Pemoline, sold under the brand name Cylert among others, is a

stimulant Stimulants (also often referred to as psychostimulants or colloquially as uppers) is an overarching term that covers many drugs including those that increase activity of the central nervous system and the body, drugs that are pleasurable and inv ...

medication which has been used in the treatment of

attention-deficit hyperactivity disorder Attention deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder characterised by excessive amounts of inattention, hyperactivity, and impulsivity that are pervasive, impairing in multiple contexts, and otherwise age-inappro ...

(ADHD) and

narcolepsy Narcolepsy is a long-term neurological disorder that involves a decreased ability to regulate sleep–wake cycles. Symptoms often include periods of excessive daytime sleepiness and brief involuntary sleep episodes. About 70% of those affec ...

. It has been discontinued in most countries to due to rare but serious problems with

liver toxicity Hepatotoxicity (from ''hepatic toxicity'') implies chemical-driven liver damage. Drug-induced liver injury is a cause of acute and chronic liver disease caused specifically by medications and the most common reason for a drug to be withdrawn fro ...

. The medication was taken

by mouth Oral administration is a route of administration where a substance is taken through the mouth. Per os abbreviated to P.O. is sometimes used as a direction for medication to be taken orally. Many medications are taken orally because they are i ...

Side effect In medicine, a side effect is an effect, whether therapeutic or adverse, that is secondary to the one intended; although the term is predominantly employed to describe adverse effects, it can also apply to beneficial, but unintended, consequence ...

s of pemoline include

insomnia Insomnia, also known as sleeplessness, is a sleep disorder in which people have trouble sleeping. They may have difficulty falling asleep, or staying asleep as long as desired. Insomnia is typically followed by daytime sleepiness, low energy ...

, decreased appetite,

abdominal pain Abdominal pain, also known as a stomach ache, is a symptom associated with both non-serious and serious medical issues. Common causes of pain in the abdomen include gastroenteritis and irritable bowel syndrome. About 15% of people have a m ...

irritability Irritability (also called as crankiness) is the excitatory ability that living organisms have to respond to changes in their environment. The term is used for both the physiological reaction to stimuli and for the pathological, abnormal or excess ...

, and

headache Headache is the symptom of pain in the face, head, or neck. It can occur as a migraine, tension-type headache, or cluster headache. There is an increased risk of depression in those with severe headaches. Headaches can occur as a resul ...

s. Rarely, the medication can cause serious liver damage, and this can result in

liver transplantation Liver transplantation or hepatic transplantation is the replacement of a diseased liver with the healthy liver from another person ( allograft). Liver transplantation is a treatment option for end-stage liver disease and acute liver failure, ...

or death. Pemoline is a

psychostimulant Stimulants (also often referred to as psychostimulants or colloquially as uppers) is an overarching term that covers many drugs including those that increase activity of the central nervous system and the body, drugs that are pleasurable and inv ...

and acts as a selective

dopamine reuptake inhibitor A dopamine reuptake inhibitor (DRI) is a class of drug which acts as a reuptake inhibitor of the monoamine neurotransmitter dopamine by blocking the action of the dopamine transporter (DAT). Reuptake inhibition is achieved when extracellular do ...

and

releasing agent A monoamine releasing agent (MRA), or simply monoamine releaser, is a drug that induces the release of a monoamine neurotransmitter from the presynaptic neuron into the synapse, leading to an increase in the extracellular concentrations of the ...

