Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0030567 (Parkinson's disease)
 63,064 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Rasagiline (N-propargyl-1-R-aminoindan) is a new selective inhibitor of MAO-B which is in development for the treatment of Parkinson's disease. The aim of the present study was to evaluate the neuroprotective properties of rasagiline and characterize the mechanism by which it exerts its neuroprotective effect in cerebellar granule cells. Cerebellar granule cells were prepared from 7 to 8 days postnatal Sprague-Dawley rats and maintained in high K(+) (25 mM) medium. Rasagiline increased the survival of cerebellar granule cells treated with cytosine beta-D-arabinofuranoside (Ara-C), L-buthionine-(S,R)-sulfoximine (BSO) or glutamate (100 microM) but did not reduce cell death induced by transferring the cells to physiological K(+) concentration (5 mM) or by serum deprivation. Examination of different derivatives of rasagiline showed that the propargyl moiety is essential to the neuroprotective effect of these molecules, as the compound 1-R-aminoindan (a major metabolite of rasagiline) was devoid of neuroprotective effect in this model system and a rasagiline derivative with a double bond in place of the acetylenic propargyl triple bond was much less effective. The S(-)-enantiomer of rasagiline was also significantly less active than R(+)-rasagiline, as was 6-fluoro rasagiline. Addition of rasagiline (0.1-10 microM) to cerebellar granule cells grown in medium containing a physiological concentration of K(+) did not have an effect on neurite outgrowth as measured by synapsin expression level but increased the density of glial cell processes. The neuroprotective effects of rasagiline may include a direct action on the neurons through inhibition of neuronal death as well as an indirect effect mediated by the astrocytes.
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PMID:Characterization of the neuroprotective activity of rasagiline in cerebellar granule cells. 1572 Nov 73

The objective of this study is to update a previous evidence-based medicine (EBM) review on Parkinson's disease (PD) treatments, adding January 2001 to January 2004 information. The Movement Disorder Society (MDS) Task Force prepared an EBM review of PD treatments covering data up to January 2001. The authors reviewed Level I (randomized clinical trials) reports of pharmacological and surgical interventions for PD, published as full articles in English (January 2001-January 2004). Inclusion criteria and ranking followed the original program and adhered to EBM methodology. For Efficacy Conclusions, treatments were designated Efficacious, Likely Efficacious, Non-Efficacious, or Insufficient Data. Four clinical indications were considered for each intervention: prevention of disease progression; treatment of Parkinsonism, as monotherapy and as adjuncts to levodopa where indicated; prevention of motor complications; treatment of motor complications. Twenty-seven new studies qualified for efficacy review, and others covered new safety issues. Apomorphine, piribedil, unilateral pallidotomy, and subthalamic nucleus stimulation moved upward in efficacy ratings. Rasagiline, was newly rated as Efficacious monotherapy for control of Parkinsonism. New Level I data moved human fetal nigral transplants, as performed to date, from Insufficient Data to Non- efficacious for the treatment of Parkinsonism, motor fluctuations, and dyskinesias. Selegiline was reassigned as Non-efficacious for the prevention of dyskinesias. Other designations did not change. In a field as active in clinical trials as PD, frequent updating of therapy-based reviews is essential. We consider a 3-year period a reasonable time frame for published updates and are working to establish a Web-based mechanism to update the report in an ongoing manner.
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PMID:Evidence-based medical review update: pharmacological and surgical treatments of Parkinson's disease: 2001 to 2004. 1581 99

The mitochondria are directly involved in cell survival and death. Drugs that protect mitochondria viability and prevent apoptotic cascade mechanisms involved in mitochondrial permeability transition pore (MPTp) will be cytoprotective. Rasagiline (N-propargyl-1R-aminoindan) is a novel, highly potent irreversible monoamine oxidase (MAO) B inhibitor, anti-Parkinson drug. Unlike selegiline, rasagiline is not derived from amphetamine, is not metabolized to neurotoxic l-methamphetamine derivative, nor does it have sympathomimetic activity. Rasagiline is effective as monotherapy or adjunct to L-dopa for patients with early and late Parkinson's disease (PD), and adverse events do not occur with greater frequency in subjects receiving rasagiline than those on placebo. Controlled studies indicate that it might have a disease-modifying effect in PD that may be related to neuroprotection. Its S-isomer, TVP1022, is a relatively inactive MAO inhibitor. However, both drugs have similar neuroprotective activities in neuronal cell cultures in response to various neurotoxins and in vivo (global ischemia, neurotrauma, head injury, anoxia, etc.), indicating that MAO inhibition is not a pre-requisite for neuroprotection. Structure activity studies have shown that the neuroprotective activity is associated with the propargyl moiety of rasagiline which protects mitochondrial viability and MPTp by activating Bcl-2 and protein kinase C (PKC), and down regulating pro-apoptotic FAS and Bax. Rasagiline and its derivatives also process amyloid precursor protein (APP) to the neuroprotective-neurotrophic soluble APP alpha (sAPPalpha) by PKC and MAP kinase-dependent activation of alpha-secretase. The neuroprotective activity of propargylamine has led us to develop novel bifunctional neuroprotective iron-chelating MAO-inhibiting drugs possessing propargyl moiety for the treatment of other neurodegenerative diseases.
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PMID:Mechanism of neuroprotective action of the anti-Parkinson drug rasagiline and its derivatives. 1585 Jun 77

