pharmacist objectives technician objectives...arif h and hirsch lj. seminars in neurology...

7/24/2013

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47th Annual Meeting ҉ August 2-4, 2013 ҉ Orlando, FL

Updates in Seizure Management: Nothing To Get All Shook Up About

Jennifer Bushwitz, PharmDClinical Pharmacy Specialist, NeuroCritical Care

Shands at the University of Florida

Melissa Ruble, PharmD, BCPSEmergency Medicine Clinical Pharmacist

St. Anthony’s Hospital

Disclosure

• I do not have a vested interest in or affiliation with any corporate organization offering financial support or grant monies for this continuing education activity, or any affiliation with an organization whose philosophy could potentially bias my presentation

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Pharmacist Objectives

• Upon completion of this activity, the participant should be able to:

– Discuss the updated status epilepticus (SE) guidelines

– Summarize the main advantages and disadvantages of the new antiepileptic drugs

– Describe any alternative administration routes and bioequivalence issues that arise with the use of these medications

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Technician Objectives

• Upon completion of this activity, the participant should be able to:

– Define status epilepticus

– Review updated treatment recommendations for status epilepticus

– Summarize the main advantages and disadvantages of new epileptic drugs

– Describe current challenges concerning the administration of new epileptic drugs

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Status Report

Jennifer Bushwitz, PharmDClinical Pharmacy Specialist, NeuroCritical Care

Shands at the University of Florida

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“..all attempts at classification of epileptic seizures are hampered by our limited knowledge of the underlying pathological

processes within the brain, and that any classification must of necessity be a tentative one and will be subject to change with

every advance in the scientific understanding of epilepsy”

‐H. Gastaut, International League Against Epilepsy

Epilepsia 1970;11:102-113

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Neurocritical Care Society Guidelines

• Published 2012; started writing 2008

• Class– I: Intervention is useful and effective. Treatment benefits clearly

exceed risks

– IIa: Evidence/expert opinion suggest intervention is useful/effective. Treatment benefits exceed risk

– IIb: Strength of evidence/expert opinion about intervention usefulness/effectiveness is less well established. More data are needed; however, using this treatment when warranted is not unreasonable

– III: Intervention is not useful or effective and may be harmful. Benefit does not exceed risk

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Neurocritical Care Society Guidelines

• Published 2012; started writing 2008

• Level of evidence

– A: Adequate evidence is available from multiple, large, randomized clinical trials or meta‐analyses

– B: Limited evidence is available from less rigorous data, including fewer, smaller randomized trials, nonrandomized studies, and observational analyses

– C: Evidence relies on expert/consensus opinion, case reports, or standard of care

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Status Epilepticus Defined

• “Sufficient in length” and “often enough”

• Continuous or repetitive seizure activity persisting for at least 30 minutes without recovery of consciousness between attacks

• Seizure lasting more than 5 minutes or 2 or more seizures during which patient does not return to baseline

• Five or more minutes of either– Continuous clinical or electrographic seizures– Recurrent seizure activity without return to baseline

Arif H and Hirsch LJ. Seminars in Neurology 2008;28(3):342-354 Jenssen S et al. Epilepsia 2006;47:1499-1503Lowenstein DH et al. Epilepsia 1999;40:120-122 Bassin et al. Critical Care 2002;6:137-142Epilepsia 1981;22:489-501 Brophy GM , et al. Neurocrit Care 2012;17:3-23

Clinical Timeline

Ictus

2 min

Spontaneous resolution

5 - 10 min

Decreased likelihood of spontaneous resolution

Theodore WH et al. Neurology 1994;44:1403-1407.Shinnar S, et al. Ann Neurol 2001;49:659-664.

Likelihood of Spontaneous Remission

Shinnar S, et al. Ann Neurol 2001;49:659-664.

Duration of seizure (min)

Probability of ongoing

seizure stopping

0 10 20 30 40 50 60

0.05

0.10

0.15

0.20

0.25

0.30

Clinical Timeline

Ictus

2 min


5 - 10 min


30 min

Infarction

Theodore WH et al. Neurology 1994;44:1403-1407. Nevander G et al. Ann Neurol 1985;18:281-290.Shinnar S, et al. Ann Neurol 2001;49:659-664. Towne AR et al. Epilepsia 1994;35:27-34.

