Inhibitor Of Monoamine Oxidase Type Research Articles

Free-water diffusion magnetic resonance imaging under selegiline treatment in Parkinson's disease

IntroductionMonoamine oxidase type B inhibitors, including selegiline, are established as anti-Parkinsonian Drugs. Inhibition of monoamine oxidase type B enzymes might suppress the inflammation because of inhibition to generate reactive oxygen species. However, its effect on brain microstructure remains unclear. The aim of this study is to elucidate white matter and substantia nigra (SN) microstructural differences between Patients with Parkinson's disease with and without selegiline treatment by two independently recruited cohorts. MethodsDiffusion tensor imaging and free water imaging indices of WM and SN were compared among 22/15 Patients with Parkinson's disease with selegiline (PDselegiline(+)), 33/23 Patients with Parkinson's disease without selegiline (PDselegiline(−)), and 25/20 controls, in the first/second cohorts. Two cohorts were analyzed with different MRI protocols. ResultsDiffusion tensor imaging and free-water indices of major white matter tracts were significantly differed between the PDselegiline(−) and controls in both cohorts, although not between the PDselegiline(+) and controls except for restricted areas. Compared with the PDselegiline(+), free-water was significantly higher in the PDselegiline(−) in the inferior fronto-occipital fasciculus, superior longitudinal fasciculus, and superior and posterior corona radiata (first cohort) and the forceps major and splenium of the corpus callosum (second cohort). There were no significant differences in free-water of anterior or posterior substantia nigra between PDselegiline(+) and PDselegiline(−). ConclusionsSelegiline treatment might reduce the white matter microstructural abnormalities detected by free-water imaging in Parkinson's disease.

Polymorphism of Drug Transporters, Rather Than Metabolizing Enzymes, Conditions the Pharmacokinetics of Rasagiline.

Rasagiline is a selective and irreversible inhibitor of monoamine oxidase type B with neuroprotective effect, indicated for the management of Parkinson’s disease. The aim of this work was to evaluate the impact of seven CYP1A2 alleles and of 120 additional variants located in other CYP enzymes (e.g., CYP2C19), UGT enzymes (e.g., UGT1A1) or other enzymes (e.g., NAT2), and transporters (e.g., SLCO1B1) on the pharmacokinetic variability and safety of rasagiline. A total of 118 healthy volunteers enrolled in four bioequivalence clinical trials consented to participate in this pharmacogenetic study. CYP1A2 alleles were not associated with the pharmacokinetic variability of rasagiline. Patients with ABCB1 rs1045642 G/A+A/A genotypes presented higher area under the curve adjusted by dose per weight (AUC0-∞/DW) than those with the G/G genotype (p = 0.012) and lower volume of distribution (Vd/F) and clearance (Cl/F) (p = 0.001 and p = 0.012, respectively). Subjects with the ABCC2 rs2273697 A/A genotype presented lower tmax (i.e., the time to reach the maximum concentration, Cmax) compared to those with G/G+G/A genotypes (p = 0.001). Volunteers with the SLC22A1 *1/*5 genotype exhibited lower Cmax/DW and higher tmax (p = 0.003 and p = 0.018, respectively) than subjects with the *1/*1 diplotype. Only one adverse drug reaction was reported: headache. Our results suggest the genetic polymorphism of drug transporters, rather than metabolizing enzymes, conditions the pharmacokinetics of rasagiline.

Selegiline Protects Against Lipopolysaccharide (LPS)-Induced Impairment of the Blood-Brain Barrier Through Regulating the NF-κB/MLCK/p-MLC Signaling Pathway.

Disruption of the blood-brain barrier (BBB) is an important hallmark of sepsis-associated encephalopathy (SAE). Selegiline, a selective and irreversible inhibitor of monoamine oxidase type B, has been applied for the treatment of nervous disorders. In this study, we aimed to investigate whether selegiline has a protective capacity in the impairment of the BBB in both in vivo and in vitro experiments. In a sepsis mouse model, administration of selegiline ameliorated lipopolysaccharide (LPS)-induced impairment of BBB integrity. Additionally, treatment with selegiline increased the expression of the tight junction protein junctional adhesion molecule A (JAM-A) against LPS. Also, we found that selegiline inhibited the production of the proinflammatory cytokines tumor necrosis factor (TNF)-α and interleukin (IL)-1β. In an in vitro experimental model, bEnd.3 brain endothelial cells were exposed to LPS. Results indicate that stimulation with LPS significantly increased the permeability of bEnd.3 cells and reduced the expression of JAM-A, both of which were rescued by treatment with selegiline. Additionally, selegiline prevented the activation of the NF-κB/MLCK/p-MLC signaling pathway in LPS-challenged bEnd.3 cells. These results indicate that selegiline exerted a protective effect on BBB dysfunction, which might be attributed to the inhibition of the NF-κB/MLCK/p-MLC signaling pathway. These findings provide a basis for further research into the neuroprotective mechanism of selegiline.

