Detailed

Selegiline, also known as (-)-deprenyl continues to be used for the clinical treatment of patients with Parkinson’s disease (PD) [6], with some antidepressant activity [Culpepper et al., 2008]. Selegiline is considered a type B MAO. Type A MAO is concentrated in the brain and intestine where primary substrates in the brain are dopamine (DA) and serotonin (5-HT) [7]. Type B MAO is focused in anatomic brain regions that are abundant in serotonergic neurons [7]. Currently, selegiline, a type B MAO, is used as an adjuvant treatment against Parkinson’s disease (PD) at a dose of 10mg/day [7]. Selegiline offers neuroprotection as evidenced by its ability to block the parkinsonism-inducing effects of MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine), a neurotoxin which induces abnormal behaviours similar to those observed in Parkinson’s Disease (PD) [8; 9]. To assess the degree of MAO-A and MAO-B inhibition in the body, -phenylethylamine (PEA) is measured in the urine since MAO-B catalyses the oxidation of this compound [10].

Treatment with selegiline carries out the following pharmacological effects:

1. Increased neurotransmitter dopamine concentration in the CNS
2. Decrease of oxidative and nutrient stress by reducing the hydrogen peroxide (H2O2) production.
3. Long-term protective mechanism against oxidative damage [11].

Selegiline is metabolised, in the liver, into three metabolites: desmethyl-selegiline, amphetamine and methamphetamine (Figure 2) [12], with all three metabolites pharmacologically active [13]. Furthermore, selegiline is metabolised by the gastrointestinal tract, lung and liver in dogs [12]. One study assessing the metabolism of selegiline hydrochloride (HCl) – doses 10, 5, and 2.5mg – in humans found nine metabolites in excreted urine after 2 days of the ranged dose [14]. In addition, metabolites of selegiline hydrochloride comprised 44-58% of the original dose [14]. In treating depression, the selegiline transdermal system allows for delivery of selegiline into the bloodstream where it selectively inhibits MAO-A and MAO-B in the brain; this is achieved without inhibiting MAO-A activity in the gastrointestinal tract, which could otherwise lead to hypertension and possible stroke [15; 16].

Dosage

Oral selegiline dosages of 0.5mg/kg and 5mg/kg in rat studies have shown a varying effect on different organs, and selegiline’s MAO inhibition [11]. When comparing MAO-A and MOA-B, selegiline, in the rat brain, liver and bowel seemed to inhabit MAO-B in higher concentrations than MAO-A [11]. A 5mg/kg dose exhibited greater MAO-B inhibition than 0.5mg/kg dose [11]. An oral dose of 10mg selegiline is rapidly absorbed and metabolised to all three metabolites (Figure 2), with an elimination half-life of ~1.5 hours [12].

Selegiline and depression

For treating depressive symptoms, the Selegiline transdermal system – EMSAM patch – has been established as a generally well tolerated system at a dose of 6mg per 24 hours, and has shown safety without tyramine dietary restrictions are not required [5; 15]. For higher doses – 9mg and 12mg – the FDA does require that a tyramine-free diet be followed [16]. Tyramine is found in many foods (70) and beverages and is normally metabolised in the gut by MAO-A [16]. At higher doses selegiline loses its selectivity to the monoamine oxidase B inhibitor (MAO-A) and has the potential to interact with tyramine [15]. In studying the efficacy and safety of transdermal selegiline in adults with major depression, and with a tyramine-restricted diet in place (up to 2-weeks post selegiline administration), a 20mg dose given for 6 weeks was found to be superior to placebo [17].

Selegiline use for treating Canine cognitive dysfunction (CDS)

Selegiline hydrochloride (HCl) at doses of 0.5 – 1.0mg/kg has been shown to be an effective treatment in canine cognitive dysfunction (CDS) [18]. 641 dogs were administered selegiline – 0.5-1mg/kg – orally, once daily for 60 days. Dog owners were asked to rate the improvement in clinical signs and after 30 days selegiline treatment 80% of dogs had improvement in clinical CDS symptoms [18].

Safety

Overall, selegiline has been generally accepted as a safe drug since its comparative effects – fatigue, vertigo, constipation, insomnia, nausea, sweating, anxiety and involuntary movements – are identical to those observed, and caused, in placebo [9]. However, selegiline has been reported to cause insomnia in a greater proportion of patients – when treating Parkinson’s disease (PD) – when compared to placebo [19]. In addition, selegiline interacts with few other drugs such as pethidine and fluoxetine [19].

Side effects

Adverse effects and events associated with selegiline, in conjunction with fluoxetine, include, agitation, hypertension, mania, sweating, shivers and tachycardia [19]. In addition, it has previously been advised to avoid combination of selegiline with pethidine [19]. Selegiline is usually well tolerated when administered alone; however, frequent adverse events include insomnia, nausea, headaches and dizziness [19]. Selegiline patches (EMSAM) has very little side effects, compared to other antidepressant drugs [16]. Skin irritations have been noted with EMSAM use, as the system is a transdermal application [16].

References

[1] Satoka Kasai, Toru Yoshihara, Olga Lopatina, Katsuhiko Ishihara and Haruhiro Higashida, 2017. Selegiline Ameliorates Depression-Like Behavior in Mice Lacking the CD157/BST1 Gene, a Risk Factor for Parkinson’s Disease. Front. Behav. Neurosci. 11:75. doi: 10.3389/fnbeh.2017.00075.

