribed medication regimens. The correct price interval was coded with a value of zero. Incorrect selections were coded as the number of intervals (positive or negative) away from the correct interval. Mean scores were calculated for each respondent and for all medications. Likert scales were used to determine physicians' attitudes about the value of familiarity with prescription drug costs. RESULTS The mean score for all physicians for all medications was -0.31, indicating physicians tend to underestimate the actual costs of medications by less than $10. Mean scores for faculty differed significantly from residents for brand (-0.710 versus -1.11; p=0.007) and generic (0.558 versus 0.808; p=0.028) medications. For all physicians, brand medications were underestimated 91.8% of the time, while generic medications were overestimated 94.7% of the time. Overall, 64.3% of physicians reported they did not receive sufficient information regarding cost of medications; 93.2% felt receiving regular updates on medication costs would help them prescribe more cost effectively. CONCLUSION: Family physicians tend to underestimate the cost of medications they prescribe and believe receiving regular information on prescription medication costs will improve their prescribing behavior. Pharmacists should address this need through directed educational efforts.

Endocrinology 43. Effectiveness of troglitazone versus metformin in poorly controlled patients with diabetes mellitus. Julienne K. Kirk, Pharm.D., Kevin A. Pearce,


M.D.; Wake Forest University, Winston-Salem, NC

PURPOSE: This study evaluated drug therapy in patients with type 2 diabetes mellitus in order to compare the effect of troglitazone to metformin, when used concomitantly with an oral sulfonylurea on HbAI,, fasting plasma glucose, and C-peptide concentrations. METHODS: Thirty poorly controlled patients with type 2 diabetes mellitus, defined by a HhA1, of greater than 8.5% (hut not greater than 16%). were selected from a family medicine practice. Patients were randomized to receive either metformin or troglitazone for 14 weeks. Home blood glucose monitoring was done twice daily, fasting and at bedtime. Patients received standardized diabetic teaching including an overview of diabetes, medication review, teaching of glucose monitoring, discussion of diabetic complications, and nutritional advice over six visits. Between group comparisons will be made for outcome study parameters. RESULTS: To date, all thirty patient have been enrolled in the trial and preliminary evaluation of the data on over half of the participants indicates an average 1 to 2% decrease in HbAI, in both treatment groups. Demographic data reveal an age range of 35 to 71 years. Similar distribution of male and female as well as Caucasian and African-Americans are included in the trial. Baseline data for HbgAl, range from 8.6-13.996 (4.2-5.9), fasting plasma glucose range from 136-393 mg/dl, and C-peptide concentrations range from 1.3-17.3 ng/ml (0.9-4.0). CONCLUSION: The overall impact of these pharmacotherapy regimens will be forthcoming. Data to date indicate that both treatment regimens result in decreases in HbgAl,.

Geriatrics 44. Once daily metrifonate dosing regimen without loading dose is favorable to a loading dose regimen in Alzheimer’s disease patients based on a randomized placebo-controlled trial. M.W. Jann, Phann.D., P.A. Cyrus, M.D.; Mercer University, Atlanta, GA Bayer Corporation, West Haven, CT.

PURPOSE: To evaluate the safety and efficacy of loading-dose and no- loading-dose regimens of metrifonate for the treatment of Alzheimer‘s disease of mild to moderate severity. METHODS: This randomized, double-blinded, placebo-controlled, parallel- grouped clinical trial enrolled patients into three groups: 134 received placebos; 133 received a 2-week, daily loading-dose of metrifonate (100 mg or 150 mg [by weight]) followed by a 4-week 50 mg daily maintenance dose; and 128 received a 6-week, 50 mg daily maintenance dose of metrifonate. Efficacy was assessed by the Alzheimer’s Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) and the Clinician’s Interview Based Impression of Change with Caregiver Input (CIBIC-Plus). Safety was assessed by premature termination; treatment-emergent events; and changes in vital signs, electrocardiographic, and neurologic findings; and laboratory abnormalities. RESULTS Efficacy for both metrifonate dosing regimens were superior to placebo. The no-load regimen showed slightly better results in the CIBIC-Plus scale whereas the loading-dose regimen showed slightly better results on the ADAS-Cog scale. Both metrifonate dosing regimens resulted in similar levels of red blood cell acetylcholinesterase inhibition by 6 weeks. The no-loading- dose regimen was somewhat better tolerated than the loading-dose regimen. CONCLUSION: The similar efficacy results with both meuifonate regimens combined with the slightly better safety profile with the no-load regimen indicates that a once daily, no-loading regimen of metrifonate is preferred in these patients.

45. Clinical efficacy and cost-effectiveness of amlodipine three-times-a- week regimen as compared with once-a-day regimen in a community nursing home. Shyam D. Karki, Phann.D., Gule-Rana Masood, M.D., William R. Patterson, B.S., Terrance J. Bellnier, M.P.A.; Monroe Community Hospital, Clifton Springs Hospital & Clinic, Rochester Psychiatric Center, Rochester, Ny.

PURPOSE: This study assessed the clinical efficacy and cost effectiveness of amlodipine three times a week (TIW) regimen compared with once a day (QD) regimen for management of hypertension in the elderly residents in a community nursing home. METHODS Pharmacy records were screened to identify residents stabilized on amlodipine 2.5 or 5 mg QD regimens for at least four weeks. Blood pressure before the next dose was measured in duplicate. After reviewing their charts, they were changed to equivalent doses of amlodipine TIW ( e g , a resident on 5 mg QD was changed to 10 mg TIW). Blood pressure was assessed again four weeks after the change. RESULTS: Twenty (14 females and 6 males) were on amlodipine 2.5 or 5 mg QD regimen. Mean age was 86 i 7 years with a range of 79-93 years. Mean systolic pressure was 120 i 10 and mean diastolic pressure was 64 i 5 mm Hg. Mean amlodipine daily dose was 4.25 mg and the average daily amlodipine cost was $0.90. After changeover to the TIW regimen, mean systolic blood pressure was 119 * 10 and mean diastolic was 65 i 5 mm Hg. Average daily amlodipine dose was 3.65 mg and the average daily medication cost was $0.38. No patient had any sign of medication intolerance and there was no change in any other medication.

CONCLUSION: Amlodipine three times a week is as efficacious as a once a day regimen in the management of hypertension in elderly residents in a community nursing home. In addition, it results in significant cost savings (57%) without any adverse impact on patient care,

46. Pain in long-term care: the patient’s perspective. Katherine Nabzdyk, B.S., Susan K. Bowles, Pharm.D., FCCP; Sunnybrook Health Science Centre, University of Toronto, Toronto, Ontario, Canada.

PURPOSE: Pain is an understudied problem in long-term care settings. We interviewed 41 patients to determine their perceptions of the effect of pain on their activities of daily living (ADL) and of their current pain management. METHODS: All patients admitted to the physical support program were eligible to participate but excluded if they were incapable of providing informed consent or unable to communicate verbally or in writing. The Present Pain Intensity Scale (PPl) was used to rate pain intensity. The Pain Experience Measure was used to determine the patient’s perspective of the effect of pain on their activities of daily living and of their current pain management. Both instruments are valid and reliable. Descriptive statistics were used for data analysis. RESULTS: Eighty-three percent of patients reported pain over the last 7 days, with an average PPI score of 2/5 (discomforting). Of those reporting pain, 47% reported constant pain. One-third indicated that one of sleep, posture, or mobility were affected by pain or its treatment. Only 12% felt a need for increased pharmacological treatment, preferring non-pharmacologic methods such as bed rest, exercise, and diversion. Thirty-eight percent stated that they did not wish to “bother” caregivers with their pain complaints and 29% displayed resignation to their pain. CONCLUSION: The frequency of pain observed in our study is consistent with other reports and indicates that it is an important issue in our facility. Crucial to improving pain management in this population is routine, standardized assessment and documentation.

47. Pharmacy-guided amantadine dosing during an influenza A outbreak in long-term care. Natalie Kennie, Pharm.D., Lisa Ruston, B.S.P., Susan K. Bowles, Phann.D., FCCP Sunnybrook Health Science Centre: University of Toronto, Toronto, Ontario, Canada.

PURPOSE Estimate the rate of adverse drug effects (ADEs) to amantadine prophylaxis, using a pharmacy-guided dosing protocol, during an influenza A outbreak. METHODS: Pharmacists dosed each patient individually according to a dosing schedule which considered serum creatinine, concomitant medications, and seizure history. ADEs were monitored by nursing staff and reported to the pharmacy department. A retrospective chart review was conducted for those patients reported to experience ADEs to compare their amantadine doses to dosing recommendations reported in the literature. RESULTS Three hundred forty-nine patients received amantadine during a 3-week period in March 1998. Twenty-six ADEs were reported in 22 patients

‘(6%). The most commonly reported ADE was confusion, occurring in 12 patients (54%). Other ADEs were gastrointestinal intolerance, hallucinations, agitation, insomnia, and lightheadedness. Most patients with ADEs (15/22) initially received 100 mg daily with 11 receiving dose reductions and four requiring discontinuation. Seven patients with ADEs initially received 100 mg Q 2 days with three receiving dose reductions and four requiring discontinuation. Comparison of our dosing schedule with others indicated that 63-82% of patients with ADEs should have received lower doses according to other dosing nomograms reported in the literature. CONCLUSION: Pharmacist-guided amantadine dosing resulted in a reported rate of ADEs of 6%. However, comparison of our dosing schedule with those reported in the literature indicates that our dosing guidelines may overestimate dosage requirements for some patients, placing them at increased risk of ADEs. We are currently re-evaluating our dosing schedule to minimize the potential for adverse effects.

48. Potentially inappropriate medication use by the elderly living in long- term care. Sarah C. Middleton, B.S., Kate L. Lapane, Ph.D., Anne L. Hume, Pharm.D., Giovanni Gambassi, M.D., the SAGE Study Group; Brown University, Providence, RI; University of Pittsburgh, Pittsburgh, PA; University of Rhode Island, Kingston, RI; Universita Cattolica del Sacro Cuore, Rome, Italy.

PURPOSE: To evaluate the use of potentially inappropriate medications used by the elderly living in nursing homes. METHODS: We used the Systematic Assessment of Geriatric drug use via Epidemiology (SAGE) dataset, an automated database linking minimum data set information collected on all nursing home residents. As part of the HCFA Multi-State Case-Mix and Demonstration Project, information on drugs used in the 7 days before their assessment were collected and subsequently coded to MedispanTM. We included all residents (n=478,503) in approximately 1500 nursing homes in five states (KS, ME, MS, NY, SD) from 1992-1996. We classified drugs as inappropriate according to explicit criteria determind by expert panel consensus (Arch Intern Med 1997;157:15314). RESULTS Overall, 31.3% used at least one inappropriate drug, with nearly 10% using a drug with a high potential for unnecessary adverse outcomes.


Inappropriate drugs most likely to he prescribed included propoxyphene (12.8%), diphenhydramine (5.5%), and amitriptyline (3.2%). Prevalence of other drugs labeled as inappropriate including doxepin. barbiturates, propranolol, reserpine, dipyridamole, diazepam, oxyhutynin, and indomethacin ranged between 1-2% each. Generally, the prevalence of inappropriate medication use was inversely related to age. However, use of both propoxyphene and dipyridamole increased with age (p<O.OOl). CONCLUSION: Although the prevalence of individual drugs labeled as inappropriate is relatively low, nearly one-third of residents are prescribed drugs that either are ineffective or are unnecessarily placing them at high risk of an adverse event. Research focusing on inappropriate prescribing in the elderly living in long-term care is needed.

Hema tology/Oncology 49. Blood transfusion versus recombinant human erythropoietin in chemotherapy-induced anemia: a cost-utility analysis. Jorge G. Avila, Pharm.D., Edward F. McKenna, Pharm.D., BCPS; Charleston Area Medical Center, Charleston, W.

PURPOSE: To perform an economic evaluation (cost-utility analysis [CUAI) of the management strategies associated with the treatment of chemotherapy- induced anemia (CIA) and identify patient populations for which erythropoietin (rHuEPO) pharmacotherapy represents a cost-effective approach. METHODS: An evidence-based decision analysis model was constructed after performance of a thorough literature search (1987-1998, Medlindmanual search techniques) to identify all published material relating to the topic. The model included three arms: transfusion alone, current practicefpackage insert, and evidence-based practice guideline. The evidence-based practice guideline incorporated the variables of chemotherapy responsiveness and aggressive optimization (tapering) of rHuEPO dosage among responders. The model stratified patients based on hemoglobin (HGB) response. Utility scores were estimated from global quality of life scores derived from medical literature. Costs were allocated to each treatment arm based on current institutional costs. CUA was performed from a health system perspective using decision-analysis software (Data 3.0, TreeAge Software). Sensitivity analysis was performed. RESULTS: Acceptable incremental cost-utility ratios ($24,OOO-$SS,O~O/QALY~ were noted in patients with at least a 1 g/dl HGB rise at 4 weeks whose disease was responsive or stable to chemotherapy. Unacceptable incremental cost-utility ratios were associated with the need for rHuEPO dose-escalation (2 $70,80O/QALY) or treatment of patients with progressive disease (2 $ZOO,OOO/QALY). Sensitivity analysis confirmed that rHuEPO cost was the driving force in the analysis. CONCLUSION: rHuEPO pharmacotherapy represents a cost-effective management strategy in the majority of patients with CIA. Dose escalation and treatment of patients with progressive disease are not cost-effective treatment strategies. The evidence-based guideline arm was associated with the lowest incremental cost ratios and should undergo prospective validation.

50. Pre-existing antidiphtheria antibodies cross-react with DT38&GMCSF, a novel fusion toxin consisting of a truncated diphtheria toxin linked to human granulocyte macrophage colony stimulating factor. Philip D. Hall, Pharm.D., BCPS, Arthur E. Frankel, M.D.; Medical University of South Carolina, Charleston, SC; Wake Forest University.

PURPOSE: We are developing a fusion toxin consisting of the catalytic and translocation subunits of diphtheria toxin (DT388) linked to human granulocyte-macrophage colony stimulating factor (DT388-GMCSF) for the treatment of acute myeloid leukemia (AML). With the majority of individuals standardly immunized against diphtheria, pre-existing antidiphtheria

!antibodies could potentially inhibit or alter the efficacy of diphtheria fusion proteins. Use of a truncated diphtheria toxin (DT388). which removes the normal tissue-binding domain of diphtheria protein, may decrease the cross- reaction between pre-existing antidiphtheria antibodies and DT388-GMCSF. METHODS Twenty-one patients previously immunized against diphtheria were tested for cross-reactivity with DT388-GMCSF, diphtheria toxin, or human granulocyte-macrophage colony stimulating factor (GMCSF). Ten of 21 patients had protective levels of antidiphtheria antibodies (> 0.16 U/ml). To detect anti-DT388-GMCSF, diphtheria toxin, or GMCSF antibodies, an indirect enzyme-linked immunosorhent assay (ELISA) with DT388-GMCSF, diphtheria toxin, or GMCSF (5 pg/ml) coated to a 96-well plate was utilized. For bioactivity, a protein synthesis bioassay against HL60 cells (AM1 cell line) was used. RESULTS: Every patients’ serum cross-reacted with DT388-GMCSF with a median concentration of 0.126 1U/ml (range of 0.02-0.829). There was a weak correlation between the antidiphtheria and anti-DT388-GMCSF antibody concentrations (r‘=0.289, p=0.003). There was a detectable cross- reaction between the patients’ sera and human GMCSF, a median of 0.79 pg/ml with a range of undetectable (n=7) to 3.68 pg/ml. Preliminary results of the bioassay show no inhibition of DT388-GMCSF activity against HL60 cells. Complete bioassay results will he presented.

CONCLUSION: Pre-existing antidiphtheria antibodies do cross-react with DT388-GMCSF, but do not appear to he neutralizing. Future work will investigate i n V I V O the effect of antidiphtheria antibodies o n the pharmacokinetics of DT388-GMCSF.

51. Pharmacokinetics of high dose topotecan in a nonhuman primate model. William C. Zamboni, Pharm.D., Merrill J. Egorin, M.D., Jason M. Dohson, B.S., Eleanor G . Zuhowski, B.S., Ann M. Farese. M.S., Thomas MacVittie, Ph.D.; University of Maryland, Baltimore, MD.

PURPOSE: The maximum tolerated dose of topotecan (TPT) is 1.S to 2.0 mglm’lday as a 30-minute infusion QD for 5 days, with hone marrow suppression as the dose limiting toxicity. TPT has a steep relationship between systemic exposure (AUC) and respome (antitumor effect and hone marrow toxicity). High dose TPT might he used as a conditioning regimen for bone marrow transplantation. Thus, we evaluated the disposition of high dose TPT. METHODS: Adult male rhesus monkeys (2.9 to 5.1 kg) received TPT 5.0 (n=4), 10.0 (n=3), and 20.0 (n=3) m g h ’ as a 30-minute IV infusion QD for 5 days. Serial plasma samples were obtained and assayed for TPT lactone (LAC) and total (TOT) by HPLC. A 2-compartment model was fit to serial plasma concentrations, and AUC and systemic clearance (CLsys) were calculated using ADAPT 11. Ratio of AUCmc to AUCro1 was calculated. RESULTS: Median (range) values for AUCuc after 5.0, 10.0, and 20.0 mg/mz were 120.5 (91.8 to 249.31, 259.4 (234.1 to 343.00), and 650.2 (295.4 to 674.3) ng/ml/hr, respectively. Median (range) values for LAC were 21.7 (17.6 to 51.6), 27.2 (4.8 to 37.81, and 15.6 (6.6 to 28.4) Uhdm’, respect’vely Median (range) values for TOT CLSS, were 11.3 (8.3 to 25.71, 19.9 (11.5 to 21.2), and 6.2 (2.4 to 10.1) Uhrlm’, respectively. Median (range) ratio of A U C ~ C to AUCT~T were 0 9 7 (0.51 to 0.631, 0.55 (0.45 to 0.551, and 0.37 (0.36 to 0.37), respectively. CONCLUSION: TPT pharmacokinetics are linear and CLsys at high and standard doses is similar.

52. Reduced systemic exposure to irinotecan and its active metabolite in pa t ien ts wi th glioma receiving concurren t an t iconvulsants and corticosteroids. William P. Petros, Pharm.D., FCCP, Larry J. Schaaf, Ph.D., llkcan Cokgor, M.D., Tracy A. Kerhy, 0. Michael Colvin, M.D., Allan H. Friedman, M.D., Dean W. Knuth, M.S.. Gary 1. Elfring, M.S., Henry S. Friedman, M.D.; Duke University Medical Center, Durham, NC; Pharmacia & Upjohn Inc., Kalamazoo, MI.

Irinotecan (CPT-11) is activated by carhoxylesterase enzymes to its active metabolite (SN-38) (-1000 fold more active than CPT-11) or can he oxidized via CYP3A4 to a relatively inactive aminopentanoic acid metabolite (APC). We recently reported the clinical results of a study in which administration of 125 mg/m’ CPT-11 to patients with glioma resulted in antitumor efficacy, despite an unexpectedly low toxicity rate (Proc ASCO 1998;17:387a, ahstr 1493). Chronic concurrent therapy with corticosteroids and metabolic enzyme-inducing anticonvulsants was expected to he used in most of these patients (actual use 91%), thus we collected 12 serial plasma samples for 24 hours following the first dose for pharmacokinetic studies. Concentrations of CPT-11, APC, SN-38, and its glucuronide (SN-38G) were determined by HPLC. Pharmacokinetic data were analyzed using a standard 2-stage approach. Results are compared to a group of GI cancer patients treated with the same CPT-11 dosdschedule and whose plasma specimens were analyzed using the same bioanalytical method and laboratory. RESULTS The mean (+ SD) CPT-11 AUC was 4430 ng.h/ml (i 1306) in the 32 glioma patients compared to 11,175 (+ 4291) ng.h/ml for the 99 patients with gastrointestinal cancer (peO.0001). Similarly, mean SN-38 AUC was 76.7 ng*h/ml (* 50.5) ng.h/ml in glioma vs 347 (i 160) ng.h/ml in GI cancer patients (pcO.0001). The ratio of SN-38/SN-38G AUC was 1.6-fold higher in the gastrointestinal cancer patients (p=0.0002). APC disposition data are currently being analyzed. CONCLUSION: Concurrent therapy with enzyme-inducing anticonvulsants and corticosteroids appears to substantially reduce systemic exposure to CPT- 11 and its active metabolite, SN-38. Additional single-agent CPT-11 dose- finding and pharmacokinetic trials in patients with glioma are needed based on these data.

53. A phase I1 trial of docetaxel in hormone-sensitive prostate cancer. Patrick J. Medina, Pharm.D., Susan Goodin, Pharm.D., Mohamed M. Rafi, Ph.D., Robert S. DiPaola, M.D.; The Cancer lnstitute of New Jersey, New Brunswick, NJ.

PURPOSE: The primary objective of this study is to determine the effect of docetaxel on prostate specific antigen (PSA) progression in patients who have not received hormonal therapy. Secondarily, bcl-2 will he assessed to evaluate the effect of docetaxel on hcl-2 expression and phosphorylation. METHODS: Thirty patients will receive docetaxel 70 mg/mz on day 1 of therapy as an 1V infusion over 1 hour every 3 weeks. Dexamethasone will he given for 3 days starting the day before docetaxel. Response, as defined by PSA, will he assessed every three cycles. Western blots for hcl-2 expression and phosphorylation will he performed on the initial tumor biopsy and mononuclear cells drawn during the first two cycles of therapy.


RESULTS: Five patients have been enrolled with two patients completing three cycles of therapy. One patient has a decrease in PSA of 19%. Western blots performed on four patients show decreased expression of bcl-2, hut not phosphotylation. Neutropenia has been the most common toxicity, hut only one patient has experienced grade 4 neutropenia. CONCLUSION: Preliminary results suggest that docetaxel may have an effect on PSA progression in patients with hormone-sensitive prostate cancer. Toxicities appear to be limited to transient neutropenia. In this small patient sample, bcl-2 phosphotylation does not appear to decrease in mononuclear cells. Further patient accrual will more accurately assess the use of docetaxel in this patient population.

54. Preclinical and clinical pharmacokinetics of COL-3. Michelle A. Rudek, B 5.. Valerie Dyer, B.S., J. Michael Hamilton, M.D., Jim Pluda, M.D., Eddie Reed, M.D.. William D. Figg., Pharm.D.; National Cancer Institute, Bethesda, MD.

Matrix metalloproteinases (MMP) inhibitors are a new class of compounds which may have antimetastatic and antiangiogenic properties. COL-3, a tetracycline analogue, is in phase 1 clinical trial at the National Cancer Institute. Preclinical data suggest concentrations between 1860 to 12,000 nglml will he sufficient to exert an effect in vivo, while lethal toxicity has been observed in animals at 10,600 to 14,800 ng/ml (data on file at CollaGenex, Inc., Southern Research Institute, Birmingham, AL and MB/DCS/NCI 1996-1998). Pharmacokinetic studies in both rats and monkeys have been performed. Terminal half-lives are 7 hours in rats and range from 28 to 1426 hours in monkeys. Bioavailability ranges from 9-56% in both species. Simulations have been performed by allometrically scaling monkey pharmacokinetic data to an average human in an attempt to predict where toxicity may occur. Currently, eleven patients are enrolled on two dosage levels (36 and 50 mglm'). COL-3 is administered as a single dose followed hy 5 days of pharmacokinetic sampling after which daily dosing commences. Concentrations of COL-3 were determined by reverse-phase HPLC. Steady- state concentrations for five patients range from 2540 to 11,040 nglml. Half- lives for five patients range from 61-96 hours after single dose administration and from 37 to 87 after multiple dosing. Grade I, 2, and 3 photosensitivity reactions have been observed in six patients at both dose levels.

55E. Phase 11 study of carboxyamido-triazole in androgen-independent prostate cancer. Kenneth S. Bauer, William D. Figg, J. Michael Hamilton, Raymond Bergan, Alice Chen, Valerie Dyer, McClellan M. Walther, W. Marsten Linehan, Eddie Reed; National Cancer Institute, Bethesda, MD.

Presented at the 10th NCI-EORTC Symposium on New Drugs in Cancer Therapy, Amsterdam, The Netherlands, June 1998.

56E. Pharmacokinetics of thalidomide in an elderly prostate cancer population. Sangeeta Raje, M.S. , Eddie Reed, M.D., Kenneth 5. Bauer, Pharm. D., Anne Tompkins, B.S.N., David Venzon, Ph.D., William D. F i g , Pharm. D.; National Cancer Institute, National Institutes of Health, Bethesda, MD.

Presented at the 1998 Meeting of the American Association of Pharmaceutical Scientists, San Francisco, CA, November 1998.

57 . Benefits of e ry thropoie t in i n t h e t r e a t m e n t of cancer a n d myelodysplastic syndrome-related anemia. Dina Glennon, B.S., Cecilia Schott, Pharm.D., Robert Herman, B.S.N.; St. Elizabeth's Medical Center of Boston, Boston, MA.

PURPOSE: To evaluate the effects of erythropoietin therapy in patients with cancer or myelodysplastic syndrome related anemia. This study had two goals: 1) to establish an adequate erythropoietin dose or dose range to increase hemoglobin by 2 g/dl within 8-16 weeks of treatment; and 2) to evaluate the possibility of predicting the response to erythropoietin treatment. METHODS: Patients were administered erythropoietin subcutaneously three times per week at an initial dose of 100-150 d k g , doses were increased to a maximum of 300 d k g . Erythropoietin levels and iron stores were monitored. RESULTS: This study evaluated eight patients with anemia related to either cancer or myelodysplastic syndrome. The overall hemoglobin mean SD at week 0 was 9.0 * 1.0 g/dl, and at week 16 was 11.6 * 2.3 gldl (p<0.05). The overall hematocrit mean * SD at week 0 was 27.7 + 3.8% and at week 16 was 35.4 + 7.2% (p<0.05). Patients with cancer-related anemia seemed to benefit from erythropoietin therapy, with an increase in hemoglobin serum level > 2.0 g/dl. However, patients with myelodysplastic syndrome proved to be refractory to erythropoietin therapy. CONCLUSION: Cancer-related anemia can he successfully treated with erythropoietin. In our patients, erythropoietin decreased transfusion requirements and improved their symptoms associated with anemia. However, patients with myelodysplastic syndrome were refractory to erythropoietin treatment, and therefore continued to require blood transfusions and present with symptoms associated with anemia.

58. Development of a limited sampling model for 5-flnorouracil to predict toxicity in patients with colorectal cancer. Frank G.A. Jansman, BCPS, Anita Herder, BCPS, Julien L.L.M. Coenen, M.D.,Jacobus RBJ. Brouwers, Phann.D.; Sophia HospitaliWeezenlanden Zwolle, The Netherlands; Hospital de

Tjongerschans, Heerenveen, The Netherlands; State University Groningen, Groningen, The Netherlands.

PURPOSE: A pilot study was carried out to study the concept of a limited sampling model to predict the toxicity of 5-fluorouracil and leucovorin in patients with colon cancer. METHODS: 5-Fluorouracil (5-FU) was administered every 4 weeks as a 10- minute infusion IV (425 mglm') from days 1-5. Folinic acid (leucovorin) was administered 30 minutes before the 5-FU at a dose of 20 mglm' on days 1-5. 5-FU plasma concentrations and saliva concentrations were determined in samples taken 5, 10, 15, 20, 25,40, 55, 70, and 100 minutes after the start of the 5-FU infusion at days 1 and 5 of the first treatment week. The study design was intention to treat after written informed consent. The toxicity score was quantified by the South West Oncology Group (SWOG) standard response listed (Inv Drugs 1992;10:239-53) on the items for mucositis, conjunctivitis, diarrhea, nausea, and vomiting. The mean toxicity score over a 15-day period (from days 1-15) was determined. RESULTS: The mean toxicity score for all items was 2.0 on the SWOG scale (n=10). The mean AUC 5-FU plasma concentration was determined in ten patients: 537 m i n m g k (range 431-721) on day 1 and 660 minamgk (range 515-835) at day 5. In saliva the results were inconsistent: AUC 276 min.mg/L (range 198-411) on day 1 and 340 min-mgk (range 240-546) on day 5. Assuming linearity between AUC and toxicity score, the mean toxicity score = 0.0010 AUC,I,,, - 0.29 (r=0.60) for day 1. For saliva the relationship was not clear. From literature, it is known that acute toxicity is correlated with 5-FU plasma levels > 3 mg/L. None of the patients reached these high plasma levels during the first 5-FU cycle. CONCLUSION: This pilot study shows a wide variability in saliva 5-FU concentrations, but a more consistent relationship between plasma 5-FU levels and the mean SWOG toxicity score.

59. Oral dolasetron mesylate is effective in Hesketh level 5 emetogenic chemotherapy. Jim Koeller, M.S., Steven Chernoff, Ph.D., D. Parizadeh, Pharm.D., D. DuBois, M.S.; University of Texas at Austin, Austin, TX; Hoechst Marion Roussel, Kansas City, MO.

PURPOSE: A single 100 mg oral dose of dolasetron was approved in the US. for management of chemotherapy-induced nausea and vomiting based on data from two pivotal trials (Canc J Sci Am 1997;3:45; Cancer 1997;79:1216). The chemotherapeutic regimens used were deemed moderately emetogenic based only o n the primary chemotherapeutic agent and not the entire regimen. A more complete assessment of the emetogenicity of the entire regimen can be made using the recently published criteria of Hesketh, et al 0 Clin Onc 1997;15:103). METHODS: The 151 patients who received 100 mg oral dolasetron in the two trials were classified based on the new Hesketh criteria, and efficacy was then determined in the most emetogenic chemotherapy studied (Hesketh level 5). RESULTS: Out of 151 patients, 75 met the criteria for Hesketh level 5 emetogenicity. Of these patients, the most common chemotherapeutic agents (and the percentage of patients receiving them) were: etoposide 56%, cisplatin 41%, carhoplatin 35%, cyclophosphamide 31%, doxorubicin 21%, fluorouracil21%, and vincristine 11%. Efficacy results were: 24-Hour Response All PatienMLevels Level 5 Patients (No Rescue Meds) (n=15 1) (n=75) No vomiting 67% 64% No nausea 51% 53% No vomiting and no nausea 49% 51% Pauents did not receive dexamethasone.

CONCLUSION: In patients receiving Hesketh level 5 chemotherapy (the most emetogenic level reported), a single 100 mg oral dose of dolasetron offers efficacy comparable to that of all levels studied.

60. Comparison of glomerular filtration rate estimations in cancer patients: impact on carboplatin dose calculated with the Calvert equation. Angela Donahue, Pharm.D., Jeannine McCune, Pharm.D., Heidi H. Gillenwater, M.D., Mark A. Socinski, M.D., Celeste Lindley, Pharm.D., M.S.; University of North Carolina, Chapel Hill, NC.

The Calvert equation (dose [mgl = target AUC x [glomemlar filtration rate (GFR) + 251) is widely used to calculate the dose of carboplatin (CARBO) required to attain a desired AUC. GFR is estimated with radiolaheled compounds (Cr-EDTA and Tc-DTPA, r=0.98), creatinine clearance calculated by Cockcroft Gault (CrC1 U G ) , or urine creatinine excretion over 2 to 24 hours. CrCl exceeds GFR due to an active secretion component of creatinine elimination. This is partially offset by falsely elevated serum creatinine values obtained with traditional creatinine analyses such as the Jaffe method. However, more accurate enzymatic methods are in use and have been demonstrated to overpredict GFR. This study compares three methods of GFR estimation (Tc-DTPA-Russell method, CrCl U G , CrCl 2-hour urine) to assess their impact on CARBO dose obtained using the Calvert equation in 13 previously untreated cancer patients (54-77 years, 7 men). Urinary and serum creatinine values were determined via a n enzymatic method


(peroxidase-antiperoxidase). The results are (means): GFR Estimate Bias Calculated Dose % of

Method (mumin) (95% CI) (mg) Tc-DTPA Dose Tc-DTPA 121 NA 73 1 NA CrCl (UG) 87a -34* 19 562 7 7% CrCl(2-hr urine) 82h -39 5 29 536 73% "Paired t-tesb relative LO Tc-DTPA p<O 004; "p<0.021

GFR was underestimated by CrCl U G and CrCl 2-hour urine analyzed using the enzymatic creatinine assay. This reduction in GFR could result in a clinically significant reduction in the dose of CARBO calculated using the Calvert equation. This unexpected finding requires further investigation since a recent report recommends lowering the CARBO dose calculated from the Calvert equation at institutions using enzymatic creatinine analyses (peroxidase-antiperoxidase).

61. Evaluation of the incidence of infection and phlebitis associated with the duration of single 1V continuous infusions 3 days or less versus 3 to 7 days in an outpatient cancer program. Dianne Brundage, Pharm.D., Barb Moran, B.S.N., Sandy Oman, B.S.N., Nan Quade, B.S.N., Julie Boots, B.S.N., Kathleen Ogle, M.D.; Healthsystem Minnesota, Minneapolis, MN.

Differences in practices between two cancer centers (CC) were observed after a merger. One CC allowed continuous outpatient infusions per IV bag or cassette to last up to 7 days while the other CC would allow only 72 hours. Several CCs were surveyed regarding the policy of duration of outpatient IV infusions, and varying results were obtained. We decided to concurrently evaluate continuous infusions in the outpatient setting for infection and phlebitis. PURPOSE: To determine the incidence of infection and phlebitis with single IV continuous infusions 24168 hours in an outpatient cancer program. For analysis purposes, the duration of each infusion category was: 24 hours (0-36 hours), 48 hours (> 3MO hours), and so forth. METHODS: Standardized criteria for phlebitis and infection were developed from the literature. Each infusion was aseptically prepared in a laminar flow hood. Nurses checked criteria present when each IV bag or cassette infusion was stopped an infection control nurse judged each form for infection or phlebitis by criteria checked. RESULTS: Predominately chemotherapy agents were used in 383 infusion events recorded. One hundred fifty-three infusions were S 84 hours (the cutoff for 72-hour infusions) and 230 infusions were more than 84 hours in duration. Two infections were found one in a 48-hour infusion and one in a 168-hour infusion. No hospitalizations were required for infection. No cases of phlebitis occurred. CONCLUSION: We conclude a single continuous 1V infusion of greater than 3 days has no greater incidence of infection or phlebitis than a shorter infusion in our outpatient oncology program.

Infectious Diseases 62. Penetration of lipid formulations of amphotericin B and nystatin into bone marrow and fat tissue in rabbits. Stephen C. Piscitelli, Pharm.D., Andreas Groll, M.D., Diana Mickiene, M.S., Thomas J. Walsh. M.D.; National Cancer Institute, National Institutes of Health, Bethesda. MD.

PURPOSE: To determine the penetration of lipid formulations of amphotericin B (AmB) and nystatin in bone marrow and fat tissue in rabbits. METHODS: Seven groups of four rabbits each were studied. Rabbits were administered standard AmB deoxycholate (1 mg/kg/d), ABLC, ABCD, or liposome AmB (5 mg/kg/d) for a total of eight doses or liposomal nystatin (Nyotranm) given at 2, 4, or 6 mgkg once daily for 15 doses. Animals were sacrificed 30 minutes after the last dose hy 1V pentobarbital. Plasma, peri- renal fat, bone marrow, and liver tissue (for comparison) were collected at autopsy. AmB and nystatin concentrations in plasma and tissue were determined using HPLC methods. RESULTS: All AmB lipid formulations achieved at least 4-fold higher concentrations in bone marrow compared to AmB deoxycholate. Concentrations in hone marrow were 62-76% of those in the liver. All AmB formulations penetrated relatively poorly into fat tissue. Nystatin concentrations in plasma and tissue exhibited nonlinear disposition and demonstrated lesser penetration into bone marrow and fat. Data are reported as mean i SD (ratio of tissue to plasma). D w Plasma Liver Marrow Fat

Amb-D 1.4 * 0.3 26.9 t4.8 (19.2) 8.02 1.7 (5.7) 1.2 i 0.3 (0.86) ABLC 0.84t0.10 57.9t5.3 (68.9) 35.4t 12.7 (42.1) 2.1 t 1.3 (25) ABCD 0.97tO08 69.5t22.0(71.6) 53.1+21.5(54.7) 1.1+0.24(1.3) Lip-AmB 59.5 1.8 59.8 * 6.9 (1.0) 39.5 t 4.7 (0.66) 8.9 t 1.9 (0.15) NysZmgkg 5.5tO9 13.2t4.4(2.4) 1.0+0.4(0.18) 0.33+.05(0.06) Nys4mgkg 13.3a0.9 18.5+1.1(1.4) 2.5t0.7(0.19) 0.97+0.40(0.07) Nys6mgkg 35.2t77 41.3t4.6(1.2) 7.5+1.5(0.21) 2.75+0.66(0.08)

CONCLUSION: High concentrations of AmB can he achieved in bone marrow after administration of lipid formulations. Higher doses of liposomal

(pdml) bp/g) (P&) ( P W

nystatin also achieve concentrations above the MIC for most fungal pathogens. Lipid formulations of polyene antifungals demonstrate poor uptake into fat tissue.

63. Comparison of vancomycin pharmacodynamics (1 gram every 12 or 24 hours) against methicillin-resistant staphylococcus isolates. Melinda K. Lacy, Phann.D., Pamela R. Tessier, B.S., David P. Nicolau, Pharm.D., Charles H. Nightingale, Ph.D., Richard Quintiliani, M.D.; University of Kansas Medical Center, Kansas City, KS; Hartford Hospital, Hartford, CT.

PURPOSE: The purpose of this study was to compare the duration of serum bactericidal activity (SBA) for two steady-state vancomycin (VAN) dosing regimens, 1 gram every 12 hours and 1 gram every 24 hours, in healthy volunteers using two strains each of methicdlin-resistant Staphylococcus au ras (MRSA) and Staphylococcus epidennidis (MRSE). METHODS: This was a prospective, randomized, open-label, 2-period crossover study with a 7-day washout period. Two VAN dosing regimens were compared 1 gram every 12 hours x 4 doses and 1 gram every 24 hours x 3 doses. All isolates were susceptible to VAN with MIC values of 2 or 4 pg/ml. Serum bactericidal titers (SBTs) were run in duplicate. Serum bactericidal activity (SBA) was defined as the time points at which 100% of all subject SBTs were 2 1:2. Time above the MIC (T > MIC) was also determined. RESULTS: Twelve subjects (nine male, three female) aged 25.5 * 4.5 years, weighing 74.1 i 9.6 kg were enrolled. For the every 12 hour regimen, 100% T > MIC was maintained against all isolates while SBA was noted for 10-12 hours of the dosing interval. For the every 24 hour regimen, T > MIC was maintained for 5475% of the dosing interval while SBA was noted for 1 hours for MRSA and 8-10 hours for MRSE. CONCLUSION: These data show that T > MIC exceeded 50% of the dosing interval for both dosing regiqwns. Decreased SBA was observed for the every 24 hour regimen for isolates with MlCs of 4 pg/ml and for both MRSE isolates. These results suggest that a VAN every 24 hour interval can he used in patients with good renal function when M F A is isolated and MIC values are 5 2 pg/ml.

64E. Surveillance of drug-resistant Streptococcus pneumoniae as a cause of community-acquired pneumonia in southern Idaho: susceptibility, treatment, and clinical outcomes. Karl J. Madaras-Kelly, Pharm.D., Deb Anzcak, B.S., Troy A. DeMasters, B.S., Rex W. Force, Pharm.D., Roger G. Hefflinger, Pharm.D., Cara A. Lawless, Pharm.D.. Linda R. Pierce, Pharm.D., Shirley J. Reitz, Pharm.D., BCPS; ldaho State University, Pocatello, ID; VA Medical Center, Boise, ID.

