Pemoline

Pemoline, sold under the brand name Cylert among others, is a stimulant medication which was formerly used in the treatment of attention-deficit hyperactivity disorder (ADHD) and narcolepsy.[2] It was taken by mouth.[2]

Pemoline
Clinical data
Trade namesCylert, others
Other namesPheniminooxazolidinone; Phenylisohydantoin; Phenylpseudohydantoin; Phenilone; 2-Imino-5-phenyl-4-oxazolidinone; 2-Amino-5-phenyl-1,3-oxazol-4(5H)-one
AHFS/Drugs.comMicromedex Detailed Consumer Information
Routes of
administration		Oral[1][2]
ATC code
Legal status
Legal status
Pharmacokinetic data
Protein binding≤50%[2][1]
MetabolismLiver[2]
MetabolitesVarious[2]
Elimination half-life7–12 hours[1][2]
ExcretionMainly urine[2]
Identifiers
  • (RS)-2-amino-5-phenyl-1,3-oxazol-4(5H)-one
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.016.763
Chemical and physical data
FormulaC9H8N2O2
Molar mass176.175 g·mol−1
3D model (JSmol)
ChiralityRacemic mixture
  • O=C2\N=C(/OC2c1ccccc1)N
  • InChI=1S/C9H8N2O2/c10-9-11-8(12)7(13-9)6-4-2-1-3-5-6/h1-5,7H,(H2,10,11,12) Y
  • Key:NRNCYVBFPDDJNE-UHFFFAOYSA-N Y
 NY (what is this?)  (verify)

Side effects of pemoline include insomnia, decreased appetite, abdominal pain, irritability, and headaches.[1][2] Pemoline is a psychostimulant and acts as a selective dopamine reuptake inhibitor and releasing agent.[1][3][2] It has little effect on norepinephrine and hence has minimal or no cardiovascular or sympathomimetic effects.[1][3][2]

Pemoline was synthesized in 1913 but was not discovered to be a stimulant until the 1930s and was not used in the treatment of ADHD until 1975.[4][5][1] It has been discontinued due to incidences of liver failure in children. Pemoline is a schedule IV controlled substance in the United States.[6][7] However, it appears to have less misuse potential than other stimulants.[1]

Medical uses

Pemoline was formerly used in the treatment of ADHD and narcolepsy.[2][1] It has also been used in the treatment of excessive daytime sleepiness.[3] The medication was typically used at doses of 18.75 to 112.5 mg once per day in the treatment of ADHD, with the effective dose for most people being in the range of 56.25 to 75 mg.[1][2] The onset of action of pemoline is gradual and therapeutic benefits may not occur until the third or fourth weeks of use.[2][1] This may be due to the cautious low initial starting dose of 37.5 mg and gradual titration in dose upwards over several weeks.[1]

Available forms

Pemoline was available in the form of 18.75, 37.5, and 75 mg oral immediate-release tablets (Cylert) as well as 37.5 mg oral immediate-release chewable tablets.[1][2] It was provided mainly in the form of the free base but also as the magnesium salt.[8]

Side effects

Side effects of pemoline include insomnia, decreased appetite, abdominal pain, irritability, and headaches.[1][2] It has minimal cardiovascular or sympathomimetic side effects.[1][2]

Liver toxicity

In some patients pemoline is suspected of causing hepatotoxicity,[1][9] so the FDA recommended that regular liver tests should be performed on those treated with it.[10] Since receiving FDA approval in 1975, it has been linked with 21 cases of liver failure, of which 13 resulted in liver replacement or death. Approximately 1–2% of patients taking the drug show elevated levels of liver transaminase enzymes, a marker for liver toxicity, though serious cases are rare. Over 200,000 children with ADHD were prescribed pemoline in the US and Canada alone during the 25 years it was available, plus a smaller number of adults prescribed it for indications such as chronic fatigue syndrome and apathy in the elderly (and not including prescriptions in the rest of the world), so the number of liver failure cases was statistically not that large. However the reactions proved idiosyncratic and unpredictable, with patients sometimes taking the drug with no issue for months or even years, before suddenly developing severe liver toxicity. There was no clear exposure-toxicity relationship, and no characteristic liver pathology findings. Some patients showed as little as one week between first appearance of jaundice and complete liver failure, and some of the patients that developed liver failure had not showed elevated liver transaminase levels when tested previously.[11]

In March 2005 Abbott Laboratories and generic manufacturers withdrew pemoline from the American market due to concerns about the liver toxicity risk.[12] Pemoline (as Betanamin) continues to be available in Japan, where no liver failure cases have been reported associated with its use, however it is only prescribed for the niche indication of narcolepsy, and at a lower dose than previously used in the USA.[13]

Overdose

Overdose of pemoline may present with choreoathetosis symptoms.[14]

Interactions

Other stimulants and monoamine oxidase inhibitors are contraindicated with pemoline.