. Hence, it functions as an indirect

agonist An agonist is a chemical that activates a receptor to produce a biological response. Receptors are cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an antagonist blocks the action of the ago ...

dopamine receptor Dopamine receptors are a class of G protein-coupled receptors that are prominent in the vertebrate central nervous system (CNS). Dopamine receptors activate different effectors through not only G-protein coupling, but also signaling through diffe ...

s. Pemoline has little effect on

norepinephrine Norepinephrine (NE), also called noradrenaline (NA) or noradrenalin, is an organic chemical in the catecholamine family that functions in the brain and body as both a hormone and neurotransmitter. The name "noradrenaline" (from Latin '' ad ...

and hence has minimal or no

cardiovascular The blood circulatory system is a system of organs that includes the heart, blood vessels, and blood which is circulated throughout the entire body of a human or other vertebrate. It includes the cardiovascular system, or vascular system, tha ...

sympathomimetic Sympathomimetic drugs (also known as adrenergic drugs and adrenergic amines) are stimulant compounds which mimic the effects of endogenous agonists of the sympathetic nervous system. Examples of sympathomimetic effects include increases in heart ...

effects, in contrast to many other stimulants. 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. It was withdrawn due to liver toxicity in many countries between 1997 and 2005, including the

United States The United States of America (U.S.A. or USA), commonly known as the United States (U.S. or US) or America, is a country primarily located in North America. It consists of 50 U.S. state, states, a Washington, D.C., federal district, five ma ...

. However, it remains available in Japan for the treatment of narcolepsy at lower doses than used for ADHD. Pemoline is a schedule IV

controlled substance A controlled substance is generally a drug or chemical whose manufacture, possession and use is regulated by a government, such as illicitly used drugs or prescription medications that are designated by law. Some treaties, notably the Sing ...

in the United States due to its relation to other stimulants and a potential for misuse. It seems to have less misuse potential than other stimulants.

Medical uses

Pemoline has been used in the treatment of ADHD and

. It has also been used in the treatment of

excessive daytime sleepiness Excessive daytime sleepiness (EDS) is characterized by persistent sleepiness and often a general lack of energy, even during the day after apparently adequate or even prolonged nighttime sleep. EDS can be considered as a broad condition encompass ...

. The medication was typically used at doses of 18.75 to 112.5mg once per day in the treatment of ADHD, with the effective dose for most people being in the range of 56.25 to 75mg. The onset of action of pemoline is gradual and therapeutic benefits may not occur until the third or fourth weeks of use. This may be due to a cautious low initial starting dose of 37.5mg and gradual titration in dose upwards over several weeks.

Available forms

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

magnesium Magnesium is a chemical element with the symbol Mg and atomic number 12. It is a shiny gray metal having a low density, low melting point and high chemical reactivity. Like the other alkaline earth metals (group 2 of the periodic ...

salt Salt is a mineral composed primarily of sodium chloride (NaCl), a chemical compound belonging to the larger class of salts; salt in the form of a natural crystalline mineral is known as rock salt or halite. Salt is present in vast quanti ...

Side effects

s of pemoline include

, decreased appetite,

, and

s. It has minimal

side effects. Pemoline is described as a lower-efficacy/milder stimulant than classical stimulants like

amphetamine Amphetamine (contracted from alpha- methylphenethylamine) is a strong central nervous system (CNS) stimulant that is used in the treatment of attention deficit hyperactivity disorder (ADHD), narcolepsy, and obesity. It is also commonly used ...

s and

methylphenidate Methylphenidate, sold under the brand names Ritalin and Concerta among others, is the most widely prescribed central nervous system (CNS) stimulant medication used to treat attention deficit hyperactivity disorder (ADHD) and, to a lesser extent ...

and is said to have fewer side effects than them.

Liver toxicity

Rarely, pemoline is implicated in causing

hepatotoxicity Hepatotoxicity (from ''hepatic toxicity'') implies chemical-driven liver damage. Drug-induced liver injury is a cause of acute and chronic liver disease caused specifically by medications and the most common reason for a drug to be withdrawn fr ...

. Because of this, the FDA recommended that regular liver tests be performed in those treated with it. Since being introduced, it has been linked with at least 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 Transaminases or aminotransferases are enzymes that catalyze a transamination reaction between an amino acid and an α-keto acid. They are important in the synthesis of amino acids, which form proteins. Function and mechanism An amino acid c ...

