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=====L-amphetamine and L-methamphetamine=====
=====L-amphetamine and L-methamphetamine=====
Selegiline is partly [[Drug metabolism|metabolized]] to [[L-methamphetamine]], one of the two [[enantiomer]]s of [[methamphetamine]] ''[[in vivo]]''.<ref name="Pmid">{{cite journal |pmid=1658311 |year=1991 |last1=Engberg |first1=G |last2=Elebring |first2=T |last3=Nissbrandt |first3=H |title=Deprenyl (selegiline), a selective MAO-B inhibitor with active metabolites; effects on locomotor activity, dopaminergic neurotransmission and firing rate of nigral dopamine neurons |volume=259 |issue=2 |pages=841–7 |journal=The Journal of Pharmacology and Experimental Therapeutics}}</ref> A characteristic metabolic pattern was noted, exemplified by a ratio of L-methamphetamine to L-amphetamine of about 2.8.<ref>www.astm.org/JOURNALS/FORENSIC/PAGES/2587.htm{{full|date=November 2012}}</ref> These stereoisomers are considered significantly less psychoactive and have little abuse potential in contrast to their D-isomers.<ref>{{cite journal |pmid=8988462 |year=1996 |last1=Yasar |first1=S |last2=Goldberg |first2=JP |last3=Goldberg |first3=SR |title=Are metabolites of L-deprenyl (selegiline) useful or harmful? Indications from preclinical research |volume=48 |pages=61–73 |journal=Journal of neural transmission. Supplementum}}</ref> 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.<ref name="Pmid" /> 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.<ref>{{cite journal |pages=106–13 |doi=10.1016/j.nlm.2009.02.001 |title=The levo enantiomer of amphetamine increases memory consolidation and gene expression in the hippocampus without producing locomotor stimulation |year=2009 |last1=Wiig |first1=Kjesten A. |last2=Whitlock |first2=Jonathan R. |last3=Epstein |first3=Mel H. |last4=Carpenter |first4=Randall L. |last5=Bear |first5=Mark F. |journal=Neurobiology of Learning and Memory |volume=92 |pmid=19368765 |issue=1}}</ref>
Selegiline is partly [[Drug metabolism|metabolized]] to [[L-methamphetamine]], one of the two [[enantiomer]]s of [[methamphetamine]] ''[[in vivo]]''.<ref name="Pmid">{{cite journal |pmid=1658311 |year=1991 |last1=Engberg |first1=G |last2=Elebring |first2=T |last3=Nissbrandt |first3=H |title=Deprenyl (selegiline), a selective MAO-B inhibitor with active metabolites; effects on locomotor activity, dopaminergic neurotransmission and firing rate of nigral dopamine neurons |volume=259 |issue=2 |pages=841–7 |journal=The Journal of Pharmacology and Experimental Therapeutics}}</ref> A characteristic metabolic pattern was noted, exemplified by a ratio of L-methamphetamine to L-amphetamine of about 2.8.<ref>www.astm.org/JOURNALS/FORENSIC/PAGES/2587.htm{{full|date=November 2012}}</ref> These stereoisomers are considered significantly less psychoactive and have little abuse potential in contrast to their D-isomers.<ref>{{cite journal |pmid=8988462 |year=1996 |last1=Yasar |first1=S |last2=Goldberg |first2=JP |last3=Goldberg |first3=SR |title=Are metabolites of L-deprenyl (selegiline) useful or harmful? Indications from preclinical research |volume=48 |pages=61–73 |journal=Journal of neural transmission. Supplementum}}</ref> However, a stimulatory effect on locomotor activity and dopamine synthesis may be partly caused by the action of L-methamphetamine, which was once thought to be an inactive metabolite.<ref name="Pmid" /> 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.<ref>{{cite journal |pages=106–13 |doi=10.1016/j.nlm.2009.02.001 |title=The levo enantiomer of amphetamine increases memory consolidation and gene expression in the hippocampus without producing locomotor stimulation |year=2009 |last1=Wiig |first1=Kjesten A. |last2=Whitlock |first2=Jonathan R. |last3=Epstein |first3=Mel H. |last4=Carpenter |first4=Randall L. |last5=Bear |first5=Mark F. |journal=Neurobiology of Learning and Memory |volume=92 |pmid=19368765 |issue=1}}</ref>


This metabolic action may cause persons taking selegiline to test positive for [[amphetamine]] and or [[methamphetamine]] on drug screening tests.
This metabolic pathway may also cause persons taking selegiline to test positive for [[amphetamine]] and or [[methamphetamine]] on drug screening tests.


