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Selegiline (deprenyl) increases nigrostriatal dopamine levels by several mechanisms, including selective and irreversible inhibition of cerebral monoamine oxidase type-B. Through this mechanism it may also protect neurons against damage by free radicals and possibly exogenous neurotoxins.
When used alone in patients with early Parkinson s disease, oral selegiline 5mg twice daily initially reduces symptom severity compared with placebo. During prolonged therapy, selegiline slows the rate of symptom progression and delays the need for levodopa therapy by 6 to 9 months.
The benefits of coadministration of selegiline with levodopa as de novo therapy in early Parkinson s disease compared with levodopa monotherapy remain unclear. Studies have shown either similar disease progression in both treatment groups after 3 years or significantly slowed disease progression and reduced levodopa requirement after 14 to 54 months in patients treated with both drugs compared with levodopa monotherapy.
In patients with more advanced disease who have mild levodopa response fluctuations, concomitant selegiline allows a reduction in levodopa dosage. Improvements in overall disability and ‘end-of-dose’ fluctuations are observed, although benefits are rarely maintainedfor longer than a year.
Improvements in cognitive function, behaviour and activities of daily living have been observed in patients with Alzheimer s disease following administration of selegiline IO mg/day for up to 15 months, and the drug appeared to be more effective in this regard than 1-acetylcarnitine, oxiracetam and phosphatidylserine in single-blind studies. In addition, preliminary findings suggest that selegiline may have an additive effect when coadministered with cholinergic therapy.
At the dosage recommended for Parkinson s disease and Alzheime~ s disease, selegiline is not associated with the tyramine (‘cheese’) reaction.
Thus, selegiline is a valuable treatment optionfor de novo therapy of patients with early Parkinson s disease, improving symptoms and postponing the needfor levodopa therapy. Whether it also offers clinically significant neuroprotection remains unclear. Selegiline is a useful adjunct to long term levodopa therapy in patients with more advanced disease experiencing response fluctuations, and recent findings suggest that it may offer some clinical benefit to patients with Alzheimer s disease.
Overview of Pharmacological Properties
Selegiline increases cerebral dopamine levels through selective irreversible inhibition of monoamine oxidase type-B (MAO-B), an enzyme involved in central dopamine metabolism.
The drug has proven to be an effective treatment for the symptoms of Parkinson’s disease, a disorder that results from a progressive loss of dopaminergic cells in the substantia nigra and consequent depletion of the neurotransmitter dopamine. While opinion remains divided as to whether selegiline is also neuroprotective in patients with early Parkinson’s disease, several mechanisms of action have been identified which may account for a neuroprotective effect of the drug. Inhibition of MAO-B by selegiline may reduce the free radical formation and oxidative stress associated with dopamine metabolism, which can cause neuronal damage and cell death. In addition, selegiline-mediated inhibition of MAO-B may prevent the conversion of environmental agents [such as 1-methyl-4- phenyl-1,2,3,6-tetrahydropyridine (MPTP)] to their active toxic forms which are capable of inducing Parkinson-like symptoms in humans. In animal studies, selegiline inhibited neurotoxin uptake into neurons and protected dopaminergic neurons against damage from neurotoxins by inhibiting MAO-B activity. Selegiline also rescued damaged neurons through a trophic-like effect independent of MAO-B inhibition. Other activities of selegiline supporting a neuroprotective effect have also been identified in in vitro and animal studies; however, no direct pathological evidence supporting a neuroprotective effect of selegiline in humans is available.
While prolonged selegiline administration increased the lifespan of aged rodents, data on such an effect in humans with Parkinson’s disease are conflicting.
Findings that patients with Alzheimer’s disease have reduced brain dopamine levels and increased MAO-B activity indicate that selegiline may be of some clinical benefit in the treatment of this disease.
The bioavailability, mean peak plasma concentration (Cmax) and time to reach Cmax following an oral IOmg dose of selegiline are, respectively, about 10%,2 µg/L and 0.6 hours. Selegiline is subjected to extensive and rapid hepatic metabolism, the main metabolites being l-methamphetamine, l-amphetamine and demethyl-selegiline. While demethyl-selegiline has some MAO-B inhibitory activity, l-methamphetamine and l-amphetamine may contribute to neuroprotective effects of the drug. The apparent volume of distribution of selegiline is 500L, although the drug is 94% bound to plasma proteins. Renal elimination is the predominant route of excretion, with 86% of an oral dose recovered in the urine, principally as l-methamphetamine (59%) and l-amphetamine (26%).