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 liver

pathology Pathology is the study of the causes and effects of disease or injury. The word ''pathology'' also refers to the study of disease in general, incorporating a wide range of biology research fields and medical practices. However, when used in ...

findings. Some patients showed as little as one week between first appearance of

jaundice Jaundice, also known as icterus, is a yellowish or greenish pigmentation of the skin and sclera due to high bilirubin levels. Jaundice in adults is typically a sign indicating the presence of underlying diseases involving abnormal heme met ...

and complete liver failure, and some of the patients that developed liver failure had not showed elevated liver transaminase levels when tested previously. 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.

Overdose

Overdose of pemoline may present with choreoathetosis symptoms.

Interactions

Other stimulants and

monoamine oxidase inhibitor Monoamine oxidase inhibitors (MAOIs) are a class of drugs that inhibit the activity of one or both monoamine oxidase enzymes: monoamine oxidase A (MAO-A) and monoamine oxidase B (MAO-B). They are best known as effective antidepressants, esp ...

s are

contraindicated In medicine, a contraindication is a condition (a situation or factor) that serves as a reason not to take a certain medical treatment due to the harm that it would cause the patient. Contraindication is the opposite of indication, which is a reas ...

with pemoline.

Pharmacology

Pharmacodynamics

The

pharmacodynamics Pharmacodynamics (PD) is the study of the biochemical and physiologic effects of drugs (especially pharmaceutical drugs). The effects can include those manifested within animals (including humans), microorganisms, or combinations of organisms ( ...

of pemoline are poorly understood and its precise

mechanism of action In pharmacology, the term mechanism of action (MOA) refers to the specific biochemical interaction through which a drug substance produces its pharmacological effect. A mechanism of action usually includes mention of the specific molecular tar ...

hasn't been definitively determined. However, pemoline has similar activity and effects to those of other

s, and in animals the medication appears to act as a

and

. By increasing dopamine levels in the brain, it functions as an indirect

s. In contrast to most other stimulants, pemoline appears to produce no significant

central Central is an adjective usually referring to being in the center of some place or (mathematical) object. Central may also refer to: Directions and generalised locations * Central Africa, a region in the centre of Africa continent, also known a ...

peripheral A peripheral or peripheral device is an auxiliary device used to put information into and get information out of a computer. The term ''peripheral device'' refers to all hardware components that are attached to a computer and are controlled by th ...

noradrenergic effects. As a result, it has minimal or no

effects. Pemoline is described as a selective dopamine reuptake inhibitor that only weakly stimulates dopamine release. While drugs like

dextroamphetamine Dextroamphetamine is a central nervous system (CNS) stimulant and an amphetamine enantiomer that is prescribed for the treatment of attention deficit hyperactivity disorder (ADHD) and narcolepsy. It is also used as an athletic performance and ...

and

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.

Pharmacokinetics

Studies of the

pharmacokinetics Pharmacokinetics (from Ancient Greek ''pharmakon'' "drug" and ''kinetikos'' "moving, putting in motion"; see chemical kinetics), sometimes abbreviated as PK, is a branch of pharmacology dedicated to determining the fate of substances administered ...

of pemoline in humans are very limited. The time to peak levels of pemoline is 2 to 4hours.

Peak levels Cmax is the maximum (or peak) serum concentration that a drug achieves in a specified compartment or test area of the body after the drug has been administered and before the administration of a second dose. It is a standard measurement in pharm ...

have been reported to be in the range of 2 to 4.5μg/mL.

Steady-state levels Pharmacokinetics (from Ancient Greek ''pharmakon'' "drug" and ''kinetikos'' "moving, putting in motion"; see chemical kinetics), sometimes abbreviated as PK, is a branch of pharmacology dedicated to determining the fate of substances administered ...

of pemoline are reached in 2 to 3days. Pemoline is variously reported to have no significant

plasma protein binding Plasma protein binding refers to the degree to which medications attach to proteins within the blood. A drug's efficiency may be affected by the degree to which it binds. The less bound a drug is, the more efficiently it can traverse or diffuse th ...

or to have 50% plasma protein binding. Pemoline is metabolized in the

liver The liver is a major organ only found in vertebrates which performs many essential biological functions such as detoxification of the organism, and the synthesis of proteins and biochemicals necessary for digestion and growth. In humans, it ...