The Monoamine Oxidase Type B Inhibitor Rasagiline in the Treatment of Parkinson Disease: Is Tyramine a Challenge?

Rasagiline is an irreversible monoamine oxidase type B (MAO-B) inhibitor indicated for the treatment of the signs and symptoms of idiopathic Parkinson disease as initial monotherapy and as adjunct therapy to levodopa. Pharmacologic inhibition of monoamine oxidase type A (MAO-A), but not MAO-B, poses a risk of the "cheese effect," a hypertensive response to excess dietary tyramine, a biogenic sympathomimetic amine. Tyramine challenge studies, conducted to characterize rasagiline selectivity for the MAO-B enzyme and tyramine sensitivity, demonstrate that rasagiline, when used at the recommended dose, is selective for MAO-B and is not associated with heightened tyramine sensitivity. This conclusion is also supported by safety results from large clinical trials of rasagiline in Parkinson disease involving 2066 rasagiline-treated patients who did not require dietary tyramine restriction per protocol. In late 2009, US labeling for rasagiline was modified to state that dietary tyramine restrictions are not ordinarily required when rasagiline is administered at recommended doses. In addition, because rasagiline has been demonstrated to be selective for MAO-B at the approved dose of up to 1 mg/d, contraindications regarding concomitant use with sympathomimetic amines, use of sympathomimetic vasopressors in conjunction with general or local anesthesia, and use in patients with pheochromocytoma also were removed.

3D-QSAR method on indole and pyrrole inhibitors of monoamine oxidase type A

Monoamine oxidase A (MAO-A) converts norepinephrine and serotonin to an oxidative form. These monoamine neurotransmitters have important roles in depression. The MAO-A inhibitors have been discovered for neurodegenerative disease therapy. In order to design novel MAO-A inhibitors, in this study, the quantitative structure-activity relationships for the combined series of indoles and pyrroles were elucidated and the structural conditions to show good inhibitory effects on MAO-A were derived. This result can help us design new inhibitors irrespective of their specific moiety.

Assessment of MAO-B Occupancy in the Brain With PET and [11C]-L-Deprenyl-D2: A Dose-Finding Study With a Novel MAO-B Inhibitor, EVT 301

Inhibition of monoamine oxidase type B (MAO-B) activity in the brain is a putative strategy for the treatment of Alzheimer's disease (AD). We performed a dose-selection and validation study of a novel, reversible MAO-B inhibitor, EVT 301. Sixteen healthy volunteers received selegiline (10 mg) or EVT 301 (25, 75, or 150 mg) daily for 7-8 days, and four subjects with AD received 75 mg of EVT 301. MAO-B occupancy in the brain was assessed using positron emission tomography (PET) with [11C]-L-deprenyl-D2. EVT 301 was found to dose-dependently occupy MAO-B in the human brain, with occupancy ranging from 58-78% at a dose of 25 mg to 73-90% at a dose of 150 mg. The corresponding occupancy after selegiline was 77-92%. Determination of MAO-B inhibition in blood platelets underestimated the actual brain occupancy achieved with EVT 301. A daily EVT 301 dose of 75 or 150 mg appears suitable for clinical efficacy studies in patients with AD.