Pharmacology

Pharmacodynamics

The pharmacodynamics of pemoline are poorly understood and its precise mechanism of action hasn't been definitively determined.[1][2] However, pemoline has similar activity and effects similar to those of other psychostimulants, and in animals pemoline appears to act as a dopamine reuptake inhibitor and releasing agent.[1] In contrast to most other stimulants however, it appears to produce no significant central or peripheral noradrenergic effects.[1] As a result, pemoline has minimal or no cardiovascular or sympathomimetic effects.[1] Pemoline is described as a selective dopamine reuptake inhibitor that only weakly stimulates dopamine release.[3]

While drugs like dextroamphetamine and methylphenidate are classified as Schedule II and have considerable misuse potential, pemoline is listed as Schedule IV (non-narcotic).[2] In studies conducted on primates, pemoline fails to demonstrate a potential for self-administration.[2] It is thought to have little potential for abuse and dependence.[1] Nonetheless, misuse may theoretically occur owing to its similarity to other psychostimulants.[2]

Pharmacokinetics

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

Pemoline is variously reported to have no significant plasma protein binding or to have 50% plasma protein binding.[1][2]

Pemoline is metabolized in the liver.[2] Its metabolites include pemoline conjugate, pemoline dione, mandelic acid, and unidentified polar metabolites.[2]

Pemoline is excreted mainly by the kidneys with around 50% excreted in unchanged form and only minor amounts present as metabolites.[2] The elimination half-life of pemoline is 7 to 12 hours.[1][2] The half-life is 7 hours in children but may increase to 11 to 12 hours with age.[1] The relatively long half-life of pemoline allows for once-daily administration.[1]

No differences in the pharmacokinetics of pemoline were found with conventional tablets, chewable tablets swallowed, or chewable tablets chewed.[1]

Chemistry

Pemoline is a member of the 4-oxazolidinone class and is structurally related to other members of the class including aminorex, 4-methylaminorex, clominorex, cyclazodone, fenozolone, fluminorex, and thozalinone.

The salts of pemoline in use are pemoline magnesium (free base conversion ratio .751), pemoline iron (.578), pemoline copper (.644), pemoline nickel (.578), pemoline rubidium, pemoline calcium, pemoline chromium, and chelates of the above which are identical in weight to the salt mentioned. Pemoline free base and pemoline cobalt, strontium, silver, barium, lithium, sodium, potassium, zinc, manganese, and caesium are research chemicals which can be produced in situ for experiments.[7][15][16] Others such as lanthanide pemoline salts such as pemoline cerium can be prepared; pemoline beryllium would presumably be toxic.

Synthesis

Pemoline is synthesized by the condensation of racemic ethyl mandelate with guanidine.

Pemoline synthesis: U.S. Patent 2,892,753 DE 462077

History

Pemoline was first synthesized in 1913[17][4] but its activity was not discovered until the 1930s.[5] Pemoline began to be used to treat ADHD in the United States in 1975.[1]

Pemoline is no longer generally available in the United States as a result of the Food and Drug Administration (FDA) withdrawing approval of pemoline as an indicated treatment for ADHD, due to its implication in liver failures among children who were receiving the medication. An FDA Alert warned against prescribing pemoline for ADHD. This spurred Abbott Laboratories, the patent owner of Cylert, to cease manufacturing Cylert. Manufacturers of the generic equivalents followed suit.

