Selegiline
Encyclopedia
Selegiline is a drug
used for the treatment of early-stage Parkinson's disease
, depression and senile dementia. In normal clinical doses it is a selective irreversible MAO-B inhibitor, however in larger doses it loses its specificity and also inhibits MAO-A. Dietary restrictions are common for MAOI treatments, but special dietary restrictions for lower doses have been found to be unnecessary, and dietary restrictions appear to be unnecessary at standard doses when selegiline is taken as Emsam
, the transdermal patch
form, as no adverse events due to diet have ever been reported with Emsam. The drug was discovered by Jozsef Knoll et al. in Hungary. Selegiline belongs to a class of drugs called phenethylamines. Selegiline is a methamphetamine derivative
with a propargyl
group attached to the nitrogen atom.
and the psychostimulant amphetamine
. Knoll was a close friend of Meszaros, the research director of Chinoin, a Hungarian pharmaceutical company (later part of Sanofi). For this project, Meszaros put Knoll in contact with a chemist called Ecsery who worked in Chinoin in the field of phenethylamines. Escery made about 30 compounds, and Knoll selected the molecule of E-250 (deprenyl) based on its surprising properties. "The great discovery" (in Knoll's words) was that the new molecule did not increase blood pressure, unlike amphetamine, and moreover, it inhibited the blood pressure raising effect of amphetamine. The first publication on deprenyl in Hungarian appeared in 1964, followed by a paper in English in 1965. Deprenyl is a racemic compound, a mixture of two isomers called enantiomers. For the further pharmaceutical development, Knoll chose the (-)-enantiomer of deprenyl, which caused less hypermotility than the opposite (+)-enantiomer. This (-)-enantiomer (l-deprenyl, R-deprenyl) later has come to be called selegiline.
In 1971, Knoll showed that selegiline selectively inhibits the B-isoform of monoamine oxidase (MAO-B) and proposed that it is unlikely to cause the infamous "cheese effect" (hypertensive crisis
resulting from consuming foods containing tyramine) that plagues non-selective MAO inhibitors. A few years later, two Parkinson's researchers based in Vienna, Peter Riederer and Walther Birkmayer, realized that selegiline could be useful in Parkinson's disease. One of their colleagues, Moussa Youdim, visited Knoll in Budapest and took selegiline from him to Vienna. In 1975, the Birkmayer's group published the first paper on the effect of selegiline in Parkinson's disease.
In 1967, a Hungarian psychiatrist Ervin Varga observed that racemic deprenyl given in large doses has an antidepressant action. This study was largely forgotten until the 2000s when Sommerset Pharmaceuticals developed selegiline patch for depression.
. It can be used on its own or in a combination with another agent, most often L-DOPA. For the newly diagnosed Parkinson's patients, selegiline appears to slow the progression of the disease. It delays the time point when the L-DOPA (levodopa) treatment becomes necessary from 10-12 to 18 months. The idea behind adding selegiline to levodopa is to decrease the dose of levodopa and thus reduce the motor complications of levodopa therapy. Comparisons of patients on levodopa + placebo vs levodopa + selegiline showed that selegiline allowed reduction of the levodopa dose by about 40%. Selegiline + levodopa also extended the time until the levodopa dose had to be increased from 2.6 to 4.9 years. As a result there were fewer motor complications in selegiline groups. In one trial, selegiline + levodopa completely halted the progress of Parkinson's disease over 14 months, while in the placebo + levodopa group the deterioration of the patients' condition continued. However, the interpretation of this trial as proving neuroprotective action of selegiline has been questioned.
As of February 28, 2006, selegiline has also been approved by the Food and Drug Administration
(FDA) to treat major depression
using a transdermal patch (Emsam
Patch). Selegiline (brand name Anipryl) is also used (at extremely high dosages relative to humans) in veterinary medicine
to treat the symptoms of Cushing's disease
and cognitive dysfunction (Canine Cognitive Dysfunction) in dog
s. As of June 26, 2006, a selegiline transdermal patch is being tested for its effectiveness in treating ADHD.
Several clinical studies are currently underway to evaluate selegiline's effectiveness in helping people stop smoking tobacco
or cannabis
.
