Rasagiline mesylate

Rasagiline mesylate is a new MAO-B inhibitor for the treatment of idiopathic Parkinson's disease.

Controlled release of rasagiline mesylate promotes neuroprotection in a rotenone-induced advanced model of Parkinson's disease.[Pubmed:22985602]

Int J Pharm. 2012 Nov 15;438(1-2):266-78.

Microencapsulation of Rasagiline mesylate (RM) into PLGA microspheres was performed by method A (O/W emulsion) and method B (W/O/W double emulsion). The best formulation regarding process yield, encapsulation efficiency and in vitro drug release was that prepared with method A, which exhibited constant drug release for two weeks (K(0)=62.3 mug/day/20mg microspheres). Exposure of SKN-AS cells to peroxide-induced oxidative stress (1 mM) resulted in cell apoptosis which was significantly reduced by RM (40.7-102.5 muM) as determined by cell viability, ROS production and DNA fragmentation. Daily doses of rotenone (2 mg/kg) given i.p. to rats for 45 days induced neuronal and behavioral changes similar to those occurring in PD. Once an advanced stage of PD was achieved, animals received RM in saline (1 mg/kg/day) or encapsulated within PLGA microspheres (amount of microspheres equivalent to 15 mg/kg RM given on days 15 and 30). After 45 days RM showed a robust effect on all analytical outcomes evaluated with non-statistically significant differences found between its administration in solution or within microparticles however; with this controlled release system administration of RM could be performed every two weeks thereby making this new therapeutic system an interesting approach for the treatment of PD.

Rasagiline mesylate, a new MAO-B inhibitor for the treatment of Parkinson's disease: a double-blind study as adjunctive therapy to levodopa.[Pubmed:11575866]

Clin Neuropharmacol. 2000 Nov-Dec;23(6):324-30.

Rasagiline mesylate (TVP-1012) is a potent, selective, non-reversible MAO-B inhibitor, without the tyramine-potentiating effect and with neuroprotective activities. The benefit of rasagiline as monotherapy in patients with early Parkinson's disease (PD) has already been reported. To evaluate the safety, tolerability, and clinical effect of rasagiline as adjunctive therapy to levodopa, a multicenter, double-blind, randomized, placebo-controlled, parallel-group study (0.5, 1, and 2 mg/d) was conducted for 12 weeks in 70 patients with PD (mean age, 57.4 y; mean disease duration, 5.7 y; 32 patients had motor fluctuations). A beneficial clinical effect was observed in fluctuating patients treated with rasagiline (all doses), expressed as a decrease in total Unified Parkinson's Disease Rating Scale (UPDRS) score (23.0% vs 8.5% in the placebo group). The treatment effect was still evident 6 weeks after drug discontinuation (in all doses). The safety and tolerability of rasagiline were good. Adverse events were no different than those of patients taking placebo. Almost complete platelet MAO-B inhibition was obtained at all rasagiline doses. This study has demonstrated that rasagiline (up to 2 mg/day) has a good safety profile and a beneficial clinical effect in fluctuating patients with PD when given as an add-on to chronic levodopa therapy.

Evaluation of different substrates for inkjet printing of rasagiline mesylate.[Pubmed:23563101]

Eur J Pharm Biopharm. 2013 Nov;85(3 Pt B):1075-83.

The main goal of the present study was to evaluate applicability of the different model substrates, namely orodispersible films (ODFs), porous copy paper sheets, and water impermeable transparency films (TFs) in preparation of the inkjet-printed drug-delivery systems. Rasagiline mesylate (RM) was used as a low-dose active pharmaceutical ingredient (API). Flexible doses of the drug in a single unit were obtained by printing several subsequent layers on top of the already printed ones, using an off-the-shelf consumer thermal inkjet (TIJ) printer. The produced drug-delivery systems were subjected to microscopic and chemical analysis together with solid-state characterization and content uniformity studies. The results revealed that RM recrystallized on the surface of ODFs and TFs, and the printed crystals were arranged in lines. No drug crystals were detected after printing on the surface of the copy paper due to absorption of the ink into the matrix of the substrate. The best linear correlation between the dose of the drug and the number of the printing layers was obtained for the porous copy paper. The other two substrates showed poor linearity and unacceptable standard deviations of the printed drug substance due to limited absorption of the API ink into the carrier. The shear stress between the substrate, the print head, and the paper feeding rollers caused smearing of the drug that had been surface-deposited during the earlier printing cycles. In conclusion, this study indicates that the edible substrates with absorption properties similar to copy paper are favorable for successful preparation of drug-delivery systems by TIJ printers.

Effect of the moist-heat sterilization on fabricated nanoscale solid lipid particles containing rasagiline mesylate.[Pubmed:25838993]

Int J Pharm Investig. 2015 Apr-Jun;5(2):87-91.