30 - 59 min>60 min

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Clinical Timeline

Ictus

2 min


5 - 10 min


30 min

Infarction


30 - 59 min

Mortality <3% 32%

>60 min

Seizure

Status Epilepticus

Generalized Convulsive

Status Epilepticus

Non‐convulsive

Status Epilepticus

Classification and Treatment

Brophy GM , et al. Neurocrit Care 2012;17:3-23

Status Epilepticus

Generalized Convulsive Status Epilepticus•Tonic/clonic movements, mental status impairment•Electrolyte abnormalities, rhabdomyolysis•Lower mortality rate at hospital discharge: 9‐21%

Non‐convulsive

Status Epilepticus



Seizure

Status Epilepticus


Status Epilepticus

Nonconvulsive Status Epilepticus•Seizures on electroencephalogram (EEG) without clinical findings•High prevalence in critically ill patients with impaired mental status•Often delayed diagnosis in the ICU•Higher mortality rate at hospital discharge: 18‐52%



Seizure

Common Causes

1. Drugs– Antiepileptic drug (AED) therapy non‐compliance

– Alcohol

– Toxicity

2. Foreign Materials– Infection

– Tumor

– Trauma

– Stroke

3. Misc– Metabolic abnormalities

– Cardiac arrest/anoxiaLowenstein DH, et al. Neurology 1993; 43:483-8.DeLorenzo RJ, et al. Epileptic Seizures: Pathophysiology and Clinical Semiology;2000:697-710.

Status Epilepticus


Status Epilepticus

Non‐convulsive

Status Epilepticus



1. Emergent Control Therapy

Seizure

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Emergent Control Therapy

• Timing: <5 minutes

• Goal: termination of seizure

• Agent of choice: benzodiazepine

– Lorazepam (IA), midazolam (IA), diazepam (IIaA)

– Multiple routes of administration

• Adverse effects: respiratory depression, hypotension

– Lower incidence than placebo

– Airway compromise due to seizures vs benzodiazepines

Brophy GM , et al. Neurocrit Care 2012;17:3-23Alldredge BK, et al. NEJM 2001;345(9):631-7

VA Cooperative Study

• 1990‐1995

• 16 VA medical centers

• Overt or subtle generalized convulsive SE

• Treatment

– Lorazepam 0.1 mg/kg

– Phenobarbital 15 mg/kg

– Diazepam 0.15 mg/kg + phenytoin (PHT) 18 mg/kg

– PHT 18 mg/kg

– Second treatment: PHT

– Third treatment: phenobarbital

• Clinical and electrical resolution of seizure within 20 min of administration

• Did not recur from 20‐60 min

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NEJM 1998;339(12):792-8

64.9%58.2% 55.8%

43.6%

17.9%24.2%

8.3% 7.7%

Overt Subtle

RAMPART

• Randomized, double blind, phase 3, noninferiority

• Convulsive status epilepticus

• Treatment– 10 mg IM midazolam

– 4 mg IV lorazepam

• Primary endpoint: Termination of seizures prior to ED arrival without need for rescue therapy

• 893 patients

• Primary endpoint– 73.4% midazolam

– 63.4% lorazepam

– Inferiority: P<0.001

– Superiority: P<0.001

• Adverse effects similar

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Silbergleit R et al. NEJM 2012;366(7): 591-600

Relationship with Time

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0 10 20

Time from treatment to cessationIV lorazepam

IM midazolam

Time from box opening to cessationIV lorazepam

IM midazolam

Time from box opening to treatmentIV lorazepam

IM midazolam

minutes

Silbergleit R et al. NEJM 2012;366(7): 591-600

Emergent Control Therapy Options

Lorazepam (IV) Midazolam (IM) Diazepam (PR)

AdvantagesLonger duration, largest amount of clinical trial data

Multiple dosage forms, short duration

Multiple dosage forms, short duration

Available Routes IV, PO IV, IM, buccal, nasal IV, PR, PO

Preferred dose IV: 0.1 mg/kg IM: 0.2 mg/kg IV: 0.15 mg/kg

Recommended max per dose

4 mg 10 mg 10 mg

Frequency 5‐10 min 5 min 5 min

Alternative dosing strategies

N/A0.1‐0.3 mg/kgIM/buccal/intranasal

10‐20 mg PR

Administration considerations

IV must be diluted 1:1 with NS/SW/D5; refrigerated

Same 5 mg/mLproduct used IV/IM/intranasal/ buccal

Rectal gel

Arif H and Hirsch LJ. Seminars in Neurology 2008;28(3):342-354 Brophy GM , et al. Neurocrit Care 2012;17:3-23Bassin et al. Critical Care 2002;6:137-142 Claassen J, et al. Neurocrit Care 2012;17:S73-8