. Its

metabolite In biochemistry, a metabolite is an intermediate or end product of metabolism. The term is usually used for small molecules. Metabolites have various functions, including fuel, structure, signaling, stimulatory and inhibitory effects on enzymes, ...

s include pemoline conjugate, pemoline dione, mandelic acid, and unidentified polar metabolites. Pemoline is

excreted Excretion is a process in which metabolic waste is eliminated from an organism. In vertebrates this is primarily carried out by the lungs, kidneys, and skin. This is in contrast with secretion, where the substance may have specific tasks after lea ...

mainly by the

kidney The kidneys are two reddish-brown bean-shaped organs found in vertebrates. They are located on the left and right in the retroperitoneal space, and in adult humans are about in length. They receive blood from the paired renal arteries; bloo ...

s with around 50% excreted in unchanged form and only minor amounts present as metabolites. The

elimination half-life Biological half-life (also known as elimination half-life, pharmacologic half-life) is the time taken for concentration of a biological substance (such as a medication) to decrease from its maximum concentration ( Cmax) to half of Cmax in the bl ...

of pemoline is 7 to 12hours. The half-life is 7hours in children but may increase to 11 to 12hours with age. The relatively long half-life of pemoline allows for once-daily administration. No differences in the pharmacokinetics of pemoline were found with conventional tablets, chewable tablets swallowed, or chewable tablets chewed.

Chemistry

Pemoline is a member of the 4-

oxazolidinone 2-Oxazolidone is a heterocyclic organic compound containing both nitrogen and oxygen in a 5-membered ring. Oxazolidinones Evans auxiliaries Oxazolidinones are a class of compounds containing 2-oxazolidone in the structure. In chemistry, they ar ...

class and is structurally related to other members of the class including

aminorex Aminorex (Menocil, Apiquel, aminoxaphen, aminoxafen, McN-742) is a weight loss (anorectic) stimulant drug. It was withdrawn from the market after it was found to cause pulmonary hypertension. In the U.S., it is an illegal Schedule I drug, meanin ...

4-methylaminorex 4-Methylaminorex (4-MAR, 4-MAX) is a stimulant drug of the 2- amino-5- aryloxazoline class that was first synthesized in 1960 by McNeil Laboratories. It is also known by its street name "U4Euh" ("Euphoria"). It is banned in many countries as a st ...

, clominorex, cyclazodone, fenozolone, fluminorex, and

thozalinone Thozalinone ( USAN) (brand name Stimsen; former developmental code name CL-39808) is a psychostimulant that has been used as an antidepressant in Europe. It has also been trialed as an anorectic. Thozalinone is described as a "dopaminergic sti ...

. 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.DEA office of Diversion Control site: Federal Register publications of CSA schedules, 2014 Q1CRC Handbook of Chemistry & Physics 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. Pemolinesynthesis

History

Pemoline was first synthesized in 1913Chemische Berichte, 1913, vol.46, p. 2083 but its activity was not discovered until the 1930s.Acta Academiae Aboensis, Series B: Mathematica et Physica, 1939, vol. 11, #14 p. 3,7 Pemoline was approved for the treatment of ADHD in the United States in 1975. Cases of serious liver toxicity and associated death related to pemoline in children and adolescents were reported to the

Food and Drug Administration The United States Food and Drug Administration (FDA or US FDA) is a federal agency of the Department of Health and Human Services. The FDA is responsible for protecting and promoting public health through the control and supervision of food ...

