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Rasagiline Information Summary

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A number of compounds were identified as candidates for further study by the Committee to Identify Neuroprotective Agents in Parkinson's (CINAPS). Of these compounds, Minocycline, Creatine , CoQ10 and GPI 1485 have been selected for testing in the Neuroprotection Clinical Trial.

RASAGILINE

Rasagiline is a novel, potent, selective second-generation irreversible monoamine oxidase type B (MAO-B) inhibitor that blocks the breakdown of dopamine. It has been shown to reduce "off" time and improve motor function in Parkinson's disease patients with levodopa-related motor fluctuations. Individual adverse event rates were low however significantly more patients on rasagiline experience anorexia, ataxia, vomiting, and weight loss.

Scientific Rationale

Although rasagiline is a known inhibitor of MAO-B, most of its neuroprotective properties have been shown to be distinct from MAO inhibition. It has direct antioxidant, anti-apoptotic and anti-excitatory effects which are all dose related. 1, 2, 3, 4 It improves the survival of mesencephalic DA neurons in culture. 5 Rasagiline is structurally related to selegiline, but it is more potent and does not have the amphetamine metabolite that selegiline possesses.5

1. Olanow, Neurology 1997 (suppl) 49:S26-S33
2. Maruyama, Mech Ageing Dev 2000; 116:181-191
3. Maruyama, Mech Ageing Dev 1999; 111:189-200
4. Alexi, Prog Neurobiol 2000;60:409-470
5. Finberg, NeuroReport 1998;9:703-707

Animal Model Data

RODENT: Mice administered AGN-1135 (rasagiline is the R- isomer of this compound and is more potent) prior to MPTP had evidence of sparing of nigrostriatal DA.1

PRIMATE: 24 marmosets were divided into 6 groups. The effects of high dose (10 mg/kg) of both selegiline and rasagiline in animals with and without MPTP 2 mg/kg sc x 4 days were evaluated. The MAO-B inhibitors were started 4 days prior to the MPTP (or saline) treatment and continued until sacrifice 7 days later. MPTP caused a 40% loss of TH positive cells in the SNpc, as well as the depletion of DOPAC and HVA in the putamen. Both selegeline and rasagiline significantly reduced the behavioral, histological and biochemical evidence of neurotoxicity. There was a decrease in the size of the TH-positive neurons, however and this was of unknown significance and was hypothesized that this may be a toxicity of high-dose therapy.

1. Heikkila, Eur J Pharmacol 1985;116:313-317 (abstract only)
2. Kupsch, J Neural Transmission - General Section 2001;108:985-1009

Pharmacokinetics (including blood brain barrier (BBB) penetration)

Presumed to cross the BBB. Dose proportionality has been observed in rasagiline's AUC. This suggests that it has linear pharmacokinetics.

Rabey, Clin Neuropharmacol 2000; 23:324-330

Safety/Tolerability in Humans

A double-blind randomized, placebo-controlled study was performed to compare various doses of rasagiline for safety and tolerability in PD patients (Hoehn & Yahr; Stage I-IV). Rasagiline in doses of 0.5, 1 or 2 mg or placebo were administered once daily in the morning. 64 patients completed the study (12 weeks of treatment followed by 6 weeks of follow up). There was a trend toward improved UPDRS scores in the treated patients, but this did not achieve statistical significance. Two patients decreased because of adverse effects (falling and syncope) in the 1 mg daily group. No significant changes in BP could be found. All other adverse effects were equal to the placebo group. Of note, MAO-B activity in platelets was completely inhibited by the 0.5 mg dose.

Rabey, Clin Neuropharmacol 2000; 23:324-330

Drug Interaction Potential

No interaction with cabergoline. May interact with fluoxetine, meperidine and TCAs.Metabolized by CYP 3A4 and CYP 2D6

Mahmood, Clin Pharmacokinet 1997;33:91-102

Clinical Trial/Epidemiological Evidence in Human PD

None

Last updated February 09, 2005