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| Trade names | Cylert, others |
| Other names | Pheniminooxazolidinone; Phenylisohydantoin; Phenylpseudohydantoin; Phenilone; 2-Imino-5-phenyl-4-oxazolidinone; 2-Amino-5-phenyl-1,3-oxazol-4(5H)-one |
| AHFS/Drugs.com | Micromedex Detailed Consumer Information |
| Routes of administration | By mouth[1][2] |
| Drug class | Stimulant; Dopamine reuptake inhibitor; Dopamine releasing agent |
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| Pharmacokinetic data | |
| Protein binding | ≤50%[2][1] |
| Metabolism | Liver[2] |
| Metabolites | Various[2] |
| Eliminationhalf-life | 7–12 hours[1][2] |
| Excretion | Mainlyurine[2] |
| Identifiers | |
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| CompTox Dashboard(EPA) | |
| ECHA InfoCard | 100.016.763 |
| Chemical and physical data | |
| Formula | C9H8N2O2 |
| Molar mass | 176.175 g·mol−1 |
| 3D model (JSmol) | |
| Chirality | Racemic mixture |
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Pemoline, formerly sold under the brand nameCylert among others, is astimulant medication which has been used in the treatment ofattention deficit hyperactivity disorder (ADHD) andnarcolepsy.[2] It has been discontinued in most countries due to rare but serious problems withliver toxicity.[4][5] The medication was takenby mouth.[2]
Side effects of pemoline includeinsomnia,decreased appetite,abdominal pain,irritability, andheadaches.[1][2] Rarely, the medication can cause seriousliver damage, and this can result inliver transplantation or death.[6][7] Pemoline is astimulant and acts as aselectivedopamine reuptake inhibitor andreleasing agent.[1][8][2][9] Hence, it functions as an indirectagonist ofdopamine receptors.[10] Pemoline has little effect onnorepinephrine and hence has minimal or nocardiovascular orsympathomimetic effects, in contrast to many other stimulants.[1][8][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.[11][12][1] It waswithdrawn due to liver toxicity in many countries between 1997 and 2005, including the United States.[13][7][14] However, it remains available in Japan for the treatment of narcolepsy at lower doses than used for ADHD.[5] Pemoline is aschedule IVcontrolled substance in the United States due to its relation to other stimulants and apotential for misuse.[15][16] It seems to have less misuse potential than other stimulants.[1]
Pemoline has been used in the treatment of ADHD and narcolepsy.[2][1][5] It has also been used in the treatment ofexcessive daytime sleepiness.[8] 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] Theonset 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 a cautious low initial starting dose of 37.5 mg and gradual titration in dose upwards over several weeks.[1]
Pemoline was available in the form of 18.75, 37.5, and 75 mgoralimmediate-releasetablets (Cylert) as well as 37.5 mg oral immediate-releasechewable tablets.[1][2] It was provided mainly in the form of the free base but also as themagnesiumsalt.[17]
Side effects of pemoline includeinsomnia,decreased appetite,abdominal pain,irritability, andheadaches.[1][2] It has minimalcardiovascular orsympathomimetic side effects.[1][2] Pemoline is described as a lower-efficacy/milder stimulant than classical stimulants likeamphetamines andmethylphenidate and is said to have fewer side effects than them.[18]
Rarely, pemoline is implicated in causing hepatotoxicity.[1][19] Because of this, the FDA recommended that regular liver tests be performed in those treated with it.[20] Since being introduced, it has been linked with at least 21 cases ofliver failure, of which 13 resulted in liver replacement or death. Approximately 1–2% of patients taking the drug show elevated levels of livertransaminase enzymes, a marker for liver toxicity, though serious cases are rare. Over 200,000 children with ADHD were prescribed pemoline in the United States and Canada alone during the approximate 25 years that it was available, plus a smaller number of adults prescribed it for other indications (and not including prescriptions in the rest of the world). As such, 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 liverpathology findings. Some patients showed as little as one week between first appearance ofjaundice and complete liver failure, and some of the patients that developed liver failure had not showed elevated liver transaminase levels when tested previously.[14] On the other hand, there are no cases of liver failure associated with pemoline in Japan, although it is used at lower doses and is only prescribed for the niche indication of narcolepsy in this country.[5]
Overdose of pemoline may present withchoreoathetosis symptoms.[21]