Presented at the 38th Interscience Conference on Antimicrobial Agents and Chemotherapy, San Diego, CA, September 2427,1998.

65. Associations between initial antimicrobial therapy and medical outcomes for hospitalized elderly patients with pneumonia. Patrick P. Gleason, Pharm.D., BCPS, Thomas P. Meehan, M.D., M.P.H., Jonathan M. Fine, M.D., Deron H. Galusha, M.S., Michael J. Fine, M.D., M.S.; University of Pittsburgh, Pittsburgh, PA; Connecticut Peer Review Organization, Middletown, CT; Nonvalk Hospital, Nonvalk, CT.

PURPOSE: To describe initial antimicrobial therapies prescribed for Medicare patients hospitalized with pneumonia and to determine associations with 30-day mortality and other medical outcomes. METHODS: This was a multicenter, retrospective cohort study. Medical records from 3512 acute care hospitals throughout the United States were reviewed for 13,515 patients 2 65 years old who were hospitalized with radiographically and clinically confirmed pneumonia. The most common initial antimicrobial regimens were identified. Associations between initial antimicrobial regimens and 30-day mortality were assessed using multivariable logistic regression analyses. Comparisons were made to the reference group of patients treated with a non-pseudomonal third-generation cephalosporin alone. RESULTS: The most common regimens were: non-pseudomonal third- generation cephalosporins alone (26.5%), second-generation cephalosporins alone (12.3%), and non-pseudomonal third-generation cephalosporins plus a macrolide (8.8%). In the total study population, use of a second-generation cephalosporin plus a macrolide (OR 0.68; 95% CI 0.49-0.961, a non-pseudomonal third-generation cephalosporin plus a macrolide (OR 0.69; 95% C1 0.55-0.88), or a fluoroquinolone alone (OR 0.64; 95% CI 0.42-0.99) was independently associated with lower 30-day mortality. Similar findings were seen in patients not requiring treatment in an intensive care unit (ICU). Use of a beta-lactadeta-lactamase inhibitor plus macrolide was associated with increased mortality in the entire study population (OR 1.84; 95% CI 1.23-2.751, with patients admitted from a chronic care facility (OR 3.15; 95% CI 1.35-7.34), and with those treated in an ICU (OR 2.44; 95% C1 1.27-4.69). CONCLUSIONS: Initial antimicrobial therapy with a second-generation cephalosporin plus a macrolide, a non-pseudomonal third-generation cephalosporin plus a macrolide, or a fluoroquinolone alone are independently associated with improved 30-day survival both overall and among patients not requiring treatment i n an ICU. The frequent use of other initial antimicrobial regimens suggest opportunities to improve the quality of

9-16


hospital care for elderly patients with pneumonia

66. Meta-analysis: broad spectrum beta-lactamase resistant antibiotics versus combination regimens for intraabdominal infections. Ru-Ming Fan, Phann.D., M.P.H., Esther Sammartano, M.S.; Brookdale University Hospital and Medical Center, Brooklyn, NY.

PURPOSE: The purpose of this study is to measure the effectiveness and occurrence of adverse events of administration of beta-lactamase resistant antibiotics (ticarcillidclavulanate, pipercillin/tazobactam, ampicillidsulbactam, and imipenem) as compared to combination regimens (clindamycin and aminoglycoside) for the treatment of intraabdominal infections. METHODS: Thirty-seven articles were identified from the literature search and nine met the selection criteria. The first and most important inclusion criteria used was that studies must be randomized, blinded, comparison group-controlled trials. Six major areas of meta-analysis, including study design, control and measurement of potential bias, combinability, statistical and weight effect size analysis, and the application of results were evaluated. A total of 936 patients were evaluated in nine trials for clinical cure, bacteria eradication, relapse rate, and adverse drug events. RESULTS: For the study selection, the raw agreement between the reviewers was 88%, the k statistic indicated substantial agreement between reviewers. Meta-analysis of the data revealed the summary odds ratio to be more effective in beta-lactamase resistant antibiotics than the combination regimen group (OR = 1.54, p=0.005, 95% Cl: 1.14, 2.09). The weight effect size (WES) demonstrated that the single broad spectrum beta-lactamase resistant antibiotic group is more effective than the combination group (WES = 0.21, 95% CI: 0.05, 0.31). Bacteria eradication, relapse rate, and adverse drug event demonstrated that there was no significant difference between two groups because the series of the studies evaluated did not address these issues. Post hoc examination of these data suggested an alternative hypothesis: narrow inclusion criteria for the meta-analysis resulted in substantial homogeneity for the definition of clinical cure, bacteria eradication, and absence of relapse in each study. CONCLUSION: Single broad spectrum beta-lactamase resistant antimicrobials can be used in place of traditional combination therapy for mild to moderate intraabdominal infection as they appear to be more effective than combination regimens in clinical cure outcome. Meta-analysis is also helpful in highlighting gaps in the literature, providing insight into new directions for research, and finding mediating or interactional relationships or trends that are either too subtle to see or that cannot be hypothesized and tested in individual studies.

67. In vitro activity and resistance development with clarithromycin and azithromycin against H. influmae and 5. aureus. David S. Burgess, Phann.D., Rhonda W. Hastings, Pharm.D., Jennifer L. Horan, Pharm.D.; University of Texas Health Science Center, San Antonio, TX.

PURPOSE: To evaluate the in vitro activity and development of resistance of H. influenzae and S. aureus against clarithromycin (CLARl) and azithromycin (AZI) using time-kill methodology. METHODS: A clinical isolate (representative of the MlCsa for CLARl and AZI) of H. influenzae and S . aureus was obtained from the Clinical Microbiology Laboratory. MICs were performed according to NCCLS guidelines. Mueller-Hinton broth and agar was used with addition of 1% supplement C for H. influenzae. Also, 14-hydroxyclarithromycin (14-OH) was utilized in the susceptibility and time-kill studies at a ratio of 2:l (CLARI:14- OH) for H. influenzae. Time-kill studies were performed using concentrations of 0.25, 0.5, 1, 2 ,4 , and 8 x MIC. The initial inoculum was approximately lo5 CFU/ml. Samples (50 pL) were plated onto appropriate solid agar at 0, 4, 8, 12, and 24 hours using a spiral plater. In addition, at time 0, 12, and 24 hours each drug concentratiodorganism combination was spiraled onto plates containing concenmtions of 1, 2, and 4 x MIC of CUR1 or CLAR1:lCOH and AZI. Plates were incubated at 35°C for 24 hours and colony counts were determined. Plots of colony counts vs time for each concentration were constructed. The maximal killing, time to maximal killing, and 99.9% killing were evaluated. RESULTS The MICs were as follows for H. influenzae and S. aureus: 1 pg/ml (AZl), 4 pg/ml (CLARl), 2 pg/ml (CLARk14-OH); and 1 pg/ml (AZI), 0.25 pg/ml (CLARI), respectively. Neither drug provided bactericidal activity against isolates at any concentration. Maximal effect was achieved with 2 x MIC for CUR1 and AZI against H. influenzae and S. aureus. Overall at 12 hours, sub-MIC concentrations of CLARI or CLARI:14-OH and AZ1 for both organisms lead to resistance. H. influenzae exposed to A21 S 1 x MIC exhibited differences on plates containing CLARl:14-OH and AZI, with fewer colonies on CLARI:l$-OH containing plates. However, MICs representative of colonies from both CLARI:lCOH and A21 containing plates were > 32 pg/ml. CONCLUSION: The maximal effect of CLARI and AZI was seen with concentrations 5 2 x MlC, whereas sub-MIC concentrations of clarithromycin and azithromycin appear to promote the development of resistance. Hence, pharmacokinetic profiles need to be evaluated in relation to the MIC for CLARl and AZI.

68E. Efficacy and safety of ciprofloxacin 750 mg BID vs clarithromycin 500

mg BID for the treatment of acute exacerbations of complicated/severe bronchitis. A. Anzueto, M. Niederman, G. Tillotson, the Bronchitis Study Group; University of Texas, San Antonio, TX; Winthrop University, Mineola, NY; Bayer Corporation, West Haven, CT.

Presented at the American College of Chest Physicians, Toronto, Ontario, Canada, November 8-12, 1998.

69E. Treatment of acute uncomplicated pyelonephritis: 7 days of ciprofloxacin vs 14 days of trimethoprim/sulfamethoxazole therapy. D.A. Talan, W.E. Stamm, J. Reuning-Scherer. L. Faulkner, D. Church, the Pyelonephritis lnvestigators Group; UCLA, Sylmar, CA; University of Washington, Seattle, WA; Bayer Corporation, West Haven, CT.

Presented at the 38th lnterscience Conference on Antimicrobial Agents and Chemotherapy, San Diego, CA. September 2627,1998.

70E. Ciprofloxacin suspension: oral bioequivalence and efficacy for acute urinary tract infection. A. Heyd, A. Shah, M-C Liu, D. Vaughan, A.H. Heller; Bayer Corporation, West Haven, CT; Bayer Inc., Etobicoke, Ontario, Canada.

Presented at the 38th lnterscience Conference on Antimicrobial Agents and Chemotherapy, San Diego, CA, September 24-27, 1998.

71. Safety of ciprofloxacin 750 mg BID for the treatment of respiratory tract infections: integrated summary. R. Pryka, D. Haverstock, G. Tillotson, 5. Kowalsky; Bayer Corporation, West Haven, CT.

PURPOSE: Fluoroquinolones (FQ) are considered to be safe antibiotics, although there are known differences among newer FQ. Eleven prospective studies from the US. Bayer database investigated the incidence rates of drug- related adverse events (DRAE) of ciprofloxacin (ClP) 750 mg BID vs comparator (COMP) agents and to rates observed in the CIP 500 mg BID respiratory tract infection (RTI) clinical trials database. METHODS A retrospective CIP RTI database review was conducted. In five uncontrolled studies, 443 patients received ClP 750 mg BID. In six controlled trials, 2524 patients (1252 ClP, 1272 COMP) were enrolled. COMP agents included clarithromycin and cefuroxime axetil. RESULTS: DRAEs were reported in 22% of CIP of 750 mg BID-treated patients in uncontrolled trials, and in 15% of CIP 750 mg BID and 13% of COMP-treated patients in controlled trials. For 1695 CIP 750 mg BID treated patients, digestive-related AEs (nausea, diarrhea, vomiting; 12%) and CNS- related AEs (nervousness, dizziness; 3%) were most commonly reported. The combined database (uncontrolled and controlled trials) revealed that individual DRAEs occurred in similar frequency, except for nausea (ClP 6%. COMP 3%). Following ClP 500 mg BID therapy, digestive-related AEs were most common (13%), followed by CNS-related AEs (6%). and body-as-a- whole-related AEs (e.g., headache, abdominal pain; 5%). CONCLUSION: CIP 750 mg BID was well tolerated. lncidence rates of digestive- and CNS-related AEs were similar following CIP 500 mg BID or 750 mg BID. CIP 750 mg BID therapy was not associated with a high rate of dizziness or other CNS AEs, prolonged QTc intervals, phototoxicity, or a metallic taste as reported for some newer FQ.

72E. Sequential (1V to PO) ciprofloxacin plus metronidazole vs piperacillin/tazobactam: treatment of patients with complicated intraabdominal infections. S. Cohn, D. Haverstock, S. Kowalsky, the lntraabdominal Study Group; University of Miami, Miami, FL; Bayer Corporation, West Haven, CT.

Presented at the 38th lnterscience Conference on Antimicrobial Agents and Chemotherapy, San Diego, CA, September 2427 , 1998.

73E. Fluconazole-induced amphotericin B antagonism: influence of fluconazole susceptibihty and staggered administration. Michael E. Klepser, Pharm.D., C. Rosemarie Petzold, B.S., Erika J. Emst, Pharm.D., Michael A. Pfaller, M.D.; University of Iowa, Iowa City, IA. Presented at the 38th lnterscience Conference on Antimicrobial Agents and Chemotherapy, San Diego. CA, September 24-27, 1998.

74. Comparative in vitro activity of gatifloxacin, a new fluoroquinolone, and ciprofloxacin against Legionella species. Susan L. Pendland, M . S . , Pharm.D., Karen J. Losnedahl, M.S., Christopher A. Schriever, M.S.; University of Illinois at Chicago, Chicago, IL.

PURPOSE: Gatifloxacin is a new fluoroquinolone antibiotic exhibiting activity against a broad spectrum of microorganisms. This study examined the in vitro activity of gatifloxacin against Legionella species and compared it to the older fluoroquinolone, ciprofloxacin, which has demonstrated both in vitro activity and clinical efficacy against these intracellular pathogens. METHODS: We performed agar dilution MlCs of these agents against 46 legionella organisms using BCYEALPHS and BSYE agar media. A final inoculum of 10' CFU/spot and lo6 CFUkpot was used on the BCYE d and BSYE media, respectively. All tests were performed in duplicate and all plates were incubated at 3 5 T in humidified room air for 48 hours. RESULTS: MIC90s and ranges for Legionella pneumophilia for gatifloxacin


BCYEa medium were 1.0 mg/L (range 0.5-1.0) and on BSYE medium 0.03 in@ (range 0.004-0 03); for ciprofloxacin BCYEu medium they were 1.0 mg/L (range 1.0-2.0) and on BSYE medium 0.03 m@ (range 0 015-0.03) CONCLUSION: Our data indicate Ihat gatifloxacin has good in vitro activity against Legionella ~pcc ics , with MlCs equal to or slightly lower than ciprofloxacin against L pneumophilia. Based on these results, gatifloxacin warrants further investigation for the treatment of legionella infections.

75E. Spinal epidural abscess organism susceptibility patterns: clinical implications of current antibiotic prescribing variation. Timothy J . Bosinski, Pharm.D., Denisc H Rhoney, Pharm.D., Kellie R. Murry, Pharm.D., William M. Coplin, M.D.; Wayne State University, Detroit Receiving Hospital, Detroit, MI.

Presented a1 the Congress ol Neurological Surgeons, Seattle, WA, October 1998.

76. Bactericidal activity of LY333328, vancomycin, and trovafloxacin against vancomycin-intermediate Sfaphylococcus aureus. Ellie Hershberger, Pharm.D , Michael J . Rybak, Pharm.D.; Detroit Receiving Hospital: University Health Center, Wayne State University, Detroit, MI

PURPOSE: Recently there have been reports of Staphylococcus aureus clinical isolates with intermediate susceptibility to vancomycin (V; MIC = 8 pg/ml). We studied the killing activity of V, LY333328 (L) , and trovafloxacin (T) against a V-intermediate Staphylococcus aureus strain (VISA 14379), a heterogenous VISA isolate 14378 (MIC = 3 pg/ml), a pre-isolate (14358) isolated from the same patient, and a standard vancomycin sensitive MRSA isola:e (494) METHODS: MlCs and MBCs of the above antibiotics were determined by broth microdilution. Time-kill studies were done in triplicate and samples were collected at 0, 8, and 24 hours. Each antibiotic was tested at concentrations of 0 5, 1, and 2x MIC. RESULTS: V, L, and T MICs/MBCs for 14358 were 3/24, 1/4, and 1/1; for 14378 were 3/6, 1/16, and 1/4; for 14379 were 8/8, 1/2, and 0.5/1; and for 494 were 0.75/1, 0.5/2, and 0.015/0.03, respectively. V alone produced significant (pS0.05) killing against the VISA strain 14379 at 0.5 and l x MlC suggesting substantial subpopulations with MlCs < 8 pg/ml. The same fractions of MIC did not demonstrate significant activity against 14358 and 14378. At 24 hours, similar fractions of MIC of L produced comparable killing to V against 14378, but at 2x MIC L was less active than V against 14358. By 24 hours L and V resulted in 99.9% kill (2 3 loglo reduction in CFU/ml) against all three isolates at 2x MIC. T did not result in 99.9% kill against 14379 at 24 hours. CONCLUSION: Susceptibility to vancomycin for VISA 14379 appears to be heterogeneous, while 14378 and 14358 appear to be more homogenous. Both the glycopeptides reduced the starting inocula by 99.9% at concentrations of 2x MIC. At 2x MIC T was not bactericidal against the VISA isolate tested and higher concentrations of T may be necessary. Based on these findings, slightly higher doses or more frequent dosing may restore the activity of V against VISA to that of vancomycin-sensitive strains Additional studies with more VISA strains are warranted to further investigate these hypotheses.

77. Implementation of a vancomycin order form on vancomycin use in the hospital. Mark T. Dickes, Joseph Ho, Pharm. D., Christopher J . Destache, Pharm D.; Creighton University, Omaha, NE.

PURPOSE: Due to the increase in vancomycin resistant enterococci (VRE) isolates and the threat of transfer of this resistance to S. aureus, the CDC published vancomycin use guidelines. Using these guidelines, the medical records at St. Joseph Hospital were evaluated for appropriateness. METHODS: Patients' medical records were retrospectively reviewed from May 1997 through August 1997. Each case of vancomycin usage was classified as appropriate or inappropriate and the reasons for appropriateness were categorized. The P&T Committee instituted a required vancomycin use form in October 1997 that must be filled out for the patient to receive vancomycin therapy. Patients' medical records were then again reviewed from January 1998 through March 1998 to assess compliance with the CDC guidelines RESULTS: A total of 63 patients received vancomycin therapy from May 1997 through August 1997 and 28 patients received vancomycin therapy January 1998 through March 1998. Before the vancomycin order form was initiated, 56.1% for the results were classified as appropriate and 43.9% inappropr ia te . Of the pa t ien ts whose therapy was categorized as inappropriate, the majority was inappropriate due to surgical prophylaxis in which unnecessary post-operative doses were administered. In the period after the institution of the vancomycin order form, 75% of the reasons for the use of vancomycin was deemed appropriate by CDC guidelines. CONCLUSION. A vancomycin order form is one method to improve the use of vancomycin and decrease the inappropriate use and development 0 1 potential resistance in nosocomially acquired VRE.

78. Length of hospitalization in community-acquired infections associated with appendicitis. Jan Young, Donalyn Mimuro, Aaron Tejani, Pharm D., Christopher J. Destache, Pharm. D.; Creighton University, Omaha, NE.

PURPOSE: The selection of antibiotics in the treatment of acute appendicitis can be problematic. Length of hospitalization after surgery may differ

hetween perforated (PERF) and nonperforated (NPERF) patients who have an appendectomy. We sought to determine if a dlfference could be obtained in patients with and without appendix perforation. METHODS. A retrospective, observational case study was undertaken The medical records of patients with an admission diagnosis of abdominal pain and appendectomy from June 1995 through December 1997 were reviewed and data collected. Patients were divided by whether the surgical procedure was for a PERF or NPERF appendectomy. Statistical analysis was determined for continuous variables by ANOVA and chi squared for discrele variables. RESULTS: The medical records of 52 patients were reviewed for this study, 28 suffered a PERF appendix and 24 had a NPERF appendix Patient age ranged from 2-75 years. PERF appendix patients had a significantly higher incidence of E. ioli (PERF 60.7%, NPERF 4*2%; p<O.Ol) and P acrugino'a (PERF 28.6%, NPERF 4.2%; p<0.05). In addition, length of antibiotics was significantly longer in the PERF group (PERF 6.4 j: 4.2 days, NPERF 3.9 i 1.3 days; p<0.005). Time patients were febrile was significantly longer in the PERF group (PERF 4.8 i 5.6 days, NPERF 2.1 i 2.6 days, p<O.05). Finally, 17.8% of PERF patients sustained complications compared with 8% of NPERF patients. CONCLUSION: Patients with a PERF appendix on admission to the hospital have a significantly higher incidence of P. aeruginosa and E. coli organisms; therefore, empiric antibiotic therapy should be directed against these organisms.

79E. Effect of a high-fat meal on the hioavailability of gatifloxacin in healthy volunteers. Frank P. LaCreta, Ph.D., Georgia D. Kollia, Ph.D., Glenn F. Duncan, M.S., Douglas Behr, B.S., Randall R. Stoltz, M.D., Denkis M. Grasela, Pharm.D.; Bristol-Myers Squibb, Princeton, NJ; GFI Pharmaceuticals, Inc., Evansville, IN. ,,,

Presented at the 38th Interscience Conference on Antimicrobial Agents and Chemotherapy, San Diego, CA, September 24-27,1998.

80E. Single-dose safety and pharmacokketics of oral gatifloxacin in subjects with hepatic impairment. Dennis M. Grasela, Pharm.D., Ph.D., Barbara Christofalo, M.S., Frank P. LaCreta, Ph.D., Georgia D. Kollia, Ph.D.. Glenn F. Duncan, M.S., Robert Noveck, M.D., Ph.D.; Bristol-Myers Squibb, Princeton, NJ; Clinical Research Center, New Orleans, LA.


81. Cost analysis of levofloxacin combination use regimens compared to trovafloxacin monotherapy. Colette Fontaine, Pharm.D. candidate, Ben M. Lomaestro, Pharm.D., Barbara Rogler, M.S.; Albany Medical Center, Albany, NY.

PURPOSE: To review the incidence of levofloxacin usage in combination with other antimicrobial agents, and to evaluate the possible role for trovafloxacin monotherapy as a cost effective alternative. METHODS: All orders for levofloxacin prescribed between March 22, 1998 and April 17, 1998 were prospectively reviewed. Data included patient demographics, indication for use, and the use of concomitant antimicrobial agents. Patients with documented P. aeruginosa, methacillin-resistant S. aureus, methacillin-resistant S. epidermidis, and C. dijjicile were excluded. Acquisition cost analysis for three days of intravenous combination therapy was compared to intravenous trovafloxacin monotherapy. Assumptions included normal se rum creatinine, a levofloxacin dose of 500 mg, a trovafloxacin (alatrofloxacin) dose of 200 mg, and $2.00 added to the drug cost per dose administered, The analysis did not take into account missing doses, adverse drug reactions, minimum inhibitory concentrations, treatment failures, monitoring, or other pharmacy and nursing time and costs. RESULTS: Of the 142 patients prescribed levofloxacin, 37 (26%) were coprescribed other antimicrobials. Of the 49 patients initiated on intravenous levofloxacin, 22 (45%) were coprescribed other antimicrobials. Added antimicrobials most often included additional gram-positive and/or anaerobic coverage. Based on the total number of patients, an estimated 500 patients per year will receive levofloxacin combination therapy (including 217 prescribed 1V levofloxacin). The mean cost for combination 1V therapy was estimated to be $127.49 vs $102.76 for alatrovafloxacin, resulting in a potential savings of $25.70 per patient. CONCLUSION: Combination therapy involving fluoroquinolones occurs frequently and may sometimes be amenable to trovafloxacin monotherapy, representing a cost effective alternative for mixed infections. Other 1V or PO antimicrobial combinations were not investigated.

82 . Differential effect of antibiotics on neutrophil CD1 l b expression. Daniel P. Healy, Phann.D., Alice N. Neely, Ph.D., Ian Alan Holder, Ph.D., George F. Babcock, Ph.D.; University of Cincinnati; Shriners Burns Institute, Cincinnati, OH.

PURPOSE. CDl lb , an important adhesion molecule on neutrophils (PMNs) necessary for opsonization and phagocytosis. i s quickly upregulated by endotoxin (LPS). Differences exist among antibiotics with respect to LPS-release. METHODS: To determine the effect of low (10 x MIC), high (100 x MIC) concentrations of ceftazidime (TAZ), ciprofloxacin (CIP), and gentamicin


(GEN) on PMN-CDllb, as determined by an increased mean channel fluorescence (MCF), K. pneumoniae (Kp), Kp plus antibiotic, or LPS 10-1000 ng/ml were incubated at 37°C for 2 hours with heparinized whole blood. Supernatants were assayed for LPS. Cells stained with anti-CDllb-PE were analyzed using flow cytometry. RESULTS: LPS 100 ng/ml resulted in maximal CDllb upregulation (5- to 11- fold) versus unstimulated PMNs. GEN and CIP (both concentrations) resulted in 12-19% increases in CDllb vs max-LPS response and had similar LPS levels (702-921 EU/ml, p=NS). TAZ 10 x MIC also produced a similar 19% increase in C D l l b vs max-LPS response despite higher endotoxin (12.095 EU/ml, p<0.05). TAZ 100 x MIC resulted in a 22-52% increase in CDllb MCF vs max-LPS response despite LPS levels (1270 EU/ml) lower than LPS 1000 ng/ml(13,089 EU/ml). CONCLUSION: CIP and GEN (10 x-,100 x MIC) and TAZ (10 x MIC) resulted in a modest (12-19%), but consistent increase in CDllb expression compared to the maximum response due to LPS. Despite the lack of bacterial filamentation and only modest endotoxin levels, TAZ 100 x MIC caused the greatest increase in CDllb expression. These data suggest that other bacterial products, especially those liberated by cell wall inhibitors, may be responsible for the additional CDllb upregulation that cannot be accounted for solely by LPS. Antibiotic-mediated immunomodulation requires further study.

83. Serum protein binding characterist ics of oxacil l in: effect of hypoalbuminemia. Jessica L. Park, Pharm.D., Susan R. Raber, Pharm.D., Sue J. Kohlhepp, Ph.D., Paul Metz, M.D., James E. Leggett, M.D.; Oregon State University; Oregon Health Sciences University; Earle A. Chiles Research Institute; Providence Portland Medical Center, Portland, OR.

PURPOSE: Oxacillin binding to serum albumin was studied at normal and low concentrations to determine whether the change in the active, unbound fraction is clinically significant in hypoalbuminemic states. Since oxacillin concentrations are not routinely measured, a model was developed to predict oxacillin protein binding based on patient albumin concentration. METHODS: Pooled human albumin, 2.5 and 4 g/dl, and patient sera ranging from 0.9 to 5 g/dl were mixed with oxacillin to yield total concentrations of 15 to 250 pg/ml. One patient’s serum was serially diluted to compare to disease-induced hypoalbuminemia. Ultrafiltration was used for separation and HPLC for measurement of total and free concentrations. Scatchard analysis was performed. Percent bound for albumin concentrations were fit to an Em, model. RESULTS: At albumin concentrations of 2.5 and 4 g/dl, the fractions unbound were 0.08-0.2 and 0.05-0.1, respectively, over the total oxacillin concentrations of 15 to 250 pg/ml. Scatchard analysis resulted in a KA of 6.97 x 10’ M-’ and n of 2.9 sitedmolecule. An E, model of undiluted patient sera resulted in an EC50 of 1.23 g/dl (95% CI: 0.94-1.52) compared to an EC50 of 0.44 g/dl (95% C1: 0.414.47) for the diluted serum, with r* of 0.68 and 0.99, respectively. CONCLUSION: Fraction unbound is dependent on both oxacillin and albumin concentrations. Hypoalbuminemic patients have up to a 100% increase in free fraction; factors in addition to albumin concentration alter binding. Extent of protein binding may be estimated from individual patient albumin using the described E,, model.

84E. Activity of simulated oral dosing of gatifloxacin against Streptococcus pneumoniae in an in vitro dynamic model. Stephen H. Zinner, M.D., Deborah H. Gilbert, B.S., Kelly Simmons, B.S.; Roger Williams Medical Center; Rhode Island Hospital; Brown University, Providence, RI.


85E. Differences in antimicrobial effect determined with three in vitro pharmacodynamic models. John A. Bosso, Pharm.D., Charles R. Bonapace, Pharm.D., Roger L. White, Pharm.D., Lawrence V. Friedrich, Pharm.D., Diane M. Cappelletty, Pharm.D., Rene-Claude Mercier, Pharm.D., Heather H. Houlihan, Pharm.D., Jeffrey R. Aeschliman, Pharm.D., Michael J. Rybak, Pharm.D.; Medical University of South Carolina, Charleston, SC; Wayne State University, Detroit, MI.

Presented at the 38th Interscience Conference on Antimicrobial Agents and Chemotherapy, San Diego, CA, September 24-27, 1998.

86E. Impact of differences in dosing recommendations among antimicrobial dosing references on pharmacodynamic parameters. Charles R. Bonapace, Pharm.D., Roger L. White, Pharm.D., Lawrence V. Friedrich, Pharm.D., J. A. Bosso, Pharm.D.; Medical University of South Carolina, Charleston, SC.

Presented at the 38th Interscience Conference on Antimicrobial Agents and Chemotherapy, San Diego, CA, September 2627,1998.

87E. Pharmacodynamics of gatifloxacin i n cerebrospinal fluid in experimental E. coli and 5. pneumoniae meningitis. Ira Lutsar, M.D., Ian R. Friedland, M.D., Loretta Wubbel, D.O., Cynthia C. McCoig, M.D., Hsan Jafri, M.D., Winston Ng, M.D., Faryal Ghaffar, M.D., Gearge H. McCracken, M.D.; University of Texas; Southwestern Medical Center, Dallas, TX.


88E. Discontinuation rates for protease inhibitor regimens containing ritonavir 600 mg versus ritonavir 400 mg plus saquinavir 400 mg. John C. Rublein, Pharm.D., Joseph J. Eron, Jr., M.D., John D. Butts, Pharm.D., BCPS, Ralph H. Raasch, Pham.D., BCPS; University of North Carolia, Chapel Hill, NC.

Presented at the AIDS Clinical Trial Group Meeting, Washington, DC, August 1998.

89. Effectiveness of initial antiretroviral therapies in naive and nucleoside analogue reverse transcriptase inhibitor experienced HIV-infected patients. Julie M. Wright, Pharm.D., BCPS; University of Missouri-Kansas City, Kansas City, MO.

PURPOSE: This study compared the antiretroviral activity of four potent antiretroviral regimens in naive and nucleoside analogue reverse transcriptase inhibitor (NRTI) experienced HIV-infected patients in order to evaluate overall clinical efficacy and individual effectiveness of evolved combinations. METHODS: NRTI history, initial potent regimen, and HIV RNA values were collected in a retrospective review of 187 medical records. Incomplete charts were excluded. The four potent combinations compared were 1) addition of a protease inhibitor (PI) to existing NRTI therapy; 2) PI plus two new NRTls; 3) two PIS with or without NRTI; and 4) a nonnucleoside analogue reverse uanscriptase inhibitor (NNRTI) plus 2 new NRTIs. Effective treatment led to undetectable HIV RNA or a 2 log decline which was maintained 6 months or through last follow up. RESULTS: Complete data were available for 90 patients. Undetectable or 2 log decline in HIV RNA was achieved by 63 (70%) and maintained in 51 (57%) patients. Regimen 2 was initial therapy for 63 patients. The four combinations were similarly effective (chi squared, p=0.32). Regimen 2 was more effective when compared only to regimen 1 (Fisher’s exact, p<O.OOl). Initial regimen was not predictive of a second regimen (Fisher’s exact, p=0.62). Side effects led to a second regimen in 11 and virologic failure in 16 patients. CONCLUSION: Consistent with 1998 NlHRlSPHS guidelines, the majority of patients were treated with a standard 3-drug regimen containing a PI and two NRTls. This regimen was more effective than previous approaches such as regimen 1. Other potent combinations need to be compared to the standard combination, however, the respective numbers were inadequate for this comparison.

90. Appropriate prophylaxis of opportunistic infections in a veteran HIVIAIDS patient population. Shvawn McPherson Baker, Pharm.D., Cindy M. Maggio, Pharm.D., John W. Triplett, Ph.D., Gordon M. Dickinson, M.D.; Veterans Affairs Medical Center, Miami, FL.

PURPOSE: This retrospective study reviewed the prophylaxis of veteran HIV/AIDS patients against certain opportunistic infections (based on historical lowest CD4 cell count) in order to do the following: 1) ensure that all patients who require prophylactic drug therapy are receiving it; 2) compare the results of this review with those from a 1996 review; and 3) use this information for the education of health care practitioners at this institution who care for this patient population. METHODS: There were 564 patients actively followed in the Special Immunology Clinic between October 1996 and July 1997 who were retrospectively reviewed. The institution’s decentralized hospital computer program was used to obtain all laboratory and medication data. RESULTS: For Pneumocystis carinii pneumonia (PCP), there was a 37% improvement in the prophylaxis of this population when compared to 1996. Eighty-four percent (84%) of patients were receiving PCP prophylaxis, 8% were not currently receiving prophylaxis, and 8% had never received prophylaxis. For Toxoplasma gondii, a 15% decline in prophylaxis for those patients meeting the indication was seen, with no improvement in obtaining baseline titers when compared to past data. Mycobacterium avium complex (MAC) prophylaxis improved by 44%, with 52% of patients with baseline cultures. Statistical analysis is pending. CONCLUSION: Prophylaxis against PCP and MAC has improved considerably, but for toxoplasmosis, there is room for improvement in patients for whom therapy is indicated. Continued pharmacy screening for appropriate prophylaxis and education of all health care practitioners will continue in an effort to ensure protection against infection for all veteran HIV patients followed in this institution.

91E. Combivir”, given BID plus a protease inhibitor compared to lamivudine 150 mg BID and zidovudine 200 mg TID plus a protease inhibitor. Ellen Yetzer, D.O., Joe Enron, M.D., Mark Shaefer, Pharm.D., FCCP, Peter Ruane, M.D., Steven Becker, M.D., Gosford Sawyerr, Ph.D., Neil Graham, M.D., M.P.H.; Pacific Oaks Research, Beverly Hills, CA; University of North Carolina, Chapel Hill, NC; Glaxo Wellcome, Research Triangle Park, NC; Tower ID, Los Angeles, CA; Pacific Horizons Medical Group, San Francisco, CA.

Presented at 38th Interscience Conference on Antimicrobial Agents and Chemotherapy, San Diego, CA, September 1998.


92E. Preliminary data of effective switchhntensification treatment with Combivir”, and Ziagen”, in therapy-experienced adults. W. Keith Henry, M.D., Mark 5. Shaefer, Pharm.D., FCCP, Paul C. Bellman, M.D., Dorece G. Noms, M.D., Robert J. Wallace, M.D., Gosford Sawyerr, Ph.D., Neil Graham, M.D., M.P.H.; Regions Hospital, St. Paul, MN; Glaxo Wellcome, New York, NY; Center for Quality Care, Tampa, FL.; University of South Florida.

Presented at 38th Interscience Conference on Antimicrobial Agents and Chemotherapy, San Diego, CA, September 1998.

93. Evaluation of patient compliance and determination of correlates with medication adherence with antiretroviral therapy at an outpatient HIV clinic. Anit Kaur, Pharm.D., Elaine M. Bailey, Pharm.D., Suzan Kucukarslan, Ph.D., David B. Wright, Pbarm.D., Norman P. Markowitz, M.D.; Henry Ford Hospital, Detroit, MI.

PURPOSE: This study aimed to establish the baseline medication compliance at an HIV clinic, and to determine correlates with medication adherence. METHODS: In stage 1, 196 clinic patients within our HMO received nucleoside analog prescriptions in 1996. Compliance was determined by retrospectively monitoring refill histories in 96 patients who had obtained refills. Noncompliance was defined as a delay in refill exceeding 5 or more days. Stage 2 involved a 3-month prospective evaluation of compliance to protease inhibitors in 50 randomly selected clinic patients using the Medication Event Monitoring System (MEMS). Noncompliance was defined as not taking three or more consecutive doses or not taking six or more nonconsecutive doses within 7 days. A questionnaire was designed and validated to identify correlates with medication adherence (self efficacy, response efficacy, and peer norms). Patients completed the questionnaire at the end of stage 2. RESULTS: Analysis of data from stage 1 revealed that 9/96 (9.37%) patients were compliant. Of the 50 patients enrolled in stage 2, 35 have returned the MEMS unit and 7/35 chose not to complete the study. Twenty-eight patients completed stage 2 and 23 patients completed the questionnaire; 10 (36%) were compliant and 18 (64%) were noncompliant. The greatest difference between compliers and non-compliers was with respect to self-efficacy (e.g., noncompliers found it more difficult to excuse themselves from their daily routine to take medication). CONCLUSION: The data indicate a need to improve medication adherence. The questionnaire results will be used to design an interventional program targeting self-efficacy to improve patient adherence.

Managed Care 94. Selective seratonin reuptake inhibitor daily dose inconsistencies: a comparison of cross-sectional and longitudinal findings. Annette M. Fehr, M.B.A., Karen Way, Ph.D., Christopher H. Young, Ph.D., Karl J. Gregor, Pharm.D., M.S.; PCS Health Systems, Inc., Scottsdale, AZ.

PURPOSE: This study compared findings from cross-sectional and longitudinal analyses of selective seratonin reuptake inhibitor (SSRI) mean daily doses to determine if these different study designs lead to different results. A better understanding of this potential methodologic effect may help pharmacy decision makers better apply findings from longitudinal SSRI-use studies that might otherwise be dismissed because of their inconsistencies with cross-sectional dosage findings. METHODS: This retrospective database study, conducted at PCS Health Systems, Inc., a prescription benefits manager based in Scottsdale, Arizona, analyzed the mean daily doses of fluoxetine, paroxetine, and sertraline prescriptions dispensed between October 1, 1996, and June 30, 1997. The cross- sectional study was conducted at the prescription level; the longitudinal study was conducted at the patient level. All patients were at least 18 years of age. RESULTS: There were 3,410,479 prescriptions in the cross-sectional study and 74,241 patients in the longitudinal study. The mean daily doses in the cross-sectional study were consistently higher than the daily doses in the longitudinal study. Both studies found that prescriptions written by psychiatrists had higher mean daily doses than those written by physicians in other specialties, and daily doses in the cross-sectional study were more likely to be above the recommended minimum than those in the longitudinal study. CONCLUSIONS: These different study methodologies lead to different SSRI mean daily dosing findings. Ideally, cross-sectional findings should he used in conjunction with longitudinal results to make complex health care decisions with long-term implications.

95. Statin conversion initiative at a staff model health maintenance organization. Thomas W. Algozzine, Pharm.D., Karen M. Whalen, B.S., BCPS; The Transplant Pharmacy, Division of Sangstat.

PURPOSE: This initiative was designed with two goals in mind. First, enhance patient cholesterol management due to provider education through the use of a unique lipid management pocket card. Second, improve provider adherence with formulary HMG Co-A reductase inhibitors (statins). METHODS: Patients treated with lovastatin (non-formulary) were identified from computerized pharmacy records. A provider specific report containing

patient name, current dose of lovastatin and recommended equivalent dose of fluvastatin or simvastatin (formulary statins) was generated using Microsoft Access (version 2.00). The report was distributed to each provider (internists, family practitioners, physician assistants, and nurse practitioners) in addition to the unique lipid management card and a letter explaining the rationale behind the conversion. Health center pharmacists distributed the report, letter, and card to each provider in addition to pre-printed prescriptions containing all information necessary to perform a switch on each patient. Prescriptions were provided to minimize provider time and simplify record keeping caused by the interchange. RESULTS: At the first follow up, 15% (n=44) of patients remained on lovastatin and there were 26 new patients that had been started on lovastatin. The process described above was repeated for the providers of these 70 patients. A t the second follow up, only 2.5% of patients remained on lovastatin (8/324). CONCLUSION: The use of a lipid management card can facilitate provider support and increase the opportunity for success. Conversion between statin products can he extremely successful through the use of provider specific reporting and pharmacist facilitated switch at a staff model health maintenance organization.

Nephrology 96. Comparison of three vancomycin dosage regimens during hemodialysis with cellulose triacetate dialyzers: post-dialysis versus intradialytic administration. Nancy A. Mason, Pharm.D., Brien L. Neudeck, Phar$.D., Norma Saab Elhasan, Pharm.D., Amy Wong, Pharm.D., Lynda S. Welage, Pharm.D.; University of MichiFan, Ann Arbor, MI.