Status Epilepticus


Status Epilepticus

Non‐convulsive

Status Epilepticus




2. Urgent Control/ Maintenance Therapy

Seizure

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Urgent Control Therapy

• Timing

– 5‐10 minutes

– Immediately following administration of benzodiazepine

• Goal

– SE resolved: begin maintenance therapy

– SE not resolved: terminate seizure activity

• Agent of choice

– Controversial

– Preferred options: valproic acid (IIaA), PHT/ fosphenytoin (IIaB), phenobarbital (IIbC), levetiracetam (IIbC)


Urgent Control Therapies: Dosing and Monitoring

Phenytoin Valproic acid Phenobarbital Levetiracetam

CommonBrands

Cerebyx ®Dilantin ®

Depakote® Luminal ® Keppra ®

TDM Yes Yes Yes No

Drug level timing¥

IV: >2 hrs PO: >6 hrs

TroughIV: >2 hrsPO: trough

N/A

Time to steady state

3‐5 days 2‐4 days 15‐20 days 0.5‐1.5 days

Goal*Total: 10‐20Free: 1‐2

Total: 50‐100Free: 5‐25

15‐40 N/A

Loading dose15‐20 mg/kg(max 2.5 gm)

20‐40 mcg/kg 15‐20 mg/kg◊ 1000‐3000 mg

Maintenance dose

5‐6 mg/kg/day 15 mg/kg/day 2 mg/kg/day 1‐2 gm/day

¥Time from last dose administered TDM = therapeutic drug monitoring*mcg/mL; higher goals may be targeted in SE ◊ Administered in divided doses of 5-10 mg/kg

Urgent Control Therapies: Additional Considerations

Phenytoin Valproic acid Phenobarbital Levetiracetam

CommonBrands

Cerebyx ®Dilantin ®

Depakote® Luminal ® Keppra ®

Adverse Reactions

Arrhythmias,hypotension, rash/SJS

Thrombocytopeniahyperammonemia, hepatotoxicity

Respiratorydepression, somnolence

Headache,dizziness

Elimination Hepatic Hepatic Hepatic Renal

Drug Interactions

Many Many Many Few

SJS = Steven Johnson’s Syndrome

Status Epilepticus


Status Epilepticus

Non‐convulsive

Status Epilepticus




2. Urgent Control/ Maintenance Therapy

RefractoryStatus Epilepticus

Seizure

Refractory Status Epilepticus

• Ongoing status epilepticus not responsive to first and second line therapies

• Timing: 20‐60 min after urgent SE control therapy administered

• Goal: stop seizures (clinical/EEG)

• General approach– Obtain seizure control with continuous infusion IV (CIVI) agents

titrating to individual goal based on continuous EEG

– Initiate maintenance therapy with longer acting AEDs

– Wean CIVI agents in 24‐48 hours

– Resume CIVI if seizures recur for an additional period of time


Therapeutic Options for RSE

• Insufficient evidence to advocate any one therapy over another

• Frequently recommended agents– Midazolam (IIaB)

– Pentobarbital (IIbB)

– Propofol (IIbB)

• Other therapies– Consider if not previously administered

– IIaB: valproate

– IIbC: phenytoing/fosphenytoin, levetiracetam, lacosamide, topiramate, phenobarbital


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Therapeutic Options for Refractory Status Epilepticus

Pentobarbital Midazolam Propofol

Loading dose 5‐15 mg/kg* 0.2 mg/kg 1‐2 mg/kg

Infusion rate <50 mg/min 2 mg/min N/A

CIVI rate 0.5‐5 mg/kg/hr 0.05‐2 mg/kg/hr 30‐200 mcg/kg/min

Max recommended infusion rate at SUF

3 mg/kg/hr 12 mg/hr 50 mcg/kg/min

Adverse reactionsHypotension, respiratory/cardiac depression

HypotensionPropofol related infusion syndrome

Elimination HepaticHepatic (active metabolite renallyeliminated)