Other stimulants andmonoamine oxidase inhibitors arecontraindicated with pemoline.[citation needed]
Thepharmacodynamics of pemoline are poorly understood and its precisemechanism of action hasn't been definitively determined.[1][2] However, pemoline has similar activity and effects to those of otherpsychostimulants, and in animals the medication appears to act as adopamine reuptake inhibitor andreleasing agent.[1] By increasing dopamine levels in the brain, it functions as an indirectagonist ofdopamine receptors.[10] In contrast to most other stimulants, pemoline appears to produce no significantcentral orperipheralnoradrenergic effects.[1] As a result, it has minimal or nocardiovascular orsympathomimetic effects.[1] Pemoline is described as aselective dopamine reuptake inhibitor that only weakly stimulates dopamine release.[8][9]
While drugs likedextroamphetamine andmethylphenidate are classified asschedule II and have considerable misuse potential, pemoline is listed asschedule 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]
Studies of thepharmacokinetics of pemoline in humans are very limited.[1] Thetime 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 significantplasma protein binding or to have 50% plasma protein binding.[1][2]
Pemoline ismetabolized in theliver.[2] Itsmetabolites include pemoline conjugate, pemoline dione, mandelic acid, and unidentified polar metabolites.[2]
Pemoline isexcreted mainly by thekidneys with around 50% excreted in unchanged form and only minor amounts present as metabolites.[2] Theelimination 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]
Pemoline is a member of the 4-oxazolidinone class and is structurally related to other members of the class includingaminorex,4-methylaminorex,clominorex,cyclazodone,fenozolone,fluminorex, andthozalinone.
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.[16][22][23] Others such as lanthanide pemoline salts such as pemoline cerium can be prepared; pemoline beryllium would presumably be toxic.
Pemoline was first synthesized in 1913[24][11] but its activity was not discovered until the 1930s.[12] Pemoline was approved for the treatment of ADHD in the United States in 1975.[1][5]
Cases of serious liver toxicity and associated death related to pemoline in children and adolescents were reported to theUnited StatesFood and Drug Administration'sMedWatch between 1977 and 1996.[7] Serious liver toxicity with pemoline was first described in the medical literature in 1984 and 1989letters to the editor.[7] Clinicians were little-aware of liver toxicity with pemoline until the 1990s.[7] Warnings for liver toxicity for pemoline were added to theUnited StatesFood and Drug Administration (FDA) label for the medication in December 1996 and ablack box warning was added in June 1999 along with requirements for written consent and frequent monitoring ofliver enzymes.[13][14][7] These warnings followed a 1995 publication on liver toxicity with pemoline.[7][25] However, findings suggested that clinicians poorly followed the FDA's directives on use of pemoline.[13] In any case, sales of pemoline in the United States increased until 1997 and declined between 1996 and 1999.[7] Pemoline waswithdrawn due to liver toxicity in theUnited Kingdom in September 1997, inCanada in September 1999, and in the United States in 2005.[13][26][14][7] Abbott Laboratories voluntarily withdrew pemoline from the United States market in May 2005 and the FDA withdrew approval of generic pemoline in November 2005.[13][14] Pemoline remains available in Japan for treatment of narcolepsy as of 2017.[5]
Pemoline is thegeneric name of the drug and itsINNTooltip International Nonproprietary Name,USANTooltip United States Adopted Name, andBANTooltip British Approved Name.[24][17]
Pemoline was formerly marketed under the brand names Cylert, Betanamin, Ceractiv, Hyperilex, Kethamed, Ronyl, Stimul, Tamilan, Tradon, Tropocer, and Volital.[17][27][24]
Pemoline has been marketed in the United States, Canada, the United Kingdom, Belgium, Luxembourg, Spain, Germany, Switzerland, Japan and Argentina.[17] It remains available in Japan for the treatment of narcolepsy as of 2017.[5] 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.[5][28]
Under theConvention on Psychotropic Substances, it is aschedule IVcontrolled substance.[15] Pemoline is Schedule IV Non-Narcotic (Stimulant) controlled substance with a DEA ACSCN of 1530 and is not subject to annual manufacturing quotas.[16]
Pemoline has been studied in and reported to be effective in the treatment offatigue due tomultiple sclerosis andHIV-related disease.[29]
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