PURPOSE: Although previous studies indicate that vancomycin is significantly removed during hemodialysis with high flux membranes, optimal dosage strategies have not been evaluated. The purpose of this study was to compare the pharmacokinetics of vancomycin following three dosing strategies. METHODS In a randomized, 3-way crossover trial, the pharmacokinetics of vancomycin were evaluated in nine hemodialysis subjects. On day 1, subjects received vancomycin 15 mg/kg following dialysis (phase 11, vancomycin 15 mgkg during the last one hour of hemodialysis (phase II), or vancomycin 30 mg/kg during the last two hours of hemodialysis (phase 111). Plasma vancomycin plasma concentrations were obtained over an 8-day period. Pharmacokinetic parameters were determined using noncompartmental methods and compared using ANOVA. RESULTS Plasma concentrations 4 hours following the end of dialysis on day 1 were highly variable, ranging from 19.3-35.4 and from 22.M3.3 pg/ml during phase I1 and phase 111, respectively. The pharmacokinetic parameters (&I, C1,,,1, % rebound, % removal) were not significantly different among the study phases. Average pre-dialysis plasma concentrations (PreHD) on day 8 were not significantly different between phase 1 and phase 111 (10.0 1.6 vs 11.7 * 1.5 pg/ml). However, PreHD concentrations were significantly lower during phase 11 (6.7 i 1.4 pg/ml). CONCLUSION: 1) As previously demonstrated, vancomycin is removed by high-flux hemodialysis. 2) The similarity in plasma concentration profiles between phases I and 111 suggests that either 15 mg/kg administered post- dialysis or 30 mgkg administered during the last two hours of dialysis on day 1 can provide therapeutic concentrations over an 8-day period.

97. In-vitro generation of chloramphenicol from chloramphenicol sodium succinate in peritoneal dialysis fluids. Michael H. Schwenk, Pharm.D., Hormaz D. Dastoor, M.D., Chaim Charytan, M.D., Bruce S. Spinowitz, M.D.; The New York Hospital Medical Center of Queens, Flushing, NY.

The impact of vancomycin resistant enterococcal (VRE) infections has increased markedly in the present decade and there are reports of CAPD- associated peritonitis caused by VRE with a high mortality rate. A possible therapeutic option is chloramphenicol (C), although there are few reports of this in the literature. The available form of C is the inactive sodium succinate salt (CSS) which must he hydrolyzed to form active C. As it is unknown whether this occurs in vivo, we examined the possible in vitro generation of C from CSS in three different types of peritoneal dialysis fluids. CSS (250 mg C equivalentn) was added to unused (“fresh”) pH-adjusted (7.3-7.4) peritoneal dialysis solutions (1.5 and 4.25% dextrose, 6 x 2 L), and uremic dialysate effluent drained from CAPD patients, both with and without peritonitis (five each). After 4 hours of incubation at 38“C, C was assayed in each solution by enzyme-multiplied immunoassay technique (EMIT). C was detected in all 4-hour samples. The mean concentration of C in the fresh dialysis fluid was 5.6 * 0.7 mgL, different (p<0.05) from both uninfected uremic dialysate effluent (13.3 * 9.4 mgiL) and infected uremic dialysate effluent (10.6 * 4.3 m@). These data demonstrate the possible generation of active C from intraperitoneally administered C.

98. An AUC approach for estimating cumulative clearance loss of high flux hemodialyzers reprocessed fifteen times with peracetic acid-hydrogen


peroxide. Meri Kay Scott, Ph.D., Kevin M. Sowinski, Pharm.D., Bruce A. Mueller, Pharm.D.; Purdue University, Indianapolis, IN.

PURPOSE: The purpose of this experiment was to estimate the effect of peracetic acid-hydrogen peroxide (PAHP) dialyzer reuse on the cumulative removal of solutes of varying molecular weights using an AUC approach. METHODS: Dialytic clearances of urea, creatinine, vancomycin, inulin, and myoglobin were determined at reuse 0, 1, 5, 10, and 15 for CT190 (Baxter) and F80A (Fresenius) hemodialyzers. Area under the clearance-reuse cuwe (AUCR; ml x reuse number/min) for each solute was calculated by the trapezoidal rule and compared with a paired t-test to the hypothetical AUC that would be obtained if a new dialyzer was not reused (AUCNR). RESULTS: Mean AUCR and AUCNR differed for urea, vancomycin, inulin, and myoglobin with CT190 (p<0.05). No significant differences were noted for F80A. AUCWAUCNR was 0.92 (urea nitrogen), 0.94 (creatinine), 0.92 (vancomycin), 0.74 (inulin), and 0.60 (myoglobin), respectively, for CT190. AUCWAUCNR for F80A was > 0.97 for urea, creatinine, and vancomycin and 0.90 for inulin. Although some solutes had a diminished AUCWAUCNR with CT190 vs F80A, the AUCR for creatinine, vancomycin, inulin, and myoglobin was larger than F80A. CONCLUSION: 1) AUCWAUCNR is an approach to estimate the influence of reuse on solute removal over time. 2) The PAHP reuse-induced AUCWAUCNR reduction appeared to be influenced by solute molecular weight suggesting that this reduction may be very important for middle molecule removal. This AUC analysis suggests that a patient’s dialysis regimen may need to he altered as a function of dialyzer reuse.

99. Comparison of fluorescence polarization immunoassays and enzyme multiplied immunoassay technique assay for the determination of vancomycin serum concentrations in patients with acute renal failure undergoing continuous venovenous hemofiltration. Tate N. Trujillo, Pharm.D., Richard A. Venezia, Ph.D., Kevin M. Sowinski, Pharm.D., William R. Clark, M.D., Meri Kay Scott, Ph.D., Bruce A. Mueller, Pharm.D.; Clarian Health Partners, Inc.; Albany Medical Center Hospital; Baxter Healthcare Renal Division; Purdue University, Indianapolis, IN.

PURPOSE: Vancomycin serum concentrations are overestimated in patients with end stage renal disease (ESRD) when determined by polyclonal fluorescence polarization immunoassay (FPlA), TDx, as compared to HPLC or enzyme multiplied immunoassay technique (EMIT). A new monoclonal FPlA assay (AxSYM) has been developed to remedy this overestimation. The purpose of this study was to compare the assay performance of TDx and AxSYM as compared to EMIT in patients with acute renal failure receiving vancomycin and continuous venovenous hernofiltration (CVVH) with AN69 hemofilters. METHODS: Fifteen serum and ultrafiltrate samples were obtained from 14 critically ill patients (mean i SD; 57 + 12 years; 8 males, 6 females). Vancomycin concentrations were determined by TDx, AxSYM, and EMIT. The CV percentage for all assays were less than 5%. RESULTS: Serum concentrations determined by TDx, AxSYM, and EMIT were 18.5 + 7.9 m a , 17.2 * 6.9 mgR, and 17.3 i 6.5 m a , respectively (repeated measures ANOVA; p<0.05). Ultrafiltrate concenuations determined by TDx, AxSYM, and EMIT were 16.1 i 6.6 m a , 14.4 i 6.1 m a , and 14.0 i 5.6 mgR (p<0.05). CONCLUSION: Our data suggest that either the manufacturer’s changes to the TDx assay have reduced overestimation (previous studies in patients with ESRD showed up to a 127% TDx overestimation compared to EMIT) or patients with acute renal failure do not produce the substances that lead to overestimation. It appears unlikely that C W H selectively removes these substances as ultrafiltrate overestimation was similar to serum values. The monoclonal FPlA AxSYM system appears to be an acceptable assay for measuring vancomycin serum concentration in patients with acute renal failure and does not significantly overestimate vancomycin serum concentrations.

Neurology 100E. Current and preferred sources of information used by primary care physicians in providing care to patients with epilepsy. James W. McAuley, Ph.D., J. Layne Moore, M.D., David A. Mott, Ph.D., Jon C. Schommer, Ph.D., Andrew L. Reeves, M.D., Barbara S. Bussa, Lucretia Long, M.S.N.; The Ohio State University, Columbus, OH.

Published in Epilepsia 1997;38:S242.

101E. Assessing the needs of community pharmacists in providing care to patients with epilepsy. James W. McAuIey, Ph.D., David A. Mott, Ph.D., Jon C. Schommer, Ph.D.; The Ohio State University, Columbus, OH.

Published in J Am Pharm Assoc 1998;38:249.

102E. Nitroglycerin model of migraine: validation of model using positron emission tomography. Edward M. Bednarcryk, Pharm.D., David S. Wack, M.A., Karen Burch, B.S., Kimberly Trinidad, M.D.; State University of New

York at Buffalo; VAWNYHS, Buffalo, NY

Published in Clin Pharmacol Therap 1998;63: 142

103. Correlation between serum and salivary valproic acid concentrations in pediatric patients. Peter H Tang, Ph.D., Michael V. Miles, Pharm.D., Tracy A. Glauser, M.D., Andrew Hershey, M.D., Ph.D., Shelley Williams, M.D., Richard Strawsburg, M.D., Anna King, B.S.N., Peggy 0. Clark, B.S.N., P.N.P., Kathy McGee, B.S.N., P.N.P.; Children’s Hospital Medical Center, Cincinnati, OH.

PURPOSE: Saliva has been suggested as a body fluid source for monitoring certain antiepileptic drugs. Previous methods have been unable to demonstrate a constant relationship between serum and saliva valproic acid (VPA) concentrations. The present study was conducted to further explore the relationship between serum (C) and salivary (Cs) VPA concentrations in pediatric patients. METHODS: This study was conducted in the neurology clinics at Children’s Hospital Medical Center (CHMC). Saliva was collected from 16 patients by either voluntarily spitting into a small cup or by using a disposable plastic pipette to draw saliva directly from the mouth. Whole, unstimulated saliva samples were collected in the clinic and frozen until time of analysis by an FPlA method. Blood was collected, processed, and serum analyzed by the CHMC Laboratory. RESULTS: VPA concentrations ranged from 26 to 120 pg/ml and from 0.2 to 3 .2 pg/ml in serum and saliva, respectively. We found an improved correlation (r=0.87, p<0.05) between Cs and C after a log-transformation of Cs. Using the equation: C = ([1.801.ln(Cs)] + 8.601)’, the predicted C were calculated using actual VPA saliva concentrations. The absolute error between actual C and predicted C was then calculated. The absolute prediction error was less than 20% in 11 patients, and less than 30% in all individuals. CONCLUSION: A significant log-linear correlation between C ind Cs was demonstrated for VPA. The saturable protein binding property of VPA may account for this improved correlation. Further studies are in progress to determine whether this method will provide reliable data for patient monitoring.

104. Safety of rapid infusion of valproic acid injection. Nita A. Limdi, Pharm.D., Diane Counce, M.D., Camilo R. Gomez, M.D., Raymond E. Faught, M.D.; University of Alabama, Birmingham, AL.

PURPOSE: The introduction of valproic acid injection has facilitated the use of valproate in situations where oral administration is not possible. This abstract reports on preliminary findings evaluating the safety of rapid infusion of valproic acid injection. METHODS: Seven patients (age 47-72 years) received a 20 mgkg dose of valproic acid injection. The package insert recommends infusing valproic acid injection at a rate of 20 mg/min. The drug was infused undiluted, at rates ranging from 33-555 mg/min. Three patients received other anticonvulsants. RESULTS Seizures were abolished in all patients. All patients tolerated the infusion without significant changes in heart rate or blood pressure. Two patients reported initial mild burning at the injection site, which resolved during the infusion.

Ranee of ChanEe of Loading Dose lnfusion Rate SBP DBP HR

Pattent Age Sex (mg) (mp/min) (mmHg) (mmHg) (bPm) 117-130 8 a 9 2 92-115 1000 33 1 51 F ~ ~~

2 72 M 1000 50 136-138 5942 93-111 3 56 F 1500 167 105-122 64-88 64-80

5 48 M 1500 300 13&155 84-99 95-105 4 47 F 5000 555 1 3 ~ 5 2 54-85 99-98

6 52 F 1000 200 i 6 a 2 o i 86-104 73-82 7 58 F 1400 280 138-179 92-101 89-101

CONCLUSION: These cases illustrate the possibility of safe use of valproic acid injection at rates greater then 20 mg/min, which enhances the clinical utility of the drug in acute situations. Further systematic study is ongoing to establish safety of faster infusion rates in acute settings.

105E. Anticonvulsant efficacy of lamotrigine in developmentally disabled adul t s as adjunctive treatment or monotherapy. Brian J. Fitrgerald, Pharm.D., Anthony J. Okos, M.D., Shea W. Wilson, B.S., Rex S. Lott, Pharm.D., Alan Wilensky, M.D.; Fircrest Residential Habilitation Center; University of Washington, Seattle, WA; Idaho State University, Pocatello, ID.

Published in Epilepsia 1998;39(Suppl6):abstract 100775

106. Evaluation of clopidogrel in stroke patients intolerable to ticlopidine therapy. Brian K. Plowman, Pharm.D., BCPS, Charles E. Weber, Pharm.D.; Veterans Affairs San Diego Healthcare Systems, San Diego, CA; University of the Pacific, Stockton, CA.

PURPOSE: To report on the use of clopidogrel for stroke patients who have failed aspirin therapy and are intolerant to the side effects of ticlopidine therapy. METHODS: Patients were identified from neurology-stroke clinic and pharmacist-run ticlopidine clinic. Seven patients who were placed on

1154 PHARMACOTHERAPY Volume 18, Number 5, 1998

ticlopidine therapy for stroke prophylaxis developed moderate to severe drug- related reactions within 3-14 days of initiating drug therapy. These reactions included one patient with neutropenia with an absolute neutrophil count of 1342 from a baseline of 5440 (patient 1) ; one patient with mild thromhocytopenia with a platelet count of 112.000 from a baseline of 235,000 (patient 2); two patients with intolerable diarrhea (patients 3 and 4); one patient with dull frontal headaches (patient 5); and two patients with drug- induced rash (patients 6 and 7). All patients were converted from ticlopidine 250 mg BID to clopidogrel 75 mg QD upon the development of their intolerable side effects. RESULTS: Upon discontinuation of ticlopidine therapy and initiation of clopidogrel in each patient, the drug-related adverse effect began to diminish by day 3 and had completely dissipated or returned to pre-ticlopidine values by day 21. Laboratory values in patients 1 and 2 returned to pre-ticlopidine levels by days 12 and 21, respectively. Patients 3, 4, 5, 6, and 7 were asymptomatic by days 4, 5, 4, 6, and 5, respectively. All patients were managed on an outpatient basis and did not require admission. CONCLUSION: Use of clopidogrel represents an alternative therapy for stroke patients who have failed aspirin therapy and cannot tolerate ticlopidine therapy due to intolerable side effects.

107E. A prospective, randomized evaluation of adverse events and length of stay associated with parenteral phenytoin or fosphenytoin in the emergency department. Denise H. Rhoney, Pharm.D., William M. Coplin, M.D., Jill A. Rebuck, Pharm.D., Elizabeth A. Lyons, Pharm.D., Brian J. ONeil, M.D., Mary 5. Cochran, B.S.N., Jan P. Muizelaar, M.D., Ph.D.; Wayne State University; Detroit Receiving Hospital, Detroit, MI.

Presented at the meeting of the American Academy of Neurology, Minneapolis, MN, May 1998.

Nutrition 108. A comparison of a specialized glucose-control enteral formula versus standard enteral formula in glucose intolerant patients. Gordon S. Sacks, Pharm.D., Anne F. Lipscomb, R.D., Scott Malinowski, Pharm.D., Lucy Weston, M.D., Galen V. Poole, M.D.; University of Mississippi Medical Center, Jackson, MS.

PURPOSE: To determine if providing a low-carbohydrate, high-fat content (LCHF) enteral formula to diabetic patients or to patients with stress-induced hyperglycemia can decrease hyperglycemic episodes, reduce sequelae from hyperglycemia, and minimize insulin requirements when compared to a standard enteral formula (SEF). METHODS: Eight patients with a history of diabetes (type 1 or 2) or stressed-induced hyperglycemia (glucose > 220 mudl x 2 consecutive days) requiring enteral nutrition were prospectively studied. Patients were randomized to receive a LCHF (n=4) or SEF (n=4) at a continuous rate for a maximum of 28 days. Glycemic control was evaluated by serum or fingerstick glucose concentrations and daily amounts of insulin were administered. Patient outcome parameters, including septic morbidity and ICU days, were also recorded. Data were analyzed by repeated measures one-way ANOVA with Scheffe's procedure and are reported as mean i SEM. RESULTS: Both groups received enteral feedings for an average of 10 hospital days. Glucose control was similar between the groups except on hospital day 4 when the LCHF group exhibited a significantly lower serum glucose concentration compared to the SEF group (254 * 17.7 vs 168 + 15.5 mg/dl, p=0.04). No differences in the amount of insulin received or ICU days were noted. Of special interest was the finding that 75% (3/4) of the SEF patients developed a documented infection requiring antibiotic treatment compared with 0% (0/4) of the LCHF patients. CONCLUSION: Preliminary data suggest that LCHF enteral formulas offer a small benefit over SEF in controlling hyperglycemia. However, LCHF enteral formulas may have a beneficial impact on septic morbidity in hospitalized diabetic patients. Further investigations are required to delineate the possible mechanisms responsible for this effect.

Pediatrics 109. Effects of gestational age on the pharmacokinetics and dosing of gentamicin in preterm infants. Kimberly K. Dunaway, Pharm.D., Christopher Rubino, Pharm.D., BCPS, FCCP, Peter Gal, Pharm.D., BCPS, FCCP, J. Laurence Ransom, M.D., Andrew Davey, M.D., Rita Carlos, M.D., McRae Smith, M.D., Annavic DiMaguila, M.D., Lilly Lou, M.D.; Moses Cone Health System, Greensboro, NC.

PURPOSE: This study was designed to describe gentamicin pharmacokinetics in neonates less than 30 weeks gestational age and less than 1500 grams birth weight and to compare individual simulated serum concentrations using current neonatal dosing guidelines. METHODS: Preterm neonates with suspected sepsis, estimated gestational age (EGA) less than 30 weeks and birth weights less than 1500 grams, in

whom gentamicin was started in the first 24 hours of life, were included. Patients received a gentamicin 5 mgkg loading dose over 30 minutes. Serum concentrations were drawn 2 and 12 hours after the loading dose. Gentamicin dosage regimens were then adjusted to achieve approximate target peak concentrations of 10 mgL and target trough 5 1 mgL. Using each patient's calculated pharmacokinetic parameters, peak and trough concentrations were simulated based upon recommended dosing guidelines in commonly used neonatal handbooks. Simulated serum concentrations were compared among all patients and wthin gestational age subgroups. RESULTS: One hundred eighty-four infants were included. Estimated gestational age ranged from 23-29 weeks and birth weight ranged from 455-1416 grams. Calculated pharmacokinetic parameters were as follows: median volume of distribution (range; 2575% interval): < 24 weeks 0.60 u k g (0.48-1.2; 0.514.78); 24-25 weeks 0.59 Ukg'(O.32-1.1; 0.51-0.67); 26-27 weeks 0.61ukg (0.25-1.4; 0.53-0.71); 28-29 weeks 0.58 U k g (0.33-1.3; 0.50-0.63); median clearance (range; 25-75% interval): < 24 weeks 0.43 ml/min/kg (0.23-1.34; 0.27-0.69); 24-25 weeks 0.44 ml/min/kg (0.25-1.2; 0.374.53); 26-27 weeks 0.56 ml/min/kg (0.59-1.7; 0.46-0.69); 28-29 weeks 0.59 ml/min/kg (0.23-1.7; 0.52-0.73); median half-life (range; 25-75% interval): < 24 weeks 16.3 hr (10.2-31.4; 12.3-22.8); 24-25 weeks 14.5 hr (9.3-30.4; 12.3-20.8); 26-27 weeks 12.2 hr (3.6-22.1; 10.5-15.1); 28-29 weeks 10.6 hr (5.4-28.9; 9.3-12.4). Simulated 24-hour peaks based upon common dosing references were suboptimal in 31-77% of all infants. Simulated steady-state trough concentrations were elevated in 2945% of all infants. CONCLUSION: The pharmacokinetics of very low birth weight and extremely low birth weight infants demonstrate great variability. Close monitoring of serum concentrations is therefore required to ensure adeduate early peak concentrations and to prevent elevated trough concentrations and drug accumulation.

110. Conventional versus rapid infusion of amphotericin B in pediatric patients: assessment of tolerance. Gladys M. El-Chaar, Pharm.D., Michele Edden, Pharm.D., J. Andrew Skirvin, Pharmp., Lorry G. Rubin, M.D.; St. John's University College of Pharmacy and Allied Health Professions, Jamaica, NY; Schneider Children's Hospital of the Long Island Jewish Medical Center; North Shore University Hospital.

PURPOSE: Amphotericin B has traditionally been infused over 4 to 6 hours when given intravenously. Infusion-related and other systemic adverse effects have been associated with its use. Studies carried out in adult patients demonstrated the safety of infusing amphotericin B over a shortened period of time. Advantages include reduced nursing and patient times, minimizing drug interactions, and potentially lessened infusion-related adverse effects. In 1995, we adopted guidelines to infuse amphotericin B over 2 hours in pediatric patients. Our hypothesis is that there is no difference in infusion- related adverse events (IRAEs) between conventional and rapid infusions of amphotericin B in pediatric patients. METHODS: This was retrospective chart review to compare the incidence of adverse reactions (infusion- and non-infusion-related) between pediatric patients who received amphotericin B over 4 to 6 hours (1989-1995; conventional group) and patients who received the drug over 2 hours (1995 to 1996; rapid group). RESULTS: Twenty-seven patients were enrolled, 14 in the conventional group and 13 in the rapid group. The conventional group had more female patients, but ages and patient weights were similar between groups. Patients in the rapid group tended to have more oncological disorders. Of the IRAEs, chills occurred more commonly in the rapid group. There was no significant difference in the development of fever, hypotension, hypokalemia, renal dysfunction, potassium supplementation, nor other IRAEs between groups. CONCLUSION: This study provides preliminary data supporting the infusion of amphotericin B over a shortened period of time in pediatric patients. A large, prospective, randomized study is needed to confirm our results.

Pharmacoeconomics 111. Restricting medication access increases total cost of care in patients with heart failure enrolled in a managed care plan. Kjel A. Johnson, Pharm.D., Deborah J . Partsch, Pharm.D., Devon McVey, M.S., Richard Weinberg, M.D.; HealthAmerica of PA, Inc.; University of Pittsburgh; West Penn Hospital of PA, Pittsburgh, PA.

PURPOSE: Many care organizations attempt to reduce patient medication costs by instituting a benefit cap which allows a certain dollar amount for medications each year, particularly in managed care Medicare risk plans. We evaluated the impact of a pharmacy benefit cap on the utilization and cost of medical versus pharmaceutical care in Medicare patients with congestive heart failure. METHODS: Patients continually enrolled for one calendar year, identified as having heart failure by an ICD-9 code of 428.0, 428.1, or 428.9, were enrolled. Only medications relating to heart disease were evaluated. The number and cost of prescriptions and medical claims related to heart disease, and total hospital bed days were measured for the 1-year period. RESULTS: Three-hundred sixty five patients, 56% men, median age 74


(range 43-96) years, were evaluated. The utilization of cardiac medications/ patiendquarter were 14% lower in the fourth quarter compared to the first quarter (20.1 vs 17.2, p<0.05) and prescription costs/patient/quarter were 24% lower ($542 vs 414, p<0.05). In contrast, bed dayslpatienVquarter increased 183% in the fourth quarter vs the first quarter (0.6 vs 1.7, p<0.05). Ultimately, medical costs/patienr/quarter increased 117% from (p<0.05). CONCLUSION: In heart failure patients with a capitated pharmacy benefit, fourth quarter medical costs significantly increased while pharmacy utilization and costs decreased.

112. The effect of drug samples on prescribing by family practice residents. Allen F. Shaughnessy, PhamD., BCPS; Harrisburg Family Practice Residency, Hamsburg, PA.

PURPOSE: Despite the extensive use of pharmaceutical samples as a marketing tool, there has been no published literature documenting their influence on physician prescribing. This study evaluated the influence of samples in three different drug classes on prescribing habits. METHODS: The setting was a model practice of a family practice training program. The study used a before-after study design, using three 5-month time periods to determine the prescribing habits when samples were not available, immediately after the samples were available for distribution, and one year following their introduction. The prescribing of antibiotics, thiazide diuretics, and nonsteroidal antiinflammatory drugs (NSAIDs) was evaluated. Agents selected for sampling were selected by a committee of practitioners and were constant for the course of the study. Data were collected using copies of prescriptions written by residents. RESULTS: The proportion of sampled drugs prescribed in the three classes was 20.4% when samples were not present. This percentage dropped to 15.3% following the introduction of samples, but increased to 25.2% one year later (C’ = 20.12, p<O.OOl). Sampling of certain antibiotics significantly increased their use from 14% before samples to 22% one year after their introduction (C’ = 11.65, p=0.003). Sampling of Maxzide” did not increase its prescribing versus other thiazide diuretics. Sampling of the NSAID oxaprozin significantly increased its use from 2% of total NSAID prescribing to 14% after one year of samples (Fisher’s exact p<O.OOOl). CONCLUSION: This study supports the widely held contention that pharmaceutical samples affect prescribing.

113. A financial impact model for pharmacy productivity and pharmacy interventions. Edward G. Tessier, Pharm.D., M.P.H., Arlinda Zhuzbuni, M.P.H., Paul J. Goerdt, Pharm.D.; Baystate Medical Center, Springfield, MA; University of Massachusetts, Amherst, MA; Express Scripts-ValueRx, Minneapolis, MN.

PURPOSE: This study created a financial impact model to document the provision of hospital-based pharmaceutical care. Goals of the model were 1) identification of interventions associated with cost avoidance; and 2) justification of staffing for the provision of pharmaceutical care. METHODS Pharmaceutical literature demonstrating the financial impact of Pharmaceutical care was applied to documented interventions at a 650-bed tertiary care teaching hospital between December 1995 and June 1997. Probability analysis was used to construct financial impact models for interventions not found in the literature. RESULTS: A total of 26,477 interventions were classified into 24 categories. Based upon published literature and probability analysis, accurate cost savings and cost avoidance data could be projected for three categories. Annual cost avoidance was estimated as follows: allergy conflict identification and management: $40,487 ($63 per intervention), IV to PO conversion: $187,336 ($875 per intervention), and therapeutic duplication: $2,642 ($8.23 per intervention). Based upon time spent per intervention, the benefit to cost ratios were calculated as follows: allergy management 26:1,1V to PO conversion 232:1, and therapeutic duplication 21. The remaining 21 categories of interventions were not readily amenable to financial analysis based upon existing published literature. CONCLUSION: The greatest cost savings were documented for 1V to PO conversion and allergy conflict identificatiodmanagement. For the majority of pharmaceutical care interventions conducted in acute care hospitals, however, direct application of existing published pharmacoeconomic literature to practice remains problematic. Additional published literature to more accurately determine financial impact of pharmacist interventions in individual settings is necessary.

114. Cost-effectiveness analysis of single-dose versus multiple-dose treatment for uncomplicated urinary tract infections. Pat 5. Raffrty, Pharm.D., Major Gregory W. Russie, M.S.; University of Texas at Austin, Austin, TX; University of Texas Health Science Center at San Antonio; Department of Defense Pharmacoeconomic Center, Fort Sam Houston, TX.

PURPOSE: To determine the cost effectiveness of various single-dose antibiotic regimens for uncomplicated urinary tract infections (UTI) in non- pregnant women versus traditional multiple-dose regimens. METHODS: Studies that included single-dose regimens for uncomplicated UTI were obtained from a search of Medline 1966 to present and a review of bibliographies. Definitions of infection and cure were obtained from

Infectious Diseases Society of America guidelines. A mathematical model of cost-effectiveness was used to determine the most cost-effective treatment of an uncomplicated UTI. Costs were evaluated from the perspective of the Department of Defense as the payer of the health care benefit and employer. Nineteen studies were included in the analysis, representing 24 different regimens and 2706 patients treated. Medications included trimethoprid sulfamethoxazole double-strength (TMP-SMX DS), cephalosporins, beta- lactams, and fluoroquinolones. RESULTS: Baseline analysis revealed the top five regimens to be: 1) single- dose ofloxacin 400 mg ($2.97 cost per bacteriologic cure); 2)TMP-SMX DS BID for 3 days ($4.28); 3) single-dose (two tablets) TMP-SMX DS ($9.43); 4) single-dose ciprofloxacin 500 mg ($11.33); and 5) TMP-SMX DS BID for 10 days ($11.66). Regimens using cephalosporins and beta-lactams, whether single- or multiple-dose, were less cost-effective than those using TMP-SMX or fluoroquinolones. Sensitivity analyses (univariate and multivariate) will be presented. CONCLUSION: The initial results indicate that several single-dose antibiotic regimens using fluoroquinolones and TMP-SMX are cost-effective for uncomplicated UTI in women. The convenience of single-dose regimens, with assured compliance if therapy is directly observed, must be weighed against local sensitivities and resistance patterns.

115. Cost-effectiveness analysis of seasonal allergic rhinitis. Robin R. Feuge, Pharm.D., Gregory W. Russie, M.S., Robert L. Talbert, Pharm.D., BCPS; University of Texas at Austin, Austin, TX; University of Texas Health Science Center a t San Antonio, San Antonio, TX; Department of Defense Pharmacoeconomic Center, Fort Sam Houston, TX.

PURPOSE: To identify the most cost-effective initial drug therapy for adults with seasonal allergic rhinitis. METHODS: Randomized studies in adults suffering from seasonal allergic rhinitis were found by a search of Medline and review of bibliographies. Data from 63 studies were included in the analysis. Treatment options included were classical, nonsedating, and topical antihistamines as well as cromolyn and topical corticosteroids. Costs included were costs of the drugs, initial physician visit, follow-up visit for drug failure, and loss of work by active duty personnel. The cost for each agent to achieve good to excellent control of symptoms was calculated using a mathematical model. A treatment period of 8 weeks was used. The analysis was performed from the perspective of the Department of Defense. RESULTS: Initial results indicate the following treatment options to be the most cost-effective: 1) beclomethasone pockethaler ($90.01); 2) brompheni- raminelpseudoephedrine sustained release tablets ($99.45); 3) triprolidinel pseudoephedrine tablets ($100.42); 4) chlorpheniramine tablets plus pseudoephedrine tablets ($100.55); and 5) mometasone nasal inhaler ($108.89). Treatment regimens including a nonsedating antihistamine were the least cost- effective. Univariate and multivariate sensitivity analyses will be presented. CONCLUSION: Classical sedating antihistamineldecongestant combinations and topical steroids are the most cost-effective options for allergic rhinitis by initial analysis. Restriction of nonsedating antihistamines to patients who fail or do not tolerate more cost-effective options may result in considerable cost savings. Patient acceptance and tolerance of these treatment options must be considered.

116. Evaluation of costs associated with antifungal use for vaginal candidiasis in a long-term care environment. Doug Joseph, Phann.D., Lany LaPalio, M.D., Carolyn Wessner, B.S.N.. Peter Lemke, Ph.D., Scott E. Glosner, Pharm.D., BCPS; Vitalink Inc, Napenille, IL; Pfiier Inc, Chicago, IL.

PURPOSE: This evaluation reviewed and modeled 1) the current procedure for administering a vaginal delivery medication; and 2) calculated the costs associated with the different services (e.g., pharmacy, nursing) and materials. METHODS: The current procedure and costs for treating vaginal candidiasis in the geriatrics population were determined through information gathering from different sources (e.g.. health care providers, the medical literature). A panel consisting of a clinical pharmacy director, a nursing manager, and two Doctors of Pharmacy discussed the overall resources required for administering a vaginal medication for vaginal candidiasis. The information was modeled entirely of experiences based from different long-term care facilities in eastern Pennsylvania. Data were gathered and compiled on an antifungal worksheet. The data included both nursing functions and materials for treating vaginal candidiasis. RESULTS: The costs involved with treating vaginal candidiasis include drug acquisition, medication administration time, materials, bedding and clothing changes, and patient refusal rates. The drug acquisition prices for fluconazole, clotrimazole, nystatin, and miconazole were based on average wholesale pricing per treatment course. The total cost in nursing time for giving a vaginal dose was $9.39 for 0.57 hours. The total cost for materials was $1.29 per dose. Patient refusal rates were assumed at 5% and clothingbedding changes at 10%. Fluconazole given orally to treat vaginal candidiasis would save nearly $60 per patient course. CONCLUSION: Oral medications (e.g., fluconazole) for treating vaginal can-didiasis require less nursing administration time and materials while pro-viding greater patient acceptance and compliance at a considerable cost savings.


Pharmacoepidemiology 117. Factors associated with cost of post-operative infections. lames D. Scott, Alan Forrest, Steve Feuerstein, Jerome J. Schentag; State University of New York at Buffalo; CGF Health Systems, Buffalo, NY.

PURPOSE: In today's environment of spiraling health care costs, it is critical to minimize the incidence and cost of post-operative infection (POI). We have developed and analyzed a large surgical prophylaxis database and, herein, report the factors significantly associated with the cost of POI. METHODS: A computerized database of surgical patients seen at our hospital from March 1, 1995 to December 31, 1997 was developed. For the 8999 evaluable patients, factors tested (ANOVA with Bonferroni adjustment) for association with total 28-day charges (TC) included: early infection (El), readmission due to infection (RA), sex, creatinine (SCR), albumin (ALB), age, prophylactic antibiotic regimen (PA), and surgery type (SG). RESULTS: Factors that were significantly associated with TC included El, RA, ALB, age, PA, and SG (all p<0.001). The mean (range) TC for all patients was $6592 ($0-$137,530). El andlor RA both added approximately $8000 to the geometric mean (GM) TC. The PA that were associated with decreased TC, and included 2 100 patients, were ampicillin alone (GM $37511, ampicillin with an aminoglycoside (GM $45191, and cefazolin alone (GM $4722); while ampicillidsulbactam alone (GM $7778) was associated with increased TC. CONCLUSION: El and RA were associated with significantly higher TC. The SG, ALB, and age were also highly significant. It was also interesting that certain PA were significant even after adjusting for the other significant factors. Interactions between SG and PA have not yet been examined.

PharmacometricsDrug Metabolism/ PharmacokineticsD'harmacodynarnics 118. Mild renal impairment does not alter the pharmacokinetics of cerivastatin in normocholesterolemic adults. Arthur L. Mazm, Ph.D., Edward Kelly, M.D., Thomas Marbury, M.D., Ramon Vargas, M.D., John T. Lettieri, Ph.D., Ming-Chung Liu, Ph.D., Pavur Sundaresan, Ph.D.; Bayer Corporation, West Haven, CT; PPD-Pharmaco, Morrisville, NC; Orlando Clinical Research Center, Orlando, FL; New Orleans Center for Clinical Research, New Orleans, LA.

Cerivastatin is a synthetic statin that undergoes hepatic and, to a lesser extent, renal elimination. PURPOSE To determine if renal impairment alters cerivastatin pharmacokinetics. METHODS: In this nonrandomized, nonhlinded, multiple-dose study, subjects with normal renal function (CrCI > 90 mVmird1.73 m') or patients with mild (CrC1 61 to 90 ml/min/1.73 mL), moderate (CrC1 30 to 60 mVmid1.73 m'), or severe (CrC1 < 30 mVmird1.73 mz) renal impairment were given cerivastatin 0.3 mg QD for seven days. Pharmacokinetic parameters (AUC*l4, C,,,, and tm) were measured on days 1 and 7. RESULTS Steady-state cerivastatin C,, and tln were similar in patients with normal and impaired renal function. The AuC0-24 was unchanged in patients with mild renal impairment, but was 40-60% higher in patients with moderate to severe renal impairment.

Renal AUCO-24 (mg-hR) C,,, (m@) t1R (hr) Impairment (n) Day 1 Day7 Day1 Day7 Day7 None (9) 19.2 (25.5) 21.4 (28.9) 3.3 (37.8) 3.9 (38.8) 3.1 (23.9) Mild (9) 19.6 (35.5) 20.8 (28.7) 3.4 (56.1) 3.5 (29.9) 3.4 (21.7) Moderate (8) 30.8 (35.3)* 36.1 (39.6)* 4.6 (34.5) 4.6 (42.2) 4.4 (25.8) Severe (9) 29.0 (50.7)* 30.0 (45.5)* 5.2 (40.5) 4.8 (36.7) 3.6 (22.0) *p<0.05 versus suhlects with normal CrCI; all values geometric mean (% CV)

CONCLUSION: In patients with mild renal impairment, cerivastatin pharmacokinetics were unaltered. In patients having CrClS 60 mVmid1.73 mz, cerivastatin 0.3 mg resulted in modestly elevated plasma levels, similar to an approximate 0.4 mg dose.

119. Bootstrap variance estimators for the parameters of small sample population pharmacokinetic study. Ene I. Ette, Ph.D., FCCP; Vertex Pharmaceuticals, Cambridge, MA.

PURPOSE: To determine the appropriateness of using the bootstrap (B) approach to the problem of standard error (SE) estimation with NONMEM when the sample s u e is small. METHODS: One hundred replicate fragmentary data sets were generated using an incomplete longitudinal population pharmacokinetic (PK) study design assuming a sample size of 19 and parameters of a drug that exhibits 2- compartment linear pharmacokinetics with single dose first order input. Standard errors (SEs) for model parameters were computed from the simulated data to serve as the true standard error of estimates. The mean parameters were then used to generate a data set which was fitted with the NONMEM program. From this data set, 250 replicate data sets were generated using the nonparametric B approach and analyzed with NONMEM.

All NONMEM runs were performed without the covariance step. Because of the sensitivity of the bootstrap to extreme values, a B run with parameter values 2 2-fold the mean was rejected. Such parameter values were regarded as outliers. Given the exclusion criterion, 200 randomly selected B samples were used for the computation of SEs. The appropriateness of using 50, 100, 150, or 200 B samples to estimate SE for population PK parameters was investigated by first testing the distributions of these samples for normality. Prediction error was used to judge the performance of the B approach for estimating SE for population PK parameters. RESULTS. The distribution of parameter estimates approximated normality with B replicates 2 150. Also, robust estimates of SE were obtained with B replicates 2 150. Estimates obtained with 200 B replicates were similar to those obtained with 150. CONCLUSION: It is often not possible to obt;rin asymptotic standard errors from NONMEM with a small sample size such as the one used in this study. With the B approach SEs can he computed for population PK parameters estimated with NONMEM when it is not possible to obtain these asymptotic SEs with the implementation of the NONMEM covariance step.

120. Characteristics of cyclosporine metabolites pharmacokinetics with grapefruit administration in healthy volunteers. Yi-Min Ku, M.S., PhamD. , David 1. Min, M.S., Pharm.D.; University of Iowa, Iowa City, 1A.

PURPOSE: Cyclosporine (CSA) is extensively metabolized by CYP3A4 and over 25 metabolites have been identified, of which M1 and M17 are two major ones. This study aims to evaluate the effect of grapefruit juice (GJ) on the pharmacokinetics of the major metabolites of microemulsion cyclospo 'ne

METHODS: Each subject received two oral doses of CSA-ME (5 mg/kg) in a fasted condition, with each dose separated by at least a 1-week washout period. CSA-ME was given with 6 ounces of GJ or water (W). Two more 6 ounce glasses of GJ or W were given at 0.5 hour and 1.5 hours after the M- CSA dose. A total of 17 blood samples were collected for a 24-hour period, and whole blood concentrations of two major metabolites, M1 and M17, were determined by gradient HPLC assay with UV detection. Its pharmacokinetics were evaluated by non-parametric analysis method. RESULTS: The summarized results were:

(CSA-ME) in 12 healthy volunteers. P

M1 M17 GI W pvalue GJ w p value

C,,, (np/ml) 1280 * 396 1622 * 540 0.04 2010 T 781 21530 * 73821 0.73 AUC (ng.hr/ml) 9751t3058 11459r4221 003 28536r14214 23259+10133 011 T,,, (hr) 2.4+0.4 2 9 a 1 0 008 3.2r15 2 1 r 0 5 004

CONCLUSION: This s tudy demonstrated that GJ affects formation pharmacokinetics of CSA metabolites, M1 and M17, differently compared to W i n healthy volunteers.

