Selegiline

Source: Wikipedia, the free encyclopedia.

Selegiline
Clinical data
Pronunciation/səˈlɛdʒɪliːn/ sə-LEJ-i-leen
Trade namesEldepryl, Jumex, Zelapar, Emsam, others[1]
Other namesL-Deprenyl; (R)-(–)-N,α-Dimethyl-N-2-propynylphenethylamine; (R)-(–)-N-Methyl-N-2-propynylamphetamine; (R)-(–)-N-2-propynylmethamphetamine
AHFS/Drugs.comMonograph
MedlinePlusa697046
License data
Pregnancy
category
  • AU: B2
Routes of
administration		By mouth, transdermal (patch)
ATC code
Legal status
Legal status
Intestines and liver
MetabolitesN-Desmethylselegiline, levoamphetamine, levomethamphetamine
Elimination half-life1.5–3.5 hours (oral),[3] 18–25 hours (transdermal)[4]
ExcretionUrine
Identifiers
  • (R)-N-methyl-N-(1-pheny lpropan-2-yl)prop-3-yn-1-amine
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, also known as L-deprenyl and sold under the brand names Eldepryl, Emsam, Selgin, among other names, is a medication which is used in the treatment of Parkinson's disease and major depressive disorder.[1] It is provided in the form of a capsule or tablet taken by mouth or orally disintegrating tablets taken on the tongue for Parkinson's disease and as a patch applied to skin for depression.

Selegiline acts as a

irreversible inhibitor of monoamine oxidase B (MAO-B), increasing levels of dopamine in the brain. In larger doses (more than 20 mg/day), it loses its specificity for MAO-B and also inhibits MAO-A, which increases serotonin and norepinephrine
levels in the brain.

Medical uses

Parkinson's disease

In its pill form, selegiline is used to treat symptoms of

levodopa (L-DOPA), although it has been used off-label as a monotherapy.[6][7] The rationale for adding selegiline to levodopa is to decrease the required dose of levodopa and thus reduce the motor complications of levodopa therapy.[8] Selegiline delays the point when levodopa treatment becomes necessary from about 11 months to about 18 months after diagnosis.[9] There is some evidence that selegiline acts as a neuroprotectant and reduces the rate of disease progression, though this is disputed.[7][8]

Selegiline has also been used off-label as a palliative treatment for dementia in Alzheimer's disease.[7]

Depression

Selegiline is also delivered via a transdermal patch used as a treatment for major depressive disorder.[10][11] Administration of transdermal selegiline bypasses hepatic first pass metabolism. This avoids inhibition of gastrointestinal and hepatic MAO-A activity, which would result in an increase of food-borne tyramine in the blood and possible related adverse effects, while allowing for a sufficient amount of selegiline to reach the brain for an antidepressant effect.[12]

A quantitative review published in 2015 found that for the pooled results of the pivotal trials, the number needed to treat (a sign of effect size, so a low number is better) for the patch for symptom reduction was 11, and for remission, was 9.[11] The number needed to harm (inverse of the NNT, a high number here is better) ranged from 387 for sexual side effects to 7 for application site reaction.[11] With regard to the likelihood to be helped or harmed (LHH), the analysis showed that the selegiline patch was 3.6 times as likely to lead to a remission vs. a discontinuation due to side effects; the LHH for remission vs. incidence of insomnia was 2.1; the LHH for remission vs. discontinuation due to insomnia was 32.7. The LHH for remission vs. insomnia and sexual dysfunction were both very low.[11]

Special populations

For all human uses and all forms, selegiline is pregnancy category C: studies in pregnant lab animals have shown adverse effects on the fetus but there are no adequate studies in humans.[5][10]

Side effects

angina pectoris, and syncope.[5] Most of the side effects are due to a high dopamine signaling, and can be alleviated by reducing the dose of levodopa.[1]

The main side effects of the patch form for depression include application-site reactions, insomnia, diarrhea, and sore throat.[10] The selegiline patch carries a black box warning about a possible increased risk of suicide, especially for young people,[10] as do all antidepressants since 2007.[13]