==Interactions==
==Interactions==

Revision as of 00:06, 9 December 2012

Selegiline
Clinical data
Trade namesEldepryl
AHFS/Drugs.comMonograph
MedlinePlusa697046
Pregnancy
category
Routes of
administration		Oral, transdermal, buccal
ATC code
Legal status
Legal status
  • prescription only (unscheduled) (US)
Pharmacokinetic data
Bioavailability4.4% (oral, fasted), 20% (oral, after food), 18% (patch)
Protein binding90%
Metabolismliver
Elimination half-life1.5 hours (oral, single dose), 9 hours (oral, chronic)
Excretionurine
Identifiers
  • (R)-N-methyl-N-(1-phenylpropan-2-yl)prop-1-yn-3-amine
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.109.269 Edit this at Wikidata
Chemical and physical data
FormulaC13H17N
Molar mass187.281 g/mol g·mol−1
3D model (JSmol)
  • C#CCN([C@@H](Cc1ccccc1)C)C
  • InChI=1S/C13H17N/c1-4-10-14(3)12(2)11-13-8-6-5-7-9-13/h1,5-9,12H,10-11H2,2-3H3/t12-/m1/s1 checkY
  • Key:MEZLKOACVSPNER-GFCCVEGCSA-N checkY
  (verify)

Selegiline (Anipryl, L-deprenyl, Eldepryl, Emsam, Zelapar) 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,[1] 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.[2] 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.

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 pargyline and the psychostimulant amphetamine. Knoll was a close friend of Meszaros, the research director of Chinoin, a Hungarian pharmaceutical company (later sold off to Sanofi). For this project, Meszaros put Knoll in contact with a chemist called Ecsery who worked in Chinoin in the field of phenethylamines. Ecsery 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.[3]

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.[3][4]

In 1967, a Hungarian psychiatrist Ervin Varga observed that racemic deprenyl given in large doses has an antidepressant action.[5] This study was largely forgotten until the 2000s (decade) when Sommerset Pharmaceuticals developed selegiline patch for depression.

Uses

The main use of selegiline is in the treatment of Parkinson's disease. It can be used on its own or in a combination with another agent, most often L-DOPA.[6] For the newly diagnosed Parkinson's patients, some claim that selegiline slows the progression of the disease, although this claim has not been widely accepted and the methodology has been rejected by the Food and Drug Administration (FDA).[7] It delays the time point when the L-DOPA (levodopa) treatment becomes necessary from 10-12 to 18 months,[8] which is beneficial despite not being definitive evidence of neuroprotection. The idea behind adding selegiline to levodopa is to decrease the dose of levodopa and thus reduce the motor complications of levodopa therapy.[9] 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.[8] As a result there were fewer motor complications in selegiline groups.[9] 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.[8]

As of February 28, 2006, selegiline has also been approved by the FDA to treat major depression using a transdermal patch (Emsam Patch).[10] 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)[11][12] in dogs.[13][14][15] As of June 26, 2006, a selegiline transdermal patch is being tested for its effectiveness in treating ADHD.[16]

Several clinical studies are currently underway to evaluate selegiline's effectiveness in helping people stop smoking tobacco or cannabis.[17][18]

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.[19]

Pharmacology

Pharmacokinetics

Selegiline has a low oral bioavailability, which increases to moderate when ingested together with a high-fat meal, the molecule being fat soluble.[20]

Selegiline's oral bioavailability is drastically increased in females taking oral contraceptives (10- to 20-fold).[21] 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.[21]

Mechanism of Action

Selegiline is a selective inhibitor of MAO-B; MAO-B metabolizes dopamine and phenylethylamine.[22] Selegiline exhibits little therapeutic benefit when used independently, but enhances and prolongs the anti-Parkinson effects of levodopa.[23]

Metabolites

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.[22] Desmethylselegiline is metabolized by CYP2C19.[24]

L-amphetamine and L-methamphetamine

Selegiline is partly metabolized to L-methamphetamine, one of the two enantiomers of methamphetamine in vivo.[25] A characteristic metabolic pattern was noted, exemplified by a ratio of L-methamphetamine to L-amphetamine of about 2.8.[26] These stereoisomers are considered significantly less psychoactive and have little abuse potential in contrast to their D-isomers.[27] However, a stimulatory effect on locomotor activity and dopamine synthesis may be partly caused by the action of L-methamphetamine, which was once thought to be an inactive metabolite.[25] 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.[28]

This metabolic pathway may also cause persons taking selegiline to test positive for amphetamine and or methamphetamine on drug screening tests.

