CLINICAL PHARMACOLOGY & THERAPEUTICS VOLUM~ 73, NUMBER2 American Society fi)r Clinical Pharmacology and Therapeutics P9 1

OII-B-3 THE BIOAVAILABILITY OF INTRANASAL AND SMOKED

METHAMPHETAMINE. J. E. Mendelson, MD, H. Boxenbaum, PhD, D. S. Harris, MD, N. Uemura, MD, PhD, R. P. Nab, MD, E. T. Everhart, PhD, R. T. Jones, MD, University of California, San Francisco, San Francisco, CA.

Methamphetamine (MA) abuse is increasing in all areas of the world and abusers use several novel mechanisms to administer doses. This study evaluated the bioavailability (F) of 50 mg intranasal (IN) and 40 mg smoked (SM) d-methamphetamine in 8 subjects. F was determined by administering 10 mg deuterium-labeled methamphetamine-d 3 (MA-d3) simultaneously with the IN and SM doses. IN dosing was performed with a 20% MA solution applied as a mist to the nasal mucosa. Smoking was accomplished with a temperature regulated pipe. Levels of MA, MA-d > and the pharma- cologically active metabolite amphetamine (Amph) were measured by GC-MS. Pharmacoldnetic (PK) parameters for MA-d 3 (t~a 10.4 hour, Vss 3.9 L/kg, clearance 280 ml/kg/hr, hepatic extraction ratio 19%) were not affected by IN or SM dosing. The F of IN metham- phetamine was 79 + 13%. Smoking can be inefficient, with substantial amounts of drug left in the smoking apparatus or destroyed by pyrolysis. Therefore, we estimated F for both the total 40 mg dose and after subtracting residual methamphetamine remaining in the pipe. F for the uncorrected 40 mg dose was 37_ + 14%, but increased to 67-+8% with correction for residual pipe MA. The fractional excretion of MA into urine varied from 10-90%, possibly due to variations in urine pH. Amph had a high renal clearance ( - 9 0 0 ml/h/kg), indicating active tubular secretion. SM produces a shorter T . . . . (1.2 vs. 3 hours), but all other PK estimates were similar between conditions.

OII-B-4 THREE DAY 12-HOUR COCAINE INFUSION PRODUCES

TOLERANCE IN CARDIOVASCULAR AND SUBJECTIVE EF FECTS, BUT DOES NOT ALTER COCAINE SELF- ADMINISTRATION BEHAVIOR IN HUMANS. N. Uemura, MD, PhD, A. Manari, BS, R. P. Nath, MD, D. S. Harris, MD, R. T. Jones, MD, J. E. Mendelson, MD, University of California, San Francisco, San Francisco, CA.

Previously we have shown that a 12 or 24-hour cocaine infusion (0.25-0.5 mg/kg/h, total dose 6 mg/kg) suppresses cocaine craving and self-administration in humans. To evaluate the safety and effi- cacy of a longer cocaine exposure, 8 cocaine-dependent volunteers underwent a double-blind, randomized, crossover study to receive 3 day t2-hour cocaine infusions (0.375 mg/kg/h, or placebo). To de- termine the efficacy in suppressing self-administration and craving or altering the pharmacologic response to cocaine, subjects were al- lowed to self-administer intravenous cocaine doses in a computer- assisted paradigm (self-administered dose, 0.15 mg/kg; minimal in- terdose interval, 15 rain; duration, 4 hours for a total maximal cocaine dose of 2.4 mg/kg) on days before and after infusion. One subject required discontinuation due to abnormal vital signs (HR>t00, SBP>160, or DBP>100 for more than 30 min) on the first day of cocaine infusion. Infusions were well tolerated in other subjects and produced only small, clinically insignificant changes in heart rate and blood pressure. Tolerance developed to cardiovascular and subjective measures during the 3 day 12-hour cocaine infusion. The degree of tolerance was greater in subjective measures and less in cardiovas- cular measures. The 3 day 12-hour infusion of cocaine (0.375 mg/ kg/hr) did not decrease the number of self-administered doses, at least in the DDRC self-administration paradigm.