BACKGROUND: Nanoscale solid lipid particles of Rasagiline mesylate (RM) were fabricated by microemulsion technique. The nanoscale particle must be sterile for intravenous administration, and several approaches are available for sterilization. However, the selection of sterilization technique for the fabricated RM loaded nanoscale solid lipid particles mainly depends on the nature of the drug that needs to be encapsulated and release pattern of the polymer. MATERIALS AND METHODS: We have preferred moist heat sterilization, as it is the most convenient and the composition of the carrier and incorporated drug should remain unchanged and the incorporated drug should not leak out of the drug carrier. The physical and chemical stability of RM loaded nanoscale solid lipid particles investigated during sterilization and to determine the average mean particle size, polydispersity index, zeta potential (ZP), transmission electron microscopy (TEM), entrapment efficiency (EE), and drug content after autoclaving. RESULT: There were no significant changes in the average mean particle size, polydispersity index, ZP, TEM, EE, and drug content of RM loaded nanoscale solid lipid particles after autoclaving (121 degrees C for 20 min [15 lbs]). CONCLUSION: These observations suggest that the moist heat sterilization by autoclaving is the most suitable method for nanoscale solid lipid formulations.

Pharmacological properties of the anti-Parkinson drug rasagiline; modification of endogenous brain amines, reserpine reversal, serotonergic and dopaminergic behaviours.[Pubmed:12504917]

Neuropharmacology. 2002 Dec;43(7):1110-8.

Rasagiline [N-propargyl-1R(+)-aminoindan; TVP1012] is a potent irreversible monoamine oxidase (MAO) inhibitor with selectivity for type B of the enzyme, which is being developed for treatment of Parkinson's disease. In this study we examined effects of rasagiline on CNS monoamine levels, modification of behavioural response to L-tryptophan, fluoxetine and L-DOPA, and reversal of reserpine syndrome. Reserpine-induced ptosis was reversed by rasagiline at doses above 2 mg x kg(-1) i.p., which inhibit MAO-A as well as MAO-B, but not at MAO-B-selective doses. However, combination of rasagiline (10 mg x kg(-1) i.p.) with L-DOPA or L-tryptophan (50 mg x kg(-1) i.p.), or rasagiline (10 mg x kg(-1) p.o.) with fluoxetine (10 mg x kg(-1) p.o.), did not induce the behavioural hyperactivity syndrome which is seen following inhibition of both MAO-A and MAO-B by tranylcypromine together with the monoamine precursors. Following oral administration, levels of noradrenaline (NA), 5-hydroxytryptamine (5-HT) and dopamine (DA) were unaffected in hippocampus and striatum after single doses of rasagiline up to 2 mg x kg(-1). Following chronic oral administration (21 days, one dose daily), levels of NA, 5-HT and DA in hippocampus and striatum were unaffected by rasagiline at doses up to 1 mg x kg(-1). Rasagiline does not modify CNS monoamine tissue levels or monoamine-induced behavioural syndromes at doses which selectively inhibit MAO-B but not MAO-A.

The anti-Parkinson drug, rasagiline, prevents apoptotic DNA damage induced by peroxynitrite in human dopaminergic neuroblastoma SH-SY5Y cells.[Pubmed:11956966]

J Neural Transm (Vienna). 2002 Apr;109(4):467-81.

Clinical trials for treatment of Parkinson's disease suggest that (-)deprenyl (selegiline), an inhibitor of type B monoamine oxidase, may slow the disease progression. However, the mechanism underlying protection of nigral dopamine neurons by selegiline remains an enigma. Recently, rasagiline, (R)(+)-N-propargyl-1-aminoindan, was reported to be neuroprotective by in vivo and in vitro experiments, which is another selective irreversible inhibitor of type B monoamine oxidase and not metabolized into amphetamine-like derivatives as in the case of selegiline. In this paper, the mechanism of the neuroprotection was examined using human dopaminergic neuroblastoma SH-SY5Y cells against apoptosis induced by peroxynitrite generated from SIN-1. After treatment with SIN-1, the apoptotic DNA damage in the cells was quantified by a single cell gel electrophoresis (comet) assay and by staining with Hoechst 33342. Change in mitochondrial membrane potential, Deltapsim, was measured by use of a fluorescent indicator, JC-1. Rasagiline reduced apoptosis with much more potency than selegiline, and the protection required 20 min pre-incubation before SIN-1 treatment. The protection by rasagiline was proved to be due to stabilization of mitochondrial membrane potential against the collapse induced by SIN-1, whereas rasagiline did not scavenge peroxynitrite directly. The studies on structure-activity relationship showed that a propargylamine group and a hydrophobic group with an adequate intermediate space were required for the protection. These results suggest that rasagiline may protect declining neurons through its anti-apoptotic activity in neurodegenerative diseases.