Interactions

Selegiline in combination with pethidine is not recommended as it can lead to severe adverse effects; selegiline in combination with the older non-selective MAOIs or in combination with the reversible MAO-A inhibitor moclobemide requires a low tyramine diet. The risk of a true serotonin syndrome with SSRIs and selegiline is quite low and the combination can be taken together without event if caution is used.[29]

Legal issues

Possibly due to the structural similarity to illegal stimulants, 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[30] (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.[31]

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 Emsam (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.[2] 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 Pharmaceuticals.[32]

Chemistry

Selegiline, N-methyl-N-(2-propynyl)-2-methyl-1-phenylethyl-2-amine, is synthesized by the alkylation of (–)-methamphetamine using propargyl bromide.[33][34][35][36]

See also

References

  1. ^ Amsterdam, J. D. (2003-02). "A double-blind, placebo-controlled trial of the safety and efficacy of selegiline transdermal system without dietary restrictions in patients with major depressive disorder". Journal of Clinical Psychiatry. 64 (2): 208–14. doi:10.4088/JCP.v64n0216. PMID 12633131. {{cite journal}}: Check date values in: |date= (help); Cite has empty unknown parameter: |coauthors= (help)
  2. ^ a b Cascade EF, Kalali AH (2007). "EMSAM: The First Year". Psychiatry 2007. Retrieved 2009-11-30. {{cite journal}}: Unknown parameter |month= ignored (help)
  3. ^ a b Healy, David (2000). "The psychopharmacology of life and death. Interview with Joseph Knoll.". The Psychopharmacologists, Vol. III: Interviews. London: Arnold. pp. 81–110. ISBN 0-340-76110-5.
  4. ^ Birkmayer W, Riederer P, Youdim MB, Linauer W (1975). "The potentiation of the anti akinetic effect after L-dopa treatment by an inhibitor of MAO-B, Deprenil". J. Neural Transm. 36 (3–4): 303–26. doi:10.1007/BF01253131. PMID 1172524.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  5. ^ Varga E, Tringer L (1967). "Clinical trial of a new type promptly acting psychoenergetic agent (phenyl-isopropyl-methylpropinyl-HCl, "E-250")". Acta Med Acad Sci Hung. 23 (3): 289–95. PMID 6056555.
  6. ^ Riederer P, Lachenmayer L, Laux G (2004). "Clinical applications of MAO-inhibitors". Curr. Med. Chem. 11 (15): 2033–43. PMID 15279566. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  7. ^ Russel Katz, M.D.; et al. "Peripheral and Central Nervous System Advisory Committee Background Package on Azilect" (PDF). FDA. Retrieved 7 December 2011. {{cite web}}: Explicit use of et al. in: |author= (help)
  8. ^ a b c Riederer P, Lachenmayer L (2003). "Selegiline's neuroprotective capacity revisited". J Neural Transm. 110 (11): 1273–8. doi:10.1007/s00702-003-0083-x. PMID 14628191. {{cite journal}}: Unknown parameter |month= ignored (help)
  9. ^ a b Ives NJ; Stowe RL; Marro J; et al. (2004). "Monoamine oxidase type B inhibitors in early Parkinson's disease: meta-analysis of 17 randomised trials involving 3525 patients". BMJ. 329 (7466): 593. doi:10.1136/bmj.38184.606169.AE. PMC 516655. PMID 15310558. {{cite journal}}: Unknown parameter |author-separator= ignored (help); Unknown parameter |month= ignored (help)
  10. ^ FDA Approves Emsam (Selegiline) as First Drug Patch for Depression
  11. ^ Lundgren, Becky. "Canine Cognitive Dysfunction". Veterinary Partner. Retrieved 8 April 2011.
  12. ^ "Cognitive Dysfunction Syndrome". Long Beach Animal Hospital. Retrieved 8 April 2011.
  13. ^ http://www.petplace.com/drug-library/selegiline-hcl-anipryl/page1.aspx
  14. ^ "Anipryl consumer information". Drugs.com Vet. Retrieved 3 April 2011.
  15. ^ Braddock JA, Church DB, Robertson ID, (2004). "Selegiline Treatment of Canine Pituitary-Dependent Hyperadrenocorticism" (PDF). Australian Veterinary Journal. Retrieved 8 April 2011.{{cite web}}: CS1 maint: extra punctuation (link) CS1 maint: multiple names: authors list (link) (PDF)