Selegiline's oral bioavailability is drastically increased in females taking oral contraceptives (10- to 20-fold). This could lead to loss of MAO-B selectivity in favor of an MAO-A selectivity, which in turn would make patients susceptible to the usual risks of unselective MAOIs such as tyramine
-induced hypertensive crisis and serotonin toxicity when combined with serotonergics such as SSRIs.
effects of levodopa
.
Desmethylselegiline may have neuroprotective antiapoptotic properties. A large multicenter study suggests a decrease in the disease progression of parkinsonism but may have reflected other symptomatic response. Desmethylselegiline is metabolized by CYP2C19
.
Selegiline is partly metabolized
to l-methamphetamine, one of the two enantiomer
s of methamphetamine
in vivo
. A characteristic metabolic pattern was noted, exemplified by a ratio of l-methamphetamine to l-amphetamine of about 2.8. These stereoisomers are considered significantly less psychoactive and have little abuse potential in contrast to their D-isomers. The stimulatory effect on locomotor activity and dopamine synthesis may be contributed to by the action of l-methamphetamine, a once thought to be inactive metabolite. This locomotor effect at therapeutic doses was not apparent in comparison to placebo, but both l-amphetamine and l-methamphetamine had positive effects on genetic expression for memory enhancement in rats and other animals.
This metabolic action may cause persons taking prescribed selegiline to test positive for amphetamine
and or methamphetamine
on drug screening tests.
s, selegiline has been classified as a controlled substance
in Japan
and thus can only be obtained with a prescription
or special government license.
In E for Ecstasy
(a book examining the uses of the street drug Ecstasy
in the UK) the writer, activist and Ecstasy advocate Nicholas Saunders highlighted test results showing that certain consignments of the drug also contained selegiline. Consignments of Ecstasy known as "Strawberry" contained what Saunders described as a "potentially dangerous combination of ketamine
, ephedrine
and selegiline," as did a consignment of "Sitting Duck" Ecstasy tablets.
Selegiline is not a controlled substance in the US but a prescription is required to obtain it within the US.
(selegiline), the first transdermal patch
for use in treating major depression. The once a day patch works by delivering selegiline through the skin and into the bloodstream. Emsam can be used without the dietary restrictions that are needed for all oral MAO inhibitors that are approved for treating major depression, although the FDA requires warnings concerning dietary restrictions for the 9 and 12 mg doses due to theoretical concerns not supported by any reports of adverse events. It comes in three sizes that deliver 6, 9, or 12 mg of selegiline per 24 hours. The patch is a matrix containing three layers consisting of a backing, an adhesive drug layer, and a release liner that is placed against the skin. EMSAM was developed by Somerset Pharmaceuticals, Inc. In December 2004, Bristol-Myers Squibb and Somerset entered into an agreement that provides Bristol-Myers Squibb with distribution rights to market EMSAM after approval in the United States.
http://www.valeant.com/researchAndDevelopment/pipeline/zelapar.jspf.
using propargyl bromide.
Medication
A pharmaceutical drug, also referred to as medicine, medication or medicament, can be loosely defined as any chemical substance intended for use in the medical diagnosis, cure, treatment, or prevention of disease.- Classification :...
used for the treatment of early-stage Parkinson's disease
Parkinson's disease
Parkinson's disease is a degenerative disorder of the central nervous system...
, depression and senile dementia. In normal clinical doses it is a selective irreversible MAO-B inhibitor, however in larger doses it loses its specificity and also inhibits MAO-A. Dietary restrictions are common for MAOI treatments, but special dietary restrictions for lower doses have been found to be unnecessary, and dietary restrictions appear to be unnecessary at standard doses when selegiline is taken as Emsam
Emsam
Emsam is the trade name of an antidepressant of the monoamine oxidase inhibitor class. Emsam is a transdermal patch containing the MAOI selegiline. Selegiline, in small doses, is most commonly used in the treatment of Parkinson's disease. It is also effective in higher doses for the treatment...
