Rasagiline: A Review of Its Use in the Treatment of Idiopathic Parkinson’s Disease

Abstract

Rasagiline (Azilect(®)) is an oral, second-generation, selective, irreversible monoamine oxidase-B (MAO-B) inhibitor approved in the US for the treatment of Parkinson's disease. In randomized, controlled trials, oral rasagiline 1 mg once daily was superior to placebo in the symptomatic treatment of early Parkinson's disease, both as monotherapy or as an adjunct to dopamine agonists. Comparisons of early-start and delayed-start treatment suggested a disease-modifying effect for rasagiline, but the results were equivocal. Rasagiline 0.5 or 1 mg/day was also superior to placebo as adjunctive therapy to levodopa in Parkinson's disease patients with motor fluctuations. Rasagiline was generally well tolerated in clinical trials, displaying a placebo-like tolerability profile in several studies. Cost-utility studies predicted that rasagiline, either as monotherapy or adjunctive therapy, would be a cost-effective treatment option. Therefore, oral rasagiline is a valuable therapeutic option for use in all stages of Parkinson's disease.

Molecular aspects of monoamine oxidase B

“…MAO B inhibition is a key part of molecules such as rasagiline used for PD (McCormack, 2014) and in trials for AD. For example, ladostigil combines part of rivastigmine to inhibit acetylcholinesterase with rasagiline to inhibit MAO (Geldenhuys and Van der Schyf, 2013).…”

Defining the Role of the Monoamine Oxidase-B Inhibitors for Parkinson’s Disease

“…Likewise, rasagiline at the approved doses of 0.5-1 mg/day is not associated with any significant tyramine pressor response [38,39]. Restrictions of tyramine consumption are no longer viewed as necessary [37,40].…”

Rational drug discovery design approaches for treating Parkinson’s disease

“…Interestingly, studies have pointed to evidence that the MAO-B inhibitors selegiline [41,42] and its analog rasagiline ( Table 1 for structures) [42,43] have neuroprotective properties, but that these properties do not depend solely on MAO-B inhibition, but rather on other related and unrelated mechanisms resulting from the drug's interaction with an array of targets along the pathoetiological pathways of PD, as has been reported by several investigators in a number of models of neurotoxicity [44]. For example, rasagiline was shown to have a significant neuroprotective effect against lactacystininduced nigrostriatal dopaminergic neurodegeneration.…”

“…These events (all putative targets for selegiline and rasagiline) include the oxidation of dopamine, both by monoamine oxidase-catalyzed oxidative deamination, and non-enzymatically through autoxidation. Hydrogen peroxide produced as a byproduct in these reactions reacts with chelatable free iron via Fenton-type chemistry, and is further oxidized to the most reactive of all reactive oxygen species, the hydroxyl radical [41][42][43][44].…”

“…This concept forms the basis for several new biopharmaceutical approaches that have at their core, sustained drug delivery in PD patients, leading to support of the underlying need for continuous --rather than spiked --dopaminergic stimulation. For example, sustained-release formulations of levodopa [79,[82][83][84][85][86]89] or dopamine receptor agonists such as the transdermal delivery of rotigotine [155], and the addition of COMT inhibitors such as tolcapone and entacapone [72,74], or MAO-B inhibitors [41,43,42,48,51] to the therapeutic regimen have been developed in order to provide more stable compartmental drug concentrations and sustained benefits while minimizing the side effect profile typical of these drugs. Traditionally, drug design programs have focused on optimizing the specificity of lead compounds against a carefully selected drug target.…”