Hepatic, extrahepatic

Affect AED concentration

Yes No No

*may administer an additional 5-10 mg/kg


Alternative Therapies

• Limited options for patients poorly responsive to conventional AEDs

• Pharmacologic options

– Ketamine

– Inhaled anesthetics

– Corticosteroids/IVIG

• Non‐pharmacologic

– Hypothermia

– Electroconvulsive/magnetic stimulation

– Surgical therapy

– Ketogenic diet32


Clinical and Treatment Timeline



30 min

Infarction


30 - 59 min >60 min2 min 5 - 10 min

Emergent0-5 min Urgent

5-10 min Refractory20-60 min

Summary

• Status epilepticus has various clinical definitions and is characterized by continuous/frequent seizures with a low probability of spontaneous remission and high risk for serious neuronal injury.

• Early initiation of AEDs to terminate seizure activity is essential.

• Emergent administration of benzodiazepines should occur within 5 minutes of seizure onset.

• If first‐line therapy is ineffective in terminating SE, there are multiple options for second‐line agents. Most data and experience is with phenytoin, valproic acid, phenobarbitaland levetiracetam.

Summary

• Failure of first/second line agents is considered to be treatment refractory status epilepticus.

• Treatment for refractory status epilepticus focuses on using general anesthetics to terminate seizure activity and prevent further neuronal injury. The agents of choice for managing refractory status epileptics are pentobarbital, midazolam and propofol.

• Numerous other AEDs are available for consideration however their role is less well defined.


New Antiepileptic DrugsAre we there yet?

Melissa Ruble, PharmD, BCPS

St. Anthony’s Hospital

St. Petersburg, Fl

7/24/2013

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Why the Sudden Urge for New Drugs?

• Within the last 20 years multiple new medications have emerged to treat seizure disorders.

• Treatment of resistant seizures remains a problem for over 1/3 of patients despite advances in therapy with at least 2 to 3 agents.

• New therapies aim to provide seizure control with low adverse drug effect profiles.

Goal: No Seizures and No Side Effects

• Ideal antiepileptic drug (AED) properties

– Improved efficacy over older therapies

– Tolerability

– Safety

– Favorable pharmacokinetics

– Broad spectrum of activity

– Low teratogenic potential

New AEDs

• Ezogabine (Potiga™)

• Zonisamide (Zonegran®)

• Tiagabine (Gabitril®)

• Perampanel (Fycompa®)

• Vigabatrin (Sabril®)

• Lacosamide (Vimpat®)

Ezogabine (Potiga™)

Mechanism of action Potassium channel openerMay also exert effects on GABA currents

Available routes PO

Starting dose 100 mg PO TID

Maintenance dose 200 to 400 mg PO TID

Renal dosing (CrCl <50) 50 mg PO TID to MDD of 600 mg/day

Administration considerations Must swallow tablets wholeHigh fat foods can increase concentrations

IndicationFDA approved in June 2011Adjunctive treatment of partial-onset seizures uncontrolled by current medications

Advantages

Absorption Rapid (Tmax 0.5 ‐ 2 hrs)

Distribution Extensive (Vd 2 ‐ 4 L/kg)

Metabolism Glucuronidation and acetylationNo involvement of CYP450 enzymes

Disadvantages

Bioavailability 60%

Protein binding 80%

Renal adjustments Yes

Administration Must swallow tablets whole

Adverse reactions Urinary retention, CNS side effects, QT prolongation

Half‐life (T50) Short half‐life – dosed three times daily

Special alerts Retinal abnormalities and skin discolorationWithdraw medication slowly

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Zonisamide (Zonegran®)

Mechanism of action Reduction in neuronal firing by blocking sodium channelsPrevents influx of calcium

Available routes PO

Preferred dose 100 mg PO daily

Maintenance dose May increase dose to 200 mg/day after 2 weeks

Renal dosing (CrCl < 50) Not recommended

IndicationFDA approved March 2000Adjunct treatment of partial seizures in children > 16 years of age and adults with epilepsy

Advantages

Absorption Rapid and complete (Tmax 2 – 4 hrs)

Distribution Extensive (Vd 1.5 L/kg)

Bioavailability 100%

Protein binding Low at 40%

Half‐life (T50) Long (105 hrs)

