Селегилин синонимы

General information

Selegiline is a relatively selective and irreversible inhibitor of monoamine oxidase type B, which has been used in the treatment of Parkinson’s disease. It was originally suggested that selegiline may be neuroprotective. However, in a prospective double-blind study no such action was seen [1]. On the other hand, selegiline does delay the start of disability, determined by the need for levodopa and progression of parkinsonian signs and symptoms [2].

However, the Parkinson’s Disease Research Group in the UK reported that after a mean follow-up period of 5.6 years, mortality was increased in randomized patients with Parkinson’s disease who took levodopa together with selegiline compared with patients who took levodopa alone [2]. This unexpected conclusion was interpreted as a result of methodological failures. In a meta-analysis of five long-term, prospective, randomized trials of selegiline, the treated group did not have an increase in mortality [3].

Pharmacology and mechanism of action

Dopamine agonist. Selegiline has been known by many names. Selegiline hydrochloride is the official United States Pharmacopeia (USP) drug name, but most clinicians know it by the older name, l-deprenyl. (l-deprenyl is distinguished from its steroisomer d-deprenyl.) A related drug is rasagiline. Selegiline has been used in humans for treatment of Parkinson disease and occasionally for Alzheimer disease with the trade name Eldepryl. (Efficacy for Alzheimer disease has not been established.)

The veterinary formulation is approved for treatment of Cushing disease in dogs and canine cognitive dysfunction. The action of selegiline is to inhibit monoamine oxidase (MAO) type B (and other MAOs at higher doses). The proposed mechanism of action is to inhibit the metabolism of dopamine in the CNS. The action for pituitary-dependent hyperadrenocorticism may be through increased dopamine levels in the brain, which decreases ACTH release, resulting in lower cortisol levels. Secondary effects are related to inhibition of the metabolism of phenylethylamine. (Phenylethylamine in laboratory animals produces amphetamine-like effects.) Two active metabolites are l-amphetamine and l-methamphetamine, but it is not known to what extent these contribute to pharmacologic effects. In horses, the metabolism to amphetamine-like metabolites is low.

Selegiline

Abstract

Selegiline, the R-optical enantiomer of deprenyl (phenyl-isopropyl-methyl-propargylamine), was almost exclusively used MAO-B inhibitor during the past decades to treat Parkinson’s disease. Oral treatment prolongs the need of levodopa administration. Selegiline is rapidly metabolized by the microsomal enzymes to amphetamine, methamphetamine, and desmethyl-deprenyl. In addition, the flavin-containing monooxigenase is synthesizing deprenyl-N-oxide. Selegiline in rather low concentrations (10^− 9–10^− 13 M), does not influence MAO-B, but it has an antiapoptotic activity in tissue culture. The neuroprotective effect of selegiline has a biphasic character. In higher concentrations than 10^− 7 M increases the rate of apoptosis (proapoptotic activity). The metabolites are also taking part in the complex pharmacological activity of selegiline. The simultaneous presence of the pro- and antiapoptotic effects of selegiline and its metabolites frequently hindered its clinical usage. During the past years rasagiline has been introduced to replace selegiline in clinical application. MAO-B inhibitors beside their effect on the enzyme MAO-B could hold different spectrum of pharmacological activities. Selegiline is administered orally and it possesses an intensive “first pass” metabolism. To circumvent the “first pass” metabolism, parenteral administration of the drug might lead to different distribution and pharmacological activity of selegiline.

34.11.1 Selegiline

Selegiline

Selegiline hydrochloride is a selective irreversible inhibitor of MAO-B subtype, which is responsible for the metabolism of neurotransmitters such as dopamine involved in the reward pathway. Selegiline may facilitate smoking cessation by inhibition of nicotine metabolism or by mimicking the effects of cigarette smoke on MAO. Selegiline demonstrated moderate success in smoking cessation treatment in preliminary studies and was found to be safe and well tolerated. However, large-scale trials failed to demonstrate an advantage for selegiline as compared with placebo in smoking cessation. For example, Weinberger and colleagues conducted a double-blind placebo-controlled randomized trial to determine the efficacy and safety of selegiline as a smoking cessation aid. Subjects received either selegiline (5 mg twice daily) or placebo in addition to brief smoking cessation counseling. No significant improvements were observed in 7-day point prevalence abstinence rates or continuous 4-week abstinence rates at the end of the trial. Other recent large trials have corroborated these negative results and therefore this medication is no longer being actively pursued as a potential treatment for smoking cessation.