Improvements in symptom severity have been observed in previously untreated patients with early Parkinson’s disease during the first 3 months of monotherapy with oral selegiline 5mg twice daily. In particular, initial improvements in the Unified Parkinson’s Disease Rating Scale (UPDRS) scores for motor function and mental state were observed. During prolonged therapy (1 to 3 years), selegiline monotherapy significantly slowed symptom progression compared with placebo. Scores for overall disability were lower in selegiline recipients after 1 to 3 years of therapy, and the need for levodopa to control symptoms was delayed by 6 to 9 months. Subsequent coadministration of selegiline with levodopa reduced the dosage of levodopa required to maintain an adequate response by up to 80% after 5 years’ combined treatment.
A single comparative study found that while levodopa monotherapy was associated with a higher incidence of motor fluctuations than selegiline, lisuride or bromocriptine monotherapy in patients with early Parkinson’s disease, fewer patients treated with levodopa required add-on therapy compared with the other treatment groups after a mean follow-up of 20 months.
Coadministration of selegiline with levodopa as de novo therapy in patients with early Parkinson’s disease significantly improved disability scores compared with levodopa monotherapy over treatment periods of 14 to 54 months in 3 recent double-blind studies. In addition, the need to increase the levodopa dose to compensate for disease progression was less common in patients who received selegiline. In contrast to these findings, a large nonblind randomised study found no clinical benefit of adding selegiline to levodopa therapy over a 3-year period.
Concomitant administration of selegiline to patients experiencing response fluctuations during long term levodopa therapy generally improved motor function, reduced disability rating scores, improved ‘end-of-dose’ fluctuations and reduced levodopa dosage requirements (by 10 to 30%). However, long term studies indicate that the benefits of adding selegiline to long term levodopa therapy are maintained in the majority of patients for only 7 to 8 months.
Double-blind placebo-controlled trials indicate that selegiline is of some clinical benefit in patients with Alzheimer’s disease. In the majority of studies, selegiline therapy was associated with greater improvements in rating scores for cognitive function, behaviour and activities of daily living compared with placebo, or the neuropsychotherapeutic agents l-acetylcarnitine (ST-200), oxiracetam and phosphatidylserine. Preliminary findings suggest that selegiline may have an additive effect when coadministered with cholinesterase inhibitors (such as tacrine or physostigmine salicylate), although this requires further investigation.
Studies evaluating the pharmacoeconomic value of selegiline in the treatment of Parkinson’s disease are unavailable at present. However, clinical studies indicate that the drug is likely to improve patient quality of life and have a favourable cost-effectiveness ratio as monotherapy in patients with early disease and when used as adjunctive therapy in patients with response fluctuations receiving long term levodopa therapy. Selegiline therapy has the potential to reduce direct costs including hospitalisation, medical care and physician fees, and indirect costs associated with the significant impairment in quality of life in patients with Parkinson’s disease. The greatest economic benefit of selegiline is anticipated to result from a delay in the onset of disability in patients with early Parkinson’s disease. It has been estimated that an agent which slowed progression of disability by around 10% would realise savings (through reduction in both direct and indirect costs) in the order of $US330 million per annum in the US. While the available evidence indicates that selegiline delays symptom progression by up to 9 months, further study is required to determine the true pharmacoeconomic value of the drug to society.
Selegiline, at the dosage used for treatment of Parkinson’s and Alzheimer’s diseases, is a selective and irreversible MAO-B inhibitor which is not associated with the tyramine (‘cheese’) reaction. Peak concentration dyskinesias may be exacerbated when selegiline is added to the levodopa treatment regimen, and mood elevation, insomnia, hallucinations and confusion have been reported during coadministration of both drugs. Insomnia and euphoria may occur during selegiline monotherapy, as well as gastrointestinal symptoms (mainly nausea) and orthostatic hypotension.
Dosage and Administration
Selegiline 5mg twice daily (with breakfast and at midday), administered orally either as monotherapy or in combination with levodopa, is recommended for the treatment of patients with Parkinson’s disease. Clinical trials to date indicate that the same dosage of selegiline may be of clinical benefit in patients with Alzheimer’s disease.
The concurrent use of selegiline with pethidine (meperidine) is contraindicated, and administration of selegiline with selective serotonin (5-hydroxytryptamine; 5-HT) reuptake inhibitors or tricyclic antidepressants should be avoided.