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RELATIONSHIP BETWEEN CORTICOSTEROID THERAPY AND ATHEROSCLEROSIS IN PATIENTS WITH SYSTEMIC LUPUS ERYTHEMATOSUS. Y. Asanuma, MD, PhD, A. Oeser, A. Shintani, PhD, P. Raggi, MD, C. M. Stein, MD, Vanderbilt Univer- sity School of Medicine, Tulane University School of Medicine, Nashville, TN.

Purpose: In patients with inflammatory diseases it is unclem" whether corticosteroids accelerate atherosclerosis through proathero- genic effects on lipids or retard it through anti-inflammatory effects. Patients with systemic lupus erythematosus (SLE) have accelerated atherosclerosis but the mechanism and relationship to corticosteroid therapy is not known.

Methods: The relationship between corticosteroid therapy (cumu- lative and maximum dose, duration and current use) and coronary calcium by electron beam computed tomography (EBCT), plasma homocysteine, lipids, lipoprotein (a) [Lp(a)] and clinical characteris- tics was determined in 42 patients with SLE (age 40 + 11 (SD) years). Results: Lp(a) concentrations correlated with duration (P=0.007) and current use (P=0.035) of corticosteroid therapy. Current therapy was associated with triglyceride (P=0.01) but not LDL cholesterol concentrations (P=0.44). Coronary calcium was present in 13 SLE patients and was associated with current (P 0.05) but not with cumulative corticosteroid use (P=0.9). There was no correlation between cumulative corticosteroid dose or duration of therapy and total cholesterol, LDL or homocysteine.

Conclusion: In patients with SLE, duration of corticosteroid ther- apy is correlated with Lp(a) concentrations, but cumulative exposure is not associated with coronary calcimn or worsening of atheroscle- rotic risk factors. Accelerated atherosclerosis in SLE appears to be independent of corticosteroid treatment.

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N-ACETYLCYSTE1NE TO PREVENT CONTRAST-INDUCED NEPHROTOXICITY: EFFECTS ON RENAL FUNCTION, NITRIC OXIDE METABOLISM AND OXIDATIVE STRESS. S. Efrati, MD, V. Dishy, MD, M. Averbuch, MD, A. Blatt, MD, R. I(rakover, MD, J. Weissgarten, MD, J. Morrow, MD, C. M. Stein, MD, A. Golik, MD, Asaf Harofe Medical Center, Vanderbilt University Med- ical Center, Zerifin, Israel.

Contrast media induced nephrotoxicity is a serious complication of coronary angiography in patients with chronic renal failure (CRF). N-acetylcysteine (NAC), a drug with antioxidant and other proper- ties, is renoprotective but the mechanism is not known. Forty-nine patients with CRF (serum creatinine 1.5-+0.07 mg/dl), undergoing coronary angiography, were randomized to receive oral NAC ( lg bid, 24 hours before and after coronary angiography, n=24) or placebo (n-25) . All patients received standard saline hydration and a low osmolar non-ionated contrast agent. Creatinine clearance (CrC1), was measured before, 24 and 96 hours after angiography. Urinary F2- isoprostanes (F2-iso), a measure of oxidant stress, and nitric oxide metabolites (NOx) were measured in the first consecutive 25 patients. Following angiography, CrC1 decreased significantly from baseline in the placebo group, (-14-+2.9 ml/min after 24 hours and .-12+3.1 ml/min after 96 hours, p<0.005 for both), while it remained un- changed in the NAC group. Urinary NOx/creatinine ratios decreased significantly 24 hours following angiography after placebo (from 63+_9x10-4 /xmol/mg to 32_+7xi0-4 p~mol/mg, p<0.005) but re- mained unchanged after NAC. Urinary F2-iso excretion was not significantly affected in either group. NAC has prolonged renopro- tective effects in patients with CRF exposed to contrast media. This effect may be due to an increase in NO production rather than antioxidant effects.