Interactions

Both the oral and patch forms come with strong warnings against combining selegiline with drugs that could produce

cough medicine dextromethorphan.[5][10][14] Selegiline in combination with the opioid analgesic pethidine is not recommended, as it can lead to severe adverse effects.[14] Several other synthetic opioids such as tramadol and methadone, as well as various triptans, are contraindicated due to potential for serotonin syndrome.[15][16]

MAOIs, such as tyramine-induced hypertensive crisis and serotonin toxicity when combined with serotonergic medications.[17]

Both forms of the drug carry warnings about

reversible MAO-A inhibitor moclobemide, require a low-tyramine diet.[14]

Pharmacology

Pharmacodynamics

Selegiline is a selective inhibitor of

MAO-A as well.[1]

Selegiline potentiates the release of catecholamines independent of its MAO-B inhibiting action. As such, it has been called the "first synthetic catecholaminergic activity enhancer substance".[22][23]

Selegiline also inhibits CYP2A6 and can increase the effects of nicotine as a result.[24] Selegiline also appears to activate σ1 receptors, having a relatively high affinity for these receptors of approximately 400 nM.[25][26]

Pharmacokinetics

Selegiline has an oral

cingulate gyrus.[7][10]

Selegiline is mostly metabolized in the

intestines and liver; it and its metabolites are excreted in the urine.[1]

Buccal administration of selegiline results in 5-fold higher bioavailability, more reproducible blood concentration, and produces fewer amphetamine metabolites than the oral tablet form.[28]

Metabolism

Selegiline is metabolized by cytochrome P450 to L-desmethylselegiline and levomethamphetamine.[29][30] Desmethylselegiline has some activity against MAO-B, but much less than that of selegiline.[20][19] It is thought to be further metabolized by CYP2C19.[31] Levomethamphetamine (the less potent of the two enantiomers of methamphetamine) is converted to levoamphetamine (the less potent of the two enantiomers of amphetamine, with regards to psychological effects).

Due to the presence of these metabolites, people taking selegiline may test positive for "amphetamine" or "methamphetamine" on drug screening tests.

glucuronyltransferase
.

A newer anti-Parkinson MAO-B inhibitor, rasagiline, metabolizes into 1(R)-aminoindan, which has no amphetamine-like characteristics.[36]

Patch

Following application of the patch to humans, an average of 25% to 30% of the selegiline content is delivered systemically over 24 hours. Transdermal dosing results in significantly higher exposure to selegiline and lower exposure to all metabolites when compared to oral dosing; this is due to the extensive first-pass metabolism of the pill form and low first-pass metabolism of the patch form. The site of application is not a significant factor in how the drug is distributed. In humans, selegiline does not accumulate in the skin, nor is it metabolized there.[10]

Chemistry

Selegiline belongs to the

deprenyl
.

Selegiline is synthesized by the alkylation of (–)-methamphetamine using propargyl bromide.[37][38][39][40]

Another clinically used MAOI of the amphetamine class is tranylcypromine.

History

Following the discovery in 1952 that the tuberculosis drug iproniazid elevated the mood of people taking it, and the subsequent discovery that the effect was likely due to inhibition of MAO, many people and companies started trying to discover MAO inhibitors to use as antidepressants. Selegiline was discovered by Zoltan Ecseri at the Hungarian drug company, Chinoin (part of Sanofi since 1993),[41] which they called E-250.[42]: 66–67  Chinoin received a patent on the drug in 1962 and the compound was first published in the scientific literature in English in 1965.[42]: 67 [43] Work on the biology and effects of E-250 in animals and humans was conducted by a group led by József Knoll at Semmelweis University which was also in Budapest.[42]: 67 

Emsam transdermal patch, 6mg/24hr dose

Deprenyl is a racemic compound (a mixture of two isomers called

levorotatory enantiomer was a more potent MAO-inhibitor, which was published in 1967, and subsequent work was done with the single enantiomer L-deprenyl.[42]: 67 [44][45]