KeywordsLevodopa MPTP Selegiline Deprenyl Levodopa Therapy
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- 3.Knoll J. The pharmacological basis of the beneficial effects of (-)deprenyl (selegiline) in Parkinson’s and Alzheimer’s diseases. J Neural Transm Gen Sect 1993; 40 Suppl.: 69–91Google Scholar
- 4.Elsworth JD, Roth RH. Deprenyl: pharmacological aspects of its clinical effects. Biog Amines 1993; 9 (5/6): 381–94Google Scholar
- 16.Sziniki I, Kardos V, Patthy M, et al. Amphetamine-metabolites of deprenyl involved in protection against neurotoxicity induced by MPTP and 2-methyl-MPTP. J Neural Transm Gen Sect 1994; 41 Suppl.: 207–19Google Scholar
- 17.Heinonen E. Selegiline in the treatment of Parkinson’s disease: pharmacokinetic and clinical studies. Research Reports from the Department of Neurology University of Turku 1995; No.33 (Y)Google Scholar
- 22.Tatton W, Wadia J, Ju W, et al. (-)Deprenyl prevents mitochondrial depolarization and reduces programmed cell death in trophically-deprived cells [abstract]. New Trends Clin Neuropharmacol 1994; 7 (1): 34–5Google Scholar
- 23.Tatton WG, Seniuk NA. ‘Trophic-like’ actions of (-)deprenyl on neurons and astroglia. In: Racagni G, Brunello N, Langer SZ, editors. Recent advances in the treatment of neurodegenerative disorders and cognitive dysfunction. Vol.7. Basel, Karger: Int Acad Biomed Drug Res, 1994: 238–48Google Scholar
- 32.Freisleben H-J, Lehr F, Fuchs J. Lifespan of immunosuppressed NMRI-mice is increased by deprenyl. J Neural Transm Gen Sect 1994; 41 Suppl.: 231–6Google Scholar
- 40.Heinonen EH, Antilla M, Karnani AM, et al. Pharmacokinetics of selegiline after oral dosing [abstract no.P248]. Mov Disord 1994; 9 Suppl.1: 57Google Scholar
- 43.Heinonen EH. Myllylä V, Sotaniemi K, et al. Pharmacokinetics and metabolism of selegiline. Acta Neurol Scand 1989; 126 Suppl.80: 93–9Google Scholar
- 46.Heinonen EH, Anttila M, Nyman L, et al. Desmethylseiegiline, a metabolite of selegiline, is an irreversible inhibitor of MAOB in human subjects [abstract]. Neurology 1993 Apr; 43Supp. 2: A156Google Scholar
- 47.Gmil J, Szekacs G, Szebeni G, et al. Neurotoxicity of DSP-4 on pigs and prevention of its neurotoxicity by deprenyl. In: 6th Amine Oxidase and 5th Trace Amine Conference, 1994; B-09Google Scholar
- 48.Magyar K, Gaal J, Lengyel J. Neuroprotective effect of (-)deprenyl against DSP-4 toxicity [abstract]. J Neurochem 1994; 63 Suppl. 1: S44Google Scholar
- 49.Fahn S, Elton RL, Members of the UPDRS Development Committee. Unified Parkinson’s disease rating scale. In: Fahn S, Marsden CD, Caine DB, et al., editors. Recent developments in Parkinson’s disease. Vol. 2. Florham Park, New Jersey: MacMillan Healthcare Information, 1987: 153–63Google Scholar
- 59.Musicco M, Caraceni T, Beghi E, et al. Dopamine agonists, deprenyl and levodopa in de novo patients with Parkinson’s disease: a multicenter randomized trial [abstract]. Neurology 1993 Apr; 43 Suppl.2: A333Google Scholar
- 60.Olanow CW, Koller W, Hauser R, et al. A prospective longitudinal controlled study of deprenyl in Parkinson’s disease [abstract]. Neurology 1994; 44 Suppl.: A258Google Scholar
- 61.Larsen JP. Effect of selegiline in Parkinson’s disease [abstract]. Satellite Symposium to the 5th Meeting of the European Neurological Society; 1995 June 19; Munich, Germany.Google Scholar
- 65.Giovannini P, Martignoni E, Piccolo I, et al. (-)Deprenyl in Parkinson’s disease: a two-year study in the different evolutive stages. J Neural Transm 1986; 22 Suppl.: 235–46Google Scholar
- 79.Riekkinen P, Koivisto K, Helkala EL, et al. Effect of selegiline in Alzheimer’s disease. Selegiline — Expanding Horizons. Satellite Symposium to the 5th Meeting of the European Neurological Society; 1995 June 19, Munich, Germany.Google Scholar
- 83.Ahlskog IE. Parkinson’s disease: update on pharmacologic options to slow progression and treat symptoms. Hosp Formul 1992; 27: 146–63Google Scholar
- 86.Jurian R, Clark S, Shoulson I, et al. Economic impact of protective therapy for early Parkinson’s disease. Ann Neurol 1988; 24 (1): 153Google Scholar
- 90.Jermain DM, Hughes PL, Follender AB. Potential fluoxetinese1egiline interaction. Ann Phannacother 1992 Oct; 26: 1300Google Scholar
- 92.West R, editor. Parkinson’s Disease. London: Office of Health Economics, 1991Google Scholar
- 98.The market for Alzheimer drugs. Scrip Mag 1992 Nov; 22Google Scholar