Selegiline (L-Deprenyl)

Selegiline is a methamphetamine derivative and a potent, irreversible, monoamine oxidase B–selective inhibitor primarily used for the treatment of Parkinson’s disease.^49,50 Low doses of selegiline do not necessitate dietary restriction as usually required with other irreversible monoamine oxidase inhibitors; 10 mg of selegiline daily has no effect on the symptoms of narcolepsy, but 20 to 30 mg improves alertness and mood and reduces cataplexy, an effect comparable to that of d-amphetamine at the same dose. Selegiline may be an interesting alternative to the more classical stimulants as its potential for abuse has been reported to be very low.

The fact that this compound is often considered a simple monoamine oxidase B inhibitor rather than an amphetamine precursor deserves special mention. Selegiline not only inhibits monoamine oxidase B irreversibly, it also is metabolized into amphetamine (20% to 60% in urine) and methamphetamine (9% to 30% in urine).⁵⁰ In the canine model of narcolepsy, selegiline (2 mg/kg orally) was demonstrated to be an effective anticataplectic agent, but this effect was found to be mediated by its amphetamine metabolites rather than by monoamine oxidase B inhibition.⁵¹ Several trials in human narcolepsy have demonstrated a good therapeutic efficacy of selegiline on both sleepiness and cataplexy with relatively few side effects.^52,53

Selegiline (L-Desprenyl)

Selegiline is a methamphetamine derivative and a potent, irreversible, MAO-B selective inhibitor primarily used for the treatment of Parkinson disease.^53,54 Because it is often considered a simple MAO-B inhibitor, it is worth mentioning that selegiline is an amphetamine precursor. This compound is metabolized into l-amphetamine (20% to 60% in urine) and l-methamphetamine (9% to 30% in urine).⁵³

In the canine model of narcolepsy, selegiline (2mg/kg given orally) was demonstrated to be an effective anticataplectic agent, but this effect was found to be mediated by its amphetamine metabolites rather than MAO-B inhibition.⁵⁵ Several trials in human narcolepsy have demonstrated a good therapeutic efficacy of selegiline in both sleepiness and cataplexy with relatively few side effects.^56,57 Selegiline 10 mg daily has no effect on the symptoms of narcolepsy, but 20 to 30 mg improves alertness and mood and reduces cataplexy, showing an effect comparable to d-amphetamine at the same dose. Selegiline may be an interesting alternative to the use of more classic stimulants because its potential for abuse has been reported to be very low.

MAO-B Inhibitors

Selegiline can protect cultured dopaminergic neurons against the toxicity of MPP⁺ and, in animal models, can reduce dopaminergic cell loss in response to MPTP.^407–410 Selegiline also protects against apoptotic cell death induced by serum and growth factor withdrawal,^411,412 possibly via an increased production of Bcl2. Selegiline, by virtue of its MAO-B activity, will reduce the turnover of dopamine and so reduce free radical generation. The production of reactive oxygen species and free radical–mediated damage to lipids and proteins have been implicated in PD pathogenesis. Thus, this property, together with the ability for selegiline to protect against MPTP toxicity, led to the evaluation of this drug in the first clinical trial for neuroprotection in PD.

The results of the DATATOP and other studies using selegiline and the TEMPO study investigating rasagiline were discussed earlier. There appeared to be some benefit for selegiline, but interpretation is difficult in view of trial design and the compound’s inherent symptomatic action. The results of the delayed start design for TEMPO rasagiline were positive and support a neuroprotective action of the drug, but additional confirmatory trials are required before this drug can be accepted as neuroprotective.