Society and culture

Names

Pemoline is the generic name of the drug and its INN, USAN, and BAN.[17][8]

Pemoline was formerly marketed under the brand names Cylert, Betanamin, Ceractiv, Hyperilex, Kethamed, Ronyl, Stimul, Tamilan, Tradon, Tropocer, and Volital.[8][18][17]

Availability

Pemoline has been marketed in the United States, Canada, the United Kingdom, Belgium, Luxembourg, Spain, Germany, Switzerland, and Argentina.[8]

Under the Convention on Psychotropic Substances, it is a Schedule IV drug.[6] Pemoline is Schedule IV Non-Narcotic (Stimulant) controlled substance with a DEA ACSCN of 1530 and is not subject to annual manufacturing quotas.[7]

References
  1. Patrick, Kennerly S.; Markowitz, John S. (November 1997). "Pharmacology of methylphenidate, amphetamine enantiomers and pemoline in attention-deficit hyperactivity disorder". Human Psychopharmacology: Clinical and Experimental. 12 (6): 527–546. doi:10.1002/(SICI)1099-1077(199711/12)12:6<527::AID-HUP932>3.0.CO;2-U. eISSN 1099-1077. ISSN 0885-6222.
  2. "Cylert (Pemoline)" (PDF). FDA. December 2002. Archived (PDF) from the original on 4 March 2016. Retrieved 15 February 2014.
  3. Nishino S, Mignot E (May 1997). "Pharmacological aspects of human and canine narcolepsy". Prog Neurobiol. 52 (1): 27–78. doi:10.1016/s0301-0082(96)00070-6. PMID 9185233. S2CID 31839355.
  4. Chemische Berichte, 1913, vol.46, p. 2083
  5. Acta Academiae Aboensis, Series B: Mathematica et Physica, 1939, vol. 11, #14 p. 3,7
  6. Annual Estimates Of Requirements Of Narcotic Drugs, Manufacture Of Synthetic Drugs, Opium Production And Cultivation Of The Archived December 5, 2005, at the Wayback Machine
  7. DEA office of Diversion Control site: Federal Register publications of CSA schedules, 2014 Q1
  8. Swiss Pharmaceutical Society (2000). Swiss Pharmaceutical Society (ed.). Index Nominum 2000: International Drug Directory. Taylor & Francis. pp. 799–. ISBN 978-3-88763-075-1.
  9. Marotta PJ, Roberts EA (May 1998). "Pemoline hepatotoxicity in children". J. Pediatr. 132 (5): 894–7. doi:10.1016/S0022-3476(98)70329-4. PMID 9602211.
  10. Willy ME, Manda B, Shatin D, Drinkard CR, Graham DJ (July 2002). "A study of compliance with FDA recommendations for pemoline (Cylert)". J Am Acad Child Adolesc Psychiatry. 41 (7): 785–90. doi:10.1097/00004583-200207000-00009. PMID 12108802. Archived from the original on 2021-05-31. Retrieved 2020-09-10.
  11. Etwel FA, Rieder MJ, Bend JR, Koren G (2008). "A surveillance method for the early identification of idiosyncratic adverse drug reactions". Drug Saf. 31 (2): 169–80. doi:10.2165/00002018-200831020-00006. PMID 18217792. S2CID 19964105.
  12. "Pemoline - Withdrawn due to liver toxicity risk". WHO Pharmaceuticals Newsletter (5). 2005. Archived from the original on 2013-12-03. Retrieved 2012-09-26.
  13. Shader RI. Risk Evaluation and Mitigation Strategies (REMS), Pemoline, and What Is a Signal? Clin Ther. 2017 Apr;39(4):665-669. Shader, Richard I. (2017). "Risk Evaluation and Mitigation Strategies (REMS), Pemoline, and What is a Signal?". Clinical Therapeutics. 39 (4): 665–669. doi:10.1016/j.clinthera.2017.03.008. PMID 28366595.
  14. Stork CM, Cantor R (1997). "Pemoline induced acute choreoathetosis: case report and review of the literature". J. Toxicol. Clin. Toxicol. 35 (1): 105–8. doi:10.3109/15563659709001175. PMID 9022662.
  15. The A-Z Encyclopaedia of Alcohol and Drug Abuse
  16. CRC Handbook of Chemistry & Physics
  17. J. Elks, ed. (14 November 2014). The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies. Springer. pp. 70–. ISBN 978-1-4757-2085-3. OCLC 1058412474.
  18. Ashutosh Kar (2005). Medicinal Chemistry. New Age International. pp. 201–. ISBN 9788122415650. OCLC 818800751.
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