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" (

Moussa B.H. Youdim, visited Knoll in Budapest and took selegiline from him to Vienna. In 1975, Birkmayer's group published the first paper on the effect of selegiline in Parkinson's disease.[45][46]

In the 1970s there was speculation that it could be useful as an

anti-aging drug or aphrodisiac.[47]

In 1987 Somerset Pharmaceuticals in New Jersey, which had acquired the US rights to develop selegiline, filed a

new drug application (NDA) with the FDA to market the drug for Parkinson's disease in the US.[48] While the NDA was under review, Somerset was acquired in a joint venture by two generic drug companies, Mylan and Bolan Pharmaceuticals.[48] Selegiline was approved for Parkinson's disease by the FDA in 1989.[48]

In the 1990s, J. Alexander Bodkin at McLean Hospital, an affiliate of Harvard Medical School, began a collaboration with Somerset to develop delivery of selegiline via a transdermal patch in order to avoid the well known dietary restrictions of MAO inhibitors.[47][49][50] Somerset obtained FDA approval to market the patch in 2006.[51]

As an anti-aging/longevity drug

Joseph Knoll and his team are credited with having developed selegiline. Although selegeline's development as a potential treatment for Parkinson's, Alzheimer's, and major depressive disorder was headed by other teams, Knoll remained at the forefront of research into the potential longevity enhancing effects of selegiline up until his death in 2018.[52][53][54] Knoll published How Selegiline ((-)-Deprenyl) Slows Brain Aging (2018) wherein he claims that:

"In humans, maintenance from sexual maturity on (-)-deprenyl (1mg daily) is, for the time being, the most promising prophylactic treatment to fight against the age related decay of behavioral performances, prolonging life, and preventing or delaying the onset of age-related neurodegenerative diseases such as Parkinson's and Alzheimer's".[55]

The mechanism of selegiline's longevity-promoting effect has been researched by several groups, including Joseph Knoll and his associates at Semmelweis University, Budapest.[56] The drug has been determined to be a catecholaminergic activity enhancer when present in minuscule concentrations far below those at which monoamine oxidase inhibitory activity can be observed, thereby potentiating the release of catecholamine neurotransmitters in response to stimuli. Knoll maintains that micro-doses of selegiline act as a synthetic analogue to a known or unknown trace amine in order to preserve the brain catecholaminergic system, which he perceives as integral to the organism's ability to function in an adaptive, goal-directed and motivated manner during advancing physical age:

" ... enhancer regulation in the catecholaminergic brain stem neurons play[s] a key role in controlling the uphill period of life and the transition from adolescence to adulthood. The results of our longevity studies support the hypothesis that quality and duration of life rests upon the inborn efficiency of the catcholaminergic brain machinery, i.e. a high performing, long-living individual has a more active, more slowly deteriorating catecholaminergic system than its low performing, shorter living peer. Thus, a better brain engine allows for a better performance and a longer lifespan.

...

Since the catecholaminergic and serotonergic neurons in the brain stem are of key importance in ensuring that the mammalian organism works as a purposeful, motivated, goal-directed entity, it is hard to overestimate the significance of finding safe and efficient means to slow the decay of these systems with passing time. The conclusion that the maintenance on (-)-deprenyl that keeps the catecholaminergic neurnsn a higher activity level is a safe and efficient anti- aging therapy follows from the discovery of the enhancer regulation in the catecholaminergic neurons of the brain stem. From the finding that this regulation starts working on a high activity level after weaning and the enhanced activity subsists during the uphill period of life, until sexual hormones dampen the enhancer regulation in the catecholaminergic and serotonergic neurons in the brain stem, and this event signifies the transition from developmental longevity into postdevelopmental longevity, the downhill period of life."[55]

As a nootropic/"smart drug"

Selegiline is considered by some to be a

glial cell-derived neurotrophic factor.[56] It has been demonstrated in numerous animal models to improve learning ability and preserve it during both ischemia and aging.[58][59][60][61]

Society and culture

In

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.[62] 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.[63]

David Pearce wrote The Hedonistic Imperative[64] six weeks after starting taking selegiline.[65]

In Gregg Hurwitz's novel Out of the Dark,[66] selegiline (Emsam) and tyramine-containing food were used to assassinate the president of the United States.