121 . l n t r a s u b j e c t var iab i l i ty a n d gender differences i n u r i n a r y dextromethorphan to 3-methoxymorphinan ratio. Celeste Lindley, Pharm.D., M.S., Jeannine McCune, Pharm.D., Amy Meadowcroft, Pharm.D., Jodi Decker, Pharm.D., Stan Carson, Pharm.D., Herbert Patterson, Pharm.D., John Pieper, Pharm.D.; University of North Carolina, Chapel Hill, NC.

The urinary ratio of dextromethorphan (DM) to its metabolites, dextrorphan (DX) or 3-methoxymorphinan (3MM), have been used to phenotype cytochrome P450 2D6 (CYP2D6) and 3A4 (CYP3A4) activity, respectively. Although DM:3MM is purpor ted to assess CYP3A4 activity dur ing inductiodinhibition, data suggest CYP2C19 and CYP2El also metabolize DM. The purpose of this pilot trial was to assess intrasubject variability in DM:3MM and to compare DM:3MM in men, women on oral contraceptives ( 0 0 , and women not on OC. The molar ratio of DM:3MM was determined by HPLC analysis of four 24-hour urine collections separated by one week each. Twenty-eight extensive CYP2D6 metaholizers (DM:DX < 0.3) were included in the analysis (7 men, 10 women on OC, and 11 women not on OC). DM:3MM ratio (mean + SD) for 28 subjects was 5.0 * 5.1 (range 0.4-25.5). Ratios for men (5.9 * 8.91, women on OC (5.0 + 3.61, and women not on OC (4.3 * 3.0) were not significantly different (p=0.73 ANOVA on log transformed data). At least 400 subjects would be required for 80% power if a 30% difference were to he detected. lntrasubject variability was calculated hy determining each subject's coefficient of variation (CV) from the four urine collections. Mean (range) CV did not differ significantly among the three groups: men = 60% (20-12096); women on OC = 70% (1040%); women not on OC = 70% (30-110%); p=0.89 ANOVA. The substantial intrapatient Variability in DM:3MM over a 1-month time period suggests it is not sensitive enough to detect small changes in CYF' activity during non-induced or non- inhibited states. Gender and OC use do not appear to significantly influence urinary DM:3MM.

122. Influence of oral contraceptives on cytochrome P450 enzyme activity: results of a pilot trial. leannine McCune, Pharm.D., John Pieper, Pharm.D., Jodi Decker, Pharm.D., Amy Meadowcroft, Pharm.D., Donald Graff, Pharm.D., J . Herbert Patterson, Pharm.D., Kristin Williamson, Pharm.D., Celeste Lindley, Pharm.D.; University of North Carolina, Chapel Hill, NC.

Fluctuating amounts of estrogen and progesterone in oral contraceptives (OCs) may influence cytochrome P450 (CUP) activity and alter drug


metabolism in women participating in clinical trials. This pilot trial investigated the effect of a triphasic OC on variability in dextromethorphan (DM) metabolic ratios throughout a 1-month period. Ten women on Triphasil" (for 2 3 cycles) self-administered DM 30 mg orally once weekly for four consecutive weeks. Twenty-four hour urine collections were analyzed for DM, dextrorphan (DX), and 3-methoxymorphinan (3MM) using HPLC (CV < 15%). Patient-maintained diaries were used to determine OC phase and, hence, levonorgestrel (LEVO) and ethinyl estradiol (EE) dose at the time of DM administration. Twice weekly estrogen and progesterone concentrations confirmed the absence of endogenous hormone production in these subjects. The urinary molar ratios of DM:DX and DM:3MM were used to assess CYP2D6 and to estimate CYP3A4 activity, respectively. Results are as follows: mg of LEVOEE # Observations DM:DXa DM:3MM 0.05/0.03 9 0.0038 (0.0009-0.0445) 3.5 (0.2&40.0) 0.075/0.04 9 0.0047 (0.000&0.0534) 2.9 (0.45-19.5) 0.125/0.03 12 0.0026 (0.0006-0.0764) 2.8 (0.18-10.2) o/o 10 0.0038 (0.0003-0.0615) 3.0 (0.69-12.6) p-value' 0.50 0.49 power/to detect 0.20/10% 0.20/100%

% difference' *median (range); hrepeat measures on log transformed data; <in extremes 01 data

The varying amounts of estrogen and progesterone contained in the oral contraceptive Triphasil' do not appear to influence CYP activity as assessed by DM metabolic ratios, although power is limited. These data suggest that, with a similar study design, at least 200 subjects would be required to achieve 80% power to detect a difference in the means of these data.

123. Inhibition of CYP2C9 by classic histamine Hi receptor antagonists. Caroline Gauvin, M.Sc. Candidate, Sylvie Pilote, MSc., Bettina A. Hamelin, Pharm.D.; Universite Lava1 and Research Center, Ste-Foy, Quebec, Canada.

PURPOSE: Classic antihistamines have been in clinical use for over 50 years, however, little is known about their interaction with cytochrome P450 isozymes. We have previously shown that six classic antihistamines inhibit CYP2D6 in vitro and in vivo as well as CYP3A4 in vitro. The current study was undertaken to determine whether a series of six classic antihistamines (diphenhydramine, chlorpbeniramine, clemastine, promethazine, hydroxyzine, and tripelennamine) interact with other CYP isozymes, namely CYPlA2 and CYPZC9. METHODS Phenacetin and tolbutamide were used as markers for CYPlA2 and CYP2C9 activities, respectively. To determine the concentrations at which 50% of maximal enzyme activity is inhibited (ICso), seven concentrations of each antihistamine (0-640 pM) were incubated with saturating substrate concentrations (200 mM), microsomes expressing high CYPlA2 or CYP2C9 activities, and a NADPH regenerating system. Incubations were done at 37°C for 20 minutes. Where significant inhibition was observed, inhibitory constants (Ki) values were determined graphically (method of Dixon) at four substrate concentrations (45, 60, 120, and 180 pM) and five inhibitor concentrations (0, 10, 20, 40, 80 p M ) . Phenacetin/acetaminophen and tolbutamide/OH-tolbutamide were determined by HPLC with UV detection. RESULTS: None of the six antihistamines tested demonstrated significant inhibition of CYPlA2. Maximal CYPlA2 inhibition ranged from 15 to 75%; Cl50 were 87 mM for promethazine, 117 pM for clemastine, and greater than 250 pM for all other antihistamines tested. Furthermore, diphenhydramine, chlorpheniramine, and tripelennamine did not inhibit CYP2C9. In contrast, significant CYPZC9 inhibition was observed for the following antihistamines:

Antihistamines Maximal inhibition % lcso (pM) Ki (pM) Clemastine 104,07 20,30 8 Hydroxyzine 102,08 22,67 10 Promethazine 96-99 34,28 7 CONCLUSION: Classic antihistamines are lipophilic molecules reaching hepatocyte concentrations 10 to 40-fold higher than their plasma concentrations. Therefore, clinical significant drug interactions may occur between classic antihistamines and substrates of CYP2C9.

124. Evaluation of the selectivity of disulfiram inhibition on in vivo cytochrome P450 activity. Reginald F. Frye, Pham.D., Ph.D.; University of Pittsburgh, Pittsburgh, PA.

PURPOSE: There is tremendous interest in identifylng selective cytochrome P450 (CUP) inhibitors for in vitro and in vivo investigations. Disulfiram and its primary metabolite diethyldithiocarbamate are selective mechanism-based inhibitors of CYP2E1 in vitro, but their selectivity in vivo is questionable. The purpose of this study was to assess the activity of CYP 1A2, 2C19, 2D6, 2E1, and 3A enzymes before and after chronic disulfiram administration. METHODS: Seven normal healthy volunteers received disulfiram (250 mg) orally for 11 days. Subjects received the probe drug chlorzoxazone (250 mg; CYP2E1) prior to disulfiram administration, after the second disulfiram dose, and after the eleventh daily disulfiram dose. Subjects also received the probe drugs caffeine (100 mg; CYPlAZ), dapsone (100 mg), dehrisoquine (10 mg; CYP2D6), and mephenytoin (100 mg; CYP2C19), prior to and after

disulfiram administration. Blood and urine samples were collected for parent and/or metabolite determinations by HPLC. Standard phenotypic trait measures were calculated for each probe drug and compared using the Wilcoxon sign-rank test RESULTS: As expected, disulfiram administration profoundly inhibited CYF'2El activity (> 95%) after both acute and chronic administration. There was no difference in 4-hydroxymephenytoin urinary recovery (CYP2C19) or the debrisoquine recovery ratio (CYP2D6). The caffeine metabolic ratio was reduced by 34% after disulfiram administration (p=0.018), while the dapsone recovery ratio was decreased by 22% (p=0.08). CONCLUSION: The results of this study confirm substantial inhibition of CYP2El activity by disulfiram, which was maximal after two disulfiram doses. Chronic disulfiram administration has no effect on CYP2D6 or CYP2C19 mediated metabolism and has only modest effects on CYPlA2 activity and dapsone hydroxylation.

125E. Effect of ritonavir on CYPlA2, 2C19, and 2El activities in vivo. Reginald F. Fiye, Phann.D., Ph.D., Richard J. Bern, Ph.D., G. bchard Granneman, Ph.D., I n s Lauva, Ph.D., J. Lamm, M.S., Susan Dennis, M.D., J. Valdes, M.D.; University of Pittsburgh, Pittsburgh, PA; Abbott laboratories, Abhott Park, 1L.

Published in Clin Pharmacol Ther 1998;63: 148.

126. The effect of the acute phase response on chlorzoxazone pharmacokinetics and CYP2El activity in rats. Kevin T. Rockich, Pham. D., Robert A. Blouin, Pharm. D., FCCP; University of Kentucky, Lexington, KY.

PURPOSE: The administration of lipopolysachamde (LPS) to rats cause at least a 60% decrease in the in vitro activity of CYP2E1. Administration of LPS to humans has shown a 3MO% decrease in the oral clearance of non-specific markers for cytochrome P-450s. The purpose of this study was to determine the systemic-clearance (CLs) of chlorzoxazone, a CYP2El probe drug, and compare this to the CYP2El in vitro activity. METHODS: Sprague-Dawley rats were randomized into a parallel study in which they received either an intraperitoneal injection of saline (n=7) or LPS ( 5 mg/kg; n=7) . Twenty-four hours later an intravenous dose of chlorzoxazone (15 mg/kg) was administered via a jugular cannula. Plasma samples were obtained and analyzed for chlorzoxazone by HPLC (CV < 5%). Livers were excised for microsomal preparation. RESULTS: The in vitro activity of CYP2El in controls was 1.78 i 0.33 nmol/mg/min compared to 0.44 i 0.1 nmol/mg/min (p<O.OOl) in the LPS group. The CLs was 3.51 i 0.24 mumin (controls) compared to 2.27 i 0.58 mumin (p<O.OOl) in the LPS group. The correlation between these two resulted in an R'=0.7 (p-zO.001). The steady-state volume of distribution was 0.39 i 0.04 Lkg (controls) compared to 0.66 i 0.12 Lkg (p<O.OOl) in the LPS group. The half-life of chlorzoxazone was 30.45 i 1.78 minutes (controls) and 81.37 i 17.37 minutes in the LPS group (p<O.OOl). CONCLUSION: This study will aid in the extrapolation of data from animal models to humans.

127. The pharmacokinetics and protein binding of eprosartan in hemodialysis-dependent patients with endstage renal disease. Steven J. Kovacs, Pham.D., David M. Tenero, Pharm.D., David E. Martin, Pharm.D., Bernard E. Ikon, M.D., Diane K. Jorkasky, M.D.; SmithKline Beecham Pharmaceuticals, Philadelphia, PA; The Clinical Pharmacokinetics Laboratory, Buffalo, NY.

PURPOSE: To compare eprosartan pharmacokinetics in hemodialysis patients to volunteers with normal renal function and determine the effect of hemodialysis on eprosartan pharmacokinetics. METHODS: An open-label, parallel group, single-dose study was conducted in ten normal volunteers and nine hemodialysis patients. An oral dose of eprosartan 400 mg was administered to normal volunteers on one study day and to hemodialysis patients on two separate study days, a non-dialysis and dialysis day. Plasma and dialysate eprosartan concentrations were assayed by HPLC; protein binding was determined by ultrafiltration. RESULTS: Eprosartan pharmacokinetics showed exaggerated variability in hemodialysis patients. However, most hemodialysis patients had exposures that were within the range observed for volunteers with normal renal function. Mean total AUC(kt, was increased approximately 60% (95% CI: -22%, 225%) in hemodialysis patients. Total C,,, was similar between groups (PE = 1.01; 95% C1: -40%, 71%). Mean percent fraction unbound (%fu) in hemodialysis patients (3.02%) was significantly increased compared to normal volunteers (1.74%). Unbound AUC(+,, and unbound C, were, on average, approximately 172% (95% CI: 28%, 479%) and 73% (95% CI: -l%, 199%) greater, respectively, i n hemodialysis patients. Following hemodialysis, the mean %fu decreased from 3.19% to 2.01%. Mean recovery of eprosartan in dialysate was 6.8 mg (range 0-23.1 mg) and hemodialytic clearance of eprosartan was approximately 11 mumin which does not represent a significant portion of the total clearance. CONCLUSIONS: Eprosartan was safe and well tolerated in both groups. Based on the known safety profile of eprosartan and because O f i ts exaggerated pharmacokinetic variability in hemodialysis patients, treatment should be individualized based on tolerability and response. Supplemental doses of eprosartan following hemodialysis are unnecessary.


128E. Gender differences in the pharmacokinetics of dehydroepiandrosterone following single and multiple-dose administration in healthy older adults. Reginald F. Frye, Pharm.D., Ph.D., Patricia D. Kroboth, Ph.D., Anna M. Linares, M.S., M. Maggie Folan, B.S.N., Charles Hakala, B.S., Roslyn Stone, Ph.D., Frank J. Krobotb, M.D.; University of Pittsburgh, Pittsburgh, PA.

Presented at the Annual Meeting of the Society for Neuroscience, 10s Angeles, CA, November 7-12, 1998.

129E. Valacyclovir bioavailability in kidney and liver transplant patients. Lisa M. Opatik, Pharm.D., Reginald F. Frye, Pharm.D., Ph.D., Jodie A. Campbell, Pharm.D., Richard J. Ptachcinski, Pharm.D., Ron Shapiro, M.D., J. Wallis Marsh, M.D.; Thomas E. Starzl Transplantation Institute, University of Pittsburgh, Pittsburgh, PA.


130. Effect of grapefruit juice on microemulsion cyclosporine absorption kinetics in healthy volunteers. David I. Min, M.S., Pham.D., Jeong M. Park, M.S., Yi-Min Ku, M.S., Pharm.D., Ronald Schoenwald, Ph.D.; University of Iowa, Iowa City, L4.

PURPOSE: The absorption of cyclosporine (CSA) is erratic and many factors influence its kinetics. The new microemulsion formulation of cyclosporine (CSA-ME) has significantly improved its absorption. The purpose of this study is to characterize the absorption kinetics of CSA-ME and to evaluate effect of grapefruit juice on its kinetics in healthy volunteers. METHODS: Each subject received two oral doses of CSA-ME (5 mgkg) and one IV CSA (1.5 mgkg) in a fasted condition, with each dose separated by at least a 1-week washout period. CSA-ME was given with 6 ounces of grapefruit juice (GJ) or water (W). Two more 6 ounce glasses of GJ or W were given at 0.5 hour and 1.5 hours after the CSA-ME dose. A total of 17 blood samples were collected for a 24-hour period. Its disposition pharmacokinetics parameters by 1V dose were estimated by WinNonLin program and the absorption kinetic characteristics of each oral doses were evaluated by Wagner-Nelson method. RESULTS: All parameters were calculated by using a 2-compartment 1V infusion model. CSA-ME with W or GJ show first order absorption kinetics and its mean absorption constant (k,) of CSA with W was significantly higher than that of CSA (GJ) (0.72 i 0.34 (W) hr-' vs 0.49 * 0.16 hr-l, p<O.Ol] and its absorption half life was significantly shorter than that with GJ (1.09 * 0.34 hr vs 1.55 * 0.49 hr, p<O.OI). However, the lag time was not significantly different between CSA-ME with W and CSA-ME with GJ (0.64 i 0.16 hr [Wl vs 0.78 i 0.24 hr [GJ], p=0.12). CONCLUSION: This study demonstrated that GJ affect absorption kinetics of CSA-ME and GJ may alter the absorption rate of CSA-ME in healthy volunteers.

131E. Amphotericin B-induced interleukin-lp expression in human monocytic cells is calcium and calmodulin dependent. P. David Rogers, Pharm.D., Robert E. Kramer, Ph.D., Stanley W. Chapman, M.D., John D. Cleary, Pharm.D.; University of Mississippi, Jackson, MS.


132. Comparison of serum concentrations achieved by 5 mgkg, 6 mgkg, and 7 mgkg single daily dose gentamicidtobramycin dosing protocols in a tertiary care medical center. Maria W. Griswold, Pharm.D., Edward G. Timm, Pham.D., M.S., Laurie L. Briceland, Pharm.D., Ben M. Lomaestro, Pharm.D.; Albany Medical Center Hospital, Albany, NY.

PURPOSE: Recent nationwide surveys have verified increasing use of single daily dose (SDD) gentamicin/tobramycin (G/T) schedules of administration and 5 m@g (G/T) as the most commonly recommended dose. To optimize the clinical benefits of SDD aminoglycosides, a peak/MICw of at least 1O:l is recommended. It is essential to establish that the dose administered achieves the desired serum concentration outcomes. This study examined the serum concentrations achieved by 5,6, and 7 m@g SDD G/T dosing protocols and offers dosing recommendations based upon organism susceptibilities. METHODS A retrospective review of all patients who received SDD G/T from June 11, 1994 through June 1, 1995 and a concurrent review of all patients who received SDD G/T from September 1, 1996 through March I, 1997 was conducted. Data collection included patient demographics, pertinent laboratory findings, and drug administration and serum concentration data. Dosing recommendations to achieve peakh4ICgo of 1O:l were determined for MlCw of 5 1 pg/ml and 2 pg/ml or greater. RESULTS: Of a total of 125 evaluable SDD G/T treatment courses, 44 were within 4% of the 5, 6, and 7 mgkg doses (e.g., actual dose for 5 mgkg was 4.8 to 5.2 mgkg). The serum concentrations (mg/L) achieved were:

n 20 11 13 Mean ( 2 SD) 11.7 (i 2.53) 14.1 (i 3.21) 15.2 ( + 3.18) 95% CI Upper 12.9 16.3 17.1 95% CI Lower 10.6 11.9 13.3

Dose ( * 4%) 5 mgkg 6 mgkg 7 mgkg

A detailed study of drug administration, sample handling, and assay procedures revealed minimal variability. CONCLUSION: The use of 5 mg/kg SDD G/T produces peak serum concentrations in excess of 10 pg/ml. Thus, for organisms with MIC 5 1 pg/ml, peakAvllC90 of 1O:l are reliably achieved. For organisms with MIC9o 22 pg/ml, 7 mgkg SDD G I I or more may be required.

133. Lack of effect of oral dirithromycin on the pharmacokinetics of oral theophylline in healthy volunteers. Scott A. McCunnell, Pharm.D., Anne N. Nafziger, M.D., M.H.S., Guy W. Amsden, Pharm.D.; Bassett Healthcare, Cooperstown, NY.

PURPOSE: Oral dirithromycin (DIR) is a macrolide antibiotic used in the treatment of respiratory infections. It has previously been reported to increase the clearance of oral theophylline (THE07 in healthy volunteers. The mechanism of this interaction is not known and DIR is not known to interact with the cytochrome P450 system like other macrolides. The objective of our study was to analyze the effects of 10 days of oral DIR o n the pharmacokinetics of oral THEO in regards to AUCa,. METHODS: Twelve healthy non-smoking adults (eight male, four female) were enrolled in an open-label, randomized, crossover study. Subjects received, in a randomized order, separated by a 3-week washout period 1) a single dose of oral THEO 5 mgkg administered as equivalent aminophylline solution; and 2) 10 days of DIR 500 mg once a day followed by a dose of THEO 5 mgkg on day 10 of DIR. Blood samples were obtained just prior to and after the dose of THEO (pre-dose and at 0.25, 0.50, 0.75, 1.0, 1.5, 2.0, 4.0, 8.0, 12.0 and 24.0 hours). Serum THEO concentrations were as ayed using a Johnson and Johnson Clinical Diagnostics, Ektachem 250 anJyzer. The main parameter of interest was AUC*. (Other parameters that were calculated were CW, V*, half-life, C,,,, T,,, and KJ. Non-compartmental analysis (weight Uy') waiperformed on the data via the TopFit V 2.0 program. Statistical testing was via the Wilcoxon sign-rank sum test using Systat. A p-value 5 0.05 was considered significant. RESULTS: Age (mean i SD) = 37.3 i 10.5 yiars; total body weight = 76.3 i 13.0 kg; and CrCl = 90.8 * 19.7 ml/min/l.73m2. Mean AUCo,.(mg.hr/L) of THEO alone vs THEO with DIR were 141.7 i 25.0 vs 136.4 f 33.1 (p=0.16), respectively. There was no significant difference between study arms for any other parameters. CONCLUSION: In healthy adults, a standard lo-day course of DIR did not significantly alter the pharmacokinetics of or overall exposure to THEO. There was also no clinically significant interaction between THEO and DIR. No dosage adjustments need to be made to THEO when giving the antibiotic DIR. In healthy adults interactions between DIR and THEO may not be of the clinical significance previously reported.

134. Evaluation of amphoter ic in B and flucytosine alone, and in combination against Candida albicans and Cryptococcus neoformans, using time-kill methodology. Veronica C. De Lallo, Pham.D. candidate, Russell E. Lewis, Pharm.D., Rosemarie C. Petzold, B.S., Michael A. Pfaller, M.D., Michael E. Klepser, Pharm.D.; University of Iowa, Iowa City, IA.

PURPOSE: We have previously described amphotericin B (AMB)-fluconazole antagonism utilizing time-kill methodology in vitro. In this study, we compared the antifungal pharmacodynamics of AMB and flucytosine (5-FC) alone, and in combination, utilizing time-kill methodology. METHODS: Three strains each of C. albicans and C. neoformans were

selected. MICs were determined prior to testing according to NCCLS guidelines. Isolates were tested against the following regimens: I) control; 2) 5-FC (50 pg/ml); 3) high-dose AMB (2.4 pg/ml); 4) low-dose AMB (0.125 pg/ml); 5) 5-FC and low-dose AMB administered simultaneously, and 6) 5- FC plus high-dose AMB (2.4 pglml) administered 8 hours after 5-FC (staggered). For time-kill procedures, antifungals were added to tubes containing growth media (RPMI 1640 with MOPS) and standardized fungal inocula (-lo6 CFU/ml). Tubes were then incubated on an orbital shaker at 32-35°C for 24 hours. At predetermined time points, aliquots were removed, serially diluted, and plated on potato dextrose agar for colony count determination. For the staggered regimen, fungi were incubated in the presence of flucytosine (50 pg/ml) for 8 hours prior to starting time-kill procedures. RESULTS: High-dose AMB alone, and in combination as a staggered regimen, exhibited fungicidal activity against both C. albicans and C. neoformans isolates. Both low-dose AMB and 5-FC alone displayed fungistatic activity against all isolates; however, when used in combination, the rate and extent of antifungal activity was enhanced against both C. albicans and C. neofomans isolates. CONCLUSION: These results confirm by time-kill methodology the additive interaction of AMB and 5-FC in vitro against candida and cryptococcus species.

135. Implementation of an institution-specific aminoglycoside dosing nomogram in adult patients. Roy A. Pleasants, Pharm.D., Patrick F. Smith, Pharm.D., D. Byron May, Pharm.D., Joanne K. Latour, Pharm.D.; Duke University Medical Center, Durham, NC; State University of New York at Buffalo, Buffalo, NY.


PURPOSE: Increased dosage requirements for aminoglycosides (AG) have been reported for specific disease states as well as general populations. Several drug-utilization reviews and clinical experience made it apparent that many patients at the study institution were being underdosed when therapy was initiated using published nomograms (NG) or manufacturer guidelines. The purpose of this study was to develop user-friendly, institution-specific AG dosing NG to achieve more appropriate serum concentrations (SO. METHODS: In phase I, AG pharmacokinetic data was prospectively collected to provide the basis for the NG. Adult patients admitted to medical and surgical intensive care units and wards were included. Data collected included patient demographics, antibiotic regimen and indication, disease states, and laboratory values. Patients w t h cystic fibrosis, bums, pregnancy, or unstable renal function were excluded. Target peak SCs were 7-9 pg/ml for nosocomial pneumonia, 6-8 pg/ml for other severe infections, and 3 4 pg/ml for urinary tract infections and gram-positive endocarditis. In phase 11, the NG was prospectively evaluated, with the percentage of patients achieving therapeutic initial peak SCs compared between phases utilizing Yates corrected chi squared. RESULTS: Pharmacokinetic parameters derived from 101 phase I patients: Vd = 0.35 i 0.13 Ukg, k,=0.203 + 0.09 h-'. Mean CrCl was 73.8 + 25.4 mVmin/70 kg. Forty-two percent of patients achieved therapeutic initial SCs in phase 1, compared to 84% of patients in phase 11 ( ~ 3 0 , pc0.001). CONCLUSION: The development of an institution-specific AG dosing NG resulted in a significant improvement over non-institution specific methods. We found a larger volume of distribution existed at the study institution than is described in the manufacturer dosing guidelines. Other institutions may similarly benefit from such institution-specific approaches.

136E. Can we predict subtherapeutic antituberculosis serum drug levels in patients with tuberculosis? Jerry J. Stumbaugh, Phurm.D., Massa Narita, M.D., David Ashkin, M.D., Elena Hollender, M.D., Arthur Pritchenik, M.D.; A. G. Holley State Hospital, Lantana, FL.; VA Medical Center, University of Miami, Miami, FL.

Presented at the meeting of the American Thoracic Society, Chicago, IL, April, 1998.

137. A single dose-ascending pharmacokinetic study of a new orally active antibiotic prodrug CS-834 in healthy adults. Ruth E. Stevens, Ph.D., Julraht Konsil, Ph.D., Sonya L. Silletti, B.S., Suman Wason, M.D., M.B.A., Lisette Gonzalez, B.S., Lee Schwocho, Ph.D.; Plloenix International Life Sciences Inc., Cincinnati, O H Sankyo U.S.A. Corporation, New York, NY.

PURPOSE: To determine the pharmacokinetics and safety of a novel orally active antibiotic prodrug CS-834 and its metabolites R-95867 (active) and R- 99861 (inactive). METHODS: Thirty-six healthy adults were divided into four dose groups. Within each dose group, six subjects received CS-834 at one of four doses; 50, 150, 300, and 600 mg; while the other three subjects received matching- placebo in a randomized, double blind fashion. Doses were administered in ascending order. The concentrations of R-95867 (plasma and urine) and R- 99861 (urine) were determined using HPLWUV and HPLWMS, respectively. Pharmacokinetics and dose-proportionality of R-95867 and R-99861 were studied using noncompartmental methods and power function analysis, respectively. Gender effects on pharmacokinetics of R-95867 were investigated using ANOVA. RESULTS: CS-834 was rapidly absorbed and excreted as reflected hy T,,, (1-1.5 hours) and half-life (45 minutes) of plasma R-95867. Roughly 26% and 12% of R-95867 and R-99861, respectively, were excreted in the urine within 4 hours post-dose. CS-834 oral bioavailability was estimated to be about 38%. Pharmacokinetics of R-95867 and R-99861 were proportional to dose. Plasma R-95867 maximum concentrations (% CV) were 0.49 (151, 1.4 (201, 2.9 (291, and 3.9 (21) pg/ml following 50, 150, 300, and 600 mg doses, respectively. There were no statistically significant differences in pharmacokinetic parameters between genders. There were no clinically significant drug-related emergent signs or symptoms. CONCLUSION: Single oral dose administration of 50 to 600 mg CS-834 under fasted conditions resulted in dose proportional pharmacokinetics of R- 95867 and R-99861. CS-834 was safe and well tolerated.

138. The pharmacokinetics of high concentration amphotericin B in patients following administration of 7.5 to 15 mgkglday of AmBisome". G a 9 W. Boswell, Ph.D., Donald N. Buell, M.D., lhor Bekersky, Ph.D., Sandra S. Kline, Pharm.D., J.D.; Fujisawa Healthcare Inc., Deerfield, IL.

PURPOSE: This study evaluated the pharmacokinetic profile of amphotericin Bin patients following the administration of 7.5 to 15 mg/kg/day AmBisome". METHODS: This open label, dose escalation, maximum tolerated dose study included at least six patients per dose group. Ten pharmacokinetic samples were collected over 24 hours after the start of a 2-hour AmBisome' infusion on day 1, day 7, and last day of therapy. Samples were analyzed using a HPLC method with a LOQ of 100 pg/ml. RESULTS: Following AmBisome" administration, plasma concentrations were exceptionally high, reaching values of >300 pg/ml with minimal apparent toxicities. On day 1 of AmBisome" administration C,,, was 75.9 *

58.4 (n=8), 118.2 + 65.4 (n=9), 126.5 t 55.3 (n=6), and 105.2 * 28.5 (n-11) pg/ml for the 7.5, 10 , 12.5, and 15 mg/kg doses, respectively. The corresponding 24-hour AUCs were 654 i 851, 1014 + 921, 854 + 397, and 549 + 167 mg.hrR. The unexpected decrease in C,,, and AUC w t h doses greater than 10 mg/kg was also seen on day 7. C,,, values were 115.1 + 105.0, 164.7 + 119.7, 147.4 + 69.2, and 178.6 i 49.0 pg/ml; AUC values were 1334 i 2154, 1718 + 1600, 1178 + 959, and 1152 t 618 mg-hrR. To further investigate the dose concentration relationship, a population pharmacokinetic analysis was conducted using NONMEM with a 2-compartment structural model. Significant covariates included in this model were: patient type, immediate prior exposure to amphotericin B products, infection classification, and patient outcome. CONCLUSION: The apparent nonlinear pharmacokinetics of high concentration amphotericin B can be described using a population model incorporating demographic covariates.

139E. Comparison of oral immediate release and extended release metronidazole bactericidal activity against Bacteroides spp. using an in vitro model of infection. Russell E. Lewis, Pharm.D., Michael E. Klepser, Pharm.D., Erika J. Ernst, Pharm.D., Patrick D. Yeramian, M.D., Ronald N. Jones, M.D.; University of Iowa, Iowa City, IA; G.D. Searle, Skokie, 1L.

Presented at the 38th Interscience Conference on Antimicrobial Agents and Chemotherapy, San Diego, CA, September 24-27, 1998.

140. Population pharmacokinetic analysis to develop a predictive pharmacokinetic-pharmacodynamic model for 9-aminocamptothecin using NONMEM and IT2S. Judith Ann Smith, Phurm.D., Stephen C. Piscitelli, Pharm.D., William Knebel, Pharm.D., Chris H. Takimoto, M.D., Ph.D.; National Institutes of Health, Bethesda, MD; National Cancer Institute-Navy.

PURPOSE: To characterize aminocamptothecin (9-AC) population pharmacokinetic parameters using NONMEM and IT25 to develop a predictive pharmacokinetic-pharacodynamic model. METHODS: Data was obtained from a phase I trial of 9-AC 72-hour continuous infusion with a dose escalation from 120 pglmYd to 1416 pg/mVd. Plasma samples were obtained from 41 patients, 15 data rich (16 pointdpatient) and 26 data sparse (3 pointdpatient). Model discrimination was accomplished by comparison of the sum of squares, AIC and observed, versus predicted concentrations. Multiple linear regression and graphical analysis techniques were used to evaluate the significance of each covariate. The observed area under the curve to infinity (AUClnf) was determined using non-compartmental pharmacokinetic methods. Pharmacodynamic (PD) relationships between change in white blood cell count (WBC) and change in platelet count with AUC1,f were evaluated graphically and verified with nonlinear regression. RESULTS: Two one-compartment models linked by conversion clearance best fit the 9-AC data. NONMEM estimated the following population parameters: clearance total drug (TD) = 1.97 Uh (CV 74.2%), volume TD compartment = 31.3 L (CV 52.6%), conversion clearance = 1.34 Uh (CV 62.2%), and clearance lactone 14.7 Uh. Volume of the lactone compartment was fixed at one to make the model identifiable. Both age and albumin were significant covariates on clearance TD for the NONMEM model. IT2S derived similar population estimates; however, no covariates were significant in lT2S model. An Em, model best described a significant PD relationship (p<0.05) between lactone AUCi,[ and the change in WBC, neutrophil, and platelets. No PD relationship existed with TD AUC1.r. CONCLUSION: NONMEM and lT2S had similar population parameter estimates. Lactone AUC1,f is a parameter that can be used to predict 9-AC PD effect on blood counts.

141. Vancomycin population pharmacokinetics in pediatric patients. Yousif A. Asiri, M.S., Paul Williams, Pharm.D., M.S., William Murray, Pharm.D., Steven Waite, Pharm.D., William Kehoe, Pharm.D., M.S., BCPS, Art Harralson, Pharm.D., BCPS; University of the Pacific, Stockton, CA San Diego Children Hospital, San Diego, CA; Valley Children Hospital, Fresno, CA.

PURPOSE: It was the purpose of this study to retrospectively derive a vancomycin population pharmacokinetic model that simultaneously considers the effect of several physiologic and demographic parameters on both clearance and apparent volume of distribution in an extensive pediatric patient population ranging in age from 2.1 to 17 years. METHOD: Data from 200 pediatric patients (120 male, 80 female) and 559 vancomycin concentrations were collected. Age, weight, height, serum creatinine, sex, vancomycin serum concentrations, and complete dosing history were collected for each patient. A stepwise approach via non-mixed linear effects modeling (NONMEM), consisting of three major phases, was pursued as follows: 1) building the basic pharmacokinetic model; 2) building the statistical model; and 3) refining the model. In the model development process, covariates (age, weight, height, serum creatinine, sex, and creatinine clearance) were tested for inclusion in relation to the pharmacokinetic parameters. The critical value for parameter inclusion was p<0.05. RESULTS: Patient's age, height, and serum creatinine were related to clearance. The clearance was stratified on the basis of age as follow: CL = 0.20 + 0.0027 x HT/SCR for 2-5 years old; CL = 0.31 + 0.0042 x HT/SCR for

*


age 5 1 3 years old; and CL = 0.40 + 0. 00546 x HT/SCR for 13-17 years old. Apparent peripheral volume (Vp) was found to be related to body surface area (BSA) as Vp = 19.5 x BSA. Inter-compartmental clearance (Q) was also reported (2.39 Uhr). The coefficient of variation (CV) for CL was 31%, the CV for Vp was 97%, and residual intra-individual variability was 44%. CONCLUSION: This model has a good correlation with the physiologic parameters of size and renal function. However, the CV for the Vp was larger than desired or expected. Further evaluation of parameter variability will be done via a bootstrap estimation procedure. The modeled estimates of clearance and volume are not similar to those estimated by previous authors. Clinicians may be able to use this pharmacokinetic model to determine improved initial dosing estimates when compared to historical methods. Further validation of this model is necessary.

142. The influences of renal function and maturation on vancomycin elimination in newborns and infants. Edrnund V. Capparelli, Pham.D., Gale L. Romanowski, Pharm.D., Edward J . McFeely, B.S., William Murray, Pharm.D., James R. Lane, Pharm.D., Paula Croutharmel, Pharm.D., Carl Kildoo, Pharm.D., James D. Connor, M.D.; UC San Diego Medical Center, La Jolla, CA; Children's Hospital San Diego; Lucile Salter Packard Children's Hospital at Stanford Long Beach Memorial Hospital.

PURPOSE: To describe the maturation of vancomycin (V) clearance and the influence of altered renal function in infants on V using population pharmacokinetic methods. METHODS Data from 374 newborns and infants < 2 years of age (median age 27 days) were evaluated with NONMEM (FOCE). A total of 1124 V levels were used in this analysis including 311 with elevated semm creatinine (CR > 0.8 mg/dl). One hundred four subjects were more than 2 months of age and 64% of newborns were premature (31% < 28 weeks gestational age [GA]). Pharmacokinetic model selection was done graphically and by changes in the objective function (MOF). RESULTS: The data were best described by a 2-compartment model (MOP change = -647, p<O.OOOOl). Weight (WT in kg) and CR greatly influenced V elimination while post-natal age (AGE) and prematurity (< 28 weeks) were significantly but less important predictors of V elimination. The final model had a residual error of 14% + 3.4 pg/ml with the following model parameters and intenubject variabilities: V, (L) = 0.793.W + 0.010 (CV = 16%); CI (Uhr) =

0.666.V,,, Q ( f i r ) = 0.0334; where AGE is postnatal age (days) if CR S 0.7; and GA28 = 1 if GA > 28 weeks and 0 if GA S 28 weeks. For the typical study infant (AGE = 27 days, CR = 0.6, WT = 1.8 kg, GA = 33.5 weeks) this results in V, = 1.44 Land CI = 0.119 f i r . CONCLUSION: Vancomycin clearance is initially reduced in premature infants and increases with post-natal age. Most of the age related changes can be explained by the concomitant fall in serum creatinine.

143. The pharmacokinetic relationship between lung epithelial lining fluid and serum al-antitrypsin concentrations following IV administration of increasing doses of al-antitrypsin. William Knebel, Pharm.D., Farshid Rouhani, M.S., James Stocks, M.D., Debra Waldrop, B.S.N., Nevilla K. Smith, B.S.N., Mark Brandy, M.D.; National Institutes of Health, Bethesda, MD; University of Texas Health Center, Tyler, TX.

PURPOSE: This study was designed to better understand the relationship between lung and blood al-antitrypsin (alAT) concentrations following escalating intravenous alAT doses in alAT-deficient individuals. METHODS Nine patients with alAT deficiency received a single dose of 30 mg/kg, 60 mg/kg, or 120 mg/kg of alAT as a 45-minute infusion. Serum samples were collected at time 0 (pre-dose), immediately upon completion of the infusion, and post-infusion at 30 minutes, 1, 3, 6, 12, and 24 hours, and daily on study days 4,7,10,14,17, and 21. Lung epithelial lining fluid (ELF) was collected via bronchoalveolar lavage with 200 ml of saline 2-40 days pre- infusion and on day 7 post-infusion. ELF and serum samples were analyzed for alAT concentrations by both functional (antineutrophil elastase capacity) and antigenic assays. The relationship between ELF and serum alAT concentrations was determined using nonlinear regression and graphical techniques. RESULTS: There was a significant correlation between the functional and antigenic alAT concentrations in both the ELF and serum. A Hill-type equation provided the best f i t of the serum vs ELF alAT antigenic concentrations, with an rz value of 0.7. The predicted maximum concentration of alAT in ELF was 2.5 mM. Based on this analysis, a serum a1AT concentration of 11.5 mM would result in an ELF alAT concentration of 1.25 mM. CONCLUSION: The results indicate that serum alAT concentrations above 20 mM are not associated with further linear increases in ELF alAT concentrations. This finding is consistent with the existence of a physiologic threshold lower respiratory tract alAT concentration.