, the transdermal patch
Transdermal patch
A transdermal patch is a medicated adhesive patch that is placed on the skin to deliver a specific dose of medication through the skin and into the bloodstream. Often, this promotes healing to an injured area of the body. An advantage of a transdermal drug delivery route over other types of...
form, as no adverse events due to diet have ever been reported with Emsam. The drug was discovered by Jozsef Knoll et al. in Hungary. Selegiline belongs to a class of drugs called phenethylamines. Selegiline is a methamphetamine derivative
Derivative (chemistry)
In chemistry, a derivative is a compound that is derived from a similar compound by some chemical or physical process. In the past it was also used to mean a compound that can be imagined to arise from another compound, if one atom is replaced with another atom or group of atoms, but modern...
with a propargyl
Propargyl
In organic chemistry, propargyl is an alkyl functional group of 2-propynyl with the structure HC≡C−CH2−, derived from the alkyne propyne.The term propargylic refers to a saturated position on a molecular framework next to an alkynyl group...
group attached to the nitrogen atom.
History
Selegiline was discovered in Hungary in the 1960s. Joseph Knoll, a chair of pharmacology at the Semmelweis University in Budapest, was interested in the physiology of "drive" and the differences between high- and low-performing individuals. For his research, he required a molecule that combined amphetamine-like psychostimulant effect with a "psycho-energic" effect of monoamine oxidase inhibitors (MAOI). To do that, he decided to combine in the same molecule the structural features of the MAOI pargylinePargyline
Pargyline is an irreversible monoamine oxidase B inhibitor. It has antihypertensive effects.- Pharmacology :It functions by inhibiting the metabolism of catecholamines and tyramine within presynaptic nerve terminals...
and the psychostimulant amphetamine
Amphetamine
Amphetamine or amfetamine is a psychostimulant drug of the phenethylamine class which produces increased wakefulness and focus in association with decreased fatigue and appetite.Brand names of medications that contain, or metabolize into, amphetamine include Adderall, Dexedrine, Dextrostat,...
. Knoll was a close friend of Meszaros, the research director of Chinoin, a Hungarian pharmaceutical company (later part of Sanofi). For this project, Meszaros put Knoll in contact with a chemist called Ecsery who worked in Chinoin in the field of phenethylamines. Escery made about 30 compounds, and Knoll selected the molecule of E-250 (deprenyl) based on its surprising properties. "The great discovery" (in Knoll's words) was that the new molecule did not increase blood pressure, unlike amphetamine, and moreover, it inhibited the blood pressure raising effect of amphetamine. The first publication on deprenyl in Hungarian appeared in 1964, followed by a paper in English in 1965. Deprenyl is a racemic compound, a mixture of two isomers called enantiomers. For the further pharmaceutical development, Knoll chose the (-)-enantiomer of deprenyl, which caused less hypermotility than the opposite (+)-enantiomer. This (-)-enantiomer (l-deprenyl, R-deprenyl) later has come to be called selegiline.
In 1971, Knoll showed that selegiline selectively inhibits the B-isoform of monoamine oxidase (MAO-B) and proposed that it is unlikely to cause the infamous "cheese effect" (hypertensive crisis
Hypertensive emergency
Malignant hypertension or hypertensive emergency is severe hypertension with acute impairment of an organ system and the possibility of irreversible organ-damage...
resulting from consuming foods containing tyramine) that plagues non-selective MAO inhibitors. A few years later, two Parkinson's researchers based in Vienna, Peter Riederer and Walther Birkmayer, realized that selegiline could be useful in Parkinson's disease. One of their colleagues, Moussa Youdim, visited Knoll in Budapest and took selegiline from him to Vienna. In 1975, the Birkmayer's group published the first paper on the effect of selegiline in Parkinson's disease.
In 1967, a Hungarian psychiatrist Ervin Varga observed that racemic deprenyl given in large doses has an antidepressant action. This study was largely forgotten until the 2000s when Sommerset Pharmaceuticals developed selegiline patch for depression.
Uses
The main use of selegiline is in the treatment of Parkinson's diseaseParkinson's disease
Parkinson's disease is a degenerative disorder of the central nervous system...
