|Systematic (IUPAC) name|
|Legal status||℞ Prescription only|
|Protein binding||88 – 94%|
|Half-life||3 hours|
|Excretion||Renal and fecal|
|Mol. mass||171.238 g/mol|
|(what is this?)|
Rasagiline (Azilect, AGN 1135) is an irreversible inhibitor of monoamine oxidase used as a monotherapy in early Parkinson's disease or as an adjunct therapy in more advanced cases. It is selective for MAO type B over type A by a factor of fourteen.
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 1 mg and 2 mg per day. The initial six-month placebo controlled part of the study yielded data that led organizers to conclude both rasagiline 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 rasagiline (2 mg) 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; the US Food and Drug administration has repeatedly denied Teva Pharmaceuticals' request for an on-label indication for neuroprotection in Parkinson disease. 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 rasagiline 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 1 mg 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 Treatment of "OFF" (PRESTO) study monitored 472 patients treated with levodopa for motor fluctuations despite attempts to optimize dopaminergic therapy. PRESTO did not have an active comparison drug; its patients randomly received a 0.5 mg dose, a 1 mg dose, or a placebo. Patients receiving both doses of rasagiline experienced 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.
Rasagiline is being investigated for the treatment of Restless Legs Syndrome. Because of its melanin binding properties, rasagiline was investigated and found to decrease melanoma growth; it may be candidate for combination therapy for melanoma.
Between the TEMPO, LARGO and PRESTO studies 530 patients were treated with the recommended dosage of 1 mg/day for a total of 212 patient-years. The number of patients who discontinued participation due to adverse symptoms was not significantly different between active drug and placebo.
Although rasagiline is an 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 since adequate studies to establish rasagiline's selectivity for MAO-B have not been conducted. 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.
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 re-uptake from the synapse. Parkinson's disease is characterized by the death of cells that produce dopamine, a neurotransmitter, resulting in a decrease in synaptic signal strength and concommitant symptomology. By inhibiting the breakdown of dopamine at the mitochondria, rasagiline permits the signaling neurons to reabsorb more of it for reuse later, somewhat compensating for the diminished quantities manufactured.
Selegiline was the first MAO 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 l-methamphetamine derivatives that have been associated with cardiac and psychiatric effects in some patients. The chief metabolite of rasagiline is 1(R)-aminoindan which has no amphetamine characteristics. Some clinicians believe rasagiline will be better tolerated in sensitive patients for these reasons. Aminoindan inhibits both MAO-A and MAO-B in a reversible manner, although considerably weaker than rasagiline.
Propargylamines such as rasagiline have neuro-protective and neuro-rescuing properties via their effect on the mitochondria which interferes with and blocks apoptosis in neurodegenerative disorders. Laboratory studies show that rasagiline 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 metabolizes an opioid-related chemical called MPTP (not an opioid itself), into a neurotoxin called MPP+ that in turn creates free radicals. 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. The ADAGIO study found that early treatment with rasagiline at a dose of 1 mg per day provided benefits that were consistent with a possible disease-modifying effect, but early treatment with rasagiline at a dose of 2 mg per day did not. One of the mechanism of a neuroprotective effect of rasagiline is via increasing anti-oxidant enzyme levels; this mechanism of neuroprotection may potentially have some anti-ageing effects. Similar to other compounds which contain a propargylamine structure, rasagiline additionally has anti-apoptotic properties, via its inhibition of voltage-dependent anion channels. Rasagiline is protective against neurotoxic insults from SIN-1, glutamate, N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, N-methyl-(R)-salsolinol as well as beta amyloid protein. Rasagiline is regarded as having superior neuroprotective properties compared to other propargylamines such as selegiline. Selegiline is metabolised to a neurotoxic methamphetamine metabolite whereas rasagaline is not.
Rasagiline 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 fluvoxamine, cimetidine, ciprofloxacin.
Rasagaline, was developed for the treatment of parkinson's disease by Teva Pharmaceuticals, although Lundbeck obtained the marketing rights for rasagiline in Europe. It was found to not only be effective in treating Parkinson's disease but to also possess neuroprotective and anti-apoptotic properties. Due to the concerns regarding neurotoxic metabolites of selegiline, rasagiline was developed as an alternative selective MAO-B inhibitor that is free of neurotoxic metabolites.
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