Role of selegiline in combination therapy of Parkinson's disease
1996
Selegiline (earlier called deprenyl) is an irreversible inhibitor of monoamine oxidase type B (MAO-B). The inhibition is based on a covalent, irreversible bond formed between the propargyl group of selegiline and the flavin part of MAO. [1] In low doses (0.25 mg/kg subcutaneously in rats and 10 mg daily in humans) selegiline is a potent and selective inhibitor of MAO-B. [2,3] MAO-B inhibition can be easily tested in humans by measuring the MAO activity of platelets, as about 95% of MAO activity in platelets is of type B. [4] Because of its selectivity it is free of the "cheese effect," i.e., increase of blood pressure after food rich in tyramine, which is a substrate for MAO-A. [5,6] In rodents selegiline does not have marked effects on the concentrations of the main catecholamines, dopamine or noradrenaline, because MAO-A is the predominant form of MAO in rodent brain. [7] In primate brain MAO-B is the predominant form with regard to degradation of dopamine, and therefore selegiline causes an increase of dopamine and decrease of 3,4-dihydroxyphenylacetic acid (DOPAC) in caudate in monkey brain. [8]
In parkinsonian rat models, such as the 6-hydroxy dopamine (6-OHDA) model in which substantia nigra has been unilaterally destroyed with the toxin, selegiline enhances the effect of levodopa. [9-11] Nonselective MAO inhibitors had earlier been reported to cause some benefit but unacceptable adverse events in the treatment of Parkinson's disease (PD), [12,13] and therefore it was logical to test selegiline in this disease. The early findings by Birkmayer et al. [14] showed that selegiline potentiated the efficacy of levodopa in the treatment of PD patients and was well tolerated. This preliminary finding was followed by a number of trials assessing selegiline therapy in PD. The studies first concentrated on the use of selegiline in advanced PD, i.e., patients with …
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