. It can be used on its own or in a combination with another agent, most often L-DOPA. For the newly diagnosed Parkinson's patients, selegiline appears to slow the progression of the disease. It delays the time point when the L-DOPA (levodopa) treatment becomes necessary from 10-12 to 18 months. The idea behind adding selegiline to levodopa is to decrease the dose of levodopa and thus reduce the motor complications of levodopa therapy. Comparisons of patients on levodopa + placebo vs levodopa + selegiline showed that selegiline allowed reduction of the levodopa dose by about 40%. Selegiline + levodopa also extended the time until the levodopa dose had to be increased from 2.6 to 4.9 years. As a result there were fewer motor complications in selegiline groups. In one trial, selegiline + levodopa completely halted the progress of Parkinson's disease over 14 months, while in the placebo + levodopa group the deterioration of the patients' condition continued. However, the interpretation of this trial as proving neuroprotective action of selegiline has been questioned.
As of February 28, 2006, selegiline has also been approved by the Food and Drug Administration
Food and Drug Administration
The Food and Drug Administration is an agency of the United States Department of Health and Human Services, one of the United States federal executive departments...
(FDA) to treat major depression
Clinical depression
Major depressive disorder is a mental disorder characterized by an all-encompassing low mood accompanied by low self-esteem, and by loss of interest or pleasure in normally enjoyable activities...
using a transdermal patch (Emsam
Emsam
Emsam is the trade name of an antidepressant of the monoamine oxidase inhibitor class. Emsam is a transdermal patch containing the MAOI selegiline. Selegiline, in small doses, is most commonly used in the treatment of Parkinson's disease. It is also effective in higher doses for the treatment...
Patch). Selegiline (brand name Anipryl) is also used (at extremely high dosages relative to humans) in veterinary medicine
Veterinary medicine
Veterinary Medicine is the branch of science that deals with the prevention, diagnosis and treatment of disease, disorder and injury in non-human animals...
to treat the symptoms of Cushing's disease
Cushing's disease
Cushing's disease is a cause of Cushing's Syndrome characterised by increased secretion of adrenocorticotropic hormone from the anterior pituitary. This is most often as a result of a pituitary adenoma...
and cognitive dysfunction (Canine Cognitive Dysfunction) in dog
Dog
The domestic dog is a domesticated form of the gray wolf, a member of the Canidae family of the order Carnivora. The term is used for both feral and pet varieties. The dog may have been the first animal to be domesticated, and has been the most widely kept working, hunting, and companion animal in...
s. As of June 26, 2006, a selegiline transdermal patch is being tested for its effectiveness in treating ADHD.
Several clinical studies are currently underway to evaluate selegiline's effectiveness in helping people stop smoking tobacco
Tobacco
Tobacco is an agricultural product processed from the leaves of plants in the genus Nicotiana. It can be consumed, used as a pesticide and, in the form of nicotine tartrate, used in some medicines...
or cannabis
Cannabis (drug)
Cannabis, also known as marijuana among many other names, refers to any number of preparations of the Cannabis plant intended for use as a psychoactive drug or for medicinal purposes. The English term marijuana comes from the Mexican Spanish word marihuana...
.
Side effects
Due to the primary metabolites of L-amphetamine and L-methamphetamine, selegiline shares many side effects seen with these sympathomimetic stimulants. Minor side effects such as dizziness, dry mouth, difficulty falling or staying asleep, muscle pain, rash, nausea and constipation have been seen. More serious side effects such as severe headache, tachycardia, arrhythmia, hallucinations, chorea, or difficulty breathing should be investigated by health professionals immediately.Pharmacokinetics
Selegiline has a low oral bioavailability, which increases to moderate when ingested together with a high-fat meal (the molecule being liposoluble).Selegiline's oral bioavailability is drastically increased in females taking oral contraceptives (10- to 20-fold). This could lead to loss of MAO-B selectivity in favor of an MAO-A selectivity, which in turn would make patients susceptible to the usual risks of unselective MAOIs such as tyramine
Tyramine
Tyramine is a naturally occurring monoamine compound and trace amine derived from the amino acid tyrosine. Tyramine acts as a catecholamine releasing agent...
-induced hypertensive crisis and serotonin toxicity when combined with serotonergics such as SSRIs.