WT*(O.O28/CR + 0.000127.AGE + 0.0123.GA28) + 0.006 (CV = 32%); V, (L) =

Pharmacy Practice 144. Use of complementary therapies in primary care. Angela M. Wisniewski,

Pharm.D., Nancy M. Waite, Pharm.D., Josephine M. Whitford, Pharm.D., Barbara Hauser, J.D., M.D., Hedy L. Migden, Ph.D., M.D.; St. Peter's Hospital; Albany Medical Center, Albany, NY.

PURPOSE: The general U.S. population and patients with chronidincurable diseases frequently use complementary therapies. However, use of these therapies in subsets of the general population remains poorly defined. The aim of this study was to examine use of complementary therapies in two demographically and geographically dissimilar primary care settings. METHODS: An anonymous, 19-question, written survey was administered to 190 adult patients attending either an urban or a rural clinic in upstate New York between July and October 1997. Information collected included demographics, health perception, presence of acutekhronic illness, use of common alternative therapies, reasons for use, and treatments employed for common ailments. RESULTS: The response rate was 73%, with 123 surveys available for analysis. The rural clinic was more likely to have patients who were college- educated (p=0.0002), Caucasian (p<O.001), 18-24 or > 64 years of age (p=0.02), with annual incomes > $35,000 (p=0.0002), and self-rated as having better health (p<O.OOOl) and improved health status (p=0.03). Overall use of complementary therapies was 34% (rural 42%, urban 16% [p=0.0041). Only patients with more education were more likely to use complementary therapies (p=0.0008). The reasons most commonly given for utilizing these therapies was that conventional medicine was generally ineffective, encouragement by a friendhelative, and alternative therapies were more "natural". CONCLUSION: There is significant use of complementary therapid in primary care, particularly in rural locations and in patients with a higher level of education. With one-third of all patients using complementary therapy, this study reinforces the importance of health care practitioners inquiring about the use of complementary therapies.

145. Pharmacy practice acts: a decade of change. Melissa Young, Pharm.D., William J. Stilling, M.S., J.D., Mark Munger, Pham.D.; University of Utah, Salt Lake City, UT.

PURPOSE When legal definitions of practice are limited to traditional roles, rather than current practice standards, the risk of legal problems increases. This survey assessed pharmacy practice statutory definitions in order to determine the direction and magnitude of change in pharmacy practice statutes from 198g-1997. METHODS: The fifty state and District of Columbia statutes were surveyed through the 1996 legislative session. Each state pharmacy statute was examined for the practice definition and specific pharmacist responsibilities. Results were tabulated and compared to previous surveys. RESULTS: Ninety-two percent of pharmacy practice acts contained a definition of pharmacy practice. Prescription evaluation increased 15% and 22% from 1993 and 1988, respectively. Compounding and dispensing were relatively unchanged. Drug product selection increased 2-fold to 96% in 1998. Pharmaceutical care functions including consultation (increased 19%), drug administration (increased 3-fold), patient assessment (increased 6-fold), and pharmacokinetics services (total three states; increased two states) through the 10 years. Ten states now authorize pharmacists to participate in drug- or drug-related research, a 5-fold increase since 1988. Fifteen state statutes (32%) include pharmacist prescribing compared to 7% in 1988. Ninety-three percent of prescribing statutes include only dependent prescribing through protocol or collaborative care agreement. CONCLUSION: Over the 10-year period, the trend in pharmacy practice statutes is to legislate individual pharmaceutical care services as integral pharmacy functions. Although this trend is positive, a broadly worded pharmacy practice statute written to encompass the diverse practice in pharmacy may better serve the profession by decreasing legal problems and providing greater professional opportunities.

146. Departments of pharmacy practice scholarly activity from 1990-1995. Mark A. Munger, Pharm.D., Marianne Weber, Pharm.D., Julie K. Kenney, Pharm.D.; University of Utah, Salt Lake City, UT.

PURPOSE: Criteria for a legitimate academic discipline includes having a unique, focused body of knowledge generated by members of the discipline. Currently, there is no data evaluating the contribution of scholarly activity across American Association of Colleges of Pharmacy (AACP) departments of pharmacy practice. To evaluate scholarship within the 73 AACP departments of pharmacy practice, the number and scope of publications were identified from 1990-1995. METHODS: AACP roster faculty with the title of professor, associate, or assistant (degree blind) during 1990-1995 were searched in Medline and International Pharmaceutical Abstracts databases. Publications were categorized by type, publication year, academic rank, and author gender. Duplicate publications from the same institution were eliminated. Institutions were ranked by total and science (research) publications. The number of productive (2 1 publicatiod5 years) and non-productive (0 publicationd5 years) faculty years were tabulated. RESULTS: A total of 5950 publications (m f SEM: 81.5 f 7.5, range: 6 3 2 3


puhlications/institution) were identified in 5248 faculty years. The most (15%) productive insti tutions produced approximately 50% of total publications. These publications were equally distributed across the 5-year period. Forty-three percent were reviews, 42% science, 10% editorialdetters, and 5% case reports. Assistant professors published 37%. associate 35%. and professors 29%. respectively. Males accounted for 73% of the publications. The majority of science publications were categorized as pharmacology, pharmacokinetics, or pharmacoepidemiology. Twenty-four percent of faculty years were classified as non-productive. CONCLUSION: The majority of AACP departments of pharmacy practice are productive in scholarship. Discussion of methods to stimulate scholarship in non-productive faculty should he entertained within the profession.

147. Physicians' adherence to prescribing guidelines for stress ulcer prophylaxis. Brian L. Erstad, Pham.D., Karen L. Cochran, Pharm.D., Emily R. Cox, Ph.D.; University of Arizona, Tucson, AZ.

PURPOSE: To determine if compliance with stress ulcer prophylaxis (SUP) guidelines by trauma physicians is sustained over time in a teaching institution without ongoing, formal educational interventions when attending physicians are involved in the guideline development and educational processes. METHODS: After developing formal guidelines for SUP with input from attending physicians on the trauma service at the university teaching hospital, a formal educational intervention was conducted to ensure physician (attending and resident) compliance with the guidelines. A concurrent two- month evaluation of SUP prescribing was conducted after the educational period (phase 1) that demonstrated significant decreases (p<0.05) in the length of inappropriate prophylaxis when compared to pre-education evaluations conducted before the institution of the guidelines. Phase 1 was used as the historical control for comparison with a one-month evaluation of SUP prescribing (phase 2) conducted approximately 18 months after the formal educational period (partial turnover of housestaff had occurred) to determine if improvements in prescribing were sustained over time. Inappropriate prophylaxis during the two phases was compared by a 2-tailed Student t-test for independent samples with significance defined as p<0.05. RESULTS: There were 134 patients in phase 1 and 46 patients in phase 2. Nine patients (6.7%) in phase 1 and four patients (8.7%) in phase 2 received inappropriate SUP. The mean length of inappropriate SUP was 3.78 2 1.79 days versus 3.75 2 1.11 days in the early and late educational periods, respectively (not significant). None of the patients in either period had clinically important bleeding. CONCLUSIONS: Physician adherence to prescribing guidelines can he sustained without ongoing, formal educational interventions when physicians, particularly attending physicians, are involved in the guideline development and educational processes.

Psychiatry 148. Effects of fluvoxamine on clozapine metabolism: in vitro and in vivo findings. Yusuf R . Kaemi, Pharm.D., W.H. Chang, B. Augustin, T. ZumBrunnen, H.Y. Lane, H.C. Liu, C.H. Chen, C.C. Chiu, M.W. Jann; Mercer University, Atlanta, GA; Taipei City Psychiatric Center; Hung-Chi Psychiatric Hospital, Taipei, Taiwan.

PURPOSE: Clozapine (CLZ) is an atypical antipsychotic agent utilized in the treatment of refractory schizophrenic patients. In vitro and in vivo studies show CLZ to he extensively hiotransformed through the liver. Various cytochrome CYP450 isoenzymes, including CYPlA2, 3A4, 2C9, and 2C19, are implicated in the metabolism of CLZ to its two major metabolites, CLZ N- oxide (CNO) and N-desmethyl CLZ (DMC). Fluvoxamine (FLV), a selective serotonin reuptake inhibitor, is a potent 1A2 and 2C19 inhihitor. Several case reports have observed increases in plasma CLZ levels following the addition of FLV. Although FLV inhibits CLZ metabolism, changes in CLZ, CNO, and DMC levels are highly variable among the various in vitro, in vivo, and case studies reported. This study will compare the interaction between FLV and CLZ with in vitro and in vivo methods to help clarify this drug interaction. METHODS: Pooled human hepatic microsomes (PHM) were used for in vitro studies. CLZ 25uM and FLV 50uM were preincuhated with PHM separately and together at 37OC for 3 minutes in quadruplet, with and without the regeneration system of NADP+, G-6P, and G-6P dehydrogenase. Reactions were started with the addition of CLZ 25 uM and incubated at 37OC for 2 hours. Reactions were terminated with the addition of acetonitrile. For the in vivo studies, nine male schizophrenic patients were given CLZ 50 mg two times, with a 2-week FLV treatment of 50 mg BID in between each CLZ dose. Blood samples were obtained over 48 hours following the administration of CLZ 50 mg. CLZ, CNO, and DMC were measured via HPLC with UV detection in both in vitro and in vivo studies. RESULTS: Compared to controls, in vitro studies noted a 20% increase (p<0.0001) in the amount of CLZ, while DMC and CNO formation was decreased by 54.6% (p<O.OOOl) and 5.27% (p<0.059), respectively. In vivo studies show mean CLZ AUC to increase from 780.8 to 2218.0 ng.ml/hr (p<O.OOI), while mean CLZ clearance decreased 0.06 to 0.01 vhr/kg. Mean

changes in AUC for DMC and CNO were 378.1 vs 344.5 ng*ml/hr (9%. p=0.69) and 159.9 vs 129.7 ng.ml/hr (1896, p=0.07), respectively. CONCLUSION: FLV was shown to increase the amount of CLZ in both in vitro and in vivo conditions. Changes in CNO amounts were not significant in in vitro findings, and resembled in vivo results. Although not observed in in vivo results, DMC amounts were significantly lower upon addition of FLV in in vitro results. These findings indicate a complex interaction between CLZ and FLV, with involvement of multiple P450 isozymes. These in vitro results appear to estimate in vivo findings for CLZ and CNO, but not necessarily with DMC.

149. Efficiency of antipsychotic therapy in a naturalistic setting: a comparison between risperidone, perphenazine, and haloperidol. Kim C. Coley, Pham.D., Cameron S. Carter, M.D., Stacey V. DaPos, M.S., RaeAnn Maxwell, Ph.D., John W. Wilson, Ph.D., Robert A. Branch, M.D.; University of Pittsburgh, Pittsburgh, PA.

PURPOSE: This study compared the therapeutic efficiency, toxicity, and cost associated with risperidone, perphenazine, and haloperidol when used in a naturalistic setting. METHODS: Inpatients receiving either risperidone, perphenazine, or haloperidol as a single antipsychotic at hospital discharge were identified. Primary outcome measures were readmission rates and inpatient costs during a 1-year follow up, anticholinergic drug use, and adverse reactions associated with EPS. RESULTS: Of 226 patients meeting study criteria, 202 patients were evaluable (81 risperidone, 78 perphenazine, 43 haloperidol). Baseline characteristics were similar between groups, except the risperidone group had more readmissions in the year prior to study suggesting that they were a more difficult to treat population. Median doses per day were 10 mg for perphenazine and 4 mg for risperidone and haloperidol. One-year readmission rates were 41% for risperidone, 26% for perphenazine, and 35% for haloperidol (p=0.03). The mean readmission hospital days were highest for risperidone at 22 days compared to 12 days for perphenazine and 14 days for haloperidol. Anticholinergic prescribing was lower in the risperidone and perphenazine groups compared to haloperidol. EPS reports were similar among groups; however, underreporting and reporting bias against new agents may have confounded this outcome. Mean inpatient costs during the 1-year follow-up period were highest for risperidone ($18,000) compared to perphenazine ($10,000) and haloperidol ($11,500). CONCLUSION: A reduction in anticholinergic prescribing supports risperidone's improved side effect profile. However, its use in more difficult to treat patients resulted in higher readmission rates and inpatient costs.

150. Continuous duration of antipsychotic therapy: are there differences between subclasses? David 5. Hutchins, M.B.A., M.H.S.A., Bryan M. Johnstone, Ph.D., Sandra L. Tunis, Ph.D., Toni R. Coleman, B.S., Felicia Gevirtz, M.S.P.H., Zhiming Li, Ph.D., M.D.; PCS Health Systems Inc., Scottsdale, AZ; Eli Lilly and Company, Indianapolis, IN.

PURPOSE: To compare the duration of continuous therapy between novel and conventional antipsychotic medications, as increased duration of therapy has been associated with beneficial results. METHODS: The first antipsychotic prescription (first prescription) dispensed between October 1 and December 31, 1996 to 105,960 patients was used to extract 2 years of data, one preceding and one following the first prescription, from a large U.S. database. Patients experiencing a new episode (i.e., no antipsychotic medication during the preceding year) were grouped into novel (clozapine, olanzapine, risperidone) and conventional cohorts from the first prescription. Continuous total days, a sum of the days supplied for each prescription, and continuous unique days, a sum of all days with exposure, were calculated for the following year. Data were summed only from prescriptions with the same medication as in the first prescription until the period ended or 46 or more days lapsed between exposures. Kaplan-Meier survival analysis was used to compare the results between cohorts. RESULTS: Two-thirds of the patients experiencing their first episode were dispensed a conventional medication (3426 vs 1656). Continuous total days of therapy (mean f SD) were significantly longer for the novel cohort (109 * 114 vs 69 * 92; pSO.001). Continuous unique days of therapy were also significantly (pS0.001) longer for the novel cohort (102 * 104 vs 64 * 83). CONCLUSION: Patients dispensed novel antipsychotics received significantly longer medication therapy than those dispensed conventional antipsychotics, suggesting potential treatment benefits from prescribing novel antipsychotic medications.

151. Valproate plasma concentrations to dose correlations in bipolar affective disorder patients. Paul J. Perry, Ph.D., Steve Amdt, Ph.D., Kristine A. Bever, Pharm.D., Shana Gunderson, Pharm.D.; University of Iowa, Iowa City, 1A.

PURPOSE: Previous work has been unable to determine if demographic factors such as gender, smoking behavior, dose, and age affect the amount of drug a patient requires to achieve a desired serum concentration of valproate. Serum valproate concentrations between 45-125 pg/ml are reported to be more likely to he effective and well-tolerated in acutely manic patients.


Without the aid of valproate serum concentration monitoring, 3 to 6 months are recommended for a therapeutic valproate tnal. METHODS: Data on 55 patients diagnosed with bipolar affective disorder were collected via retrospective chart review and/or patient interview. None of the patients were receiving any other anticonvulsant drugs. Valproate steady-state serum concentrations were drawn 9 to 16 hours after the last dose. The demographic variables collected included age, gender, smoking behavior, weight, and race. Concurrent medications were noted so as to exclude any potential patients whose valproate serum concentration may have been affected by a drug interaction. Multiple-linear regression was utilized to examine the relationship between the serum valproate concentration and the independent variables. RESULTS: Two dosing model optimally predicted steady-state valproate serum concentrations. The first equation included two variables that significantly correlated with the valproate serum concentration. These included dose (mg/day) and smoking (yes = 0 and no = 1) where valproate (pg/ml) = 0.010 (dose) - 11.1 (smoke) + 66.0. The model explained 25% of the variance in the valproate concentrations (F = 8.439, p<0.0007, rz =0.25). The second equation also included two variables that significantly correlated with the valproate serum concentration. These included the variables dose (mg/kg/day) and again smoking (yes = 0 and no = 1) where valproate (pg/ml) = 0.71 (dose) - 10.2 (smoke) + 66.6. The model explained 24% of the variance in the valproate concentrations (F = 8.019, p<0.0009, rz =0.24). Thirty of the 55 valproate concentrations exceeded 70 pg/ml. There was no indication that for these concentrations the serum concentration to dose relationship was curvilinear. CONCLUSION: Although a multiple linear regression model can be constructed that correlates valproate serum concentration with valproate dose and smoking status, its clinical usefulness is questionable as it only explains 25% of the variability in the valproate serum concentrations.

152. Evaluation of the dose equivalency of risperidone to haloperidol in the management of agitation in the elderly in a community nursing home. Shyam D. Karki, Pharm.D., M.A., Terrance J. Bellnier, B.S., M.P.A., Gule-Rana Masood, M.D., William R. Patterson, B.S.; Monroe Community Hospital, Rochester Psychiatric Hospital; Clifton Springs Hospital & Clinic, Rochester, NY.

PURPOSE: This study looks into finding the dose equivalency ofrisperidone, an atypical antipsychotic, to haloperidol, a high potency typical antipsychotic, in the management of agitation in elderly patients in a community nursing home. METHODS: Charts of 20 elderly residents treated with haloperidol for the management of agitation and later switched to risperidone for optimization of pharmacotherapy were reviewed as to dosage, agitation management, and use of as needed (PRN) sedatives for a period of 30 days, before the switch and 90 days after the dosage of the risperidone was stabilized. Clinical Global Impression (CGI) and Abnormal Involuntary Movement Scale (AIMS) were used for assessing clinical efficacy and side effect. RESULTS Mean age of the residents (12 females and 8 males) switched from haloperidol to risperidone was 83 * 9 years and the mean daily haloperidol dose was 0.85 * 0.30 mg. Number of times PRN medication was used in the 30-day period before the switch was 9 * 3. Mean score on the AIMS was 4 * 2. After the switch, the mean daily dose of risperidone was 0.91 * 0.35 mg. The use of PRN medication in the 30-day period, 90 days after the stabilization of risperidone dose, was 7 + 3. There was no significant difference in CGI of the nurse and the attending physician for both 30-day periods. Mean score on AIMS was 3 * 2. Regression analysis indicated the conversion factor from haloperidol to risperidone as 1.0 and the correlation coefficient 0.87. CONCLUSION: Based on our study, there was a strong correlation between the dose of haloperidol and risperidone and the conversion factor from haloperidol to risperidone was one to one. A testing of the conversion factor is underway.

153. Changes in distribution of dispensed antipsychotic agents and doses 6 months after introduction of a new antipsychotic medication. David S. Hutchins, M.B.A., Bryan M. Johnstone, Ph.D., Sandra L. Tunis, Ph.D., William F. Signa, B.S., Lisa L. Dwyer, M.S.P.H., Zhiming Li, Ph.D., M.D.; PCS Health Systems Inc., Scottsdale, AZ; Eli Lilly and Company, Indianapolis, IN.

PURPOSE: To observe changes in the distribution of dispensed antipsychotic agents and daily doses occurring during the first year after the introduction of a novel antipsychotic medication. METHODS: Two cohorts, one from October 1996 and another from April 1997, were identified from among individuals dispensed antipsychotic medications in a large US. prescription database. The percentage dispensed chlorpromazine, clozapine, haloperidol, olanzapine, or risperidone was calculated as was the percentage of new episodes (no antipsychotic medications in previous 6 months). For patients experiencing a new episode, the initial, final, and mean daily doses over a 6-month period were determined. RESULTS: The distribution of patients for the five medications was significantly (p<O.OOl) larger in the April cohort (41.9% vs 37.0%), but the percentage of patients with a new episode (17.8% April vs 17.3% October)

was not significantly different. Initial daily doses for the April cohort were significantly (p=0.0082) higher for haloperidol and significantly (pSO.0001) lower for olanzapine. Mean daily doses were significantly (pS0 0001) higher for haloperidol and risperidone and significantly (p=0.0002) lower for olanzapine Final daily doses for the April cohort were significantly (pSO.0001) higher for haloperidol and risperidone. CONCLUSION: The significantly lower initial and mean overall daily doses for the olanzapine April cohort, considered in light of significantly higher or unchanged daily doses for the other medications, may reflect underlying changes in diagnostic composition, severity, or comorbidities of the olanzapine group 6 months after introduction.

154. Clinical characteristics and health care utilization in patients with panic disorder. Sara R. Grimsley, PharmD., Chad VanDenBerg, Pharm.D., Vicki Spratlin, M.D., Michael W. Jann, Pham.D ; Mercer University; Brawner Hospital System, Atlanta, GA.

PURPOSE: To document the clinical characteristics and patterns of health care utilization in patients with panic disorder. METHODS: Twenty-six patients with panic disorder were recruited through local panic disorder support group networks. Participants were interviewed regarding characteristics of their illness and the health care services they had utilized due to panic disorder. A 47-item questionnaire was completed during each 2-3 hour interview period. RESULTS: The mean age at onset of panic disorder was 25 years (range 5-51), and a mean time period of 10 years had elapsed between symptom onset and diagnosis of panic disorder. Participants reported visiting 5.4 + 1 9 different physicians and making 10.9 * 4.1 physician office visits during the previous 2-year time period. Types of physicians seen included cardiologists (n=10), neurologists (n= l l ) , ,endocrinologists (n=5), gastroenterologists (n=7), and psychiatrists (n=23). The mean number of emergency room visits and hospitalizations due to panic disorder were 4.5 * 2.2 and 1.4 * 0.6, respectively. Caffeine and various OTC medications were common precipitants of panic attacks; 73% of patients ;voided caffeine use for this reason. Agoraphobia was reported by 88% of subjects; 23% had been completely housebound at some time. Interviews were conducted in the patients’ homes in 42% of cases because individuals were unable to drive due to their panic disorder. Severe impairment in areas of work, family relationships, and social functioning due to panic disorder was reported by 64%, 40%, and 32% of subjects. respectively. CONCLUSION: Panic disorder is associated with high utilization of health care services and significant functional impairment.

155. Pharmacotherapeutic interventions in patients with panic disorder. Chad M. VanDenBerg, Pharm.D., Sara R. Grimsley, Pharm.D., Vicky Spratlin, M.D., Michael W. Jann, Pharm.D.; Mercer University; Brawner Hospital System, Atlanta, GA.

PURPOSE: The purpose of this study is to document and evaluate the pharmacotherapeutic and non-pharmacotherapeutic interventions in patients with diagnosed panic disorder. METHODS: Twenty-six patients with panic disorder were recruited through local panic disorder support group networks. Participants were interviewed regarding characteristics of their illness and the medications used to treat their disorder. A 47-item questionnaire was administered by the clinical pharmacist during each 2-3 hour interview period. Each treatment with a medication for each patient was considered a separate trial. RESULTS: Panic disorder patients (n=26) report a mean of 1.43 + 1.06 panic attacks per week. Further, panic patients report a mean of 4.5 + 3.05 of the 13 defining DSM-IV symptoms to “always” occur during a panic attack. An additional 3.23 2 1.88 symptoms are “usually” experienced during a panic attack. A wide variety of psychotherapeutic agents are used to treat these patients throughout their illness. The mean number of different medications used to treat panic disorder after the initial diagnosis was 4.57 i 3.40 per patient. There were 36 different trials of tricyclic antidepressants (TCAs) reported; 47% (n=17) of these trials were considered to be effective, but 64% (n=23) produced significant adverse events. Of 29 benzodiazepine trials, 72% (n=21) were effective and 38% (n=ll) produced adverse events. There were 15 trials of selective serotonin reuptake inhibitors (SSRls); 67% (n=10) were considered to be effective and 73% ( n = l l ) produced adverse events. lmipramine (n=17), alprazolam (n=14), and fluoxetine (n=13) were the most commonly prescribed agents in each drug category. CONCLUSION: Panic disorder patients reported henzodiazepines to he a highly effective and well tolerated. SSRIs were reported to be highly effective but caused a high incidence of adverse effects. TCAs were reported to have limited efficacy and caused a high degree of adverse events.

156E. Gender-specific prolactin response to treatment with olanzapine versus haloperidol in schizophrenia. Bruce J. Kinon, M.D., Bruce R. Basson, M.S., Gary D. Tollefson, M.D., Ph.D.; Lilly Research Laboratories, Indianapolis, IN.

Presented at the 151st Annual Meeting of the American Psychiatric Association, Toronto, Ontario, Canada, June 4, 1998.

1 ’


157E. Gender-specific prolactin response to treatment with olanzapine versus risperidone in schizophrenia. Bruce J. Kinon, M.D., Bruce R. Basson, M.S., Gary D. Tollefson, M.D., Ph.D.; Lilly Research Laboratories, Indianapolis, IN.

Presented at the 151st Annual Meeting of the American Psychiatric Association, Toronto, Ontario, Canada, June 3, 1998.

158E. Risperidone use in the Maryland Mental Health System: dosing trends and rehospitalization rates. Deanna L. Kelly, Pharm.D., Robert R. Conley, M.D., Raymond C. Love, Pharm.D.; University of Maryland, Baltimore, MD.

Presented at the 53rd Annual Scientific Convention of the Society of Biological Psychiatry, Toronto, Ontario, Canada, May 27-31, 1998.

159E. Higher cost of olanzapine compared to risperidone in acute psychotic relapse. Henry Nasrallah, M.D., VA Medical Center, Jackson, MS.

Presented at the 151st Annual Meeting of the American Psychiatric Association, Toronto, Ontario, Canada, May 30-June 4, 1998.

160E. Follow-up study of risperidone in the treatment of patients with dementia: results on tardive dyskinesia and dyskinesia severity. Martin Brecher, M.D., D.M.Sc.; Janssen Pharmaceutica, Titusville, NJ.


161E. Risperidone in the treatment of behavioral disturbances in dementia. Andrew Chanlam, Pharm.D., Peter P. DeDeyn, M.D., Philippe Lemmens, Ph.D., Goedele DeSmedt; Janssen Research Foundation, Titusville, NJ; Middelheim Ziekenhuis, Belgium; Janssen Research Foundation, Belgium.


162E. Clinical and quality of life superiority of risperidone over conventional antipsychotics under usual care conditions: a prospective randomized trial in schizophrenia and schizoaffective disorder. Ramy A. Mahmoud, M.D., Luella M. Engelhart, M.S., the Risperidone Outcomes Study of Effectiveness (ROSE) Group; Janssen Research Foundation, Titusville, NJ.


163. Long-term efficacy, safety, and tolerability of risperidone in elderly psychotic patients. Rick A. Martinez, M.D., Michael Davidson, M.D., the Risperidone Working Group; Janssen Research Foundation, Titusville, NJ; Sheba Medical Center, Israel.

PURPOSE: The purpose of this study was to assess the long-term efficacy, safety, and tolerability of risperidone in elderly psychotic patients. METHODS: A 12-month, open-label, multicenter trial assessed the effects of risperidone in 180 elderly psychotic patients (median age, 72 years; range, 54 to 89 years). Diagnoses included schizophrenia (n=170, 94.4%) and schizophreniform disorder (n=10; 5.6%). Ninety-seven patients (54%) were treated for 12 months. The most common reasons for cessation of treatment were adverse events (n=30, 16.7%) and lack of efficacy (n=26, 15%). In this flexible dose trial, the mean dose of risperidone (oral solution) at endpoint was 3.7 mglday. RESULTS: Risperidone treatment resulted in statistically significant improvements from baseline in psychopathology; the mean PANSS total score decreased -17.2 from baseline to endpoint (p<O.OOl) and -27.7 from baseline to month 12. Mean PANS subscale scores (positive, negative, and general psychopathology) and BPRS total scores also decreased significantly from baseline to endpoint (p<O.OOl). The CGI severity of illness score improved significantly from baseline to endpoint (p<O.OOl). The severity of pre-existing extrapyramidal symptoms decreased significantly; the mean ESRS total score (parkinsonism plus dystonia plus dyskinesia) decreased -2.0 from baseline to endpoint (p<O.OOl). Forty patients (22.2%) reported EPS-like adverse events; 46 (25.6%) patients used antiparkinsonian medications during the trial compared to 74 (41.1%) patients prior to this risperidone trial. In this chronically ill, elderly population, adverse events were reported by 155 (86.1%) patients. The most common adverse events were insomnia (17.8%), agitation (15.6%), urinary tract infection (11.7’61, constipation (10.6%), and dizziness (10.0%). No clinically relevant abnormalities were observed in laboratory tests, vital signs, or ECG results. During this 1-year trial there were no reports of tardive dyskinesia. CONCLUSION: Long-term treatment with low-dose risperidone significantly reduced psychotic symptoms in these elderly psychotic patients. Furthermore, pre-existing EPS decreased and there were no cases of tardive dyskinesia in patients treated for a year.

164. A survey of factors that affect prescribing of the newer antidepressants. Virginia G. Daubney, Pharm.D., Gary M. Levin, Pharm.D., BCPP; Albany College of Pharmacy, Albany, NY.

PURPOSE: The objective of this study was to survey various prescriber types and specialties to determine if differences exist in prescribing patterns for the newer antidepressants.

METHODS: A three-page survey of 31. close-ended questions regarding prescribing of the newer antidepressant (all agents since and including fluoxetine) was mailed to 1500 New York state licensed prescribers randomly selected from membership rosters. Nurse practitioners, physician assistants, primary care physicians, and psychiatrists were included. Analyzable data included surveys returned in July and August, 1997. The main outcome measure was prescriber responses regarding factors involved with choosing among the newer antidepressants. RESULTS: There were 508 surveys returned (36%), of which 398 were acceptable for analysis (29%). In choosing among the newer antidepressants, most prescribers ranked patient diagnosis and past success as high priority, and free drug samples and drug-representative detailing as low priority. The majority of each prescriber type preferred fluoxetine for major depression and depression associated with fatigue; paroxetine for concomitant anxiety and depression and panic disorder; and sertraline for geriatric patients, and patients with suicidal ideation. Significant differences existed between the prescnher groups when asked if newer antidepressant prescribing habits are based on familiarity with a particular agent (p=0.0009) and on labeled indications (p=0.002). CONCLUSIONS: This study is the first to show prescribing preferences for the newer antidepressants among different prescriber groups. Additional study is needed to determine predictors of patient response to newer antidepressants and clinical guidelines for their use.

165E. Endogenous dehydroepiandrosterone, DHEA-S, and saccadic eye movement function in older adults. Patricia D. Kroboth, Ph.D., Tanya J. Fabian, PhanmD., M. Maggie Folan, B.S.N., Roslyn A. Stone, Ph.D., Reginald F. Frye, Pharm.D., Ph.D., Frank J. Kroboth, M.D., John A. Sweeney, Ph.D.; University of Pittsburgh, Pittsburgh, PA.

Presented at the Annual Meeting of the Society for Neuroscience, Los Angeles, CA, November 7-12,1998,

Pulmonary 166. Asthma and work outcomes. Steven R. Erickson, Pharm.D., Duane M. Kirking, Ph.D., Pharm.D.; University of Michigan, Ann Arbor, MI.

PURPOSE: Examine relationships between work outcomes and patient, disease, and treatment characteristics for asthma. METHODS: This cross-sectional study surveyed all adults with asthma (1139 surveyed, 609 respondents) enrolled in a managed care organization (MCO). The behavioral model for health services use was used as a framework to examine relationships between patient, disease, and treatment variables, and work outcomes (WO). A mailed questionnaire and MCO claims provided the data. Self-reported WO included missed work days (five categorical responses) and work performance (WP) from the functional status questionnaire, a 6-item scale using 5-point Likert responses transformed to a score range of 0 (poorest) to 100 (optimal). A 4-week time reference was used for self-reported WO. Three hundred sixty-nine respondents reported working outside the home, making up the sample. Analysis included ANOVA and chi squared to differentiate level of WO based on disease severity. General linear (for WP) and logistic (for missed days, dichotomized to 0 or 2 1) regression analysis explored relationships between disease and treatment characteristics with WO, controlling for patient-related variables. RESULTS: Respondents’ mean age was 39.2 * 11.4 years; 69.7% were female; 45% had an annual family income of greater than $40,000; 90.5% were Caucasian; and 86.1% had some college education or more. Forty-three percent of respondents perceived their asthma as mild in severity, 43% moderate, and 14% severe, with a similar pattern for evaluated severity. Most (84.7%) did not miss any work. The mean WP score was 87.9 * 16.8 (range 22-100). Cronbachs alpha for this scale was 0.79. WP scores declined (mean 97.6 to 76.2, p<O.OOl) and the percentage missing more than one day of work increased (7.6% to 39.2%, p<O.OOl) as perceived severity worsened, similarly for evaluated severity. The final regression model for WP produced a multiple R of 0.57 and adjusted R’ of 0.32. Variables included: the number of other illnesses, health beliefs, race, income, perceived severity, and prescribing appropriateness. The final regression model for missed days of work included number of other illnesses, race, health beliefs, prescribing appropriateness, and compliance. CONCLUSIONS: Controlling for patient-related characteristics using regression techniques, it appears that prescribing appropriateness is influential for both missing work and self-reported work performance. Certainly, one must consider the influence that other illnesses, race, income, health beliefs, compliance, and disease severity have on work outcomes.

167. Improved patient quality of life with appropriate drug therapy in children with persistent asthma. Paul J. Munzenberger, Pharm.D., Ricardo 2. Vinuya, M.D., Michelle C. Benn, Pharm.D.; Wayne State University; Children’s Hospital of Michigan; Detroit Medical Center, Detroit, MI.

PURPOSE This study documented the quality of life (QOL) of children with persistent asthma before and after the initiation of appropriate drug therapy to determine if compliance with the National Heart, Lung, and Blood

.


Institute's (NHLBI) drug therapy recommendations resulted in an improved patient QOL. METHODS: Patients included were between 7 and 17 years of age with persistent asthma treated inappropriately at the time of enrollment as defined by the NHLBI guidelines. Patient QOL was determined with the Pediatric Asthma Quality of Life Questionnaire (PAQOLQ) at enrollment and 1.5 to 3 months following initiation of appropriate therapy with the NHLBI guidelines. Statistical and clinically significant changes in overall QOL, activity, symptom, and emotional domains were determined by t-tests and published PAQOLQ guidelines, respectively. RESULTS: Thirty patients have been enrolled. Following the change to NHLBI-recommended drug therapy, there was a mean increase in overall QOL from 3.68 to 4.71 (1.03). There were increases in each of the QOL domains. Activity increased from 3.66 to 4.69 (1.031, symptoms increased from 3.56 to 4.83 (1.271, and emotional increased from 3.90 to 4.54 (0.64). All changes were statistically (p<0.05) and clinically significant. CONCLUSION: A change from inappropriate to appropriate drug therapy, as defined by the NHLBI guidelines, improves patient QOL in children with persistent asthma.

168. Comparative efficacy of continuous infusion ceftazidime in adults with cystic fibrosis. Charles R. Bonapace, Pharm.D., Patrick A. Flume, M.D., Roger L. White, Pharm.D., J. A. Bosso, Pharm.D.; Medical University of South Carolina, Charleston, SC.

Pharmacodynamic principles suggest that the ideal way to administer beta-lactam antibiotics may be by continuous infusion (CI) to provide ongoing concentrations in excess of the minimum inhibitory concentration (MIC) of the infecting pathogens. We compared the clinical and laboratory efficacy of continuous infusion ceftazidime (CTZ) to that observed with intermittent dosing in this pilot trial. Five cystic fibrosis (CF) patients ranging in age from 19 to 31 years were enrolled. At the time of a pulmonary exacerbation requiring antibiotic therapy, patients were admitted and treated with traditional CTZ therapy (2 g three times daily for 10 days). At that time, CTZ kinetics were determined as were the MlCs of all Pseudomonas aeruginosa (PA) isolates. At the next hospitalization for a pulmonary exacerbation, CTZ was administered as a CI at a rate determined to achieve a serum concentration 6.6 times the MIC of the least susceptible PA isolate from the first hospitalization (but not exceeding 6 g/d). This concentration represents that related to maximum antibacterial effect based upon earlier in vitro studies. Outcome parameters of interest included day 1 to day 4 and day 1 to day 10 changes in peripheral white blood cell count, PA density in sputum, and pulmonary function tests. No other forms of therapy were varied between the two treatment periods. With the exception of one patient who received 6 g/d with both regimens, the average reduction in dosage with the continuous infusion regimen was 50% (range of doses: 1.5-4.3 g/d). In no case was the difference in outcome parameter for the two forms of administration significantly different (Wilcoxon signed rank test). In one case the maximum PA MIC changed more than 2-fold during a course of therapy. These preliminary data suggest that CI CTZ produces the same safety and efficacy normally observed with intermittent dosing. This form of CTZ administration, which could involve lower total daily doses, merits further investigation.

169. Regulation of IL- lp through lung epithelial cells and defective interleukin-1 type 11 receptor expression. Daren Knoell, Pharm.D., Mark D. Wewers, M.D., Kristin R. Coulter, Ph.D.; The Ohio State University, Columbus, OH.

Release of the pleiotropic cytokine interleukin-lp (IL-1p) in the airway microenvironment induces the production of pro-inflammatory factors (including IL-8) from parenchymal lung cells. PURPOSE: Regulation of lung epithelial cell responsiveness to IL-lp is poorly understood and therefore was studied in the human type 11-like airway epithelial cell line, A549, and primary human bronchial epithelial cells (NHBE). Specifically, known IL-1 response modifiers including IL-1 type I receptor (IL-lR0, IL-1 type 11 receptor (IL-lRIl), IL-1 receptor accessory protein (IL-lRAcP), and the 1L-1 receptor antagonist (IL-1Ra) were analyzed. METHODS AND RESULTS: Constitutive expression of IL-lRI, IL-lRAcP, and IL-1Ra was detected in both immortalized and primary human airway epithelial cells. A striking absence of IL-1 RII expression was demonstrated under all study conditions in both A549 and NHBE cells. Both cell types were responsive to IL-lP at concentrations as low as 50-500 pg/ml when measured by IL-8 release into cell supernatants. IL-lp-induced chemokine production and release was inhibited by a 10 to 1000-fold molar excess of recombinant IL-1RII or IL-lRa, whereas IL-1 R1 was a less effective inhibitor. CONCLUSION: We propose that human lung epithelial cells lack the ability to down-regulate IL-lp activity extracellularly due to an inability to express the IL-1RII. Release of extracellular IL-l inhibitors, including soluble 1L-1Ra and soluble IL-lRII, by other inflammatory cells present in the airway may be critical for regulation of IL-lp activity in the airway microenvironment.

170. Effects of estrogen on bronchiole myocyte adhesion molecule expression and cyclic AMP production. George R. Dickens, Pharm.D.,

Christopher J. Matheny, Pharm.D., Peter E. Morris, M.D., G. Dennis Clifton, Pharm.D., Mary H.H. Ensom, Pharm.D.; University of Kentucky Medical Center; Washington State University; University of British Columbia.

PURPOSE: Exogenous administration of estrogen has been shown to attenuate premenstrual asthma (PMA). The mechanisms underlying estrogen's effect on PMA are unknown but may involve direct activity on bronchiole smooth muscle cells. Two possible mechanisms are estrogen- induced attenuation of cell adhesion molecule expression and augmentation of intracellular cyclic AMP (CAMP) production. Cell adhesion molecules (ICAM-1 and VCAM-1) may play a role in the pathogenesis of asthma by facilitating the immune response and cAMP is a second messenger that facilitates relaxation of bronchiole smooth muscle. In this in vitro study, TNF-a-induced expression of ICAM-1 and VCAM-1 was quantified in the absence and presence of estradiol. Production of cAMP in human bronchiole smooth muscle cells (BSMC) was compared to forskolin, a direct stimulant of cAMP production via adenylate cyclase. METHODS: Four experiments were performed, each in triplicate: 1) untreated BSMC (control group); 2) TNF-a stimulation of ICAM-1 and VCAM-1 expression; 3) estradiol prior to TNF-a; and 4) forskolin prior to TNF-a. RESULTS: ICAM and VCAM expression, reported as mean + SEM, measured by flow cytometry was:

Control TNF Estradiol ICAM 3 2 2 19 930 2 583 720 * 528 VCAM 2 4 i 15 5 2 i 18 49 * 9

cAMP expression as measured by radioimmunoassay was: 1 Forskolin Estradiol

Basal CAMP (pmoVl0' cells) 0.601 * 0.04 0.789 + 0.05 Stimulated cAMP (pmoV105 cells) 1.911 i 0.01 2.325 + 0.04 StimulatedBasal cAMP (%I 218 i 19 195 i 14

CONCLUSION: A trend in the reduction of ICAM-1 by estradiol was observed. Estradiol's effect on cAMP production was equivalent to that produced by forskolin. Further studies are needed to assess the potential antiinflammatory and smooth-muscle relaxing properties of estradiol in BSMC.