Disadvantages

Administration Only available as oral capsulesMust be swallowed whole

Adverse reactions CNS side effects, metabolic acidosis, oligohidrosis (children)

Hypersensitivity Absolute contraindication in sulfonamide hypersensitivity

Renal dosing Renal adjustments are necessary

Age limitations Insufficient data for patients older than 65 years

Metabolism Metabolized through CYP450 enzyme system – substrate of CYP3A4 and 2C19

Tiagabine (Gabitril®)

Mechanism of action Inhibits the reuptake of GABA

Available routes PO

Dosing in patients receiving enzyme‐inducing AED

4 mg PO once daily for 1 week; may increase by 4‐8 mg weekly to response or 56 mg daily in 2‐4 divided doses

Dosing in patients NOT receiving enzyme‐inducing AED

Start dosing lower and titrate slower

Pediatric dosing Children 12‐18 years of age should increase to max of 32 mg/day

IndicationFDA approved 1997Adjunctive therapy in adults and children ≥ 12 years of age in the treatment of partial seizures

Advantages

Absorption Rapid (Tmax of 45 mins)Lipid soluble – crosses the blood brain barrier

Bioavailability 90%

Hepatic/Renal dosing No adjustments are necessary

Administration Oral suspension formulations can be compounded

Disadvantages

Protein binding 96 %

Metabolism Substrate of CYP3A4Dosing is dependent on current AEDs

Adverse reactions CNS side effects

Administration Only oral formulations are availableMust take with food

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Perampanel (Fycompa®)

Mechanism of action Selective, noncompetitive AMPA glutamate receptor antagonist

Available routes PO

Dosing in patients receiving enzyme‐inducing AED

4 mg PO HS; may increase by 2 mg/day weekly based upon response to 8 – 12 mg PO HS

Dosing in patients NOT receivingenzyme‐inducing AED

2 mg PO HS; may increase by 2 mg/day weekly based on response to 8 – 12 mg PO HS

IndicationFDA approved in 2012Adjunctive treatment for partial onset seizures with or without secondary generalized seizuresChildren ≥ 12 years and adults

Advantages

Absorption Rapid (Tmax 0.5 – 2 hrs)Food does not effect AUC


Half‐life (T50) Long (105 hrs)

Disadvantages

Protein binding 95 %

Metabolism Primarily by CYP3A4Dosing is dependent on current AEDs

Hepatic/Renaldosing

Adjustments are necessary

Administration Only oral formulations are available

Special alerts • Use in caution in patients with pre‐existing aggressive behavior or psychosis

• Avoid driving or operating machinery• Increased risk of falls in elderly

Vigabatrin (Sabril®)

Mechanism of action Synthesized in 1974 as analog of GABAIrreversibly inhibits GABA transaminaseIncreases levels of GABA within the brain

Available routes PO

Starting dose 500 mg PO BID; increase daily dose by 500 mg at weekly intervals

Maintenance dose 3 g/day

IndicationTreatment of infantile spasmsTreatment of refractory complex partial seizures not controlled by usual treatments in patients ≥ 16 years of age

Advantages

Absorption Rapid (Tmax of 1 hr)

Distribution Extensive (Vd 1.1 L/kg)

Metabolism No significant CYP450 enzyme involvement

Protein binding No protein binding

Bioavailability 100%Tablets = oral solution

Disadvantages

Renal dosing Dose adjustments are necessary

Half‐life (T50) Short half‐life (7.5 hrs)

Administration Only available orally

Adverse reactions Weight gainDecreases ALT and AST in 90% of patients

Age restrictions Mostly studied in younger patients

Special alerts Risk of permanent vision lossSHARE program

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Lacosamide (Vimpat®)

Mechanism of action Enhances the slow inactivation of sodium channelsInhibits repetitive firing

Available routes PO, IV

Starting dose 50 mg PO/IV BID; increase at weekly intervals by 100 mg daily

Maintenance dose 200 ‐ 400 mg daily

IndicationFDA approved 2009 Adjunctive therapy in the treatment of partial-onset seizures in patients ≥ 17 years of ageC-V controlled substance

Advantages

Absorption Rapid (Tmax 1 – 4 hrs)Not affected by food


Formulations PO and IV

Protein binding Only 15%

Drug interactions No interactions with other AEDs

Tolerability Good tolerability compared with other agents

Disadvantages

Half‐life (T50) Short (BID dosing)