Mechanism of Action
Selegiline is a selective inhibitor of MAO-B; MAO-B metabolizes dopamine and phenylethylamine. Selegiline exhibits little therapeutic benefit when used independently, but enhances and prolongs the anti-ParkinsonParkinson's disease
Parkinson's disease is a degenerative disorder of the central nervous system...
effects of levodopa
Levodopa
L-DOPA is a chemical that is made and used as part of the normal biology of some animals and plants. Some animals including humans make it via biosynthesis from the amino acid L-tyrosine. L-DOPA is the precursor to the neurotransmitters dopamine, norepinephrine , and epinephrine collectively...
.
Desmethylselegiline
Desmethylselegiline may have neuroprotective antiapoptotic properties. A large multicenter study suggests a decrease in the disease progression of parkinsonism but may have reflected other symptomatic response. Desmethylselegiline is metabolized by CYP2C19
CYP2C19
Cytochrome P450 2C19 , a member of the cytochrome P450 mixed-function oxidase system, is involved in the metabolism of xenobiotics in the body. It is involved in the metabolism of several...
.
L-amphetamine and L-methamphetamine
Selegiline is partly metabolized
Drug metabolism
Drug metabolism is the biochemical modification of pharmaceutical substances by living organisms, usually through specialized enzymatic systems. This is a form of xenobiotic metabolism. Drug metabolism often converts lipophilic chemical compounds into more readily excreted polar products...
to l-methamphetamine, one of the two enantiomer
Enantiomer
In chemistry, an enantiomer is one of two stereoisomers that are mirror images of each other that are non-superposable , much as one's left and right hands are the same except for opposite orientation. It can be clearly understood if you try to place your hands one over the other without...
s of methamphetamine
Methamphetamine
Methamphetamine is a psychostimulant of the phenethylamine and amphetamine class of psychoactive drugs...
in vivo
In vivo
In vivo is experimentation using a whole, living organism as opposed to a partial or dead organism, or an in vitro controlled environment. Animal testing and clinical trials are two forms of in vivo research...
. A characteristic metabolic pattern was noted, exemplified by a ratio of l-methamphetamine to l-amphetamine of about 2.8. These stereoisomers are considered significantly less psychoactive and have little abuse potential in contrast to their D-isomers. The stimulatory effect on locomotor activity and dopamine synthesis may be contributed to by the action of l-methamphetamine, a once thought to be inactive metabolite. This locomotor effect at therapeutic doses was not apparent in comparison to placebo, but both l-amphetamine and l-methamphetamine had positive effects on genetic expression for memory enhancement in rats and other animals.
This metabolic action may cause persons taking prescribed selegiline to test positive for amphetamine
Amphetamine
Amphetamine or amfetamine is a psychostimulant drug of the phenethylamine class which produces increased wakefulness and focus in association with decreased fatigue and appetite.Brand names of medications that contain, or metabolize into, amphetamine include Adderall, Dexedrine, Dextrostat,...
and or methamphetamine
Methamphetamine
Methamphetamine is a psychostimulant of the phenethylamine and amphetamine class of psychoactive drugs...
on drug screening tests.
Legal issues
Possibly due to the structural similarity to illegal stimulantStimulant
Stimulants are psychoactive drugs which induce temporary improvements in either mental or physical function or both. Examples of these kinds of effects may include enhanced alertness, wakefulness, and locomotion, among others...
s, selegiline has been classified as a controlled substance
Controlled substance
A controlled substance is generally a drug or chemical whose manufacture, possession, or use are regulated by a government. This may include illegal drugs and prescription medications ....
in Japan
Japan
Japan is an island nation in East Asia. Located in the Pacific Ocean, it lies to the east of the Sea of Japan, China, North Korea, South Korea and Russia, stretching from the Sea of Okhotsk in the north to the East China Sea and Taiwan in the south...
and thus can only be obtained with a prescription
Medical prescription
A prescription is a health-care program implemented by a physician or other medical practitioner in the form of instructions that govern the plan of care for an individual patient. Prescriptions may include orders to be performed by a patient, caretaker, nurse, pharmacist or other therapist....
or special government license.