171. Effect of exogenous estradiol administration on premenstrual symptoms in females with premenstrual asthma. Mary H.H. Ensom, Pharm.D., FCCP, Elaine Chong, B.Sc. Pharm. candidate, Diana Carter, MBBS, CRCP (C); University of British Columbia; Children's and Women's Health Centre of British Columbia, Vancouver, BC, Canada.

PURPOSE: In a previous clinical study, we found estradiol administration to be associated with improvements in asthma symptoms and pulmonary function in females with premenstrual asthma (PMA). However, the association between premenstrual symptoms and asthma symptoms remains unclear. The objectives of the current analysis, using premenstrual symptoms data collected during the previous study, are: 1) to characterize and compare premenstrual (mood and physical) symptoms throughout two menstrual cycles, with and without estradiol administration; and 2) to determine whether a relationship exists between asthma symptoms and premenstrual symptoms in females with PMA. METHODS: We followed, for two complete menstrual cycles, 14 women (35.6 * 6.6 years) who had PMA and a baseline FEVlFVC ratio of 0.72 5

0.12. During the second menstrual cycle, subjects received estradiol 2 mg orally between cycle days 23 and 28. The subjects recorded peak expiratory flow rate (PEFR), visual analog scales of asthma symptoms (cough, wheezing, breathlessness, and chest t ightness), and premenstrual symptoms questionnaire scores (15 symptoms graded 0-3 each) upon awakening every day throughout both cycles. RESULTS: Seven subjects showed a classic pattern of premenstrual symptoms. Interestingly, 4 of the 5 subjects who complained of PMA symptoms at study enrollment also demonstrated these classic premenstrual symptoms. Following estradiol administration, four subjects had lower premenstrual symptoms scores, eight had higher scores, and two had the same scores. However, overall, estradiol had no significant effect on premenstrual symptoms (n=14, AUC 18.9 * 14.8 versus 20.3 * 14.8, p>0.05). A moderate relationship existed between asthma symptoms and premenstrual symptoms k0 .49 , p<0.05) and a weak relationship existed between PEFR and premenstrual symptoms (m0.23, p<0.05). CONCLUSIONS: In PMA, exogenous estradiol administration had no significant effect on premenstrual symptoms. However, premenstrual symptoms demonstrated significant, albeit moderate and weak, relationships with asthma symptoms and pulmonary function, respectively.

172. Oropharyngeal removal of inhaled fluticasone propionate using two mouth-washing vehicles. Judy S. Kelloway, Pharm.D., Andrea J. Anderson, Pharm.D., Nancy N. Wyatt, M.S., Susan Adlis, M.S., William F. Schoenwetter, M.D.; Healthsystem Minnesota, Minneapolis, MN; Glaxo Wellcome Inc., Research Triangle Park, NC.

Rinsing the mouth with water is recommended to remove inhaled cortico- steriod (ICS) deposited on the oropharyngeal mucosa (OMA). Given the


lipophilicity of fluticasone propionate (FP), an ethanol-based mouthwash was hypothesized to be superior to water. PURPOSE: Comparative effectiveness of water versus ListerineTM (LIS) in removing FP from the OMA. METHODS: Asthma patients were randomly assigned water or a LIS rinsing vehicle. A 440 pg dose of FP was inhaled. After the second puff of FP, patients rinsed for 30 seconds after each of two 20 ml rinses and spit both washes into a cup. A t visit two, patients used the alternate vehicle and repeated the procedure. Samples were frozen until analyzed using liquid chromatography/mass spectrophotometry (lower limit of detection 0.067 pg/ml). RESULTS: Thirty-six patients, mean age 44 years (66% female) participated. Mean inhaler technique score was 11.3 (scale of 1-12). Eighty-three percent used closed mouth technique. The mean concentration of FP removed by LIS was not statistically different than that removed by water (1.67 pg/ml [range 0.0674.195 pg/ml] and 1.42 pg/ml [range 0.067-5.107 pg/mll, respectively). Regression analysis using sex, age, and inhaler technique showed no statistical relationship to the amount of FP removed. CONCLUSION: LIS was not more effective than water in removing FP from the OMA (p=0.53). Rinsing removed 1-57% of the amount of FP deposited in the OMA (assuming 80% deposition), independent of the vehicle. Thus, additional factors also affect the amount of 1CS removed. Water is a cost- effective nnsing vehicle.

173. Increased expression of the interleukin-1 type I1 receptor in a murine model of acute lung inflammation. Kristin R. Coulter, Ph.D., Daren L. Knoell, Pham.D.; The Ohio State University, Columbus, OH.

Interleukin-lp (IL-lp) is a potent mediator of lung inflammation. Bacterial lipopolysaccharide (LPS) rapidly induces IL-lp production and release by alveolar macrophages. IL-lp in the airway microenvironment leads to the rapid induction of potent chemokines known to recruit inflammatory cells. PURPOSE: This work identifies differences in the expression of known IL-1 response modifiers and the chemokine, murine KC, in parenchymal lung tissue and migratory airway cells in a murine model of acute lung inflammation. METHODS: LPS was administered intranasally to adult Balb/C mice. Treated and control mice were sacrificed at 2, 4, 6, 12, 24, and 48 hours after treatment. Bronchoalveolar lavage (BAL) was performed and lung tissue was harvested. An aliquot of BAL cells was analyzed by standard histologic analysis. RT-PCR was used to analyze the expression of IL-16, the 1L-1 type I receptor (IL-lRl), IL-1 type 11 receptor (IL-IRII), 1L-1 receptor accessory protein (IL-IRAcP), mouse KC and GAPDH mRNA from lung tissue, and BAL cells. RESULTS: Neutrophils became prevalent 4 hours after LPS administration and peaked at 12 hours. At 48 hours, neutrophils remained the dominant cell type; however, lymphocytes increased dramatically compared to earlier time points. IL-lp, IL-lRI, IL-IRAcP, and KC were constitutively expressed in all lung tissue samples, whereas, IL-1RII was only detected in the LPS treated mice. Only IL-1RII and KC were detected in BAL samples of LPS treated mice. CONCLUSION: Our results demonstrate upregulation of IL-1RII message in lung tissue and airway cells following LPS challenge. Histologic analysis suggests that alveolar macrophages and/or neutrophils are responsible for increased IL-1RII detection.

174. Superiority of beclomethasone over cromolyn in the self-treatment of seasonal allergic rhinitis. Donald J. Kellerman, Pharm.D., Eli 0. Meltzer, M.D., Frank C. Hampel, M.D., Paul Chervinsky, M.D., Larry E. East, B.S., Karen D. Dunn, M.D., Lisa M. Petty, B.S.; Glaxo Wellcome Inc., Research Triangle Park, NC; Allergy & Asthma Medical Group; Central Texas Health Research; New England Research Center.

PURPOSE: We compared the efficacy, safety, and effects on rhinitis quality of life (RQL) of beclomethasone (Beconasem [BI), cromolyn (Nasalcrom@ IN]), and placebo (P) in patients with fall seasonal allergic rhinitis (SAR) symptoms. METHODS: A total of 321 patients with moderate nasal SAR symptoms (200 of 400 on a visual analog scale) during a 2-week lead-in period were randomly assigned to B 1-2 sprays BID; N 1 spray 3 4 times a day (or up to 6 times a day, if needed), or P 1-2 sprays BID for 4 weeks. Patients received limited verbal instructions on treatment, but were instructed to complete daily diary cards for the four weeks of treatment and return to the clinic every 1-2 weeks. RQL questionnaires were completed pre-study and at the end of treatment. RESULTS: Mean percentage change from baseline in patient-rated nasal symptom scores for the treatment period and statistical comparisons are shown.

B (n=107) N (11407) P (n=107) B vs P N vs P B vs N Sneezing -26% -18% -16% 0.008 0.614 0.030 Rhinorrhea -29% -20% -18% 0.015 0.730 0.036 Nasal itching -31% -21% -21% 0.013 0.852 0.020 Nasalobstruction -30% -20% -16% 0.001 0.252 0.006 Overall nasal score -29% -20% -18% 0.002 0.548 0.010

B was also superior (p<0.05) to N and P for overall quality of life for the domains of sleep, nasal, practical, and non-nosdeye. Side effects were similar

and uncommon in all treatment groups. CONCLUSION: B is superior to N for self-treatment of allergic rhinitis. N is an ineffective self-treatment and should not be recommended.

Substance Abusfloxicology 175. High-flux hemodialysis without hemoperfusion is effective management of acute valproic acid overdose. Sandra L Kane, Pharm.D., Marigel Constantiner, M.S., John R Sedor, M.D.; Ohio State University, Dublin, OH; Metrohealth Medical Center.

A 25-year-old female with a history of multiple suicide attempts and schizophrenia presented after ingesting an unknown amount of valproic acid. She became comatose and developed hypotension and lactic acidosis as valproic acid levels increased to greater than 1200 pg/ml (therapeutic concentration 50-100 pg/ml). Previous reports have used charcoal hemoperfusion alone or in combination with hemodialysis to accelerate valproic acid clearance. The pharmacokinetic properties of valproic acid suggest that hemodialysis alone would be effective therapy for an acute valproic acid overdose. To our knowledge, this is the first case report of acute valproic acid overdose treated exclusively with high-flux hemodialysis. The patient was initiated on high-flux hemodialysis for 4 hours; the calculated kl during the procedure was 0.247 h r ' with a tl,2 of 2.8 hours. Post- hemodialysis, the k1 was 0.033 hr-' with a tln 20.74 hours. Concomitant with acute reduction in valproic acid levels, the patient's hernodynamic status and mental function improved. After the hemodialysis procedure, a 31% rebound in concentration was noted without incident to the patient. Her subsequent hospital course was complicated only by a transient thrombocytopenia. which previously has been associated with valproic acid overdose. We suggest that toxic concentrations of valproic acid can be effectively reduced with high-flux hemodialysis without the addition of charcoal hemoperfusion and its attendant risks for the patient.

Transplantation 176. The efficacy of cytomegalovirus hyperimmune globulin in prevention of cytomegalovirus disease among transplant allograft recipients at high risk for primary infection. Yi-Min Ku, M.S., Pham.D., Claudia Convin, M.D., David I. Min, M.S., Pharm.D., Megan Vorhies, B.S.N., Stephen Rayhill, M.D., You-Min Wu, M.D., Lawrence G. Hunsicker, M.D.; University of Iowa, Iowa City, IA. PURPOSE: Cytomegalovirus (CMV) disease remains an important cause of morbidity and mortality following solid organ transplantation, particularly in the setting of donor CMV positive to recipients CMV negative (Dcm-). The purpose of the study is to evaluate the efficacy of CMV hyperimmune globulin (CMV-HG) in allograft recipients at high risk of CMV disease. METHODS: We conducted a retrospective, case-controlled study in D+/R- patients undergoing kidney, liver, or combined kidney/pancreas transplantation from May 1993 to December 1997. The study group received CMV-HG every 2 weeks for 8 doses (starting dose 150 m&), as well as IV ganciclovir 5 mg/kg BID for 14 days beginning immediately after transplantation, followed by oral acyclovir 800-3200 mg/day (dosages of both drugs were adjusted for renal function) for 10 weeks. The control group at high risk received the same prophylactic antiviral regimens except CMV-HG. Patients were regularly monitored for seroconversion as well as for other evidence of symptomatic infection and CMV disease. The actuarial incidence of CMV disease was estimated by using the method of Kaplan-Meier. Log- rank test was used to determine statistical significance. RESULTS Organ # D+R- % of CMV disease

Study Control Study Control

KidneyRancreas 14 5 14 (U14) 20 (U5) Liver 12 3 33 (4/12) 33 (113) Total 100 20 15 (15/100) 10 (U20) The incidence rate of CMV disease for various organ types was 15% for the study group vs 10% for the control group (p=0.5). The incidence rate of CMV disease at 3 and 6 months after transplantation were similar in both groups (4% and 8% for study group and 5% and 11% for the control group,

Kidney 74 12 12 (9/74) 0

respectively). CONCLUSION: The overall incidence of CMV disease among allograft recipients with high risk in this study was not influenced by using CMV-HG.

177. Metoclopramide inhibits tumor necrosis factor alpha induction in human leukocytes stimulated with alloantigens or radiation. Val R. Adams, Pharm.D., Sony Tuteja, Pharm.D., John S. Bryson, Ph.D.; University of Kentucky, Lexington, KY.

PURPOSE: Metoclopramide has been reported to inhibit lipopolysaccharide- induced tumor necrosis factor alpha (TNF-a) levels in mice. Since there is a


high correlation between TNF-a levels and graft-versus-host disease (GVHD) in allogeneic bone marrow transplant (BMT) patients, we designed this study to determine if metoclopramide could inhibit TNF-a production in human leukocytes stimulated with alloantigens or radiation. METHODS: Human peripheral blood mononuclear cells (PBMCs) or monocytes were isolated from whole blood using a density gradient (Histopaque and FicoLyte monocytes). The PBMCs were exposed to metoclopramide at various concentrations and stimulated in a mixed lymphocyte reaction (MLR). TNF-a in the media was measured with ELISA techniques. Proliferation was measured using 'H-thymidine incorporation. Monocytes were exposed to metoclopramide for 60 minutes, then treated with 2000 rads of radiation. TNF-a mRNA levels were quantified with an RT- PCR assay which utilizes beta actin as a control. RESULTS: TNF-a levels were 44, 8 , 19, and 6% that of controls after exposure to 313, 625, 1250, and 2500 ng/ml of metoclopramide. The levels were decreased independently of cell proliferation which was unaffected by metoclopramide. TNF-a mRNA levels in monocytes exposed to 2500 ng/ml of metoclopramide and radiation were undetectable, while the control cells treated with radiation produced high levels of mRNA. The beta actin controls were very similar between treatment groups. CONCLUSION: Metoclopramide inhibits in vitro TNF-a production at pharmacologically achievable concentrations. We believe metoclopramide will decrease GVHD in allogeneic BMT patients. Current studies are evaluating this hypothesis in a murine BMT model.

178. Population pharmacokinetics of cyclosporine A in pediatric renal transplant recipients. Edmund V. Capparelli, Pharm.D., Jacques C. Lemire, M.D., Nadine Benador, M.D., Vivian Resnik, M.D., William R. Griswold, M.D., James D. Connor, M.D.; UC San Diego, La Jolla, CA.

PURPOSE: This study evaluated population pharmacokinetics (PK) of cyclosporine A (CSA) in pediatric renal transplant recipients receiving Sandimmune' ( S ) and/or Neoral" (N). Sources of PK variability were investigated. METHODS: Thirty-two stable pediatric renal transplant recipients (S=25/N=31), mean age 13.5 years, weight 44.3 kg, and body surface area (BSA) 1.30 m*, were evaluated. A total of 482 steady-state whole blood CSA levels (TDX assay) were obtained: 143 on S and 339 on N. Three hundred thirty-one levels were obtained during a full AUC evaluation ( 5 4 levels after a dose; S=82/n=249); 151 were troughs, I-hour or 6-hour post-dose (S=6l/n=90). Data were fit to a 2-compartment model using NONMEM version IV (FO subroutine). Individual models were assessed and compared graphically and by changes in the objective function. RESULTS: BSA best explained intersubject variability due to size for both CVF and VcliF. Age was also a significant covariate for CVF. Estimates of typical PK parameters and inter-subject variability were: CUF ( f i r ) = 25.8.BSA.Age / 48%; VdJF (L) = 260.BSA /55%; VJF (1) = 63.BSA; where Age = 1 if age 2 12 years (n=20) and Age = 1.31 if age < 12 years (n=12). Neoral' had significantly less within subject day-to-day variability (28% versus 59%, p<O.OOl) and lower residual error (43% versus 62%, p<O.OOI) compared to Sandimmune". CONCLUSION: There is significant intersubject CSA pharmacokinetic variability in stable pediatric renal transplant recipients even after accounting for differences in age and size. The Neoral" formulation is associated with lower intrasubject PK variability resulting in more stable CSA levels.

179. Gender difference of microemulsion cyclosporine bioavailability in healthy volunteers. David I. Min, M.S., Phann.D., Yi-Min Ku, M.S., Pharm.D.. Hsiang-Yin Chen, M.S., Pharm.D.; University of Iowa, Iowa City, IA.

PURPOSE: To evaluate the gender difference of bioavailability of microemulsion cyclosporine (CSA-ME) in healthy volunteers. METHODS: As part of an ongoing study, the pharmacokinetic data of CSA- ME was analyzed to evaluate the gender difference of bioavailability in healthy volunteers. A total of four female and eight male subjects participated in the study. Each subject received oral doses of CSA-ME (5 mg/kg) and one intravenous dose of CSA (1.5 mg/kg) infused for 3 hours in a fasted condition, with each dose separated by at least a 1-week washout period. A total of 17 blood samples were collected for a 24-hour period, and whole blood concentrations of cyclosporine (CSA) were determined by HPLC method with UV detection. The pharmacokinetic parameters were analyzed by using non-compartmental analysis. Non-parametric Mann-Whitney test were used to compare the parameters of the two groups with each other and p<0.05 was of statistical significance. RESULTS: The mean absolute bioavailability (i SD) of CSA-ME in females was larger by 20% compared to that in males (42.3 i 2.1% [Fl vs 35.3 * 6.5% [MI, p<0.05). All other pharmacokinetic parameters of CSA-ME between female and male were not significantly different. CONCLUSION: This study shows that the absolute bioavailability of CSA-ME in female subjects was significantly larger than that in male subjects. Further study may be needed to confirm whether this is true for transplant patients.

180. Effect of concument versus separated administration of sirolimus solid formulation with cyclosporine. Patrick A. Kelly, Pharm.D., Kimberly 1 .

Napoli, Ph.D., Kathleen Dunne, B.S.N., Barry D. Kahan, Ph.D., M.D.; University of Houston; University of Texas-Houston, Houston, TX.

PURPOSE: Sirolimus (SRL), a new immunosuppressant, is currently undergoing investigation in phase 111 trials for the prevention of renal allograft rejection. Since SRL will be used clinically in conjunction with cyclosporine (CSA) therapy and both compounds are known to be metabolized by CYP3A4, we investigated the impact of concurrent versus separated administration of SRL with CSA in stable renal allograft recipients. METHODS: Nine stable renal transplant recipients who had received SRL for greater than 1 year and who had been converted from the liquid formulation of SRL to the solid formulation participated in this study. Twenty-four hour pharmacokinetic profiles of SRL were performed after patients had received a minimum of two weeks concurrent CSA administration and again following a minimum of 2 weeks dosing with a 4-hour separation between drug administration times. Whole-blood samples were drawn immediately prior to and at 0.5, 1, 2, 3, 5, 8, 12, and 24 hours after dosing. SRL concentrations were determined by HPLC. Companson between concurrent versus separated administration was by Student's t-test. RESULTS: Concurrent administration of SRL with CSA resulted in a significantly increased exposure to SRL as measured by the area under the concentration time curve (372 + 97 vs 271 + 94 ng.hr/ml) and a significant increase in C,,, (27.8 + 9.2 vs 17.1 + 5.8 ng/ml). Time to maximum SRL concentration remained unchanged. There were no episodes of acute rejection nor were there any observed changes in creatinine, white blood counts, platelets, AST, ALT, triglycerides, or cholesterol. CONCLUSION: Concurrent administration of SRL with CSA resulted ip a greater exposure to SRL during the dosing interval without apparent adverse effects. This observed effect may be related to inhibition of SRL metabolism by CSA in the intestine.

181. Effects of rifampin on tacrolimus pharmacokinetics in healthy volunteers. Mary F. Hebert, Pharm.D., Richard M. Fisher, B.S., Christopher L. Marsh, M.D., Dawna Dressler, B.S., lhor Bekkrsky, Ph.D.; University of Washington, Seattle, WA; Fujisawa USA, Inc., Deerfield, 11.

PURPOSE: To quantify the effects of rifampin, an anti-tuberculosis agent and potent inducer of CYP3A4 and P-glycoprotein, on the pharmacokinetics of tacrolimus, a substrate of CYP3A4 and P-glycoprotein. METHODS: The pharmacokinetics of tacrolimus were studied in six healthy male volunteers. Tacrolimus was administered at doses of 0.1 mgkg orally and 0.025 mgkg every 4 hours intravenously. The pharmacokinetics of tacrolimus were obtained from serial blood samples collected over 96 hours, after single oral and intravenous administration prior to and during an 18-day concomitant rifampin dosing (600 mg orally at bedtime) phase. Whole blood tacrolimus pharmacokinetic parameters (mean + SD) before and with rifampin were estimated using noncompartmental techniques. RESULTS: Coadministration of rifampin significantly increased tacrolimus clearance (36.0 i 8.1 ml/hr/kg versus 52.8 i 9.6 ml/hr/kg; p=0.03) and decreased tacrolimus bioavailability (14.4% i 5.7% versus 7.0% + 2.7%; p=0.03). No significant change was observed in tacrolimus steady-state volume of distribution (1.4 i 0.2 L/kg versus 1.5 + 0.5 Llkg) with coadministration of rifampin. Tacrolimus hepatic bioavailability (FH; 97.2% + 0.6% versus 95.9% + 0.7%; p=0.03) and intestinal bioavailability (Fa& x Fgur; 14.8% + 5.9% versus 7.3% + 2.9%; p=0.03) as well as intravenous mean residence time (41.8 + 9.7 hours versus 28.5 + 8.2 hours; p=0.03) were all significantly reduced with coadministration of rifampin. CONCLUSION: Rifampin appears to induce both intestinal and hepatic metabolism of tacrolimus, most likely through induction of CYP3A and P- glycoprotein in the liver and small bowel.

182. Glucocorticoid pharmacokinetics in premenopausal renal transplant recipients. Kristin A. Gillitand, Kris A. Reed, Mahfooz Farooqui, M.D., Rocco C . Venuto, M.D., Kathleen M. Tornatore, Pharm.D.; Erie County Medical Center; State University of New York at Buffalo, Buffalo, NY.

PURPOSE: No pharmacokinetic data of immunosuppressives is available describing the impact of gender in renal transplant recipients (RTR). Methylprednisolone (MePn) clearance is described to be more rapid in healthy women compared to men and could impact on adequate immunosuppression. The objective of this study was to compare the pharmacokinetics of methylprednisolone in premenopausal renal transplant recipients with previously studied male RTR. METHODS: Thirteen stable premenopausal RTR (ages 30 to 49 years) with creatinine clearance 51.7 + 21.3 ml/min receiving chronic MePn therapy (mean dose 7 mg) were evaluated during a 24-hour study. Serial blood samples were collected over 24 hours following a 2&30 minute 1V infusion of MePn. Samples were analyzed by HPLC, with pharmacokinetic parameters determined by WINNONLIN. RESULTS: The mean clearance (CL) of MePn for females (15.6 Uhr) differed significantly from males (21.5 L/hr; p=0.05). However, no significant difference between groups was noted when CL was normalized for total body weight (females 225 i 89.4 ml/hr/kg versus males 260 ml/hr/kg; p=0.614) as well as for volume of distribution, elimination rate constant, or half life. Dose

, '


normalized MePn AUC reflected greater drug exposure in the female RTR (66.1 + 19.8 ng.hr/ml) than males (46.4 + 19.7 ng*hr/ml; p=O 174). No significant correlations were determined between demographics and pharmacokinetic parameters Patients exhibited moon facies with buffalo hump in the majority of women. CONCLUSION: No significant difference in MePn clearance in female RTR was noted compared to male counterparts. These findings contradict information documenting a more rapid MePn CL in healthy females and should be incorporated into steroid dosing protocols.

183. Glucocorticoid pharmacokinetics in postmenopausal renal transplant recipients. Andrea M. Ciminelli, Kris A. Reed, Mahfooz Farooqui, M.D., Rocco C. Venuto, M.D., Kathleen M. Tornatore, Pharm.D ; Erie County Medical Center; State University of New York at Buffalo, Buffalo, NY.

PURPOSE: The most rapidly growing patient group requiring renal transplant are individuals over the age of 55. Over 40% of these patients are post-menopausal women No pharmacokinetic information is available describing immunosuppressives in this group This study compares the pharmacokinetics of methylprednisolone in postmenopausal renal transplant recipients (RTR), ages 39-69, with retrospectively studied male patients. METHODS: Eight stable postmenopausal renal transplant recipients (serum creatinine 1.30 * 0.47 mg/dl) receiving chronic methylprednisolone therapy (mean dose 6.25 i 2 mg) were recruited and assessed for specific steroid- induced adverse effects. Baseline blood sample was obtained prior to intravenous infusion of methylprednisolone and followed by 24-hour serial sample collections. Methylprednisolone was analyzed by high performance liquid chromatography. RESULTS: Women exhibited a significantly slower methylprednisolone clearance (146 i 32.5 ml/h/kg; p=0.009) and a smaller volume of distribution (0.74 i 0.102 Lkg; p<0.05) when compared to nine black males (Cl 206 70 ml/hr/kg; Vd 0.95 * 0.32 U k g ) and nine white males (CI 327 * 129 ml/hr/kg; Vd 1.33 + 0.27 LAP). Methylprednisolone AUC (normalized for dose) was significantly greater for the females (103.7 i 20.9 ng-hr/ml/kg) versus black (51.7 * 16.8 ng.hr/ml/kg; p=0.002) and whi te males (50 .5 * 23.9 ng.hr/ml/kg; p=O.OOl). Cushingoid manifestations were seen in seven of eight females with 75% demonstrating hirsutism requiring depilatories or shaving. Development of Cataracts was noted in 38% of patients. No correlation was noted between pharmacokinetic parameters and adverse effects or demographics. CONCLUSION: The reduced methylprednisolone and increased MePn AUC found in post-menopausal RTR suggest that increased drug exposure may impact upon the development of steroid-induced adverse effects. These findings suggest that post-menopausal RTR should have judicious dose adjustments of their glucocorticoid regimen to avoid chronic adverse effects or over-immunosuppression.

184E. Aerosol cyclosporine absorption in lung transplant recipients. Gilbert J. Burckart, Pharm.D., Aldo T. lacono, M.D., James Dauber, M.D., Adriana Zeevi, Ph.D., Gerald Smaldone, M.D., Ricardo R. Vega, M.D., Bartley P. Griffith, M.D.; University of Pittsburgh, Pittsburgh, PA.

Presented at the XVll World Congress of The Transplantation Society, Montreal, Quebec, Canada, July 13, 1998.

185E. Risk factors for steroid-induced bone disease in renal transplantation. Melanie S. joy, Pharm.D., Kimberly D. Hollar, Pharm.D., Clara D. Neyhart, B.S.N., Mary Anne Dooley, M.D., Susan L. Hogan, M.P.H., Robert E. Dupuis, Pharm.D., William F. Finn, M.D.; University of North Carolina, Chapel Hill, NC.

Presented at the 17th Annual Meeting of the American Society of Transplant Physicians, Chicago, IL, May 1998.

186. Low-dose OK13 with mycophenolate versus standard-dose OKT3 without mycophenolate induction in high risk kidney transplant recipients. Iman E. Bajjoha, Pharm.D., BCPS, Viken Douzdjian, M.D., Brian Seng, Suzette Habowski, Pharm.D., Marwan Abouljoud, M.D.; Henry Ford Hospital, Detroit, MI.

PURPOSE: The purpose of this study is to compare the safety and efficacy of standard-dose OKT3 (SD-OKT3) and azathioprine (AZA) versus low-dose (LD-OKT3) and mycophenolate mofetil (MMF). METHODS: The records of 73 high-risk kidney transplant recipients were reviewed. High risk was defined as African-American (AA) or panel reactive antibodies greater than 50%. LD-OKT3 2.5 mg (n=41) with MMF/ cyclosporine/steroids was compared to SD-OKT3 5 mg (n=32) with AZNcyclosporindsteroids. Delayed graft function (DGF) was defined as the need for dialysis 5 7 days. RESULTS: Groups were comparable with regard to recipients’ age, etiology of renal disease, and cold ischemic time. A higher proportion of AA were in the LD-OKT3 group (85% vs 56%, ~ ~ 0 . 0 0 5 ) .

SD-OKT3 LD-OKT3 p Biopsy-proven acute rejection (AR) 13 (41%) 11 (27%) 0.04 DG’F’ . 24 (75%) 15 (37%) <0.005 Steroid-resistant AR 8 (25%) 5 (12%) 0.16 Interval to first AR (median days) 51 * 55 47*57 NS

Recurrent AR was seen in five patients in SD-OKT3 compared to none in LD- OKT3. Cytomegaloviral disease occurred in one patient in SD-OKT3 and three in LD-OKT3. There was no difference at six months in graft survival (85% vs 83%). CONCLUSION: In high-risk primary kidney transplant recipients, induction therapy with LD-OKT3 in conjunction with MMF was superior to SD-OKT3 with AZA in decreasing the incidence of biopsy-proven AR and DGF.

187. Correlation with and prediction of phenytoin protein binding using standard laboratory parameters in patients following renal transplantation. Michael S. Monaghan, PharmD., Michael A. Marx, Pharm.D., Keith M. Olsen, Pharm.D., Aaron M. Tejani, Pharm.D., Kimberly 1. Bergman, Pharm.D.; Creighton University, Omaha, NE; University of Arkansas; University of Nebraska Medical Center.

PURPOSE: Renal transplant recipients provide a unique model for protein- binding studies in that patients experience hypoalbuminemia and renal dysfunction, both of which alter protein binding. The purpose of this investigation was 1) to model the relationship between serum creatinine (SCR), blood urea nitrogen, albumin (ALB), and the free fraction of phenytoin (DPHff, as a percentage) measured in post-renal transplant patients; and 2) to determine the value of these measurements in predicting DPHff. METHODS: Blood from 29 patients was collected at various time points after establishment of graft function. Sera were spiked with phenytoin to a concentration of 15 mgR, and totallunbound phenytoin concentrations were determined. Correlations between DPHff and laboratory values were determined using multiple regression. The best equation describing DPHff at all times post-transplant became the method to predict future DPHff. Twenty- three samples from 14 independent patients were used to validate this method. Samples were analyzed as above and the corresponding laboratory data were used to generate DPHff values. Accuracy of the predictions was evaluated using prediction-error analysis. RESULTS: The best relationship between DPHff and laboratory data incorporated SCR and ALB (y = 24.314 t 0.586lSCRl - 3.873[ALB]) and served as the method for DPHff prediction. Prediction-error analysis resulted in a bias of -5.105% (95% C1: -6.258%, -3.951%) and a precision of 5.733% (95% C1: 4.348%, 6.843%). CONCLUSION: This is the first method which attempts to compensate for both renal function and hypoalbuminemia. This method estimates DPHff within approximately 5% of the actual value, although the value is consistently underestimated.

188E. Long-term prophylactic pentoxifylline for cyclosporine-associated nephrotoxicity: a prospective, randomized trial. Shi-Hui Pan, Pharm.D., Glyn Morgan, M.D., Allen Hoffman, M.D., Linda Sher, M.D., Patrick Folk, B.S.N., Richard Lopez, M.D.; St. Vincent Medical Center, Los Angeles, CA.

Published in Liver Transpl Surg 1997;3:C83

Women’s Health 189. Assuring reliable contraception in women with epilepsy: a survey of the community pharmacist knowledge base. Carol A. Roby, Pharm.D., M.S., Aaron H. Burstein, Pharm.D., Catherine E. Cooke, Pharm.D.; University of Maryland, Baltimore, MD.

PURPOSE: To evaluate the existence, extent, and application of the pharmacist’s knowledge regarding the interaction of antiepileptic medications (AEDs) and hormonal contraceptives. METHODS: A survey instrument designed to collect specific data concerning the pharmacist’s practice site, patient population, practice habits, knowledge, and demographics were sen t to 487 randomly selected community pharmacists licensed to practice in the state of Maryland. Survey responses were recorded, tabulated, and analyzed to create a profile of the knowledge base of community pharmacists and their practice conventions with regard to dispensing the combination of AEDs and hormonal contraceptives. RESULTS: Phenytoin, phenobarbital, carbamazepine, and primidone are known reduce the efficacy of hormonal contraceptives by inducing their metabolism. Results from the 82 (16.8%) surveys returned indicate that 85.4%, 69.5%, 68.3%, and 57.3% of respondents possess awareness of these respective interactions. Thirty-seven (45.1%) correctly indicated that Norplant” is not a reliable form of contraception for women with epilepsy. Twenty-four (29.2%) reported that they routinely counseled women receiving these medication combinations regarding alternative contraception to avoid unplanned pregnancy. Sixteen (19.5%) indicated that they routinely contact physicians regarding these interactions. Fifty percent responded that they routinely counsel women receiving AEDs regarding the risk of associated birth defects. CONCLUSIONS: Our results indicate a deficit in community pharmacists’ knowledge of, and response to, the interactions between antiepileptics and ’lormonal contraceptives. While these interactions affect a small proportion of the general population, for epileptic women, an unplanned pregnancy and


risk of fetal antiepileptic syndrome is often clinically significant. A wide availability of continuing education materials is needed to increase awareness and improve practice activities regarding these drug interactions.

190. Influence of endogenous progesterone on alprazolam pharmacodynamics. James W. McAuley, Ph.D., Chad 1. Friedman, M.D.; The Ohio State University, Columbus, OH.

PURPOSE: The objective of this study in premenopausal women was to determine whether the response to a benzodiazepine is altered when endogenous progesterone concentrations are high (luteal phases of a menstrual cycle) in comparison to when progesterone concentrations are low (follicular phases of a menstrual cycle). METHODS: The pharmacokinetics and pharmacodynamics of oral alprazolam were evaluated in 12 healthy, normally-menstruating, women not receiving oral contraceptive agents. On two separate occasions, once during each phase of the menstrual cycle, the women randomly received an oral alprazolam 2 mg dose. Blood was collected and psychomotor performance tests were conducted at selected times before and after dosing. RESULTS: These data show that fluctuations of endogenous progesterone across the menstrual cycle do not influence alprazolam pharmacodynamics. Despite endogenous progesterone concentrations being significantly higher during the mid-luteal rather than the mid-follicular drug administrations, no differences were observed in effect ratios for either the digit-symbol substitution test, card-sorting by suit, or sedation scores on these two occasions. No pharmacokinetic differences were observed. CONCLUSIONS: The lack of changes during the menstrual cycle in demonstrable cognitive impairment and pharmacokinetics following alprazolam is reassuring. This implies that dose adjustment based on menstrual timing is not required.

191. Use of hormone replacement therapy at a university-based adult internal medicine clinic. Barbara L. Kaltenbach, Pharm.D., Jacqueline D. Joss, Pharm.D., Beth Bryles Phillips, Pharm.D.; University of Iowa Hospitals and Clinics, Iowa City, IA. PURPOSE: Less than one in four post-menopausal women in the United States is receiving hormone replacement therapy (HRT). We evaluated the use of HRT at a university-based adult internal medicine clinic in order to: 1) characterize the use of HRT in this population; and 2) identify those women who are candidates for HRT. METHODS: Patient data and HRT status were assessed prospectively by an investigator-administered questionnaire. Women were considered eligible for HRT if they had one or more risk factors for coronary artery disease (CAD) or osteoporosis (OP) and no contraindications to HRT. RESULTS: A total of 188 post-menopausal women (age 60 i 11) were interviewed over a 4-week period. All women had one or more risk factors for either CAD or OP. Ninety-six women (51%) were receiving HRT; ten women (5%) were ineligible due to the presence of a contraindication to HRT. The remaining 82 eligible women (44%) were not on HRT. Of these, 43 had never considered HRT, 27 were previously on HRT but stopped therapy due to unwarranted concerns about the risks of HRT, and 12 thought HRT was of no benefit. CONCLUSION: The use of HRT at this university-based adult internal medicine clinic is higher than the national average. However, a significant number of eligible women remain that are not receiving HRT or who may have discontinued HRT inappropriately. Efforts to explain the benefits and risks of HRT may help optimize the number of patients on HRT.

Clinical Pharmacy Forum These abstracts describe the delivery, development, justification, or documentation of innovative clinical pharmacy services; they may be descriptive only and need not contain an evaluative component.

192. Identification of potential physician prescribing errors using a pharmacist intervention program. Robert M. Fink, Pharm.D.; Baylor University Medical Center, Dallas, TX.

PURPOSE: To use data collected through pharmacist clinical interventions to determine potential physician prescribing errors as an effort to improve organizational performance and comply with JCAHO standards. METHODS Data gathered from manually recorded pharmacist interventions were categorized as either potential physician prescribing errors or pharmacotherapy interventions. Potential physician prescribing errors were defined to include incorrect dose, inappropriate route of administration, therapeutic duplication, potentially significant drug interactions, or prescribing an agent to which a patient was possibly allergic or which may have resulted in an adverse reaction. Pharmacotherapy interventions were defined as recommendations for intravenous to oral route adjustment, dosage adjustment based on therapeutic drug monitoring, change to a formulary or cost-saving alternative, agent no longer needed, or untreated indication. RESULTS: Five thousand sixty-two pharmacist interventions were reported for the period April 1997 through March 1998. Of these interventions, 2685

(53%) were related to potential physician prescribing errors and 2377 (47%) resulted from pharmacotherapy interventions. The overall acceptance rate for combined recommendations was 87%. CONCLUSION: Prior to this, physician prescribing errors were not included in the medication error reporting process. A program to reduce potential prescribing errors and improve therapeutic outcomes is being implemented. This program, developed by interdisciplinary committees, includes protocol development, staff education, automation, and formulary restriction.

193. Development and implementation of a competency standards program for pharmacists in a tertiary care facility. Pamela S. Smith, Phann.D., Danny J. Hackett, B.S., Michael G. O'Neil, Pharm.D., BCNSP, Shelley Schliesser, Pharm.D., Melanie Wolfe, Pharm.D., Corleen Patterson, B.S., Beth Koenig, Pharm.D.; Charleston Area Medical Center, Chadeston, WV.

The development of and experience with a competency standards program for pharmacists in a multi-campus, tertiary care system is described. The program was developed to ensure that pharmacists practicing in the hospital setting maintain the level of knowledge and skills necessary to provide optimal patient care. As competency measurement has come to the forefront with national pharmacy organizations, including requirements from the Joint Commission on Accreditation of Healthcare Organizations in 1993, as well as at our institution, it became necessary for the evolvement of staff development tools for incorporation into pharmacists' career ladders. An additional goal of the newly developed pharmacy standards of care committee was to improve the clinical skills of pharmacists (i,e,, to ensure proficiency in particular areas of practice). The initial objective was to identify twe ve

through staff development and quality improvement measures to ensure that all patients entering the health system can benefit from a minimum standard of clinical care. Three of these Clinical activities were targeted to be developed into competency standards to include training programs, quality measurement systems, and competency evaluation for the first year of the program. The three standards include clinical bharmacokinetics, advanced cardiac life support by pharmacists, and anticoagulation in an ambulatory service. A standardized template was developed to be utilized by clinical staff for a detailed description of each standard of care. The template includes the impetus for the standard, goals, objectives, validators, training methodology, assessment method and evaluation, time frame required for completion of training, revision requirements, quality measures, and references. Currently, the three clinical activities have been developed into competency standards and will be implemented as staff development tools throughout the next year. The development and implementation of the competency standards program will allow pharmacists practicing in the hospital setting to accept responsibility for ensuring optimal drug therapy outcomes in specific areas of practice.