Rasagilin im klinischen Alltag

Rasagiline (Azilect) is a potent, highly selective and irreversible inhibitor of monoamine oxidase type B of the second generation. Rasagiline is indicated for the treatment of Parkinson's disease (PD) as monotherapy (without levodopa) or as adjunct therapy (with levodopa) in patients with end of dose fluctuations. The efficacy and tolerability of rasagiline has been demonstrated in large-scale, controlled clinical studies in patients with early PD as well as with more advanced PD. This multicentred post-marketing observational study included an investigation of the efficacy and tolerability of rasagiline in a large patient population under conditions of the daily routine in neurologic practice with a special attention on the collection of data regarding a patients' subjective evaluation of quality of life. A total of 754 patients with Parkinson's disease were enrolled, 545 of the patients (63% male patients, mean age 68 years, mean duration of PD 6 years, Hoehn & Yahr stage II to III in 69% of the patients) started rasagiline 1 mg/day as adjunct therapy for up to 4 months. The PD symptoms were rated by the physicians using the Columbia University Rating Scale (CURS) and the clinical fluctuations subscale of the Unified Parkinson's Disease Rating Scale (UPDRS, part IV B). Different aspects of quality of life were rated by the patients using the self-rating Parkinson's Disease Questionaire (PDQ-39). In addition, patients documented the number of hours spend in the OFF-state in "24-hour" home diaries prior to each of the assessment visits. During the treatment period rasagiline was most frequently co-administered with levodopa/DCI (81.7%) and/or dopamine agonists (65.8%). The mean treatment duration was 117.4 (+/-36.4) days, during which PD medication remained unchanged in 86.6% of the cases. The improvement rates in each of the CURS items ranged between 31.1% to 48.4% and the total score was reduced by 22% under the therapy of rasagiline. In the motor part (tremor, rigidity, bradykinesia) the total score was reduced from 6.2 to 4.8, within the other items from 14.7 to 11.5. The proportion of patients without OFF-periods increased from 33.3% to 49.5%. Determined from "24-hours" home diaries, time spend in the OFF-state during wake time decreased from 120 minutes to 45 minutes. In all 8 aspects of quality of life rated by the patients an reduction of the disability could be documented. The PDQ-39 total score was reduced from 36.4 by 7.3 points (20.1%). In total, 29 of the 545 patients who received rasagiline as combination therapy had switched directly from previous combination therapy with selegiline. In this subgroup CURS total score improved from 17.0 to 12.9 points during treatment. The proportion of patients without OFF-periods increased from 36% to 48% and the daily time spent in the OFF-state was reduced from 45 minutes to 30 minutes. The PDQ-39 total score improved by 6.5 points (22.2%). All in all, adverse events were reported by 8.4% of the patients. In conclusion this post-marketing observational study has shown that in patients with pre-existing combination therapy the add-on medication of rasagiline resulted in improvements of motor and non-motor functions. Furthermore, motor complications were significantly reduced and led to an improved quality of life in the self-estimation of the patients. This also applies to those patients with selegiline pre-treatment.

Spotlight on Rasagiline in Parkinsonʼs Disease1

Rasagiline (Azilect) is a novel, selective, irreversible second-generation inhibitor of monoamine oxidase type B (MAO-B). It is administered orally once daily and is approved in the US, Canada, Mexico, Israel and the EU for use as monotherapy and as adjunct therapy in the treatment of Parkinson's disease. Results of well designed clinical studies indicate that rasagiline is effective as initial monotherapy and improves Parkinson's symptomatology in patients with early Parkinson's disease. In addition, when administered in conjunction with levodopa, in patients with moderate to advanced disease and motor fluctuations, rasagiline reduces mean daily 'off' time and increases daily 'on' time without troublesome dyskinesias, compared with controls. Rasagiline is generally well tolerated as monotherapy and adjunctive therapy and is administered once daily. Thus, rasagiline, administered as a simple and convenient dosage regimen, is a well tolerated and effective option for monotherapy in patients with early Parkinson's disease and for adjunctive therapy in patients with moderate to advanced disease.

Determination of gentisin, isogentisin, and amarogentin in Gentiana lutea L. by capillary electrophoresis

A novel, fast, and simple capillary electrophoresis method has been developed for the analysis of gentisin, isogentisin, and amarogentin in roots of Gentiana lutea (yellow gentian), an herb traditionally used as gastric stimulant. Gentisin and isogentisin are xanthones showing potent inhibition of monoamine oxidase type A and B, amarogentin represents one of the bitter principles of Gentiana, responsible for its gastric-roborant effects. Optimal CE-separation conditions comprise a 100 mM sodium tetraborate buffer of pH 9.3, containing 10 mM beta-cyclodextrin as additive; optimum temperature and applied voltage were found to be 30 degrees C and 25 kV, respectively. Direct diode array detection at 260 nm (gentisin, isogentisin) and 242 nm (amarogentin) was performed, and the required analysis time was only 11 min. The developed method was validated for linearity, sensitivity, precision, and accuracy, and utilized to assay several commercially available G. lutea samples. Quantitative data obtained with the developed CE method are compared with HPLC results, and the advantages of each approach are discussed.

