Selegiline

From Longevity Wiki

Selegiline, also known as Deprenyl and sold under the brand names Eldepryl and Emsam among others, is a medication which is used in the treatment of Parkinson's disease and major depressive disorder. For basic information, see Wikipedia.

History

Hungarian Joseph Knoll and his team at Semmelweis University developed selegiline and explored it potential longevity enhancing effects of selegiline up until his death in 2018 at age 93. Knoll was the founding member of the Hungarian Society for Experimental and Clinical Pharmacology and until 1982 its president and then honorary life president. Between 1984 and 1987 he was the first vice-president of the board of the Executive Committee of the International Union of Pharmacology (IUPHAR).[1]

Animal studies

Flies

Deprenyl led to a significant increase in mean and maximal life-span of galactose-treated, but not control flies.[2]

Rodents

In rodents, Selegiline has been reported to increase, decrease, or have no change in lifespan in animal models. The mechanism for an increase in lifespan is unclear.[3] Life extension ranged from no change (4 studies), to slight single-digit increases (2 studies), to increases between 13%-24% (2 studies), to increases in lifespan above 30% (2 studies). Most of these studies come from Knoll and a Japanese group led by Kenichi Kitani of the National Institute for Longevity Sciences (NILS) of Japan. The greatest increases in lifespan were seen in doses of 0.25 mg/kg, 3 times per week, subcutaneously.[3] In a 2016 study, Knoll found that a lower dose of 0.001 mg/kg three times a week did not prolong lifespan significantly while 0.1 mg/kg three times a week prolonged life by 12%.[4]

In Syrian hamsters, low-dose selegiline (0.05 mg/kg) significantly increased life span in females but not in males.[5]

In 2023, Hungarian researchers from Semmelweis University found that BPAP (a deprenyl derivative) did not improve cognitive performance nor prolong lifespan.[6]

Kitani reported an inverted U-shape dose-relationship effect on the expression of uperoxide dismutase 1 (SOD1) and catalase in the striatum of rats.[3]

In rat models of Parkinson's disease, Selegiline delayed α-syn aggregation and dopaminergic neuronal loss.[7]

Dogs

Selegiline is approved to treat canine cognitive dysfunction, a form of dementia that mimics Alzheimer's disease in humans. It is given at doeses of 0.5mg/kg/day.[3] Geriatric dogs treated with selegiline show improvements in sleeping pattern, reduced incontinence, and increased activity level; most show improvements by one month. Though it is labeled for dog use only, selegiline has been used off-label for geriatric cats with cognitive dysfunction.[8]

One study showed that 1 mg/kg of Deprenyl once daily prolonged life in elderly dogs.[9]

Cats

Selegiline is also used off-label for geriatric cats with cognitive dysfunction.[10]

Horses

Selegiline does not appear to have a clinical effect on horses, although it hasn't been studied specifically for longevity on horses.[11]

In humans

In Parkinson's patients, Selegiline delays the point when levodopa treatment becomes necessary from about 11 months to about 18 months after diagnosis.[12] Selegiline + levodopa has been reported to increase, decrease, or have no change in lifespan of Parkinson's compared to levodopa alone.[3] There is some evidence that selegiline acts as a neuroprotectant and reduces the rate of disease progression, though this is disputed.[13][14]

In a 2016 study, authors identified deprenyl as one of the 11 compounds (with acarbose, d-glucosamine, dihydroergocristine methanesulfonate, ellagic acid, fenofibrate, glutathione, metformin, spermidine, tyrosol, and vinpocetine) that fulfill all their proposed nine criteria for the evaluation of geroprotectors (Primary criteria: increased lifespan, amelioration of human aging biomarkers, acceptable toxicity, minimal side effects at therapeutic dosage, improving health-related quality of life. Secondary criteria: evolutionary conservatism of target or mechanism of action, reproducibility of geroprotective effects on different model organisms, simultaneous influence on several aging-associated causes of death in mammals, increase in stress resistance).[15]

Rasagiline, another irreversible inhibitor of monoamine oxidase-B used in Parkinson's disease, may also be neuroprotective. The FDA refused to grant disease-modifying label to rasagiline because in trials the lower dose was effective at slowing progression, but the higher dose was not.[16][17] Rasagiline failed to show any cognitive benefits in Parkinson's patients with cognitive impairment. Rasagiline 1 mg has however shown some benefits in a 24-week double-blind parallel group placebo-controlled trial (n=50) with mild to moderate Alzheimer's, with favourable change in FDG-PET in middle frontal, anterior cingulate and striatal regions along with benefits in measures of quality of life.[18]

According to a 2018 review by the Alzheimer’s Drug Discovery Foundation (ADDF): "Selegiline may provide a small, though possibly not clinically meaningful, benefit for Alzheimer’s disease; the longevity research is mixed."[3]