194. Intensive inpatient and outpatient pharmaceutical care of patients with congestive heart failure. Robert M. Malone, Phann.D., Sandra H. Lilley, Pharm.D., Angela J. Mayo, B.S., Gary I. Levine, M.D., Emily L. Bray, M.D., Christy W. Whitley, Pharm.D., Mark D. Darrow, M.D.; East Carolina University, Greenville, NC.

PURPOSE: This health care interventions study will evaluate the impact of providing intensive pharmaceutical care on the overall quality and cost of care for patients with congestive heart failure in a primary care practice. METHODS: Congestive heart failure (CHF) is the most common indication for hospitalization among older adults. Since readmissions for CHF frequently occur within the first month of discharge, efforts to improve the management of these patients in the transition from the hospital to the home environment may have a profound impact on the cost of care as well as the patients' quality of life. This investigation will compare the outcomes of patients with heart failure due to systolic dysfunction in a control group given standard care to a study group given standard care plus intensive inpatient and outpatient pharmaceutical care. Inpatient pharmaceutical care will include medication review and patient counseling on the day of hospital discharge. Outpatient pharmaceutical care will include frequent telephone and clinic follow up over a 3-month period after hospital discharge to reinforce patient counseling, solve medication-related problems, monitor drug therapy, and assist the primary provider in therapeutic decisions. The primary outcome measure of the investigation is the number of readmissions over a 3-month period after discharge. Secondary endpoints include the number of ED visits, length of stay for readmissions, compliance with treatment standards, overall cost of care, and patient satisfaction and quality of life scores. RESULTS: Details of our management care plan and data from an interim analysis will be presented.

195. Results of pharmacy intervention on lipid profiles of hyperlipidemic patients in a family practice clinic setting. Billie Nhu Nguyen, PhamD., John G. Gums, Pharm.D.; Family Practice Medical Group, Gainesville, FL.

PURPOSE: The purpose of this ongoing, prospective study is to assess the impact of a pharmacist-managed lipid consult service on lipid profiles of patients referred by family physicians.

clinical activities that would be standardized, measured, and impro 4 ed


METHODS: Patients with hyperlipidemia are enrolled by physician referral. Two baseline lipid profiles and rule-out labs for secondary causes are obtained prior to enrollment. During the initial visit and every follow-up visit, patients receive individualized medication and dietary counseling. Lipid profiles are obtained every 3 to 6 months depending on clinical status. Interventions result from either verbal or written consult with the physician; a formal consult note is provided to the physician after each follow-up visit. Treatment protocols are based on the NCEP ATP I1 guidelines. RESULTS: Of 64 currently enrolled patients (45 females, 19 males), 35 have a history of CAD documented by acute myocardial infarction o r cerebrovascular accident. The average age is 60 * 12 years. Average baseline lipid values include TC 258, LDL 181, HDL 42. and TG 269. After 3, 6, and 9 months, average TC decreased significantly to 229 (p=0.0001), 219 (p=O.OOOOS), and 21 1 (p=0.00009), respectively. Significant decreases in LDL were achieved at 3, 6, and 9 month follow-up visits: 152 (p=0.003), 144 (p=O.OOl), and 134 (p=0.0008). Significant reductions in triglycerides were also observed; however, no statistically significant change in HDL was found. CONCLUSION: By working with family physicians, pharmacists have significant impact on the lipid profiles of patients enrolled in the lipid consult service. The ultimate goal of this ongoing study is to determine whether a pharmacist-run lipid service can significantly reduce the incidence of CAD.

196. Development and implementation of a pharmacist-managed 24-hour ambulatory blood pressure monitoring service in an ambulatory care clinic. John D. Barksdale, Stephanie F. Gardner, Pharm.D., Eric F. Schneider, Pharm.D., Nancy S. Carthan, PharmD; University of Arkansas, Little Rock, AR.

PURPOSE: According to JNC-Vl guidelines, ambulatory blood pressure monitoring (ABPM) may be a useful adjunct in the evaluation of patients with suspected white coat hypertension (HTN), drug-induced orthostasis, drug resistance, episodic HTN, and autonomic dysfunction. A 24-hour ABPM pharmacist-managed service was developed to evaluate these patients and to provide written recommendations to their primary providers. METHODS: Patients t 55 years old were referred from the geriatric, family medicine, and cardiology clinics. Medical histories and medication lists were obtained. Patients were instructed on how to wear, remove, and replace the monitor. Patients completed activity diaries to record pertinent information, which was correlated to the ABPM reports to explain abnormal readings. Based on 24-hour BP control, recommendations were forwarded to their primary physician. For previously untreated HTN, initial treatment recommendations were given. RESULTS: Twenty-six patients have been evaluated to date. Patients were 68.0 i 7.2 years old, 11 males, and received up to four antihypertensive medications. Based on 24-hour data, 21 of 26 patients were inadequately controlled while on antihypertensive medications. Nine of these 21 patients had normal 24-hour average BP. However, 74.6 i 21.0% of the SBP readings and 34.9 * 26.3% of the DBP readings were above period limits for SBP (> 140 mm Hg day, > 120 mm Hg night) and DBP (> 90 mm Hg day, > 80 mm Hg night). Written recommendations have been sent to all 26 patients’ primary physicians. CONCLUSION: A pharmacist-managed 24-hour ABPM service can facilitate the management of difficult-to-control elderly hypertensive patients. A long- term outcome study is planned to determine the cost-effectiveness and impact of these recommendations and interventions.

197. Results and impact of a pharmacy-driven monitoring program to ensure appropriate use of carvedilol in a tertiary care academic medical center. Toby C. Trujillo, Pharm.D., Kenneth A. Lawrence, Pharm.D.; Beth Israel Deaconess Medical Center; Massachusetts College of Pharmacy and Allied Health Sciences, Boston, MA.

PURPOSE: Carvedilol (CV) is a non-selective beta-blocker that has been approved for the treatment of patients with CHF. Due to the risk of acute decompensation, CV is recommended only in patients with chronic, stable CHF, who are on stable doses of both an ACE-inhibitor and diuretic. Given the potential for adverse events, a pharmacy-driven monitoring program was implemented. METHODS: Upon receiving a new order for CV, the inpatient pharmacist contacted the prescribing physician to assess whether the patient was an appropriate candidate for CV therapy. Assessment consisted of a 5-part questionnaire where the indication, ACE inhibitoddiuretic dose stability, and any contraindications to CV therapy were ascertained. If the patient was not a suitable candidate for CV therapy, the pharmacist documented the physician’s response to education regarding the appropriate use of CV. A retrospective chart review will be conducted to obtain information regarding the patient’s hospital stay. PRELlMlNARY RESULTS: From 11/1/97 to 4/1/98, 30 patients were placed on CV therapy during hospitalization, of which 13 have completed the chart review process. Six out of 13 patients were identified as not meeting appropriate usage criteria for CV. No adverse evens were noted in any of these patients during hospitalization. While the program was successful in educating the prescribing physician on the appropriate use of CV, the program did not prevent the use of CV in patients who did not meet

appropriate usage criteria. CONCLUSION. Based on preliminary data, CV may be relatively safe to initiate in patients who were considered unstable and excluded from large, randomized, controlled trials. Full results from all 30 patients will he presented.

198. Do patients followed in pharmacist-managed anticoagulation clinics have an increased warfarin knowledge and perception of care? Anne Marek, Pharm.D., Jennifer Bolding, Pharm.D., Holly Rickman, Pharm.D , Melissa Santiago, B.S.; John McClellan VAMC, Little Rock. AR; Overton Brooks VAMC.

PURPOSE: The objectives of this study were 1) to determine whether patients managed in specialized anticoagulation clinics are better educated and have a greater knowledge about warfarin and their warfarin therapy than patients followed by other health care professionals; and 2) to identify if pharmacist-managed patients’ attitudes and perception of care differed with respect to whether the necessary education and appropriate time is spent with them in order to he better educated and controlled. METHODS: The information was obtained from surveys composed of 19 questions which were used to ascertain demographic information, general warfarin knowledge of patients with respect to therapy, adverse effects, drugfood interactions, goal 1NR values or ranges for patients, and basic perception of care issues. The surveys were mailed to 1544 patients currently receiving warfarin treatment, of which 495 were being followed by pharmacists in anticoagulation clinics. RESULTS: A total of 1045 surveys (67%) were completed. Patients managed by pharmacists felt they had received the right amount of education for their warfarin therapy as compared to patients followed by other health care professionals (94% vs 80%. p<O.OOl). A greater number of patients who stated they had received adequate education were more likely to achieve satisfactory laboratory results (p<0.003). CONCLUSION: This survey demonstrates adequate education is important for achieving the desired benefits of warfarin therapy. The patients followed by pharmacists were more likely to state they had received adequate education regarding warfarin therapy as opposed to patients followed elsewhere.

199. Pharmacist impact on phenytoin concentration monitoring in the neuroscience intensive care unit. Gretchen M. Tush, Pharm.D., BCPS, William R. Gamett, Pharm.D., FCCP; Virginia Commonwealth University; Richmond, VA.

PURPOSE: Most patients in the neuroscience intensive care unit (NSICU) have phenytoin levels monitored which could lead to higher patient charges if inappropriate levels are drawn. An evaluation was conducted in the NSICU to determine the impact a pharmacist had on improving the rationale for phenytoin concentration monitoring. METHODS: In January 1997, a pharmacist began rounding in the NSICU. She educated the physicians and nurses on phenytoin pharmacokinetics and the rationale for monitoring levels and adjusting doses. Patients were monitored prospectively. Data were collected for the calendar years 1996, the year before the pharmacist’s participation, and 1997 to evaluate the pharmacist’s impact. RESULTS: The number of patients monitored for phenytoin increased from 299 in 1996 to 326 in 1997 and the number of phenytoin levels decreased from 1578 to 974, averaging 5.28 versus 2.99 levels per patient for 1996 and 1997, respectively. The number of days in which more than one level was drawn also decreased from 404 to 102 days. There was no change in the average length of stay in the NSICU for 1996 and 1997. The minimum savings in patient charges in 1997 were $61,125. In addition to the reduction in patient charges observed in 1997, phenytoin therapy was followed more closely by the health care team and more appropriate dosing adjustments were made. CONCLUSION: A pharmacist in the NSICU can positively impact patient care by educating physicians about the rationale for phenytoin monitoring, decreasing inappropriate monitoring of phenytoin levels, and reducing patient charges.

200 . Util ization of pat ien t medication assistance programs in a n ambulatory care setting. Audra R. Thomas, Pharm.D.; Rush Presbyterian St. Luke’s Medical Center, Chicago, IL.

The lack of prescription coverage for Medicare patients often presents a significant harrier to patient compliance. Various pharmaceutical manufacturers make medications available free or at reduced costs to eligible patients. In the Medical Care Group, an ambulatory internal medicine practice, indigent patients are referred by physicians, nurses, or utilization management to the clinical pharmacist for potential enrollment in patient medication assistance programs (PMAPs). A systematic approach to accessing medications for indigent patients has been developed utilizing PMAPs information. This ongoing PMAPs enrollment began in September 1997. As of June 1998, 30 patiens have been enrolled in 25 different PMAPs, resulting in submission of 103 applications. Of these, 82 applications for 42 different medications have been approved, totaling

$16,007.52 (1998 AWP). Currently, 36 applications to 21 pharmaceutical manufacturers for 27 medications (n=19 patients) are pending approval. If all 36 applications are approved, the medication reimbursement to patients will total $2288.66. The Pharmaceutical Research and Manufacturers of America publishes an annual Directory of Patient Assistance Programs used to locate various PMAPs for enrollment. A problem with The Directory is i ts organization alphabetically by manufacturer and lack of a complete listing of medications available. An Access 2.0 database is being created for a more systematic method of finding PMAPs information. The database will query by drug class, generic or brand name, or manufacturer. The database will be distributed to utilization management and Rush clinics. These areas will be able to rapidly retrieve enrollment information for indigent patients. The effect of PMAPs on compliance and patient satisfaction will be studied in the future.

201. Development and implementation of a smoking cessation service in a family medicine physician residency program. Stacey L. Abby, Pharm.D., Ila V. Mehra, Pharm.D., BCPS, Aaron Bjorn, D.O.; Deaconess Hospital; St. Louis College of Pharmacy, St. Louis, MO.

PURPOSE: A smoking cessation service was initiated in a family medicine residency program to educate smokers, create a personalized plan for cessation, and educate physicians-in-training on smoking cessation methods, patient education, and follow up. METHODS: Patients are identified by chart review prior to clinic visits, or by referral. All patients are advised to quit and educated on the risks of smoking and benefits of cessation. The patient is asked if hdshe wants to quit smoking and is assessed for self-efficacy. Patients with moderate to high self-efficacy are evaluated for cessation motivators and barriers. The Fagerstrom Tolerance Test helps assess nicotine dependence. Patients establish a quit date, identify a support system, and self-directed strategies for coping with cravings are discussed. An individualized cessation strategy is developed and most patients receive buproprion with or without nicotine replacement. Finally, the patient develops a reward system and is followed periodically by phone for 3 months. Phone follow up provides encouragement, identifies difficulties, and allows for therapy adjustment. First year physician residents learn to effectively help patients stop smoking by observing and then conducting patient visits for smoking cessation with the clinical pharmacist. RESULTS: In the 9 months since inception, 35 patients and nine physician residents have participated in the service. Of the 32 patients contacted, 17 quit (53%). Of the 15 non-quitters, 47% cut down significantly and 40% did not use buproprion. All patients were satisfied with the service. Physician learning is currently under evaluation. CONCLUSION: A smoking cessation service in a family medicine residency program offers patient-directed assistance, while also educating physicians.

202. Doctoral clerkship students and pharmaceutical care: a 4-year analysis. Marie A. Chisholm, PhamD., David W. Hawkins, A. Thomas Taylor, Pharm.D.; University of Georgia, Athens, Georgia; Medical College of Georgia, Augusta, GA.

PURPOSE: This study evaluated 4 years of pharmaceutical care provided by Doctor of Pharmacy (Pharm.D.1 students on acute care clerkships at the Medical College of Georgia. Objectives of the study included 1) teaching pharmacy s tudents how to identify, document, solve, and prevent medication-related problems; 2) documenting the number and types of recommendations made by Pharm.D. students to medical teams; 3) determining the acceptance rate of these suggestions; and 4) determining the potential impact of students' recommendations on patient care. METHODS: Fifty-nine Pharm.D. students enrolled at the University of Georgia College of Pharmacy assigned to a general medicine or family medicine service at the Medical College of Georgia Hospital during September 1994 through March 1998 were included in the study. Under the supervision of a faculty preceptor, the students were responsible for preventing and resolving patient medication-related problems and providing appropriate pharmacotherapy recommendations. RESULTS: Of the 514 recommendations that were made, approximately 88% (n=452) were accepted by the medical teams. Improper medication selection (24.6%), untreated indication (22.1%), and overdosage (18.6%) accounted for greater than 65% of the medication-related problems. The most commonly accepted recommendations involved anti-infectives (34.3%) and cardiovascular (16.8%) medications. Two pharmacists evaluated each accepted recommendation by using Hatoum's criteria for assessing potential impact on patient care. This evaluation indicated that 73% of the accepted recommendations would have a significant (56.2%), very significant (15.7%), or extremely significant (1.3%) potential impact on patient care outcomes. CONCLUSION: During the 4-year study period, pharmacy students performed pharmaceutical care activities that had a positive impact on patient care.

203. Practice-based pharmacotherapy education for medical students. Charles T. Taylor, Pharm.D., Debbie C. Byrd, Pharm.D., William A. Curry, M.D.; Auburn University, University of Alabama, Tuscaloosa, AL.

PURPOSE: Preventable adverse drug events due to errors in prescribing and

drug management account for many (3-28%) hospitalizations annually. Prescribing patterns may be improved by establishing means for early and continuous pharmacotherapy education. However, most medical curricula do not traditionally include applied longitudinal pharmacology instruction. Our purpose was to measure baseline perceptions of third year medical students regarding medication management and evaluate the influence of a comprehensive pharmacotherapy program integrated into a 2-month internal medicine clerkship. METHODS: Twenty-four students participated between August 1997 and June 1998. Baseline questionnaires were completed to ascertain individual perceptions toward medication management. A pharmacy faculty educator identified patient-specific teaching points each day during rounds. Supplemental instruction consisted of handouts, dosing guides, and mini- lectures. Core topics included pharmacokinettts, diabetes, hypertension, hyperlipidemia, anticoagulation, asthma, and antibiotic selection. An evaluation form was completed to elicit attitudes (1 = strongly disagree, 5 = strongly agree) regarding the quality of pharmacotherapy education. RESULTS: Nineteen (79%) students completed baseline questionnaires and eleven (58%) felt inadequately trained to apply basic pharmacotherapeutic principles. Students' perceived knowledge deficiencies regarding pharmacology (68%), medication costs (84%), and drug monitoring (79%). All students perceived a lack of competence in providing appropriate drug therapy. Twenty-one (88%) evaluation forms were completed with a positive overall rating (5.0). Students strongly agreed pharmacotherapy education was thought provoking (90961, effective (90%), and improved overall knowledge (81%). CONCLUSION: The overwhelming majority of medical students fouhd practice-based, applied pharmacotherapy education to be thought provoking and effective in improving overall knowledge of medication management.

204. Development of a pharmacotherapy curriculum for family medicine resident physicians. Debbie C . Byrd, Pharm.D., Charles T. Taylor, Pharm.D., Bobbi B. Adcock, M.D.; Auburn University; University of Alabama.

PURPOSE The adequacy of physicians' pharmacotherapy training has often been questioned; numerous examples of inappropriate and irrational medication management have been documented. A vast number of new medications are marketed each year. Patients receive more medications on average, thus increasing the risk of adverse drug events and interactions. Therefore, incorporation of applied pharmacotherapy education in medical residencies is critical. Unfortunately, most medical residency curricula do not include formal pharmacology and therapeutics instruction. Our purpose is to describe the development of a pharmacotherapy curriculum for family medicine (FM) resident physicians. METHODS Development of curriculum content included a literature review for models of clinical pharmacotherapy instruction and a survey of FM faculty to identify specific practice needs. In addition, a pharmacotherapy survey was administered to FM residents to determine knowledge of new medications, adverse drug events, and interactions. The curriculum emphasizes evidence-based medicine by incorporating a review of consensus statements for common disease states. The course is a 6-month longitudinal experience, with first year FM residents meeting weekly for approximately two hours. Teaching methods are centered on problem solving and application, utilizing actual patient cases to reinforce medication management principles. Course instructors include pharmacy faculty and residents. Course evaluations and re-administration of the pharmacotherapy survey will document cumculum effectiveness. RESULTS: Based on resident pharmacotherapy survey scores (mean = 56.9%), the FM department and FM residency program director approved the pharmacotherapy curriculum. CONCLUSION: Pharmacotherapy instruction in medical residencies is another approach clinical pharmacists may employ to influence prescribing and improve patient care.

205. Development of an anticoagulation service in a family medicine residency program. Zla V. Mehra, Pharm.D., BCPS, Stacey L. Abby, Pharm.D.; Deaconess Hospital; St. Louis College of Pharmacy, St. Louis, MO.

PURPOSE: An anticoagulation service was developed within a family medicine physician residency program to standardize warfarin therapy and educate family medicine residents. METHODS: Patients are scheduled for an initial education session with a clinical pharmacist when warfarin is started. All INR results are forwarded to a clinical pharmacist, who calls the patient for assessment of compliance, dose, other medications, diet, and symptoms of bleeding or thrombosis. Doses are adjusted as needed according to a protocol which has been reviewed and signed by all attending physicians and residents in the clinic. A postcard is sent with dose information and date of next INR. A voice mail message and chart note, detailing how and why dosage adjustments were made, are left for the physicians to allow for learning. In addition, all first year physician residents spend one-on-one time with the clinical pharmacists as part of a required pharmacotherapy rotation learning guideline-based warfarin management, directly evaluating INR results, adjusting doses, and educating patients.


RESULTS: Twenty patients in this clinic are enrolled in the service to date. Nine family medicine residents have completed the anticoagulation training. We are in the process of evaluating if this experience has been of educational value to the medical residents. Preliminary survey results show an improvement in understanding about warfarin management based on a 5- point Likert scale. CONCLUSION: This anticoagulation service in a family medicine residency program promotes standardized warfarin management and is a method of teaching physician residents appropriate evaluation, dosage adjustment, follow up, and education of patients on warfarin.

206. The impact of a conjointly taught hioethics course on future clinical practices of pharmacy and medical students. Natalia Kujdych, Pharm.D., Douglas Anderson, Pharm.D., Sara Noble, Pharm D., Nancy Tatum, M.D; University of Mississippi, Jackson, MS.

PURPOSE: This study determined whether a bioethics course taught conjointly to medical and to pharmacy students would have the same impact on both sets of studenls regarding their future clinical practices. METHODS: A student survey was distributed to 34 pharmacy and 31 medical students after completing a conjointly taught biomedical ethics course. The survey consisted of questions evaluating the influence the course had on the students’ future clinical practices. The survey included questions regarding use of complementary medicine, assisted suicide, and beginning of life issues. RESULTS: Both pharmacy and medical students felt the course provided them with a better understanding of assisted suicide and beginning of life issues. However, neither group felt that the course influenced their future clinical practices. A significant portion of medical students (66.7%) felt the course would influence their practice regarding complementary medicine; however, only 34.37% (p=0.013) of the pharmacy students’ practices would be influenced. The course provided more medical students than pharmacy students (77.4% vs 40%, p=0.0025) with a better understanding of their professional ethical responsibilities. Medical students gained a better understanding of pharmacy’s ethical responsibilities than pharmacy students did of medicine’s ethical responsibilities (83.9% vs 37.1%, p=O.OOOl). The course influenced the future practices of medical students more than it did pharmacy students (19.4% vs 8.6%, p=0.0598). CONCLUSION: A greater percentage of medical students’ future practices were influenced by the conjointly taught bioethics course. It will be necessary to further examine why pharmacy students were not as influenced. It may require modifying the course.

207. Improving HbAI, values and adherence to the standards of care for patients with diabetes mellitus. Kelly R. Snyder, Pharm.D., Alexander Chessman, M.D., Dena Clair, B.S.N., Lori L. MacFarlane, Pharm.D., BCPS; Medical University of South Carolina, Charleston, SC.

PURPOSE: Diabetes mellitus is the third most common reason for visiting the MUSC Family Medicine Center, where approximately 900 patients carry the diagnosis. Using a multidisciplinary continuous quality improvement (CQI) approach, our goal is to improve HbAI, values and adherence to the American Diabetes Association (ADA) standards of care for this population. METHODS: The CQI team reviews the computerized record of randomly selected diabetic patients and evaluates adherence to ADA standards of care. Recommendations regarding drug therapy and laboratory monitoring are formulated and provided to the primary physician upon the patient visit. The physician can then assess the recommendations and make appropriate interventions. In addition, computerized flags are placed in selected patient charts to remind providers to measure HbA1, values. RESULTS: Significant improvements in HbA1, values have occurred for the Center as a whole. For example, in 1996, 10% of patients had a HbA1, less than 7.0%. As of February 1998, this percentage of patients increased to 25%. In 1996,60% of patients had a HbAi, greater than 9.0%. As of February 1998, this percentage of patients decreased to approximately 35%. For patients specifically assigned to the CQI chart review, HbA1, values have also improved. Improved adherence to a yearly urinalysis and lipid profile and use of angiotensin-converting enzyme inhibitors for documented proteinuria has been observed as well. CONCLUSION: The CQI approach may benefit patients with diabetes in terms of blood glucose control and receiving the appropriate standards of care. The overall patient population may benefit from the efforts of the CQI team as physicians may apply recommendations beyond the selected population.

208. Patient satisfaction and safety of a community pharmacy-based influenza vaccination program. Mary F. Hebelt, Pharm.D., John F. Hebert, B.S., Kathleen R. Hebert, B.S.; University of Washington, Seattle, WA; Manhattan Pharmacy, Seattle, WA.

PURPOSE: This study was designed to evaluate patient satisfaction and adverse reaction rate of a community pharmacy-based influenza vaccination program. METHODS: ~ l l 211 patients receiving influenza vaccines at the community pharmacy during the 1996-1997 influenza season were included in this study. Immediately after administration of the vaccine, patients completed an

anonymous survey measuring patient satisfaction with the vaccination service. Patient satisfaction was ranked on a scale from 1 (poor) to 5 (excellent). Two weeks following vaccinations, patients mailed back to the pharmacy a questionnaire reporting the presence or absence of adverse effects. RESULTS: Patient satisfaction was in the very good to excellent range for the overall visit (mean rank 4.6). the technical skill of the pharmacist had a mean rank of 4.7, the convenience of receiving the vaccine in the pharmacy had a mean rank of 4.7, and the vaccination cost relative to other providers had a mean rank of 4.6. Eighty-four percent of the questionnaire responders had no adverse reactions. Nine percent of the responders developed mild flu-like symptoms, and seven percent developed soreness at the injection site. No serious adverse reactions, allergic reactions, or infections were reported. CONCLUSION: Patient satisfaction was very good to excellent and appeared to enhance the professional atmosphere of the pharmacy. The influenza vaccine can safely be given in the community pharmacy setting with adverse reaction rates approximating those previously reported.

209. Pharmacist interventions regarding nonsteroidal antiinflammatory drug therapy in a geriatric nursing facility: a 1-year study of costs and outcomes. James W. Cooper, Ph.D., William E. Wade, Pharm.D.; University of Georgia, Athens, GA.

\ PURPOSE: The purpose of this project was to document cost savings which would occur with pharmacist interventions regarding nonsteroidal antiinflammatory drug (NSAID) therapy in the treatment of osteoarthritis in a long-term care facility. METHODS Interventions were prospectively made in all patients resident for 30 or more days over the 12-month study period receiving NSAID therapy for osteoarthritis. These interventions consisted of 1) requested hemoglobin and hematocrit baseline and repeat determinations every two months; 2) physical assessment of lower eyelid and nailbed as well as stool color; and 3) recommendation for replacement of NSAID with acetaminophen or the ~

addition of gastroprotective pharmacotherapy (misoprostil) if the NSAID was continued. Patients not receiving an NSAID for osteoarthritis served as a non- intervention (control) group. Cost minimization calculations were performed for existing regimens versus cost savings which would be experienced with suggested pharmacotherapeutic interventions. These costs were compared to the costs of the non-intervention group. RESULTS: Fourteen intervention subjects and 16 patients receiving regularly scheduled acetaminophen (non-intervention group) over the study year were identified. Five patients in the intervention group developed gastrointestinal bleeding, necessitating six hospitalizations for a total cost of $85,200. Total NSAID-related costs of this group was $91,554.71. Two of these patients died. No non-intervention patients experienced gastrointestinal bleeding and total costs of their analgesic therapy was $3,410.06. Cost savings with acetaminophen substitution in the intervention group would exceed $91,000, while cost savings with the addition of hemoglobinlhematocrit determinations would exceed $84,200. Finally, the addition of misoprostil to the NSAID would result in cost savings exceeding $73,000. CONCLUSION: Refusal to accept pharmacist interventions regarding NSAID pharmacotherapy in this nursing facility is associated with considerable costs, morbidity, and mortality.

210. Pharmacist-managed home low molecular weight heparin treatment program: a report of patient outcomes and clinical experience. Tara L. Posey, Pharm.D., Meredith L. Rose, Pharm.D., Kerry A. Cholka, Pharm.D., Richard J. Ptachcinski, Pharm.D., Kristine E. Santus, Pharm.D., Melissa A. Somma, Pharm.D., Patrick P. Gleason, Pharm.D.; University of Pittsburgh Medical Center, Pittsburgh, PA.

PURPOSE: Home use of low molecular weight heparin (LMWH) in combination with warfarin enables patients to be discharged from the hospital prior to achieving a therapeutic INR. Our objective was to develop and evaluate a pharmacy-based program using LMWH as bridge therapy for patients requiring therapeutic anticoagulation. METHODS: Medically stable patients with deep vein thrombosis (DVT), pulmonary emboli (PE), status-post cardiothoracic (CT) surgery, or other thromboemholic diagnosis requiring anticoagulation were eligible. Upon discharge, patients received subcutaneous injections of enoxaparin (1 mgkg BID) until two consecutive therapeutic INRs were obtained. Clinical pharmacists provided patient education, dispensing of enoxaparin, adjustment of warfarin doses, patient follow up, and communication with the patients’ physician. The primary efficacy outcome was the incidence of thromhoembolic events. Outcomes to evaluate safety included minor bleeding, major bleeding, and death. Assuming the patient would have remained hospitalized on intravenous unfractionated heparin until oral anticoagulation was therapeutic, a decrease in hospital length of stay was calculated from the number of outpatient days of LMWH. RESULTS: Complete follow-up data is available on 79/89 treated patients. Indications for treatment included DVT (n=29), CT surgery (n=26), PE (n=5), atrial fibrillation (n=10), and other (n=9). Three patients experienced R new or recurrent thromboembolic event within the follow-up time period. While the most common adverse effect was bruising at the injection site


(45.5%). three major bleeding events occurred in two patients following enoxaparin therapy. One death attributed to a stroke occurred in a 90-year- old patient. Five additional deaths were due to causes unrelated to thromboembolism or bleeding. Seventy-one of the patients self-reported that they were “very satisfied with the service. Patients treated with this program had a mean hospital length of stay decrease of 4.9 days resulting in a savings of over $350,000. CONCLUSION: A pharmacy-based program using the LMWH enoxaparin as bridge therapy represents a safe, effective, lower cost means for managing anticoagulation that is well accepted by patients.

211. A multidisciplinary approach to developing and implementing a novel low molecular weight heparin treatment program. Maureen E. Knell, Pharm.D., Mark Woods, Pharm.D.; University of Missouri at Kansas City; Saint Luke’s Hospital, Kansas City, MO.

PURPOSE: With the advent of low molecular weight heparins (LMWH) and the potential to provide full anticoagulation using weight-based doses, practitioners and institutions are now faced with evaluating their role for new indications. Pharmacokinetic advantages of LMWH over unfractionated heparin allow once or twice daily subcutaneous administration and require no routine anticoagulation monitoring. Consequently, as an alternative to continuous infusion heparin, LMWH w t h or without conversion to warfarin can be managed on an outpatient basis, thus reducing costs by eliminating or decreasing the length of stay. However, few models exist from which to develop a LMWH treatment program for multiple therapeutic indications. METHODS: A multidisciplinary committee of physicians, nurses, and pharmacists was convened to I ) assess LMWH use for new indications; and 2) develop a treatment program emphasizing cost-effective, quality, and continuity of care initiatives in the cases where LMWH treatment was considered beneficial. RESULTS: Development of a LMWH treatment protocol was structured in four phases: I ) evaluation of literature; 2) development of the protocol, including creation of a novel standing order promoting collaboration across a continuum of care; 3) education program for medical and hospital staff prior to protocol implementation; and 4) follow up for quality improvement and cost-efficacy outcomes. Staff pharmacists play a key role in the process by providing consults on dosing and monitoring, patient education prior to discharge, and follow-up phone calls to assess patient outcomes. CONCLUSION: A multidisciplinary team developed a LMWH treatment protocol in which pharmacists play a valuable role in drug therapy consulting and patient education.

212. HIV pharmaceutical care specialist: an alternative model of care for patients with HIV. Lori D. Esch, Pharm.D., Mark J. Shelton, Pharm.D., Gene D. Morse, Pharm.D., Ross G. Hewitt, M.D.; State University of New York at Buffalo; Erie County Medical Center, Buffalo, NY.

PURPOSE: Medication adherence is a critical factor in determining virologic and clinical responses to antiretroviral therapy (ARVT). A program was designed involving pharmacist interventions to enhance medication adherence. METHODS Our model of care integrates a Pharm.D.-trained pharmaceutical care specialist (PCS) into the existing multidisciplinary team, focusing on improved patient care. Services are provided both on a consultant basis and routinely for prospectively identified patients. An interactive database allows the PCS to monitor all medications, intolerances, adherence, surrogate markers, medical events, hospitalizations, genotyping, and PCS interventions. Prospectively, drug interactions are identified and education, coaching, and follow up are provided. All plasma HIV-RNA results are reported to the PCS for review, adherence assessment, computerization, and recommendations. RESULTS: The PCS received 438 consultations to see 234 HIV-infected ambulatory patients. Referrals were from physician assistants (24%), physicians (20%), nurses (16%), nurse practitioners (3%), social workers (1.5%), patients (9%), and 26% were identified by the PCS. Reasons for referral included unacceptable HIV-RNA results (24%), non-adherence (17%), initiation of new antiretrovirals (16%), adverse drug reactionddrug interactions (12%), follow up after medication changes ( l l%), and interpretation of genotype results (4%). Two hundred one patients (46%) were seen during regular clinics, 25% were consulted by phone, 13% were seen specifically by the PCS, and 16% were chart reviews only. Virologic responses to these interventions are currently being analyzed. CONCLUSION: The HIV PCS is highly qualified to evaluate the patients with complex drug regimens who are facing barriers to successful care, target the appropriate interventions, and follow up with the patients on a long-term basis.

213. Comprehensive pharmaceutical care in a dialysis unit. Jamie M. Finley, Pharm.D., Richard K. Lewis, Pharm.D., M.B.A., Stephen Lietz, M.D., Jose A.L. Arruda, M.D.; University of Illinois at Chicago, Chicago, IL.

PURPOSE: Pharmacy services for the dialysis unit are being provided to over 110 patients with the goal of optimizing drug therapy through pharmacotherapist consultation. This service consists of the provision of on-

site pharmaceutical care services (i.e.. INR monitoring, diabetes education, pharmacokinetics. lipid monitoring) including drug preparation and prescription dispensing. METHODS: As a member of the dialysis team, the pharmacotherapist works with patients and health care providers in selecting and monitoring drug therapy, while educating and training pharmacy students and residents. This role is based in ambulatory care, but also includes the provision of drug information to inpatient services. Also, the pharmacotherapist participates in dialysis care conferences and provides medical residents with instruction on the pharmacotherapeutic considerations of the dialysis patient. As a member of the pharmacy team, the pharmacotherapist assures the continuity of pharmacy services between the clinic site and the areas of pharmacy drug preparation and distribution. This includes “chairside” delivery of medications to the patients while receiving dialysis. Continuity of care between the hospital and clinics is also a responsibility of the pharmacotherapist. This requires active communication with the inpatient pharmacy staff and medical resident, as well as time on the inpatient unit. CONCLUSION: This is a unique and promising role for providing pharmaceutical care in an environment where continuity in the provision of health care is desperately needed. It is also an opportunity for the pharmacist to establish hidherself as an indispensable part of the health care team.

214. Multidisciplinary management of corticosteroid-induced osteoporosis in an outpatient nephrology clinic. Melanie 5. Joy, Pharm.D., Clara D. Neyhart, B.S.N., Mary Anne Dooley, M.D., Susan L. Hogan, M.P.H.; University of North Carolina, Chapel Hill, NC.

A multidisciplinary clinic for complicated bone disease was established on the basis of a high prevalence of osteoporosis in corticosteroid-dependent renal insufficiency patients with a history of transplantation or chronic glomerulonephritis. Referral to the clinic was based on documented osteoporosis or high risk of fractures. Multidisciplinary assessments were performed by a clinical pharmacist, nephrology nurse, and rheumatologist. The components of the clinic included medicatioti histories with emphasis on drugs affecting calcium balance, medical history documenting risk factors, and a physical examination focusing on the musculoskeletal system. The team discusses the results of the visit with the patient and referring nephrologist, with subsequent medication, dietary, and physical activity prescribing and counseling. Follow-up bone densitometries are scheduled 6-12 months after the baseline visit to guide interventions. Twenty-nine patients (15 male, 14 female) have been evaluated in this clinic since its initiation in December 1997. Forty-five percent of patients had established osteoporosis, whereas 66% had either osteoporosis or a fracture history or both. Analysis revealed low 1,25-hydroxyvitamin D, levels (n=8), hormone deficiency (n=8), elevated parathyroid hormone (n=15), and a history of receiving at least one other risk medication in addition to corticosteroids (n=27). Thirty-eight percent of patients had a documented height loss (mean 1.5 inches). Other risk factors included 16 episodes of graft rejection requiring additional corticosteroids, smoking history (n=l2), poor physical activity (n=9) and low dietary calcium intake (n=15). Medication interventions included calcium and vitamin D (n=20), calcitonin (n=7), alendronate (n=8), and hormonal replacement therapy (n=6). An organized clinic which assesses osteoporosis risks can uncover a large population of patients with documented bone loss. Appropriate medication and lifestyle interventions may modify existing disease and decrease the predisposition to long-term complications.

215. A new perspective in practicing ambulatory care pharmacy: a comprehensive pharmaceutical care model at the University of Illinois at Chicago neurology clinic. Mahtab Hariri-Salehi, Pharm.D.; University of Illinois at Chicago, Chicago, IL.

PURPOSE: This model of practice was designed to provide a comprehensive pharmaceutical care service at all outpatient clinics, which uses a multidisciplinary clinical approach and dispensing functions via a remote prescription entry, in order to optimize economical, clinical, and humanistic outcomes of patient care. METHODS: A pharmacy office is setup at the University of Illinois neurology and neurosurgery clinic which is operated by one full-time pharmacist to provide both acute and chronic care clinical services, such as walk-in services, refill services, therapeutic management and compliance monitoring, drug information services, indigent patient management, discharge counseling, and medication teaching. The unique feature of this practice is the re-engineering of dispensing functions, so that the prescriptions are entered remotely by the clinic pharmacist, via an access to the outpatient pharmacy computer and then filled at the outpatient pharmacy while the patient is at clinic. Hard to manage, moderate to high complexity patients who are at risk for developing drug-related problems are identified by physicians and nurses and referred to the pharmacist for further follow up or therapeutic management. RESULTS: This practice encounters an average of five walk-in patients, reviews and processes 13 refill requests, three follow up patients for therapeutic management and compliance monitoring, five drug information questions and consultations, two indigent patient management, five discharge


medication counseling, and fills ten prescriptions daily. CONCLUSION: This accessible pharmacy model contributes to a decrease in unnecessary health care utilization, generates prescription revenue, provides continuity of care, optimizes therapy, prevents drug-related problems, promotes patient-pharmacist relationships, and improves patients' quality of life and overall satisfaction.

216. Decreased gentamicin and vancomycin levels in a level 111 neonatal intensive care unit. Temple L Bolhgcr, Cindy D. Stowe, Pharm D , Laura P. James, M.D., Michelle Pohlkamp, Pharin.D., Henry C. Farrar, M.D., Garry Enderlin, M.S.; Arkansas Children's Hospital; University of Arkansas, Little Rock, AR.