Effect of Methylene Blue and Related Redox Dyes on Monoamine Oxidase Activity; Rat Pineal Content of N‐Acetylserotonin, Melatonin, and Related Indoles; and Righting Reflex in Melatonin‐Primed Frogs

The ability of methylene blue (MB) to inhibit the nitric oxide-induced stimulation of N-methyl-D-aspartate receptors has been suggested as a possible mechanism of MB's clinical antidepressant action. This study evaluated the alternative/additional mechanisms of the antidepressant effect of MB on biochemical and behavior levels. Selective inhibition of monoamine oxidase type A (MAO-A) is widely accepted as a major mechanism of the clinical antidepressant effect. MB and the related redox dyes toluidine blue O (TBO), thionine (TN), brilliant cresyl blue (BCB), and toluylene blue (TB) were reversible competitive inhibitors of both MAO-A and MAO-B and were highly selective toward MAO-A. TBO was the most potent inhibitor, followed by TN, BCB, MB, and TB. The dyes studied increased rat pineal N-acetylserotonin (NAS) and melatonin content, in accordance with our previous observations of the stimulating effect of selective inhibition of MAO-A on pineal melatonin biosynthesis. The redox dyes exerted antidepressant-like activity in frogs; that is, they suppressed the righting reflex in melatonin-primed frogs. This study's results indicate that selective inhibition of MAO-A might mediate the clinical antidepressant effect of MB through NAS stimulation and melatonin biosynthesis.

The LTC View on Rasagiline and Sitagliptin

The LTC View on Rasagiline and Sitagliptin

Rasagiline

Rasagiline (Azilect) is a novel, selective, irreversible second-generation inhibitor of monoamine oxidase type B (MAO-B). It is administered orally once daily and is approved in the US, Canada, Mexico, Israel and the EU for use as monotherapy and as adjunct therapy in the treatment of Parkinson's disease. Results of well designed clinical studies indicate that rasagiline is effective as initial monotherapy and improves Parkinson's symptomatology in patients with early Parkinson's disease. In addition, when administered in conjunction with levodopa, in patients with moderate to advanced disease and motor fluctuations, rasagiline reduces mean daily 'off' time and increases daily 'on' time without troublesome dyskinesias, compared with controls. Rasagiline is generally well tolerated as monotherapy and adjunctive therapy and is administered once daily. Thus, rasagiline, administered as a simple and convenient dosage regimen, is a well tolerated and effective option for monotherapy in patients with early Parkinson's disease and for adjunctive therapy in patients with moderate to advanced disease.

The use of rasagiline in conjunction with levodopa in Parkinson's disease

The key goals of drug treatment for idiopathic Parkinson's disease are to control symptoms, maintain function and minimize side effects. Modern therapeutic strategies aim to introduce levodopa as late as possible, thereby postponing the development of levodopa-related motor complications, as well as preventing the emergence of drug-related symptoms such as confusion and hallucinations. Levodopa-sparing strategies include the use of dopamine agonists and catechol-o-methyltransferase inhibitors. While these drugs are effective, some patients cannot tolerate them at the doses required to control their symptoms, and they lack a simple dosage regimen or titration schedule. As a result, new treatments are needed. Rasagiline is a second-generation, potent, irreversible and selective inhibitor of monoamine-oxidase type B. A 1 mg tablet is licensed in the UK for use as monotherapy in idiopathic Parkinson's disease and as adjunct therapy to levodopa in those patients with end-of-dose motor fluctuations. It offers once-a-day dosing, with no need for titration, which makes it simple to use in a condition where complicated dosing regimens are common. It has an acceptable side-effect profile and three key trials show it to be effective in, and well tolerated by, patients in early and advanced Parkinson's disease, including the elderly. Trials have also shown a high rate of compliance that should be mirrored in practice. For nurses managing Parkinson's disease patients with end-of-dose fluctuations and for newly diagnosed patients, rasagiline offers a promising new treatment option.

