Pemoline

Effects

Overview

A stimulant of the 4-oxazolidinone class. Was used as a medication for ADHD and Narcolepsy, yet was pulled from most markets due to liver failures among children. TS

Pemoline, formerly sold under the brand name Cylert among others, is a stimulant medication which was used in the treatment of attention deficit hyperactivity disorder (ADHD) and narcolepsy. It has since been discontinued in most countries due to rare but serious liver toxicity. The medication was taken by mouth.[1][2][3] WP

Common side effects include insomnia, decreased appetite, abdominal pain, irritability, and headaches, while rare cases of serious liver damage requiring liver transplantation or causing death have been reported. As a stimulant, pemoline acts as a selective dopamine reuptake inhibitor and releasing agent via indirect agonism of dopamine receptors. In addition, it shows little activity with respect to norepinephrine, thus minimal to no cardiovascular or sympathomimetic effects in comparison to many other stimulants.[1][4–9] WP

Pemoline was first synthesized in 1913, but its stimulant activity was not discovered until the 1930s, nor used for ADHD until 1975. Between 1997 and 2005, many countries, including the United States, withdrew the drug due to liver toxicity. However, it remains available in Japan for the treatment of narcolepsy at lower doses than those used for ADHD. Pemoline is a schedule IV controlled substance in the United States due to structural and functional similarity to other stimulants, and potential for misuse. However, it is noted to have less misuse potential than other stimulant drugs.[3][4][6][10–15] WP

History

History

Pemoline was first synthesized in 1913 but its activity was not discovered until the 1930s. Pemoline was approved for the treatment of ADHD in the United States in 1975.[3][4][10][11][16] WP

Cases of serious liver toxicity and associated death related to pemoline in children and adolescents were reported to the United States Food and Drug Administration's MedWatch between 1977 and 1996. Serious liver toxicity with pemoline was first described in the medical literature in 1984 and 1989 letters to the editor. Clinicians were little-aware of liver toxicity with pemoline until the 1990s. Warnings for liver toxicity for pemoline were added to the United States Food and Drug Administration (FDA) label for the medication in December 1996 and a black box warning was added in June 1999 along with requirements for written consent and frequent monitoring of liver enzymes. These warnings followed a 1995 publication on liver toxicity with pemoline. However, findings suggested that clinicians poorly followed the FDA's directives on use of pemoline. In any case, sales of pemoline in the United States increased until 1997 and declined between 1996 and 1999. Pemoline was withdrawn due to liver toxicity in the United Kingdom in September 1997, in Canada in September 1999, and in the United States in 2005. Abbott Laboratories voluntarily withdrew pemoline from the United States market in May 2005 and the FDA withdrew approval of generic pemoline in November 2005. Pemoline remains available in Japan for treatment of narcolepsy as of 2017.[3][6][12][13][17][18] WP

Legal status

Names

Pemoline is the generic name of the drug and its INN (International Nonproprietary Name), USAN (United States Adopted Name), and BAN (British Approved Name).[16][19] WP

Pemoline was formerly marketed under the brand names Cylert, Betanamin, Ceractiv, Hyperilex, Kethamed, Ronyl, Stimul, Tamilan, Tradon, Tropocer, and Volital.[16][19][20] WP

Availability

Pemoline has been marketed in the United States, Canada, the United Kingdom, Belgium, Luxembourg, Spain, Germany, Switzerland, Japan and Argentina. It remains available in Japan for the treatment of narcolepsy as of 2017. However, the medication is said to be rarely used in Japan as narcolepsy is a niche indication and as clinicians are wary of the liver toxicity that it has been associated with.[3][19][21] WP

Legal status

Under the Convention on Psychotropic Substances, it is a schedule IV controlled substance. Pemoline is Schedule IV Non-Narcotic (Stimulant) controlled substance with a DEA ACSCN of 1530 and is not subject to annual manufacturing quotas.[14][15] WP

Pharmacology

Pharmacodynamics

The pharmacodynamics of pemoline are poorly understood and its precise mechanism of action hasn't been definitively determined. However, pemoline has similar activity and effects to those of other psychostimulants, and in animals the medication appears to act as a dopamine reuptake inhibitor and releasing agent. By increasing dopamine levels in the brain, it functions as an indirect agonist of dopamine receptors. In contrast to most other stimulants, pemoline appears to produce no significant central or peripheral noradrenergic effects. As a result, it has minimal or no cardiovascular or sympathomimetic effects. Pemoline is described as a selective dopamine reuptake inhibitor that only weakly stimulates dopamine release.[1][4][7][8][9] WP

While drugs like dextroamphetamine and methylphenidate are classified as schedule II and have considerable misuse potential, pemoline is listed as schedule IV (non-narcotic). In studies conducted on primates, pemoline fails to demonstrate a potential for self-administration. It is thought to have little potential for abuse and dependence. Nonetheless, misuse may theoretically occur owing to its similarity to other psychostimulants.[1][4] WP

Pharmacokinetics

Studies of the pharmacokinetics of pemoline in humans are very limited. The time to peak levels of pemoline is 2 to 4 hours. Peak levels have been reported to be in the range of 2 to 4.5 μg/mL. Steady-state levels of pemoline are reached in 2 to 3 days.[1][4] WP

Pemoline is variously reported to have no significant plasma protein binding or to have 50% plasma protein binding.[1][4] WP