PURPOSE: The objective of this project was to evaluate a prospective therapeutic drug monitoring (TDM) program designed to cliininate unnecessary gentamicin (GENT) and vancomycin (VANC) levels. METHODS: Data from the second quarter (October through December) of three consecutive years (1995-1997) were compared with data from 1995 serving as baseline. Implementation of the TDM program occurred July 1996, and beginning in February 1997, a decentralized pharmacist was stationed in the neonatal intensive care unit (NICU) five days a week. The number of courses, length of therapy, and number of levels for GENT and VANC therapy were recorded and compiled in spreadsheet format (Microsoft Excel%o). A one-way analysis of variance with a Bonferroni comparison to determine location of differences was used. All data are presented as mean * SD with the level of significance set at a = 0.05. RESULTS: Three hundred twenty-one courses of GENT and 198 courses of VANC were evaluated. There was no difference in length of therapy between years for either GENT or VANC. The number of levels per day of GENT and VANC therapy significantly decreased (p<0.00005) and was maintained over the study period (GENT leveldday: 0.39 * 0.3 in 1995; 0.27 * 0.3 in 1996; 0.16 * 0.2 in 1997 and VANC leveldday: 0.54 I 0.4 in 1995; 0.37 * 0.3 in 1996; 0.27 * 0.3 in 1997). There was a significant reduction in the number of levels per day of therapy in those courses that were 5 7 days in length (GENT, p<0.005 and VANC, p<0.05). CONCLUSION: A prospective TDM program developed and maintained by both physicians and pharmacists reduced the number of unnecessary levels per day of therapy for both GENT and VANC.

217. Prospective therapeutic drug monitoring program in a tertiary care, pediatric hospital. Cindy D. Stowe, Pharm.D., Temple L. Bolliger, Laura P. James, M.D., Henry C. Farrar, M.D., Garry Enderlin, M.S.; Arkansas Children's Hospital; University of Arkansas, Little Rock, AR.

PURPOSE: The objective of this project was to evaluate a therapeutic drug moni tor ing (TDM) program designed to e l imina te unnecessary aminoglycoside (AG) and vancomycin (VANC) levels. METHODS Data from the second quarter (October through December) of two consecutive years (1995 and 1996) were compared. The TDM program started in July 1996, therefore data from the second quarter of 1995 served as the pre-TDM program baseline for comparison. The number of courses, length of therapy, and number of levels per course and day for AG and VANC therapy were recorded and compiled in spreadsheet format (Microsoft ExcelTM). A two-sample t-test with a Bonferroni adjustment was used to compare 1995 to 1996 data. All data are presented as mean + SD with the level of significance set at a = 0.05. RESULTS: Two hundred eighty-nine courses of AG and 230 courses of VANC were evaluated. The AG courses cowist of 205 courses of gentamicin (GENT) and 84 courses of tobramycin (TOB). There was no difference in length of therapy for either the AG or VANC. The number of levels per day of AG therapy significantly decreased (p<0.05; leveldday of therapy: 0.72 * 0.9 in 1995 and 0.48 f 0.4 in 1996). The greatest impact of the TDM program was found on GENT therapy (p<0.05; leveldday of therapy: 0.73 + 1 in 1995 and 0.40 * 0.4 in 1996). There was a positive trend of decreased number of levels per day of therapy for VANC (0.79 * 1.1 in 1995 and 0.57 * 0.6 in 1996) but it was not statistically significant. CONCLUSION: A prospective TDM program developed and maintained by both physicians and pharmacists resulted in a positive impact o n the reduction of unnecessary AG and VANC levels per day of therapy.

218. Implementation and evaluation of an indigent patient medication assistance program in a multi-specialty community group practice. Rachel D. Leder, Pharm.D., BCPS; St. Louis College of Pharmacy, St. Louis, MO.

PURPOSE: Practitioners in this multi-specialty community group practice recognized that a large percentage of their patients were unable to afford their medications. The purpose of this project was to implement and evaluate a system to help uninsured patients receive medications from industry- sponsored indigent assistance programs. METHODS: Patients without medication insurance were referred to the pharmacist . Medication histories were performed and reviewed for appropriateness, therapeutic duplication, and possibility of substituting less expensive therapies. When all medications were assessed as proper, and an affordable substitution could not be found, patient financial status was assessed. If patients qualified for an industry-sponsored indigent assistance

program, the pharmacist helped complete applications and then forwarded these forms to the physician Companies that offered "easy to access" assistance programs were most commonly used. Patients were supplied with samples, i f available, during the intcrini period between application submission and receipt of medication by the clinic. When the medications were received, patients were scheduled for pick-up and counseling on proper use. RESULK During a 6-month period, 81 applications were completed and mailed to pharmaceutical companies for 47 patients. Seventy-nine (98%) of the requests were honored with a 3-mouth supply ot medication. A total of eleven different companies were accessed successfully with an average turnaround time of 25 days (range 7 4 3 days). CONCLUSION: Many pharmaceutical companies will supply indigent patients with selected chronic incdications. A program designed to identify, refer, and follow up qualifying indigent patients is successful in obtaining chronic medications within a reasonable time period.

219. Optimizing erythropoietin utilization using an interactive on-line ordering system. Susnii M. IlntJield, Phu1ni.D , Naoini V. Dahl, Pharm.D., Jaqueline L. Fein, Pharm.D., Sonia M. Arias, Pharm D., Gail Stratemeier, B.S.N., Maureen M. Bueno, B.S.N., Ph.D., Edward F. Foote. Pharm.D., Michael J . Nissenblatt, M.D., Andrew B. Covit, M.D., Richard A. Sherman, M.D.; Robert Wood Johnson University Hospital, New Brunswick, NJ; UMDNJ-Robert Wood Johnson Medical School, New Brunswick, NJ; Rutgers, The State University of New Jersey, Piscataway, NJ.

PURPOSE: Erythropoietin (EPO) was the third largest item in the pharmacy budget of our 400-bed academic medical center. While evidence-based guidelines for EPO use i n renal failure and oncology patients exist, no specific strategies to maximize effect and minimize waste have been published. To optimize utilization, we addressed all five components of the medication use process in adult inpatients and implemented a computerized ordering and tracking system. METHOD: Starting in 1996, a multidisciplinary committee addressed 1) formulary (multidose vials); 2) prescribing (computer and guidelines); 3) dispensing (centralized distribution using zero-deadspace syringes); 4) administration (use of SQ route); and 5) monitoring (computer printout to identify outliers, reason for use, relevant laboratory values, prescriber). Computerized prescribing prompts included patient selection, dosage guidelines, optimal administration route, concurrent therapy, and laboratory monitoring. Use outside the guidelines prompted pharmacist intervention. RESULTS:

DUE Pre and Post-Implementation Renal Oncology Pre Post Pre Post

(n=20) (n=34) (n=60) (n=24) Dosed according to guidelines 25% 54% 45% 100% - . SQ route 25% 56% 18% 33% Fe studies documented, 30% 75% 17% 52%

Hct > 36% 25% 0% 23% 8% Mean weekly EPO dose (units&) 392 324 584 420

Restructuring drug preparation and delivery process did not result in missed doses or significant increases in workload. Based on five m o n t h s data, annualized cost savings are approximately $100,000 (census did not change during the time periods). CONCLUSION: An interactive computerized order form and tracking system along with centralized distribution had a substantial impact on EPO utilization, but necessitated frequent intervention by a pharmacist.

220. Development and implementation of a pharmacist-managed diabetes care clinic. Scott R. Drab, B.S., Patrick Gleason, Pharm.D., BCPS; University of Pittsburgh, Pittsburgh, PA.

PURPOSE: To describe the development and implementation of a diabetes care clinic (DCC) in a community pharmacy setting. METHODS: The DCC is located in a community pharmacy and staffed by a certified diabetic educator (CDE) pharmacist, podiatrist, dietician, and exercise physiologist. Policies a n d procedures addressing purpose , responsibilities, guidelines for patient enrollment, patient education, and reimbursement were written and approved. Patient insurance billing forms were created. The state of Pennsylvania and the DCC have also entered into a capitated agreement to manage 20 patients who had three or more emergency department visits for diabetes-related complications in the past 12 months. Patients are referred by their physician, pharmacist, or through self-referral. New patients undergo four 2.5-hour group comprehensive sessions: 1) introduction and overview; 2) meal planning, hypoglycemia, medications, and blood glucose monitoring; 3) food labels, recognition and treatment of complications, and specialized care; and 4) dining out, sick days, exercise, stress management, review, and evaluation. Patients are assigned a, CDE pharmacist for care plan development and follow up. Follow-up visits are scheduled for review of all medications, specialized education, determination of control, and dosage adjustments. All activities are billed, documented in the medical record, and communicated to the physician.

appropriate supplementation


RESULTS: Of the 12 DCCs in Southwestern Pennsylvania, data is presented from one clinic. Thirty-eight patients ranging in age from 49-84 years have been followed in the DCC for more than 6 months The mean baseline average fasting blood glucose (AFBG) was 174 mg/dl; after 6 months, the mean AFBG was 144 mg/dl (17% decrease). Thirty-two patients experienced a decrease in blood glucose while six patients experienced either no change or an increase. AFBG was used in place of glycosylated hemoglobin due to Clinical Laboratory Improvement Amendment restrictions. Patients’ visits were 15-30 minutes and billed, on average, at the rate of $l/minute. Compensation was received from both patients and insurers. CONCLUSIONS: This pharmacist-managed approach to diabetes care resulted in mean AFBG reductions while generating additional revenues for the pharmacy. Future research should be done to demonstrate improved medical outcomes

221. Pharmaceutical care in a comprehensive asthma clinic. Jerome F. Pierson, Ph.D , Daren L. Knoell, Pharm.D., Dev 5. Pathak, D.B.A., Clay B. Marsh, M.D., James N. Allen, M.D; U.S. Army Medical Research and Material Command, Fort Detrick, MD; The Ohio State University Medical Center; Columbus, OH.

PURPOSE: Describe the implementation and evaluation methodology of a pharmaceutical care program in a comprehensive asthma clinic at a university medical center. Pharmaceutical care was incorporated into the process of care provided by a group of pulmonologists based on National Heart Lung Blood Institute guidelines for asthma care. Evaluation of care was based on the structure, process, and outcomes methodology proposed by Donabedian; and the economic, clinical, and humanistic outcomes (ECHO) model proposed by Kozma, Reeder, and Schulz. The results from a pre-test, post-test non- equivalent control group experiment involving this clinic have been submitted for publication in Pharmacotherapy. This poster presentation describes only the establishment of the pharmaceutical care program. METHODS: The structural change to this pulmonary medicine practice was the addition of the pharmacist to the care provided by a group of three pulmonologists who scheduled their asthma patients for an “asthma clinic”. As part of the clinic team, the pharmacist interacted directly with the physician and the patient. Process variables measured included delivery of information necessary for self-treatment and assessment of patient capability to correctly use inhaled medications and a peak flow meter. Data collection methodology regarding economic, clinical, and humanistic outcomes involved multiple instruments and methods for obtaining data. CONCLUSION: Incorporation of pharmaceutical care into the comprehensive asthma clinic provided an opportunity to improve patient outcomes, serve as a demonstration project of pharmaceutical care in a specialty clinic, and demonstrate a methodology for documenting outcomes important to the patient, the institution, and the pharmacy profession.

222. Pharmacist-managed smoking cessation clinic i n an inner city population. Lori A. Wilken, Pharm.D., Susan R. Winkler, Pharm.D., BCPS, Julia L. Seabolt, Pharm.D., BCPP University of Illinois at Chicago, Chicago, 1L.

PURPOSE: To describe the implementation and outcomes of a pharmacist- managed smoking cessation clinic (PMSCC) in a predominately inner city patient population. METHODS: The clinic meets one-half day per week and incorporates behavioral counseling with drug therapy, if appropriate. All patients must agree to attend a minimum of four 1-hour group sessions held weekly. The pharmacist initially takes a complete medical and smoking history. The method of smoking cessation is individualized based on the patient’s preference and medication contraindications. Nicotine dependence is assessed using the Fagerstrom Tolerance Test. Expired air carbon monoxide (CO) readings are taken at baseline and at each follow-up visit. Patients are subsequently assessed at 6 weeks, 3 months, and 6 months regarding smoking status and CO readings. RESULTS: Between January 1997 and May 1998,44 patients attended at least one session. Twenty- percent (nine) of the patients completed all four sessions. The majority of patients were female (59961, African-American (64%), and received Medicaid (52%). They had an average smoking history of 31 pack-years and 20% were receiving an antipsychotic medication. Data for the 6-month follow up was available in 26 patients. At 6 months, 19% (five) of the patients remained abstinent. Of the successful patients, two utilized nicotine replacement therapy, two quit cold turkey, and one selected the tapering method. CONCLUSION: Many barriers to success exist in this patient population, including co-morbid conditions and financial considerations. The PMSCC shows a positive impact on the quit rate in these patients and is similar to that reported in the literature.

223. Cost analysis of renal transplantation recipients’ medications 1-year post t ransplan ta t ion : identification of s t ra teg ies for pharmacis t intervention. Marie A. Chisholm, Pharm.D., Tana R. Bagby, Pharm.D., Joseph T. DiPiro, Pharm.D., William E. Wade, Pharm.D., J . Russell May, Pharm.D.; University of Georgia, Athens, GA; Medical College of Georgia, Augusta, GA.

PURPOSE: Medication-intensive treatments used in renal transplant patients present opportunities to reduce drug cost through pharmacist interventions. This study was undertaken to analyze the outpatient cost of pharmacotherapeutic regimens prescribed to renal transplant recipients during the first year after transplantation and identify strategies to reduce medication cost. METHODS: All patients who received a renal transplant at the Medical College of Georgia (MCG) in 1995 and 1996 and who received follow-up care at the MCG Renal Transplant Outpatient Clinic during the first year following transplantation were included in the study. Data collected included each patient’s age, gender, race, transplant donor type, and medications prescribed (including strength, frequency, and duration of therapy). The AWP for each medication was used to calculate the cost of medication therapy to the patients. Medications were classified according to treatment indications. RESULTS: Of the 110 renal transplants performed, 91 patients (82.7%) were included in the study. The population was 48% female, 45% Caucasian, 55% African-American, and had a mean age of 47.4 f 13.9 years. Donor types were as follows: 44% living related, 44% cadavers, 8% living unrelated, and 4% living related with identical matches. The mean AWP for medication therapy dur ing the first-year post transplantation was $14 ,557 f $4193. lmmunosuppressives (73.5%), antibiotics (13%), antihypertensives (6.3%), antisecretory (3.6%), anti-diabetic (0 .5%) , cholesterol lowing (0.7961, antidepressants (0.7%), and other medications (1.7%) accounted for total cost. CONCLUSION: The analysis revealed a mean AWP of greater than $14,5 0

agents accounting for greater than 95% of the total outpatient drug cost. Pharmacist intervention programs should focus on other costly medication classes such as antibiotic, antihypertensive, and antisecretory therapy in addition to immunosuppressant therapy. As of October 1997, a pharmacist intervention program designed to promote therapeutic substitution with less costly but equally effective drugs and discorltinuation of unnecessary medications has been established in this population.

224. Analysis of pharmaceutical care provided by a clinical pharmacist in a renal transplant clinic. Marie A. Chisholm, Pharm.D., Tana R. Bagby, Pharm.D., Joseph T. DiPiro, Pharm.D., J. Russell May, Pharm.D.; Medical College of Georgia, Augusta, GA; University of Georgia, Athens, GA.

PURPOSE: Data regarding pharmaceutical care activities were prospectively collected for six months after beginning the program in October 1997. Objectives included 1) identifying, documenting, solving, and preventing medication-related problems; 2) documenting the number and types of recommendations made by the clinical pharmacist to the clinic’s physicians; 3) determining the physician acceptance rate of these suggestions; and 4) determining the potential impact of the clinical pharmacist’s recommendations on patient care. METHODS: The clinical pharmacist visited clinic patients, performed medication reviews, and was responsible for preventing or resolving patients’ medication-related problems and providing appropriate pharmacotherapy recommendations. All recommendations that were made by the renal transplant clinical pharmacist from October 1997 to April 1998 were classified according to medication-related problem and class of medication. Two pharmacists (other than the renal transplant pharmacist) independently evaluated each accepted recommendation by using Hatoum’s criteria for assessing potential impact on patient care. RESULTS During the 6-month study period, approximately 96% (n=275) of the recommendations were accepted by the clinic’s physicians. Untreated indication (31%), overdosage (25%), and subtherapeutic dosage (16.4%) accounted for greater than 72% of the medication-related problems. The most commonly accepted recommendations involved cardiovascular (33.8%) and immunosuppressant (33.5%) medications. More than 96% of the recommendations were judged to have a significant (72%) or a very significant (24.4%) potential impact on patient care. CONCLUSION: During the first six months of the renal transplant clinical pharmacy services, the pharmacist performed pharmaceutical care activities that were well received by the clinic’s physicians and had a positive potential impact on patient care.

with immunosuppressive, antibiotic, antihypertensive, and antisecret B y

Research Institute The following papers, based on Fellowships and Research Awards provided by the ACCP Research Institute, will be presented. Full title and authors are listed, although a complete abstract may not be available for all papers at the time of this printing.

225. Merck and Company Pharmacoeconomics Fellowship: Economic outcomes of medication noncompliance. Sarah J. Billups, Pharm.D., BCPS, Barry L. Carter, Pharm.D., BCPS, Daniel C. Malone, Ph.D.; Kaiser Permanente; University of Colorado, Denver, CO.

PURPOSE: The objectives of this study were to 1) determine the relationship


between medication noncompliance and economic outcomes; and 2) identify potential indicators of medication noncompliance. METHODS: We used computerized prescription records from 1055 patients at nine different Veterans Administration Medical Centers who were at high risk for drug-related problems. A medication compliance ratio was calculated for a 12-month period and correlated with health care resource utilization (hospitalizations, clinic visits, laboratory, medication usage), demographic variables (age, gender, marital status, number of chronic conditions). medication-related variables (number of medications in regimen, number of changes in past year, taking a drug requiring therapeutic monitoring), and scores for health-related quality-of-life as measured by three domains of the SF-36. RESULTS: Correlation of the thirteen variables studied with medication compliance produced an adjusted rz=O.l 1 (p=O.OOOl). Four variables significantly correlated with medication noncompliance. Increased age (p=0.046), a higher number of chronic conditions (p<O.OOl), and more medications in a regimen (p<O.OOl) were positively correlated with medication compliance. That is, increased values for these variables were associated with better medication compliance. A higher number of medication changes in the past year was negatively correlated with medication compliance (p=0.004). An analysis correlating cost of health care usage (including hospitalizations, clinic visits, laboratory utilization, and medication usage) and medication compliance is underway. CONCLUSION: In this population, patients who were older had more comorbidities, and better medication compliance was associated with regimes having more medications. However, numerous changes in a medication regimen were associated with poorer medication compliance.

226. OrthoMcNeil Infectious Diseases Fellowship: Pharmacodynamic outcome parameters as predictors for fluoroquinolones in the treatment of anaerobic infections. M.L. Peterson, L.B. Hovde, D.H. Wright, A.D. Hoang, J.C. Rotschafer; University of MinnesoWRegions Hospital, St. Paul, MN.

Several fluoroquinolones (FQ) possess antibacterial properties against anaerobic (ANA) bacteria; however, optimal pharmacodynamic (PD) outcome parameters have not been defined for FQ in the treatment of these infections. FQ have been shown to he concentration dependent killers against aerobic gram negative bacteria with maximal bacterial killing achieved with an area under the concentration time curve divided by the MIC (AUUMIC) t 125. Application of these data to the treatment of ANA infections, however, would he an invalid assumption. The purpose of this investigation was to explore the PD parameters AUWMIC, peak drug concentration divided by the MIC (C,,/MIC) and time above MIC (T > MIC) as generic predictors of FQ activity against three strains of Bacteroidesfragilis (BF). Trovafloxacin (T) and levofloxacin (L) were used to generate time-kill curves with AUUMIC ratios of 50, 150, 250, 350, and 500. BF time-kill curves were produced using an in vitro PD model and Bactron IV anaerobic chamber. All experiments were performed in duplicate over 24 hours with a starting bacterial inoculum of lo6 CFUfrnl. AUUMIC, C,,/MIC, and T > MIC were analyzed for their effect on time to 3 log kill (T3K) and potential for regrowth at 24 hours. MICs for BF (ATCC 252851, BF (ATCC 23745), and a clinical isolate of BF were T: 0.25 mgiL, 1 mg/L, and 0.5 mg/L and L: 2 r n o , 4 mgfL, and 2 mg/L, respectively. Evaluation of the in vitro data showed, despite a 10-fold increase in AUUMIC ratios, no apparent decrease in T3K. T3K for T and L against the three strains of BF ranged from 4 to 8 hours and 3 to 8 hours, respectively. Despite an increase in C,,JMIC ratios from 3.5 to 35 for T and 4.4 to 44 for L, no significant change in T3K was observed. When time above MIC was evaluated for an effect on regrowth, no regrowth was observed for T or L unless the concentration fell below the MIC over the 24-hour time period. These data suggest FQ activity against BF cannot he enhanced by increasing T > MIC or C,,MIC, nor does an optimal AUUMlC ratio appear to exist.

227. RhSne-Poulenc Rorer Oncology Fe l lowship : Polymorphic trinucleotide repeat region in the androgen receptor as a predictor of clinical outcome. Hea-Kyoung H. Cho, Pharm.D., Shannon C. Dixon, Ph.D., Margaret E. Johnson, John H. Lee, Jing J. Yu, M.D., Yi Guo, B.S., William D. Figg, Pharm.D.; National Cancer Institute, National Institutes of Health, Bethesda, MD.

PURPOSE: Prostate cancer is the most commonly diagnosed cancer in men in the United States. Prostate carcinoma often progresses to a hormone- refractory state where it is no longer dependent on androgens for growth. Exon 1 of the androgen receptor (AR) contains a highly polymorphic trinucleotide (CAG) repeat region that has been implicated in mediating transcriptional transactivation activity of the receptor. Shorter repeat lengths lead to increased transactivation, while longer repeats lengths lead to androgen insensitivity. A correlation between shorter repeat lengths and distant metastases, high stage and grade of cancer, and mortality has heen reported (Giovannucci, et al., Canc Res 1997). METHODS: We have developed a reliable and efficient method for extraction and amplification of DNA for this repeat region from stored frozen sera. These methods were developed to utilize large hanks of frozen sera stored from patients entered onto clinical trials. Several DNA extractions procedures were tested and DNA was assessed for quantity and quality based on

spectrophotometry, a fluorescence-based assay, and by PCR amplification. A modified extraction protocol of the QIA amp blood kit, a highly optimized PCR, and polyacrylamide gel analysis using SYBR green 1 staining has allowed us to successfully amplify 88.5% of the DNAs. Addition of a second nested PCR amplification prior to gel analysis increases the number of amplifiable DNAs to greater than 98%. Each PCR fragment is sequenced using a radio- labeled dideoxy terminator cycle sequencing approach to determine the number of CAG repeats. We are currently optimizing the sequencing methods for use on an ABI 377 automated DNA sequencer. As a control for possible cross-contamination and also as a potential independent risk factor for prostate cancer (Ingles, et al., J Natl Cancer Institute 19971, we are optimizing conditions for amplification and sizing of a polymorphic polyadenine repeat in the 3' untranslated region of the vitamin D3 receptor. RESULTS: Using this approach, we have begun to analyze a cohort of 200 hormone-refractory prostate cancer patients (> 98% Caucasian). In addition, the average CAG repeat length has been shown to he different in raciavethnic groups and this difference has been correlated with differences in prostate cancer risk for these groups (Coetzee and Ross, J Natl Cancer lnst 1994). We are currently collecting and analyzing the CAG repeat length of several raciavethnic groups (i.e., Native American, Hispanic, African American). To date, we have analyzed the CAG repeat length on 44 out of the 200 hormone- refractory patient sera. The CAG length ranges from 8-24 repeats with an average of 19.8 * 2.8 (mode = 18, median = 20). CONCLUSION: The study by Coetzee and Ross reported an average CAG repeat length of 22.0 i 0.2 in Caucasian men. Giovannucci, et al. has reported a CAG repeat range of 6-39 repeats in their study population. Thus, our preliminary results suggest that the CAG repeat length in these patients is slightly shorter than previously reported. Results from these patients will he compared to a normal control group. These data will be analyzed and correlations with clinical outcome will he made.

228. Wyeth-Ayerst Laboratories Psychopharmacy Fellowship: ~ - H T z A and 5-HT2c receptor polymorphism responsible for predicting clinical response to the antipsychotic agent olanzapine. Kristine A. Boer, Phatm.D., Paul J. Perry, Ph.D., BCPP, Vicki Ellingrod, Pharm.D , BCPP, Del Miller Pharm.D., M.D., Tim Holman M.A., Frank Fleming, B.S.N.; University of Iowa, Iowa City, IA.

Thirty acutely ill schizophrenics (DSM-IIIR) were administered olanzapine at fixed doses ranging from 7.5-17.5 m u d for 1-6 weeks. The mean plasma olanzapine concentration was 30.0 + 20.3 ngfml. The mean baseline Brief Psychiatric Rating Scale (BPRS) score was 50 2 12 with a final score 39 i 13. Fourteen (47%) of the subjects responded with the percentage change in the BPRS equal to or exceeding 20%. The Scale for Assessment of Negative Symptoms (SANS) score was 14 * 4 with a final score 10 * 4. Sixteen (53%) of the subjects responded with the percent change in the SANS equal to or exceeding 20%. The allele frequencies of the four ~ - H T ~ A receptor polymorphisms and the one 5-HT2c polymorphism were:

~ H T ~ A Genotype Distribution Response Rate Response Rate* 102TfC t TlOUTlO2 6 (20%) 416 (67%) 6/6 (100%) TlOUClO2 19 (63%) 9/19 (47%) 8/18 (44%) c l 0 U c l 0 2 5 (17%) 1/5 (20%) U5 (40%) Thr25Asn Thr25nhr25 25 (75%) 11/25 (53%) 14/24 (58%) Thr25/Asn25 5 (25%) 3/5 (60%) U5 (40%) His452Tyr

14/26 (54%) His45UHis452 27 (90%) 1U27 (44%)

Allele Olanzapine BPRS Olanzapine SANS

His45UTyr452 2 (7%) U2 (100%) U2 (100%) Tyr45UTyr452 1(3%) Of1 (0%) Of1 (0%)

516CfI C516fC516 29 (97%) 13/29 (52%) T516n516 1(3%) 111 (100%) 1/1 (100%)

5HT2, Genotype 23CydSer cys23/ cys23 25 (83%) 12/25 (61%) 14/24 (58%)

Ser23/Ser23 3 (10% U3 (67%) U3 (67%) *one SANS rating score was unavailable; tolanzapine SANS response rate distribution for 5HTLA-102TlC genotype significant (x' = 6 178; p=0.05); all other distributions were not significant

Two multiple linear regression analyses using the percentage change in the BPRS or SANS score as the individual dependent variables and the olanzapine steady-state plasma concentration, the number of weeks of olanzapine treatment at steady-state, and the five 5-HT polymorphism alleles, categorized as either homozygous dominant, heterozygous, or homozygous recessive, as the independent variables were performed. Of the five polymorphisks. the l02T to C substitution on the 5HTzA receptor appeared to he the most promising. Overall, the BPRS change score model explained 26% of the variance (F = 1.109, df = 7, RL0.26, p=0.39) while the SANS change score

15/28 (54%)

Cys23fSer23 2 (7%) 0/2 (0%) Of2 (0%)

1176 PHARMACOTHERAPY

model also explained 26"h of the variance (F = 1 0 6 9 , df = 7, R'= 0.26, p=0.42). The majority of the change score variance was explained by the model percenrage decrease BPRS = 0.121 (5HTra) allele + 0.004 (olanzapine concentration) - 0.159 (F = 3.655, dl =2, R'=0.21, p= 0.04). The inajority of the SANS change score was explained by the model percentage decrease SANS = 0.214 ( ~ H T L A ) - 0.209 (F = 5.732, df = I , R'=0.18, p= 0.02). These preliminary data suggest that the 5HT24 receptor 102 T tn C polymorphism is a potentially useful marker to predict response to olanzapine in acutely ill schizophrenic patients.

229. Amgen Biotechnology Research Award: Alteration in indinavir clearance during interleukin-2 infusions in HIV-infected patients. Sfuphen C. Piscirelli, Pharnt.D., Susan Vogel, B.S.N., William D. Figg, Pharm.D., Sangeeta Raje, M S., Alan Forrest, Pharm.D., Julia A . Metcalf, B A , Michael Baseler, Pb.D., Judith Falloon, M.D., National lnstitutes of Allergy and Inlections Diseases; National Cancer Institute, National lnstitutes of Health. Bethesda, MD; State University of New York at Buffalo, Amhrrst, NY; SAlC, Frederick, MD.

PURPOSE: To evaluate the effect of interleukin (111-2 infusions o n the pharmacokinetics of indinavir in H1V-infected patients. METHODS: Nine patients with CD4 counts less than 300 cells/nim' received indinavir 800 mg q8h and a 5-day continuous infusion of recombinant 1L-2 at doses ranging from 3-12 million international units (MIU) per day. Serial plasma samples were collected on days 1 and 5 of IL-2 for determination of indinavir concentrations. Samples were also collected over the study penod for determination of IL-6 concentrations. lndinavir concentrations were determined by a validated HPLC method and 11.-6 concentrations were measured with a commercial ELISA. lndinavir pharmacokinetic parameters were determined using both compartmental and noncompartmental methods. The data were fit by a 1-compartment model that allowed clearance to change based on IL-6 production. RESULTS: The area under the curve of indinavir increased in eight of nine patients by a mean of 88% (range 29-21596) between day 1 and day 5 of the 11-2 infusion. Mean * SD oral clearance of indinavir significantly decreased from 57.1 i 12.9 uh on day 1 of 1L-2 to 25.3 i 7.9 uh on day 5. Over this period, all patients demonstrated an increase in IL-6 between day 1 and 5 of 1L-2, ranging from 4-fold to over 100-fold. CONCLUSION: lndinavir concentrations were altered during 1L-2 infusions, possibly by the induction of pro-inflammatory cytokines leading to inhibition of indinavir metabolism.

230. Bristol-Myers Squibh Central Nervous System Research Award: Response of patients with adrenal insufficiency to alprazolam with and without DHEA co-administration. Patricia D. Kroboth, Ph.D , Amy L. Pittenger, Pharm.D., M.S., M. Maggie Folan, B S.N., Sharon E. Corey, Ph.D., Frank J. Kroboth, M.D., Janet A. Amico, M.D.; University of Pittsburgh, Pittsburgh, PA.

PURPOSE: In vitro, DHEA (DH) and its sulfated metabolite DHEA-S (DS) are negative modulators of the GABAA-benzodiazepine receptor complex (GBRC). The overall hypothesis is that DHEA (DH) administration decreases the intensity of response to the GBRC agonist, alprazolam (AL). The hypothesis was tested in patients with adrenal insufficiency, as DH and DS are largely of adrena l origin a n d th i s popula t ion has low circulating concentrations of endogenous DH and DS. METHODS: Three patients with adrenal insufficiency participated in a randomized, double-blinded, crossover of DH plus AIL and placebo (PL) plus AL. Patients received AL 1.5 mg at 0 hour (9:30). DH or PL was administered at -2 hours (150 mg) and again at 4 5 hours (50 mg). Serial blood samples were obtained and GABA-mediated responses were assessed, including digit symbol substitution (DSS), immediate recall (IR), and nurse-rated sedation (NRS). Data are reported as observations from the individual subjects. RESULTS: DH plus Al. resulted in increases in DH of 10-13 ng/ml and 7.2- to 90-fold increases i n DS relative to PL p lus AL AL maximum concentrations (C,,,*J were unexpectedly 22% to 36% higher in DH plus AL. Despite h igher Al. C,,,,, maximum impai rment o n DSS and IR was consistently less than in P1. plus AL. Maximum sedation scores were equivalent (n=2) or less (n=l ) in DH plus AL. CONCLUSION: These data from three patients with adrenal insufficiency support the hypothesis that DH and/or DS modulate GABA-mediated responses. The study will be continued using a 4-way crossover study that includes two additional treatments: PL and DH. Age and gender-matched control subjects will also be evaluated.

231. Bristol-Myers Squihb Central Nervous System Research Award: Competitive inhibition of gahapentin brain uptake in the rat. Murk S. Luer-, Pharm.D., Melissa Shannon, Bill J. Gurley, Ph.D., Barry E. Gidal, Pharm.D., James H. Fischer, PharmD; University of Arkansas for Medical Science, Little Rock, AR; University of Wisconsin, Madison, W1; University of Illinois at Chicago, Chicago, 11..

232. Glaxo Wellcome Pharmacotherapy Research Award: Effect of peracetic acid-hydrogen peroxide dialyzer reuse on drug and solute

Volume 18, Number 5 , 1998

removal. Meri K Scott, Ph.D , Bruce A . Mueller. Pharm.D., Kevin M . Sowin~ki, Phurm.D.; Purdue Ilniversity, Wrst Lafayette, 1N.

PURPOSE: Previous studies have not fully characterized the effects of peracetic acid-hydrogen peroxide (PAHP) reprocessing o n high-flux polysulfone (F80A, Fresenius) hemodialyzer permeability. We assessed the effects of 15 PAHP reuses o n the membrane permeability to water and driidsolutes of varying molecular weight. METHODS: Dialyzers (n=6) were exposed to blood for at least 40 minutes prior to first use while reuse cycles consisted of blood exposure for at least 40 minutes (Kunas, et al., ASAlO J 1996) followed by PAHP reprocessing. During in vitro heinodialysis (HD), a 6 L buffer wlution containing urea (60 Da), creatiniiie (113 Da), vancomycin (1448 Da), inulin (5200 Da), inyoglobin (1 7 k l h ) , and albumin (66 kDa) was. recirculated at 400 inVinin for 60 minutes. HD was performed on dialyzers previously exposed to blood only (RO) and after undergoing 1, 5, 10, and 15 (R15) reuse cycles. Solute clearance (GI, mumin), sieving coefficients (SC), and hydraulic permeability (K,l(, ml/hr/mm Hg) were determined for each HD. Repeated measures ANOVA and subsequent multiple comparisons (Duncan) were used to determine differences parameters between reuses (a = 0.05, RESULTS: Mean * SD uredcreatinine CI during RO were 311.8 * 21.91257.6 * 18.2, while the same values during R15 were 311.9 i 19.U267.7 i 24.2 (urea, p=0.83; creatinine, p=0.97). The vancomycin CVpost SC values at RO and R15 were 135.4 * 9.0/0.82 + 0.05 and 129.6 * 9 . U 0 . 7 5 * 0.06, respectively (CI. p=0.37; SC, p=0.24). The same values for inulin were 48.3 f 10.1/0.36 * 0.07 and 36.4 * 6.5/0.31 * 0.05 (CI, p=0.08; SC, p=0.06). Myoglohin and albumin CI and SC were immeasurable at all reuses. F,,f values declined slightly over 15 reuses (RO = 51 2 i 4.1 and R15 = 48.8 i 5.1,

CONCLUSION: 1) Small solute and vancomycin clearances by the F80A membranes are not significantly altered with increasing number of PAHP reuses; 2) the F80A membrane is impermeable to larger solutes at 0-15 PAHP reuses; and 3) given that the molecular weight pf the majority of drugs are smaller than 1450 Da, PAHP reprocessing is not likely to influence drug removal by F80A membranes.

233. GIaxo Wellcome Pharmacotherapy Research Award: Determination of human HI-histamine receptor mRNA using competitive RT-PCR. Sally Usdin Yusudu, M.S., PharmD., Curtis Rosebraugh, M.D., Robert P. Yasuda, Ph.D.; Georgetown University Medical Center, Washington, DC.

PURPOSE: Reverse transcription (RT) of inRNA followed by polymerase chain reaction (PCR) to amplify the cDNA product is a sensitive non- radioactive method to detect mRNA. We have developed a RT-PCR approach to measure human HI-histamine receptor mRNA using competitive RT-PCR. METHODS: A competitive internal reference standard RNA (RNA-CRS) was made using 1321N1 cells, a human-derived cell line containing HI-receptors. Primers were based o n the published nucleotide sequence for the cloned human HI-receptor. RT-PCR was used, followed by T7 polymerase to make the RNA-CRS. The 5' CRS primer has an 82-base deletion in the final PCR product compared to wild type (WT) 5' primer. The 3' CRS primer is identical to WT 3' primer, but with an additional 25 bases coding for the binding region of the T7 RNA polymerase. Samples of WT RNA extracted from tissue exposed chronically to the presence or absence of chlorpheniramine are then subjected to RT followed by PCR in the presence of known amounts of CRS. RESULTS: The PCR product of the CRS runs at 166 bp and the WT product runs at 248 base pairs, and can thus be distinguished on a 2% agarose gel. This allows for a relatively quantitative approach to determination of human HI-histamine receptor mRNA. CONCLUSION: This method can be used to examine HI-histamine receptor regulation in human-derived tissue followmg exposure to antihistamines.

234. Pharmacia & Upjohn Pharmacoeconomics Research Award: QALY weights for the New York Heart Association heart failure classes. Karen Bluntenschein, Phur-ni.D., Magnus Johannesson, P1i.D.; University of Kentucky; Stockholm School of Economics.

= 0.10).

p=0.05).

235. Pharmacia & Upjohn Pharmacoeconomics Research Award: Health- related quality of life of cystic fibrosis patients. Jeffrey A. Johnson, Ph.D., Melinda Connolly, M.A., Peter Zuberbuhler, M.D., Neil Brown, M.D.; Institute of Pharmaco-Economics; Cystic Fihrosis Clinic; Faculties of Pharmacy, University of Alberta, Edmontnn, Alberta, Canada.

PURPOSE: The objectives of this study were to 1) to examine the general health-related quality of life (HRQOL) of adult and pediatric cystic fibrosis (CF) patients using available instruments; and 2) to compare the results to normal population scores for these instruments, where possible. METHODS: In a baseline, cross-sectional survey, general HRQOL instruments were mailed to 59 adult and parents of 88 pediatric patients seen at the CF clinic in Edmonton, Alberta. Adult patients received the SF-36 and EuroQol (EQ-5D); parents of pediatric patients received the Functional Status 11 (R), RAND Child Health Status, and EuroQol Visual Analog Scale (EQ- VAS). Observed scores were stratif ied o n demographic and clinical parameters obtained from the questionnaires and compared to published


population normal scores where available. RESULTS: Questionnaires were returned from 39 adults and parents of 69 children (response rates of 66.1% and 78%, respectively) The respondent sample accurately represented the clinic population in terms of age and gender. For adults, no significant differences were found to exist when SF36 or EQ5D scores were compared by gender. However, mental health scores on both instruments were significantly lower for respondents reporting lower household income. Hospitalized individuals tended to have lower scores in general health status and pain. For pediatric patients, there were n o differences by gender or household income. Scores o n all scales were significantly lower for children who had CF-related hospital admission in the previous 12 months. Functional Status I I (R) scores were lower, in this sample of children with CF (mean 84.31, than published normal scores for “well” (mean 96.0) and “sick” (mean 86 .5) children. Assessment of relationships with clinical parameters and treatment variables, including use

of rhDNase, and comparison with a 1-year follow-up survey will also he presented. CONCLUSlON: As these questionnaires have not been used in the CF population before, important baseline information was generated from these results. This sample of CF patients rated their HRQOL lower than that of the general adult and pediatric populations. Further evaluation of these general HRQOL instruments in this population is required, including reliability and construct validity. (Additional funding from institute of Pharmaco-Economics.)

236. Rhbne-Poulenc Rorer Oncology Research Award: IGF-I inhibition of doxoruhicin activity in breast cancer. Carla Van Den Berg; University of Colorado Health Sciences Center, Denver, CO.

237. Rhijne-Poulenc Rorer Pulmonary Research Award: Tuberculosis therapy i n an intracellular pharmacodynamic model. D.M. Cappelletty, Wayne State University, Detroit, MI.

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