[2] Yoshikuni Mizuno, Nobutaka Hattori, Tomoyoshi Kondo, Masahiro Nomoto, Hideki Origasa, Ryosuke Takahashi, Mitsutoshi Yamamoto, and Nobuo Yanagisawa, 2017. A Randomized Double-Blind Placebo-Controlled Phase III Trial of Selegiline Monotherapy for Early Parkinson Disease. Clin Neuropharm 2017;40: 201–207.

[3] J. Knoll, K. Baghy, S. Eckhardt, P. Ferdinandy, M. Garami, L.G. Harsing Jr, P. Hauser, Z. Mervai, T. Pocza, Z. Schaff, D. Schuler, I. Miklya, 2017. A longevity study with enhancer substances (selegiline, BPAP) detected an unknown tumor-manifestation-suppressing regulation in rat brain. Life Sciences 182 (2017) 57–64.

[4] Eric C.K. Siu and Rachel F. Tyndale, 2008. Selegiline Is a Mechanism-Based Inactivator of CYP2A6 Inhibiting Nicotine Metabolism in Humans and Mice. THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS, Vol. 324, No. 3 133900/3306896.

[5] James E. Frampton and Greg L. Plosker, 2007. Selegiline Transdermal System In the Treatment of Major Depressive Disorder. Drugs 2007; 67 (2): 257-265.

[6] Huba Kalász, Julianna Thuróczy, Gellért Karvaly, Lajos Balogh, István Gyertyán, Edit Tóth- Molnár, Ernest Adeghate and Kornélia Tekes, 2017. Effects on Sperms’ Quality of Selegiline in Aged Rats. The Open Medicinal Chemistry Journal, 2017, 11, 138-145.

[7] Larry Culpepper, M.D., M.P.H and Lawrence J. Kovalick, Pharm.D., C.G.P, 2008. A Review of the Literature on the Selegiline Transdermal System: An Effective and Well-Tolerated Monoamine Oxidase Inhibitor for the Treatment of Depression. Prim Care Companion J Clin Psychiatry 2008;10:25–30.

[8] _{Juhani Sivenius, Taneli Sarasoja, Helena Aaltonen, Esa Heinonen, Olavi Kilkku and Kari Reinikainen, 2001. Selegiline Treatment Faciltiates Recovery After Stroke. Neurorehabilitation and Neural Repair, 15:183-190.}

[9] M. Ebadi, S. Sharma, S. Shavali, and H. El Refaey, 2002. Neuroprotective Actions of Selegiline. Journal of Neuroscience Research 67:285–289 (2002) DOI 10.1002/jnr.10148.

[10] Kathleen L Poston & Cheryl Waters, 2007. Zydis selegiline in the management of Parkinson’s disease. Expert Opin. Pharmacother. (2007) 8(15):2615-2624.

[11] Kalman Magyar, 2011. THE PHARMACOLOGY OF SELEGILINE. INTERNATIONAL REVIEW OF NEUROBIOLOGY, VOL. 100, DOI: 10.1016/B978-0-12-386467-3.00004-2.

[12] Iftekhar Mahmood, 1997. Clinical Pharmacokinetics and Pharmacodynamics of Selegiline

An Update. Clin. Pharmacokinetic. 1997 Aug; 33 (2): 91-1 02 031 2-5963/97/0008-QQ91/S06.OQ/O

[13] A. Clarke, E. S. Johnson, N. Mallard, T. H. Corn, A. Johnston, M. Boyce, S. Warrington, and D. G. MacMahon, 2003. A new low-dose formulation of selegiline: clinical efficacy, patient preference and selectivity for MAO-B inhibition. J Neural Transm (2003) 110: 1257–1271.

[14] HO-SANG SHIN, 1997. METABOLISM OF SELEGILINE IN HUMANS

Identification, Excretion, and Stereochemistry of Urine Metabolites. DRUG METABOLISM AND DISPOSITION, Vol. 25, No. 6.

[15] Jayasree J Nandagopal & Melissa P DelBello, 2009. Selegiline transdermal system: a novel treatment option for major depressive disorder. Expert Opin. Pharmacother. (2009) 10(10):1665-1673.

[16] Gregory M Asnis, Margaret A Henderson, 2014. eMSAM (deprenyl patch): how a promising antidepressant was underutilized. Neuropsychiatric Disease and Treatment 2014:10 1911–1923.

[17] J. Alexander Bodkin, M.D. Jay D. Amsterdam, M.D, 2002. Transdermal Selegiline in Major Depression: A Double-Blind, Placebo-Controlled, Parallel-Group Study in Outpatients. Am J Psychiatry 2002; 159:1869–1875).

[18] Sharon Campbell, Amy Trettien, Brenda Kozan, 2001. A Noncomparative Open-Label Study Evaluating the Effect of Selegiline Hydrochloride in a Clinical Setting. Veterinary Therapeutics, Vol. 2, No. 1.

[19] Esa H. Heinonen and Vilho Myllyla, 1998. Safety of Selegiline (Deprenyl) in the Treatment of Parkinson’s Disease. Drug Safety 1998 Jul; 19 (1): 11-22 0114-5916/98/0007-0011/$06.00/0.