According to Longevity.Technology, Selegiline is at the stage "Late proof of concept demonstrated in real-life conditions"/"Technology refined and ready for initial human trials".[19]

Mechanism

According to Knoll's theory, Deprenyl is a catecholaminergic activity enhancer (CAE) and a small daily dose of a CAE is a suitable anti-aging therapy to fight the age-related slow decay of the catecholaminergic system.[20]

Forms

Selegiline is commercially available under three forms:

  • Capsule or tablet taken by mouth (to swallow), sold under various brand names and also available in generics.
  • Orally disintegrating tablets (to dissolve on the tongue) also called ODT. Sold under the brand name Zelapar and not available in generic as of 2023.[21] Flavored (grapefruit) and sweetened. Mainly used by Parkinson's patients with swallowing difficulties who need high doses.
  • Transdermal patch (to apply on the skin), mainly used for depression.


The ODT is about 10 times more potent than the normal tablet.[22] Only the normal tablet (swallowed) has been studied for its life extension properties.

Dosage

Typical doses for Parkinson's are 5 to 10 mg/day (swallowed) or 1.25 mg/day (ODT).[23]

Most pills are 5 mg. Knoll suggested 1 mg per day. Late in his life he reportedly took two 5 mg Deprenyl tablets per week.[24]

Life Extension Foundation (LEF) recommended in 1999 "a conservative dose of 5 mg of deprenyl to be taken twice a week".[25]

Dean, Fowkes and Morgenthaler recommend the following age-adjusted titrated dosage schedule in their book, Smart Drugs 2. They don't provide scientific evidence for their recommendation:[24]

  • 30–35: 1 mg twice a week
  • 35–40: 1 mg every other day
  • 40–45: 1 mg every day
  • 45–50: 2 mg every day
  • 50–55: 3 mg every day
  • 55–60: 4 mg every day
  • 60–65: 5 mg every day
  • 65–70: 6 mg every day
  • 70–75: 8 mg every day
  • 75–80: 9 mg every day
  • 80 and older: 10 mg every day

Combination

In experiments with rodents, root extract of Polyscias fruticosa (also called Ming aralia or by its Vietnamese name Dinh lang) has been demonstrated to extend life span.[26]

In rats administered with rotenone to reproduces Parkinson’s disease, the beneficial effects of deprenyl were augmented when combined with N-acetylcysteine (NAC).[27]

Counter indications, risks and side effects

According to the ADDF: "Despite the potential for some side-effects, these are generally not serious. However, there are many potential drug interactions."[3] In particular, Selegiline should not be taken by individuals with liver or kidney disease, high blood pressure, or phenylketonuria. Additionally, you should not take it if you have taken fluoxetine within the past five weeks. It should also not be taken with cough medicines that contain dextromethorphan, cyclobenzaprine (Flexeril), meperidine or any other opioid pain medicine, methadone, St. John’s wort, tramadol (Ultram), any antidepressants or MAO inhibitors.[3] There's a risk of cheese effect with high doses.[22]