's MedWatch between 1977 to 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

(FDA) label for the medication in December 1996 and a

black box warning In the United States, a boxed warning (sometimes "black box warning", colloquially) is a type of warning that appears on the package insert for certain prescription drugs, so called because the U.S. Food and Drug Administration specifies that it ...

was added in June 1999 along with requirements for written consent and frequent monitoring of

liver enzyme Liver function tests (LFTs or LFs), also referred to as a hepatic panel, are groups of blood tests that provide information about the state of a patient's liver. These tests include prothrombin time (PT/INR), activated partial thromboplastin t ...

s. 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 The United Kingdom of Great Britain and Northern Ireland, commonly known as the United Kingdom (UK) or Britain, is a country in Europe, off the north-western coast of the European mainland, continental mainland. It comprises England, Scotlan ...

in September 1997, in

Canada Canada is a country in North America. Its ten provinces and three territories extend from the Atlantic Ocean to the Pacific Ocean and northward into the Arctic Ocean, covering over , making it the world's second-largest country by tota ...

in September 1999, and in the United States in 2005. Abbott Laboratories voluntarily withdraw 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.

Society and culture

Names

''Pemoline'' is the generic name of the drug and its , , and . Pemoline was formerly marketed under the brand names Cylert, Betanamin, Ceractiv, Hyperilex, Kethamed, Ronyl, Stimul, Tamilan, Tradon, Tropocer, and Volital.

Availability

Pemoline has been marketed in the

, the

Belgium Belgium, ; french: Belgique ; german: Belgien officially the Kingdom of Belgium, is a country in Northwestern Europe. The country is bordered by the Netherlands to the north, Germany to the east, Luxembourg to the southeast, France to ...

Luxembourg Luxembourg ( ; lb, Lëtzebuerg ; french: link=no, Luxembourg; german: link=no, Luxemburg), officially the Grand Duchy of Luxembourg, ; french: link=no, Grand-Duché de Luxembourg ; german: link=no, Großherzogtum Luxemburg is a small land ...

Spain , image_flag = Bandera de España.svg , image_coat = Escudo de España (mazonado).svg , national_motto = '' Plus ultra'' ( Latin)(English: "Further Beyond") , national_anthem = (English: "Royal March") , ...

Germany Germany, officially the Federal Republic of Germany (FRG),, is a country in Central Europe. It is the most populous member state of the European Union. Germany lies between the Baltic and North Sea to the north and the Alps to the sou ...

, Switzerland, and

Argentina Argentina (), officially the Argentine Republic ( es, link=no, República Argentina), is a country in the southern half of South America. Argentina covers an area of , making it the second-largest country in South America after Brazil, t ...

. 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.

Legal status

Under the

Convention on Psychotropic Substances The Convention on Psychotropic Substances of 1971 is a United Nations treaty designed to control psychoactive drugs such as amphetamine-type stimulants, barbiturates, benzodiazepines, and psychedelics signed in Vienna, Austria on 21 Februar ...

, it is a schedule IV

.Annual Estimates Of Requirements Of Narcotic Drugs, Manufacture Of Synthetic Drugs, Opium Production And Cultivation Of The
Pemoline is Schedule IV Non-Narcotic (Stimulant) controlled substance with a DEA ACSCN of 1530 and is not subject to annual manufacturing quotas.

Research

Fatigue

Pemoline has been studied in and reported to be effective in the treatment of

fatigue Fatigue describes a state of tiredness that does not resolve with rest or sleep. In general usage, fatigue is synonymous with extreme tiredness or exhaustion that normally follows prolonged physical or mental activity. When it does not resolve ...

due to multiple sclerosis and

HIV The human immunodeficiency viruses (HIV) are two species of '' Lentivirus'' (a subgroup of retrovirus) that infect humans. Over time, they cause acquired immunodeficiency syndrome (AIDS), a condition in which progressive failure of the immu ...

-related disease.

References

{{Monoamine releasing agents AbbVie brands Aminorexes Hepatotoxins Norepinephrine-dopamine releasing agents Oxazolidinones Stimulants Substances discovered in the 1910s Withdrawn drugs