Veterinary use

In

cats with cognitive dysfunction.[71]

Selegiline's efficacy in treating pituitary-dependent hyperadrenocorticism has been disputed.

abdominal distention.[69]

Side effects in dogs are uncommon, but they include vomiting, diarrhea, diminished hearing,

disorientation, and repetitive motions.[68][72]

Selegiline does not appear to have a clinical effect on horses.[72]

ADHD research

Selegiline has been limitedly studied in the treatment of attention deficit hyperactivity disorder (ADHD) in both children/adolescents and adults.[73][74] In a small randomized trial of selegiline for treatment of ADHD in children, there were improvements in attention, hyperactivity, and learning/memory performance but not in impulsivity.[75] A small clinical randomized trial compared selegiline to methylphenidate, a first line treatment for ADHD, and reported equivalent efficacy as assessed by parent and teacher ratings.[76] In another small randomized controlled trial of selegiline for the treatment of adult ADHD, a high dose of the medication for 6 weeks was not significantly more effective than placebo in improving symptoms.[74][77][78]

References

  1. ^ a b c d e f g "Selegiline". Drugs.com. Retrieved February 7, 2016.
  2. ^ Anvisa (March 31, 2023). "RDC Nº 784 - Listas de Substâncias Entorpecentes, Psicotrópicas, Precursoras e Outras sob Controle Especial" [Collegiate Board Resolution No. 784 - Lists of Narcotic, Psychotropic, Precursor, and Other Substances under Special Control] (in Brazilian Portuguese). Diário Oficial da União (published April 4, 2023). Archived from the original on August 3, 2023. Retrieved August 16, 2023.
  3. ^ "Résumé des Caractéristiques du Produit".
  4. ^ https://www.accessdata.fda.gov/drugsatfda_docs/label/2007/021336s002lbl.pdf [bare URL PDF]
  5. ^ a b c d e Selegiline oral label. Updated December 31, 2008
  6. PMID 15279566.{{cite journal}}: CS1 maint: DOI inactive as of April 2024 (link
    )
  7. ^ a b c d "Selegiline Hydrochloride Monograph for Professionals". Drugs.com. Retrieved February 23, 2018.
  8. ^
    PMID 15310558
    .
  9. S2CID 20232921
    .
  10. ^ a b c d e f g h Emsam label Last revised Sept 2014. Index page at FDA
  11. ^
    PMID 23890583
    .
  12. PMID 19300583
    .
  13. PMID 17485726
    .
  14. ^
    S2CID 9632549
    .
  15. ISSN 2210-5336
    .
  16. PMID 16051647
    .
  17. ^
    PMID 10215747
    .
  18. PMID 19750165
    .
  19. ^
    ISBN 978-1-934559-87-1
    .
  20. ^
    ISBN 978-0-07-141092-2
    .
  21. PMID 34244591
    .
  22. ^ a b Miklya I (March 13, 2014). "The History of Selegiline/(-)-Deprenyl the First Selective Inhibitor of B-Type Monoamine Oxidase and The First Synthetic Catecholaminergic Activity Enhancer Substance". International Network for the History of Neuropsychopharmacology. Archived from the original on February 7, 2016. Retrieved January 7, 2016.
  23. PMID 9503565
    .
  24. PMID 18065502
    .
  25. ISBN 978-0-12-376350-1
    .
  26. ISBN 978-0-7484-0063-8
    .
  27. S2CID 24654277
    .
  28. S2CID 711419
    .
  29. PMID 1658311
    .
  30. ^
    ISBN 978-1609133450
    .