Double-blind, placebo-controlled trial of selegiline transdermal system (STS) for the treatment of cocaine dependence

Background Cocaine dependence is a major public health problem for which there is no FDA-approved pharmacological treatment. Selegiline is an irreversible selective inhibitor of monoamine oxidase type B (MAO-B) which may affect cocaine addiction through several potential mechanisms. In this study, selegiline transdermal system (STS) was compared to placebo as a treatment for cocaine dependence. This multi-site, double-blind trial of 300 subjects with cocaine dependence assessed the efficacy of selegiline using subject self-reported cocaine use substantiated by urine benzoylecgonine (BE) as the primary outcome measure. Analysis of the data did not show a significant effect for selegiline over placebo. This study does not support a role for selegiline in treating cocaine dependence. The contrast of this result to earlier, promising preclinical and human pilot data could be due to factors associated with sample size, patient characteristics, dose, or poor predictive validity of preclinical models.

Extracting value from case reports: lessons from serotonin toxicity

Extracting value from case reports: lessons from serotonin toxicity

Selegiline orally disintegrating tablets for the treatment of Parkinson’s disease

Selegiline orally disintegrating tablet is a potent, selective and irreversible inhibitor of monoamine oxidase type B. It is delivered in an innovative formulation that largely bypasses the gut and first-pass hepatic metabolism by allowing transbuccal absorption. Selegiline orally disintegrating tablet dissolves in the mouth within seconds and is rapidly absorbed directly into the systemic circulation, increasing parent drug bioavailability and lowering plasma metabolites compared with conventional oral formulations. Adding selegiline orally disintegrating tablet to levodopa in patients experiencing ‘wearing-off’ episodes significantly decreases off time and increases dyskinesia-free ‘on’ time. Adding selegiline orally disintegrating tablet to levodopa also significantly improves Unified Parkinson’s Disease Rating Scale motor scores and patients’ and physicians’ ratings of disease severity. Selegiline orally disintegrating tablet has been demonstrated to be safe and well tolerated in placebo-controlled clinical trials.

Role of the Redox Protein Thioredoxin in Cytoprotective Mechanism Evoked by (-)-Deprenyl

Through the inhibition of monoamine oxidase type B (MAO-B), (-)-deprenyl (selegiline) prevents the conversion of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to the toxic metabolite 1-methyl-4-phenylpyridinium ion (MPP+) and also prevents the neurotoxicity in the dopaminergic neurons in animal models. Cumulative observations suggest that selegiline may also protect against MPP+-induced neurotoxicity, possibly through the induction of pro-survival genes. We have observed that thioredoxin (Trx) mediates the induction of mitochondrial manganese superoxide dismutase (MnSOD) and Bcl-2 during preconditioning-induced hormesis. We therefore investigated whether the redox protein Trx plays any role in the neuroprotective mechanism of selegiline against MPP+-induced cytotoxicity in human SH-SY5Y neuroblastoma cells and also in primary neuronal cultures of mouse midbrain dopaminergic neurons. After confirming that selegiline protects against MPP+-induced cytotoxicity, we observed further that selegiline, at 1 microM or less, induced Trx for protection against oxidative injury caused by MPP+. The induction of Trx was blocked by protein kinase A (PKA) inhibitor and mediated by a PKA-sensitive phospho-activation of mitogen-activated protein (MAP) kinase Erk1/2 and the transcription factor c-Myc. Selegiline-induced Trx and associated neuroprotection were concomitantly blocked by the antisense against Trx mRNA, but not the sense or antisense mutant phosphothionate oligonucleotides, not only in human SH-SY5Y cells but also in mouse primary neuronal culture of midbrain dopaminergic neurons. Furthermore, the redox cycling of Trx may mediate the protective action of selegiline because the inhibition of Trx reductase by 1-chloro-2,4-dinitrobenzene ameliorated the effect of selegiline. Trx (1 microM) consistently increased the expression of mitochondrial proteins MnSOD and Bcl-2, supporting cell survival (Andoh et al., 2002). In conclusion, without modifying MAO-B activity, selegiline augments the gene induction of Trx, leading to elevated expression of antioxidative MnSOD and antiapoptotic Bcl-2 proteins for protecting against MPP+-induced neurotoxicity.

