Parkinson's disease — rasagiline
Parkinson's disease is a degenerative neurological disorder, characterised by trembling, weakness and stiffness. Nerve cells within the basal ganglia in the brain degenerate, affecting movement. It is caused by a deficiency of dopamine in the central nervous system, and levodopa was the earliest drug treatment. However, although it initially improves symptoms, its effect suddenly wears off, only becoming effective once more when its administration is withdrawn for a few weeks.
Selegiline has been in clinical use since the 1970s for the treatment of parkinsonism, either alone or in combination with levodopa. It is a selective irreversible MAO-B (monoamine oxidase) inhibitor.1,2 Selegiline is believed to potentiate the activity of levodopa, by blocking the MAO-B receptors, as levodopa is metabolised equally well by both MAO-A and MAO-B receptors. It is metabolised in the body to 1-amphetamine and 1-methamphetamine, and hence has amphetamine-like sympathomimetic actions.3
More recently, another MAO-B inhibitor, rasagiline, previously known as TVP-1012, has been investigated.4 Structurally related to selegiline, it is metabolised in the body to aminoindan, which has few of the amphetamine-like properties of the selegiline metabolites. In addition, the main metabolite, aminoindane, improves both motor and cognitive functions in experimental models, and may well contribute to the drug's beneficial pharmacological profile.
Rasagiline is the R-enantiomer separated from the racemic selective MAO-B inhibitor AGN1135. The S-enantiomer has little of the desired activity.
Rasagiline has been shown to have potent irreversible MAO-B inhibitory properties, and has a good uptake across the blood–brain barrier. In vivo tests in the rat indicate it is 3–15 times more potent than selegiline, with a similar selectivity for MAO-B over MAO-A. It is administered orally, once a day.
Two Phase II double-blind clinical studies have been completed in 404 Parkinson's patients. Rasagiline at doses of 1 and 2mg/day produced beneficial effects as monotherapy, and pivotal studies as an adjunctive therapy to levodopa are under way.
Preclinical in vivo studies have also shown rasigiline to have activity in models for depression, stroke, head trauma, ADHD, amyotrophic lateral sclerosis and other neurological diseases.
Its cleaner pharmacological profile, notably the absence of amphetamine-like side-effects, along with recently-discovered neuroprotective and antiapoptotic properties, mean it may prove to be preferable to seligiline in the treatment of Parkinson's disease.