Pemoline is metabolized in the liver. Its metabolites include pemoline conjugate, pemoline dione, mandelic acid, and unidentified polar metabolites.[1] WP

Pemoline is excreted mainly by the kidneys with around 50% excreted in unchanged form and only minor amounts present as metabolites. The elimination half-life of pemoline is 7 to 12 hours. The half-life is 7 hours in children but may increase to 11 to 12 hours with age. The relatively long half-life of pemoline allows for once-daily administration.[1][4] WP

No differences in the pharmacokinetics of pemoline were found with conventional tablets, chewable tablets swallowed, or chewable tablets chewed.[4] WP

Chemistry

Formula

C9H8N2O2 PC

CAS number

2152-34-3 PC

Molar mass (g/mol)

176.17 PC

IUPAC name (computed by PubChem)

2-amino-5-phenyl-1,3-oxazol-4-one PC

SMILES

C1=CC=C(C=C1)C2C(=O)N=C(O2)N PC

InChIKey

NRNCYVBFPDDJNE-UHFFFAOYSA-N PC

PubChem CID

4723

IUPAC name

(RS)-2-amino-5-phenyl-1,3-oxazol-4(5H)-one WP

Pop culture

No references added yet.

References

1. Journal / agency Cylert (Pemoline). December 2002
2. Journal / agency Billiard M. Narcolepsy: current treatment options and future approaches. Neuropsychiatr Dis Treat. June 2008. PMID 18830438 · PMC2526380
3. Journal / agency Shader RI. Risk Evaluation and Mitigation Strategies (REMS), Pemoline, and What Is a Signal?. Clin Ther. April 2017. doi:10.1016/j.clinthera.2017.03.008 · PMID 28366595
4. Journal / agency Patrick KS, Markowitz JS. Pharmacology of methylphenidate, amphetamine enantiomers and pemoline in attention-deficit hyperactivity disorder. Human Psychopharmacology: Clinical and Experimental. November 1997. doi:10.1002/(SICI)1099-1077(199711/12)12:6<527::AID-HUP932>3.0.CO;2-U
5. Journal / agency Nakamura H, Blumer JL, Reed MD. Pemoline ingestion in children: a report of five cases and review of the literature. J Clin Pharmacol. March 2002. doi:10.1177/00912700222011292 · PMID 11865963
6. Journal / agency Safer DJ, Zito JM, Gardner JE. Pemoline hepatotoxicity and postmarketing surveillance. J Am Acad Child Adolesc Psychiatry. June 2001. doi:10.1097/00004583-200106000-00006 · PMID 11392339
7. Journal / agency Nishino S, Mignot E. Pharmacological aspects of human and canine narcolepsy. Prog Neurobiol. May 1997. doi:10.1016/s0301-0082(96)00070-6 · PMID 9185233
8. Journal / agency Fuller RW, Perry KW, Bymaster FP, Wong DT. Comparative effects of pemoline, amfonelic acid and amphetamine on dopamine uptake and release in vitro and on brain 3,4-dihydroxyphenylacetic acid concentration in spiperone-treated rats. The Journal of Pharmacy and Pharmacology. March 1978. doi:10.1111/j.2042-7158.1978.tb13201.x · PMID 24701
9. Journal / agency Solanto MV. Neuropsychopharmacological mechanisms of stimulant drug action in attention-deficit hyperactivity disorder: a review and integration. Behav Brain Res. July 1998. doi:10.1016/s0166-4328(97)00175-7 · PMID 9708845
10. Other Chemische Berichte, 1913, vol.46, p. 2083
11. Other Acta Academiae Aboensis, Series B: Mathematica et Physica, 1939, vol. 11, #14 p. 3,7
12. Journal / agency Zito JM, Derivan AT, Kratochvil CJ, Safer DJ, Fegert JM, Greenhill LL. Off-label psychopharmacologic prescribing for children: history supports close clinical monitoring. Child Adolesc Psychiatry Ment Health. September 2008. doi:10.1186/1753-2000-2-24 · PMID 18793403 · PMC2566553
13. Journal / agency Etwel FA, Rieder MJ, Bend JR, Koren G. A surveillance method for the early identification of idiosyncratic adverse drug reactions. Drug Saf. 2008. doi:10.2165/00002018-200831020-00006 · PMID 18217792
14. Other List of psychotropic substances under international control. August 2003
15. Other DEA office of Diversion Control site: Federal Register publications of CSA schedules, 2014 Q1
16. Other The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies. 14 November 2014
17. Journal / agency Berkovitch M, Pope E, Phillips J, Koren G. Pemoline-associated fulminant liver failure: testing the evidence for causation. Clin Pharmacol Ther. June 1995. doi:10.1016/0009-9236(95)90233-3 · PMID 7781270
18. Journal / agency Shah RR. Can pharmacogenetics help rescue drugs withdrawn from the market?. Pharmacogenomics. September 2006. doi:10.2217/14622416.7.6.889 · PMID 16981848
19. Other Swiss Pharmaceutical Society. Index Nominum 2000: International Drug Directory. 2000
20. Other Ashutosh Kar. Medicinal Chemistry. 2005
21. Journal / agency Takeda T. Psychopharmacology for attention-deficit/hyperactivity disorder in Japan. Current Attention Disorders Reports. March 2009. doi:10.1007/s12618-009-0004-5

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