Notable users

References

  1. ↑ IN MEMORIAM JOSEPH KNOLL (1925-2018), Hungarian Society for Experimental and Clinical Pharmacology
  2. ↑ Jordens, R., Berry, M., Gillott, C. et al. Prolongation of Life in an Experimental Model of Aging in Drosophila Melanogaster . Neurochem Res 24, 227–233 (1999). https://doi.org/10.1023/A:1022510004220
  3. ↑ 3.0 3.1 3.2 3.3 3.4 3.5 3.6 3.7 Selegiline (L-deprenyl), Cognitive Vitality Report, Alzheimer’s Drug Discovery Foundation, May 14th 2018
  4. ↑ Longevity study with low doses of selegiline/(−)-deprenyl and (2R)-1-(1-benzofuran-2-yl)-N-propylpentane-2-amine (BPAP), Knoll & Miklya, Life Sciences, Volume 167, 15 December 2016, pp 32-38
  5. ↑ Chronic Treatment of Syrian Hamsters With Low-Dose Selegiline Increases Life Span in Females But Not Males, S. Stoll, U. Hafner, B. Kränzlin, W.E. Müller, Neurobiology of Aging, Volume 18, Issue 2, March–April 1997, Pages 205-211
  6. ↑ Ernyey, A.J., Kassai, F., Kozma, K. et al. Age-related decline of various cognitive functions in well-experienced male rats treated with the putative anti-aging compound (2R)-1-(1-benzofuran-2-yl)-N-propylpentane-2-amine ((-)BPAP). GeroScience (2023). https://doi.org/10.1007/s11357-023-00821-6
  7. ↑ Nakamura Y, Arawaka S, Sato H, Sasaki A, Shigekiyo T, Takahata K, Tsunekawa H, Kato T. Monoamine Oxidase-B Inhibition Facilitates α-Synuclein Secretion In Vitro and Delays Its Aggregation in rAAV-Based Rat Models of Parkinson's Disease. J Neurosci. 2021 Sep 1;41(35):7479-7491. doi: 10.1523/JNEUROSCI.0476-21.2021. Epub 2021 Jul 21. PMID: 34290084; PMCID: PMC8412984.
  8. ↑ Anipryl Tablets
  9. ↑ Ruehl WW, Entriken TL, Muggenburg BA, Bruyette DS, Griffith WC, Hahn FF. Treatment with L-deprenyl prolongs life in elderly dogs. Life Sci. 1997;61(11):1037-44. doi: 10.1016/s0024-3205(97)00611-5. PMID: 9307048.
  10. ↑ Riviere JE, Papich MG (2013). Veterinary Pharmacology and Therapeutics. John Wiley & Sons. p. 530. ISBN 978-1-118-68590-7.
  11. ↑ Papich MG (2015). Saunders Handbook of Veterinary Drugs: Small and Large Animal. Elsevier Health Sciences. p. 722. ISBN 978-0-323-24485-5.
  12. ↑ Riederer P, Lachenmayer L (November 2003). "Selegiline's neuroprotective capacity revisited". Journal of Neural Transmission. 110 (11): 1273–1278. doi:10.1007/s00702-003-0083-x. PMID 14628191. S2CID 20232921.
  13. ↑ "Selegiline Hydrochloride Monograph for Professionals". Drugs.com. Retrieved February 23, 2018.
  14. ↑ Ives NJ, Stowe RL, Marro J, Counsell C, Macleod A, Clarke CE, et al. (September 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.
  15. ↑ Moskalev A, Chernyagina E, Tsvetkov V, Fedintsev A, Shaposhnikov M, Krut'ko V, Zhavoronkov A, Kennedy BK. Developing criteria for evaluation of geroprotectors as a key stage toward translation to the clinic. Aging Cell. 2016 Jun;15(3):407-15. doi: 10.1111/acel.12463. Epub 2016 Mar 11. PMID: 26970234; PMCID: PMC4854916.
  16. ↑ Sviderski V (19 October 2011). "FDA Advisers Refuse Teva Plea to Expand Azilect Label". Reuters and Haaretz.
  17. ↑ Katz R, et al. "Peripheral and Central Nervous System Advisory Committee Background Package on Azilect" (PDF). FDA. Retrieved December 7, 2011.
  18. ↑ O’Brien, J.T., Chouliaras, L., Sultana, J. et al. RENEWAL: REpurposing study to find NEW compounds with Activity for Lewy body dementia—an international Delphi consensus. Alz Res Therapy 14, 169 (2022). https://doi.org/10.1186/s13195-022-01103-7
  19. ↑ Deprenyl Parkinson’s drug increases lifespan in rats, Harriet Grantham, July 10, 2019
  20. ↑ Miklya, I. The significance of selegiline/(−)-deprenyl after 50 years in research and therapy (1965–2015). Mol Psychiatry 21, 1499–1503 (2016). https://doi.org/10.1038/mp.2016.127
  21. ↑ Generic Zelapar Availability - Drugs.com
  22. ↑ 22.0 22.1 Tábi, T., Vécsei, L., Youdim, M.B. et al. Selegiline: a molecule with innovative potential. J Neural Transm 127, 831–842 (2020).
  23. ↑ Selegiline Dosage, Drugs.com, Last updated on Aug 10, 2023.
  24. ↑ 24.0 24.1 Deprenyl- A Multi-Functional Anti-aging Drug, DEAN, M.D., Ward
  25. ↑ Deprenyl, Life Extension Magazine
  26. ↑ Yen, T T; Knoll, J (1991). "Extension of lifespan in mice treated with Dinh lang (Policias fruticosum L.) and (-)deprenyl". Acta Physiologica Hungarica. 79 (2): 119–124. PMID 1304677.
  27. ↑ Khashab, R.; Gutman-Sharabi, N.; Shabtai, Z.; Landau, R.; Halperin, R.; Fay-Karmon, T.; Leibowitz, A.; Sharabi, Y. Dihydroxyphenylacetaldehyde Lowering Treatment Improves Locomotor and Neurochemical Abnormalities in the Rat Rotenone Model: Relevance to the Catecholaldehyde Hypothesis for the Pathogenesis of Parkinson’s Disease. Int. J. Mol. Sci. 2023, 24, 12522. https://doi.org/10.3390/ijms241512522
  28. ↑ Not A Bad Place to Be
  29. ↑ Sam Bankman-Fried Confirmed He Wears an Emsam Patch. What’s an Emsam Patch?, Slate, HEATHER TAL MURPHY, DEC 14, 2022
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