  16. ^ http://www.selegiline.com/adhd.html
  17. ^ "Effectiveness of Selegiline in Treating Marijuana Dependent Individuals". ClinicalTrials.gov. National Institute on Drug Abuse. 2005. Retrieved 2007-02-16. {{cite web}}: Cite has empty unknown parameter: |coauthors= (help); Unknown parameter |month= ignored (help)
  18. ^ "Usefulness of Selegiline as an Aid to Quit Smoking". ClinicalTrials.gov. National Institute on Drug Abuse. 2004. Retrieved 2007-02-16. {{cite web}}: Cite has empty unknown parameter: |coauthors= (help); Unknown parameter |month= ignored (help)
  19. ^ http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=medmaster&part=a697046[full citation needed]
  20. ^ Barrett, Jeffrey S.; Szego, Peter; Rohatagi, Shashank; Morales, Richard J.; Dewitt, Kimberly E.; Rajewski, Gregory; Ireland, Joyce (1996). "Absorption and presystemic metabolism of selegiline hydrochloride at different regions in the gastrointestinal tract in healthy males". Pharmaceutical Research. 13 (10): 1535–40. doi:10.1023/A:1016035730754. PMID 8899847.
  21. ^ a b Laine, Kari; Anttila, Markku; Helminen, Antti; Karnani, Hari; Huupponen, Risto (2001). "Dose linearity study of selegiline pharmacokinetics after oral administration: Evidence for strong drug interaction with female sex steroids". British Journal of Clinical Pharmacology. 47 (3): 249–54. doi:10.1046/j.1365-2125.1999.00891.x. PMC 2014223. PMID 10215747.
  22. ^ a b Katzung, Bertram G. Basic & Clinical Pharmacology. 9th Edition. 2004. page 453. Lange Medical Books - McGraw Hill Publishers.
  23. ^ Katzung. Page 453
  24. ^ Taavitsainen, Paivi; Anttila, Markku; Nyman, Leena; Karnani, Hari; Salonen, Jarmo S.; Pelkonen, Olavi (2000). "Selegiline Metabolism and Cytochrome P450 Enzymes:In vitro Study in Human Liver Microsomes*". Pharmacology and Toxicology. 86 (5): 215–21. doi:10.1034/j.1600-0773.2000.d01-38.x. PMID 10862503.
  25. ^ a b Engberg, G; Elebring, T; Nissbrandt, H (1991). "Deprenyl (selegiline), a selective MAO-B inhibitor with active metabolites; effects on locomotor activity, dopaminergic neurotransmission and firing rate of nigral dopamine neurons". The Journal of Pharmacology and Experimental Therapeutics. 259 (2): 841–7. PMID 1658311.
  26. ^ www.astm.org/JOURNALS/FORENSIC/PAGES/2587.htm[full citation needed]
  27. ^ Yasar, S; Goldberg, JP; Goldberg, SR (1996). "Are metabolites of L-deprenyl (selegiline) useful or harmful? Indications from preclinical research". Journal of neural transmission. Supplementum. 48: 61–73. PMID 8988462.
  28. ^ Wiig, Kjesten A.; Whitlock, Jonathan R.; Epstein, Mel H.; Carpenter, Randall L.; Bear, Mark F. (2009). "The levo enantiomer of amphetamine increases memory consolidation and gene expression in the hippocampus without producing locomotor stimulation". Neurobiology of Learning and Memory. 92 (1): 106–13. doi:10.1016/j.nlm.2009.02.001. PMID 19368765.
  29. ^ Heinonen EH, Myllylä V (1998). "Safety of selegiline (deprenyl) in the treatment of Parkinson's disease". Drug Saf. 19 (1): 11–22. doi:10.2165/00002018-199819010-00002. PMID 9673855. {{cite journal}}: Unknown parameter |month= ignored (help)
  30. ^ Saunders, N., & Heron, L., (1993) E for Ecstasy (Paperback), N. Saunders, London. (ISBN 0950162884)[page needed]
  31. ^ See: [1] for details online.
  32. ^ http://www.valeant.com/researchAndDevelopment/pipeline/zelapar.jspf[full citation needed]
  33. ^ J. Knoll, E. Sanfai, DE 1568277  (1966).
  34. ^ J. Hermann Nee Voeroes, Z. Ecsery, G. Sabo, L. Arvai, L. Nagi, O. Orban, E. Sanfai, U.S. patent 4,564,706 (1986)
  35. ^ B. Brunova, M. Ferenc, EP 344675  (1989)
  36. ^ Fowler, Joanna S. (1977). "2-Methyl-3-butyn-2-ol as an acetylene precursor in the Mannich reaction. A new synthesis of suicide inactivators of monoamine oxidase". The Journal of Organic Chemistry. 42 (15): 2637–7. doi:10.1021/jo00435a026. PMID 874623.

External links

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