Rasagiline

Rasagiline (trade name Azilect®) is a selective irreversible inhibitor of monoamine oxidase B used as a monotherapy in early Parkinson's disease or as an adjunct therapy in more advanced cases. It was developed by Teva Neuroscience.

Mechanism of Action

Human cells contain two forms of monoamine oxidase, MAO-A and MAO-B. Both are found in the brain, but MAO-B is far more prevalent and is responsible for the breakdown of dopamine after its release into the synapse. Parkinson's disease is characterised by the death of cells that use dopamine to transmit their signals, this results in a decrease in synaptic signal strength and concommitant symptomology. By inhibiting the breakdown of dopamine in the synapse, rasagaline permits the signalling neurons to reabsorb more of it for reuse later, somewhat compensating for the diminished quantities manufactured.

Selegiline was the first selective MAO-B inhibitor approved for use in Parkinson's disease in the United States. It is chemically similar to methamphetamine and its metabolic breakdown path eventually yields methamphetamine derivatives that have been associated with cardiac and psychiatric effects in some patients. The chief metabolite of rasagaline is aminoindan which has no amphetamine characteristics. Some clinicians believe rasagaline will be better tolerated in sensitive patients for these reasons.

Laboratory studies show that rasagaline has in vitro and in vivo neuroprotective effects but its neuroprotective effect in Parkinson's disease patients is unknown at present. These studies show that MAO-B can, under some circumstances, create a harmful chemical called MPP+ that in turn creates free radicals. These studies show that amphetamines may block this neuroprotective effect; since rasagaline does not metabolize to amphetamines or their metabolites it may have superior neuroprotective properties when compared to selegiline. There is uncertainty because the mechanism of cell death in human PD may or may not involve the actions of free radicals, but there is suggestive evidence that the drug slows disease progression.

Metabolism

Rasagaline is broken down via CYP1A2, part of the cytochrome P450 metabolic path in the liver. It is probably contraindicated in patients with hepatic insufficiency and its use should be monitored carefully in patients taking other drugs that alter the normal effectiveness of this metabolic path. Examples include but are not limited to cimetidine, ciprofloxacin and omeprazole. Rasagiline is not broken down to amphetamine metabolites like selegiline.

Usage

Monotherapy in Early PD

A study called TVP-1012 (an early name for rasagiline) in Early Monotherapy for Parkinson's Disease Outpatients (TEMPO) enrolled 404 patients. A double-blind, randomized, delayed start study, it evaluated patients for a year using a placebo and doses of 1mg and 2mg per day. The initial six-month placebo controlled part of the study yielded data that led organisers to conclude both rasagaline doses were superior to placebo. The evaluation compared patients' Unified Parkinson's Disease Rating Scale (UPDRS) scores. The UPDRS is a standard method of measuring PD severity. Starting at six months the placebo treated group received the higher dosage of rasagaline (2mg) until the conclusion of the study at twelve months and patients' UPDRS scores were compared again. Patients who had consistently received the higher dose had significantly better scores than patients who had received the placebo, and somewhat better scores than other groups. These data suggest but do not prove a neuroprotective effect. Some patients entered an open-label follow up study. About half of them did not require additional dopaminergic therapy two years later. Over a six and a half year period the mean deterioration in UPDRS scores for patients receiving some level of rasagaline therapy was 2-3 points. Other clinical studies of placebo treated patients with early PD reported a diminution of 8-12 points per year.

Adjunct Therapy in Advanced PD

An eighteen week double-blind placebo-controlled study called the Lasting Effect in Adjunct Therapy with Rasagiline Given Once Daily (LARGO) compared the drug to entacapone and a placebo in 687 patients experiencing motor fluctuations, a hallmark symptom of PD. Rasagiline at a 1mg dose significantly reduced daily off time (1.18 hours) compared to the placebo (0.4 hours) and increased on time without dyskinesia by 0.85 hours. This was approximately the same benefit granted by entacapone.

The Parkinson's Rasagiline: Efficacy and Safety in the Treatement of "OFF" (PRESTO) study monitored 472 patients treated with levodopa for motor fluctuations despite attempts to optimise dopaminergic therapy. PRESTO did not have an active comparison drug; its patients randomly received a 0.5mg dose, a 1mg dose, or a placebo. Patients receiving both doses of rasagiline experienced less significantly less off time (1.4 hours and 1.8 hours) than did those who received the placebo.

These studies suggest patients with advanced and fluctuating PD benefit in the short term from rasagiline therapy but do not comment on long term effects.

Safety

Between the TEMPO, LARGO and PRESTO studies 530 patients were treated with the recommended dosage of 1mg/day for a total of 212 patient-years. The number of patients who discontinued participation due to adverse symptoms was not signficantly different between active drug and placebo.

Although rasagiline is considered to be a specific inhibitor of MAO-B, some concern still exists regarding possible drug interactions with medications that are normally considered contraindicated when taken with general MAO inhibitors. The concern revolves around a possible serotonin-syndrome effect, which was not known to occur during clinical trials despite patients being allowed to take certain antidepressant drugs that are normally contraindicated with general MAO inhibitors. Concern for a possible interaction between rasagiline and tyramine also exists, although no dietary restrictions were imposed during the TEMPO, PRESTO and LARGO studies and no hypertensive crises resulted due to the possible interaction of tyramine and rasagiline.

Source: wikipedia GFDL

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