In E for Ecstasy
E for Ecstasy
E for Ecstasy is a book written by Nicholas Saunders and published in May of 1993. Available freely online, it describes in detail the psychoactive substance MDMA, also known as ecstasy, the people that use it and the law concerning it, all enhanced through the backdrop of the author's personal...
(a book examining the uses of the street drug Ecstasy
Methylenedioxymethamphetamine
MDMA is an entactogenic drug of the phenethylamine and amphetamine class of drugs. In popular culture, MDMA has become widely known as "ecstasy" , usually referring to its street pill form, although this term may also include the presence of possible adulterants...
in the UK) the writer, activist and Ecstasy advocate Nicholas Saunders highlighted test results showing that certain consignments of the drug also contained selegiline. Consignments of Ecstasy known as "Strawberry" contained what Saunders described as a "potentially dangerous combination of ketamine
Ketamine
Ketamine is a drug used in human and veterinary medicine. Its hydrochloride salt is sold as Ketanest, Ketaset, and Ketalar. Pharmacologically, ketamine is classified as an NMDA receptor antagonist...
, ephedrine
Ephedrine
Ephedrine is a sympathomimetic amine commonly used as a stimulant, appetite suppressant, concentration aid, decongestant, and to treat hypotension associated with anaesthesia....
and selegiline," as did a consignment of "Sitting Duck" Ecstasy tablets.
Selegiline is not a controlled substance in the US but a prescription is required to obtain it within the US.
Emsam
In February 2006 the US Food and Drug Administration approved EmsamEmsam
Emsam is the trade name of an antidepressant of the monoamine oxidase inhibitor class. Emsam is a transdermal patch containing the MAOI selegiline. Selegiline, in small doses, is most commonly used in the treatment of Parkinson's disease. It is also effective in higher doses for the treatment...
(selegiline), the first transdermal patch
Transdermal patch
A transdermal patch is a medicated adhesive patch that is placed on the skin to deliver a specific dose of medication through the skin and into the bloodstream. Often, this promotes healing to an injured area of the body. An advantage of a transdermal drug delivery route over other types of...
for use in treating major depression. The once a day patch works by delivering selegiline through the skin and into the bloodstream. Emsam can be used without the dietary restrictions that are needed for all oral MAO inhibitors that are approved for treating major depression, although the FDA requires warnings concerning dietary restrictions for the 9 and 12 mg doses due to theoretical concerns not supported by any reports of adverse events. It comes in three sizes that deliver 6, 9, or 12 mg of selegiline per 24 hours. The patch is a matrix containing three layers consisting of a backing, an adhesive drug layer, and a release liner that is placed against the skin. EMSAM was developed by Somerset Pharmaceuticals, Inc. In December 2004, Bristol-Myers Squibb and Somerset entered into an agreement that provides Bristol-Myers Squibb with distribution rights to market EMSAM after approval in the United States.
Zelapar
Zelapar is a transmucosal preparation for human administration of selegiline. The quickly-dissolving lozenge is placed between cheek and gum and the medication enters the bloodstream directly. Because hepatic first-pass metabolism is bypassed, the effective dose is lower than oral (swallowed) selegiline. GI side effects are reportedly reduced compared to oral (swallowed) selegiline. Zelapar is manufactured by Valeant PharmaceuticalsValeant Pharmaceuticals International
Valeant Pharmaceuticals International, Inc. is a pharmaceutical company with activities spanning the drug discovery pipeline from target identification through clinical trials and commercialization. The focus of the company is on neurology, dermatology and infectious disease with several drugs in...
http://www.valeant.com/researchAndDevelopment/pipeline/zelapar.jspf.
Chemistry
Selegiline, N-methyl-N-(2-propynyl)-2-methyl-1-phenylethyl-2-amine, is synthesized by the alkylation of (–)-methamphetamineMethamphetamine
Methamphetamine is a psychostimulant of the phenethylamine and amphetamine class of psychoactive drugs...
using propargyl bromide.
External links
- Deprenyl (Selegiline) Can Slow Parkinson's Disease Safely According to the British Medical Journal
- FDA Approves Emsam (Selegiline) as First Drug Patch for Depression