Human recombinant monoamine oxidase B as reliable and efficient enzyme source for inhibitor screening

Interest in inhibitors of monoamine oxidase type B (MAO B) has grown in recent years, due to their therapeutic potential in aging-related neurodegenerative diseases, such as Parkinson’s disease and Alzheimer’s disease. This study is devoted to the use of human recombinant MAO B obtained from a Baculovirus expression system (Supersomes™ MAO B, BD Gentest, MA, USA) as reliable and efficient enzyme source for MAO B inhibitor screening. Comparison of inhibition potencies (pIC 50 values) determined with human cloned and human platelet MAO B for the two series of MAO B inhibitors, coumarin and 5 H-indeno[1,2- c]pyridazin-5-one derivatives, showed that the difference between pIC 50 values obtained with the two enzyme sources was not significant ( P > 0.05, Student’s t-test). Hence, recombinant enzyme is validated as convenient enzyme source for MAO B inhibitor screening.

Effects of 3,4-methylenedioxymethamphetamine (MDMA, ‘Ecstasy’) and para-methoxyamphetamine on striatal 5-HT when co-administered with moclobemide

3,4-Methylenedioxymethamphetamine (MDMA, “ecstasy”) and para-methoxyamphetamine (PMA) are commonly used recreational drugs. PMA, often mistaken for MDMA, is reported to be more toxic in human use than MDMA. Both of these drugs have been shown to facilitate the release and prevent the reuptake of 5-hydroxytryptamine (5-HT, serotonin). PMA is also a potent inhibitor of monoamine oxidase type A (MAO-A), an enzyme responsible for the catabolism of 5-HT, and this characteristic may contribute to its increased toxicity. In humans, co-administration of MDMA with the reversible MAO-A inhibitor moclobemide has led to increased apparent toxicity with ensuing fatalities. In the present study, using microdialysis, we examined the effects of co-administration of MDMA and PMA with moclobemide on extracellular concentrations of 5-HT and 5-hydroxy indol acetic acid (5-HIAA) in the striatum of the rat. 5-HT-mediated effects on body temperature and behavior were also recorded. Rats were pretreated with saline or 20 mg/kg (i.p.) moclobemide and 60 min later injected with 10 mg/kg MDMA, PMA, or saline. Dialysate samples were collected every 30 min for 5 h and analyzed by HPLC-ED. Both MDMA and PMA produced significant increases in extracellular 5-HT concentrations (590% and 360%, respectively, P < 0.05). Rats treated with PMA and MDMA displayed significantly increased 5-HT-related behaviors ( P < 0.05). Furthermore, only MDMA was capable of producing additional significant increases in 5-HT concentrations (980%, P < 0.05) when co-administered with moclobemide. These data suggest that co-administration of MDMA with moclobemide increases extracellular 5-HT and 5-HT-mediated behaviors and may cause increased 5-HT related toxicity similar to that reported with PMA.

Rasagiline

Rasagiline is a second-generation potent, irreversible and selective inhibitor of monoamine-oxidase type B (MAO-B), which has been evaluated for the treatment of Parkinson's disease. Rasagiline also possesses neuroprotective properties that are independent of its MAO inhibitory activity. Unlike selegiline, rasagiline has no amphetamine-like metabolites and its major metabolite, 1-(R)-aminoindan, has demonstrated favourable pharmacological activity in experimental studies. Rasagiline has shown significant beneficial effects as monotherapy in the treatment of early Parkinson's disease. Monotherapy with rasagiline 1 or 2 mg once daily significantly attenuated the worsening of symptoms, compared with placebo, in patients with early Parkinson's disease in a randomised, double-blind trial (n = 404). Furthermore, patients treated with rasagiline for 12 months had less functional decline than patients whose treatment was delayed for 6 months (n = 371). In patients with moderate-to-advanced disease receiving background therapy with levodopa and additional anti-parkinsonian medications (n = 1159), rasagiline 0.5 or 1 mg once daily reduced the daily 'off' time by 0.49-0.94 hours relative to that in placebo recipients in two randomised, double-blind trials. The efficacy of rasagiline 1 mg once daily was similar to entacapone 200 mg administered with each levodopa dose. Rasagiline was generally well tolerated in clinical trials as both monotherapy and when administered with other antiparkinsonian drugs. Adverse events with rasagiline were generally similar in frequency to those seen in placebo or entacapone recipients.