Hepatic/Renal dosing • Not recommended in patients with severehepatic impairment

• Dose supplementation is necessary if patient receives dialysis

Dependence Psychological dependence may be possible due to euphoria‐type reactions

Adverse reactions • May prolong PR interval; EKG recommended at baseline and at steady state

• CNS side effects


No IV? No ProblemAlternative Administration Routes

Non‐Oral Routes of Administration

• Rectal

• Skin

• Buccal

• Nasal

• Inhaled

• Direct delivery to the CNS

Intranasal Administration

• Ideal intranasal properties

– Potent medication < 20 mg/dose

– Low molecular weight < 1000 Daltons

– Excellent water solubility

– Isotonic to slightly hypertonic

– Stable in processing and storage

– Compatible with sprayer component

– Rapidly absorbed

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Intranasal Benzodiazepines

• 1st choice

– Midazolam

• Other options

– Diazepam

– Lorazepam

– Clonazepam

Things to Consider

• Increased nasal mucus production

– Common with actively seizing patients

– Could decrease absorption

– Suction patient’s nasal cavity before administering

• Insert spray device fully into the nasal vestibule and aim laterally toward tubinates

• Special formulations or IV solutions?

Intrapulmonary Medications

• Rapid absorption and onset

• Easy to use

• Large surface area

• Medication is delivered via carotid directly to the brain

• Propofol and midazolam are currently being studied

Inhaled Propofol

• Properties

– Excellent anti‐seizure profile

– Rapid onset

– Short duration of action

• Propofol hemisuccinate

– Water‐soluble prodrug

– Well tolerated

– Slower onset but still rapid

• Need to metabolize to active metabolite

Inhaled Midazolam

• Rapid onset permits several new uses for midazolam in epilepsy therapy

• Administered using a miniaturized portable inhaler system

• Great for patients experiencing a seizure aura

– Helps prevent full‐blown seizure

Conclusion

• Response to AED in newly diagnosed epilepsy is only 50%.

• There is a need for new AED with increased safety profiles.

• Many more medications are in the pipeline using virus transfer mechanisms and gene transfers.

• As pharmacists we can help inform others about the new options in seizure management along with alternative administration routes when necessary.

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References• Dhir, Ashish, Dorota Zolkowska, Randall Murphy, and Michael Rogawski. "Seizure Protection by

Intrapulmonary Delivery of Propofol Hemisuccinate." Journal of Pharmacology and Experimental Therapeutics 1st ser. 336 (2011): 215‐22. Print.

• Rogawski, Michael. "Pipeline Program." Intrapulmonary Propofol Analogs. Proc. of 2010 ASENT 12th Annual Meeting, Hyatt Regency Bethesda, Bethesda.

• Gururajan, Ria. "Intrapulmonary Midazolam for the Treatment of Seizures ‐ Available Technology for Licensing from the University of California, Davis."Intrapulmonary Midazolam for the Treatment of Seizures ‐ Available Technology for Licensing from the University of California, Davis. American Epilepsy Society, 2011. Web. 29 May 2013.

• Wermeling, Daniel P. "Intranasal Delivery of Antiepileptic Medications for Treatment of Seizures." Neurotherapeutics 6.2 (2009): 352‐58. Print.

• "Antiepileptic Custom Medications for Treatment of Seizures." Antiepileptic Custom Medications for Treatment of Seizures. N.p., n.d. Web. 29 May 2013.

• "Therapeutic Midazolam Intranasal Drug Delivery." Treating Seizures with Intranasal Medications. N.p., n.d. Web. 29 May 2013.

• Fisher, Robert S., and David K. Chen. "New Routes for Delivery of Anti‐Epileptic Medications." Acta Neurologica Taiwanica 15.4 (2006): 225‐31. Print.

• Ochoa, Juan, and Selim Benbadis. "Antiepileptic Drugs ." Antiepileptic Drugs. Medscape, 14 May 2013. Web. 29 May 2013.

• Lexi‐Comp, Inc (Lexi‐Drugs™). Lexi‐Comp, Inc.; May 24, 2013.

• Clinical Pharmacology [database online]. Tampa, FL: Gold Standard, Inc.; 2006. URL: http://cp.gsm.com. Updated May 2013.

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pharmacist objectives technician objectives...arif h and hirsch lj. seminars in neurology...

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