  31. PMID 10862503
    .
  32. PMID 8522918
    .
  33. S2CID 20471004
    .
  34. PMID 8988462. {{cite book}}: |journal= ignored (help
    )
  35. S2CID 221440315
    .
  36. S2CID 24350277. Archived from the original
    on July 11, 2012.
  37. ^ DE 1568277, Ecsery Z, Kosa I, Knoll J, Somfai E, "Verfahren zur Herstellung von neuen,optisch aktiven Phenylisopylamin-Derivaten [Process for the preparation of new, optically active phenylisopylamine derivatives]", published 1970-04-30, assigned to Chinoin Gyógyszer-és Vegyészeti Termékek Gyára RT 
  38. ^ J. Hermann Nee Voeroes, Z. Ecsery, G. Sabo, L. Arvai, L. Nagi, O. Orban, E. Sanfai, U.S. patent 4,564,706 (1986)
  39. ^ EP 344675, Hájicek J, Hrbata J, Pihera P, Brunová B, Ferenc M, Krepelka J, Kvapil L, Pospisil J, "Method for the production of selegiline hydrochloride", published 989-12-06, assigned to SPOFA Spojené Podniky Pro Zdravotnickou Vyrobu 
  40. PMID 874623
    .
  41. ^ "Sanofi Extends Holding in Chinoin". The Pharma Letter. September 19, 1993.
  42. ^
    ISBN 978-0-12-386468-0
    .
  43. PMID 4378644
    .
  44. PMID 5595908
    .
  45. ^
    ISBN 978-0-340-76110-6
    .
  46. S2CID 38179089. Archived from the original
    on February 12, 2013.
  47. ^ a b Cromie WJ (November 7, 2002). "Bodkin is Patching up Depression". Harvard University Gazette. Retrieved September 8, 2007.
  48. ^
    ISBN 978-1-61168-269-4
    .
  49. S2CID 42425086
    .
  50. ISSN 0362-4331
    .
  51. PMID 20711332
    .
  52. S2CID 208185366
    .
  53. PMID 27777099
    .
  54. ^ "In memoriam Joseph Knoll (1925-2018) | Hungarian Society for Experimental and Clinical Pharmacology". Retrieved April 10, 2023.
  55. ^
    ISBN 978-1608055944
    .
  56. ^
    PMID 27480491
    .
  57. ^ "Selegiline: Benefits, Dosing, Where To Buy, And More!". February 1, 2023. Retrieved September 2, 2023.
  58. PMID 19043511
    .
  59. PMID 7997074
    .
  60. S2CID 22769187
    .
  61. PMID 1608919
    .
  62. OCLC 29388575.[page needed
    ]
  63. ^ Saunders N. "Test results of 30 samples of Ecstasy bought in British clubs between 11/94 and 7/95".
  64. OCLC 44325836
    .
  65. ^ "Sam Barker and David Pearce on Art, Paradise Engineering, and Existential Hope (With Guest Mix) | The FLI Podcast". Future of Life Institute (audio, transcript). June 24, 2020.
  66. ISBN 9780718185480
    .
  67. ^ a b Braddock JA, Church DB, Robertson ID (2004). "Selegiline Treatment of Canine Pituitary-Dependent Hyperadrenocorticism" (PDF). Australian Veterinary Journal. Archived from the original (PDF) on November 29, 2010. Retrieved April 8, 2011. (PDF)
  68. ^
    ISBN 978-1-4918-0010-2
    .
  69. ^ a b "Anipryl Tablets for Animal Use". Drugs.com. Retrieved August 31, 2017.
  70. ^ Lundgren B. "Canine Cognitive Dysfunction". Veterinary Partner. Retrieved April 8, 2011.
  71. ^
    ISBN 978-1-118-68590-7
    .
  72. ^
    ISBN 978-0-323-24485-5
    .
  73. S2CID 3402756
    .
  74. ^
    S2CID 33004517
    .
  75. PMID 16958566
    .
  76. S2CID 23234928
    .
  77. S2CID 37417459
    .
  78. S2CID 73193888
    .
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