Neuronal death in Parkinson's disease (PD) may originate from the reciprocal interactions of a restricted number of conditions, such as mitochondrial defects, oxidative stress and protein mishandling, which would favor a state of apoptotic cell death in the nigrostriatal pathway. The search for pharmacological treatments able to counteract the nigrostriatal degeneration, possibly by interfering with these phenomena, has recently raised considerable interest in rasagiline [R(+)-N-propargyl-1-aminoindan], a potent, selective, and irreversible inhibitor of monoamine oxidase B (MAO-B). Rasagiline, like selegiline, is a propargylamine, but is approximately 10 times more potent. Unlike selegiline, rasagiline is not metabolized to amphetamine and/or methamphetamine and is devoid of sympathomimetic activity. Numerous experimental studies, conducted both in vitro and in vivo, have shown that rasagiline possesses significant protective properties on neuronal populations. The pro-survival effects of the drug appear to be linked to its propargyl moiety, rather than to the inhibitory effect on MAO-B. Rasagiline's major metabolite, aminoindan--which possesses intrinsic neuroprotective activity--may also contribute to the beneficial effects of the parent compound. Rasagiline has been recently evaluated in early PD patients, with results that are consistent with slowing the progression of the disease. Therefore, the neuroprotective activity shown by the drug under experimental conditions may be reflected in the clinic, thus providing new perspectives for the treatment of PD.
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PMID:Neuroprotection by rasagiline: a new therapeutic approach to Parkinson's disease? 1600 39

Rasagiline is a novel second-generation propargylamine that irreversibly and selectively inhibits monoamine oxidase type B (MAO-B). For the management of Parkinson disease (PD), rasagiline is efficacious across the span of PD stages ranging from monotherapy in early disease to adjunctive treatment in patients with advancing disease and motor fluctuations. Rasagiline completely and selectively inhibits MAO-B with a potency 5 to 10 times greater than selegiline. Unlike the prototype propargylamine selegiline, which is metabolized to amphetamine derivatives, rasagiline is biotransformed to aminoindan, a non-amphetamine compound. Rasagiline is well tolerated with infrequent cardiovascular or psychiatric side effects, and at the recommended therapeutic dose of up to 1 mg once daily, tyramine restriction is unnecessary. In addition to MAO-B inhibition, the propargylamine chain also confers dose-related antioxidant and antiapoptotic effects, which have been associated with neuroprotection in multiple experimental models. Thus, in addition to symptomatic benefits, rasagiline offers the promise of clinically relevant neuroprotection.
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PMID:Clinical pharmacology of rasagiline: a novel, second-generation propargylamine for the treatment of Parkinson disease. 1602 98

Rasagiline (N-propargyl-1R-aminoindan) is a novel, highly potent, irreversible monoamine oxidase (MAO)-B inhibitor designed for use as an antiparkinsonian drug. Unlike selegiline, rasagiline is not derived from amphetamine or metabolized to neurotoxic l-methamphetamine derivative, and it does not have sympathomimetic activity. Moreover, at selective MAO-B inhibitory dosage, it does not induce a "cheese reaction." Rasagiline is effective as monotherapy or as an adjunct to L-dopa for patients with early and late Parkinson's disease. Adverse events do not occur with greater frequency in subjects receiving rasagiline than in those on placebo. Its S-isomer, TVP1022, is more than a thousand times less potent as an MAO inhibitor. However, both drugs have neuroprotective activities in neuronal cell cultures in response to various neurotoxins, as well as in vivo (e.g., in response to global ischemia, neurotrauma, head injury, anoxia, etc.), indicating that MAO inhibition is not a prerequisite for neuroprotection. The neuroprotective activity of these drugs has been demonstrated to be associated with the propargylamine moiety, which protects mitochondrial viability and mitochondrial permeability transition pore by activating Bcl-2 and downregulating the Bax family of proteins. Rasagiline processes amyloid precursor protein (APP) into the neuroprotective-neurotrophic soluble APPalpha (sAPPalpha) by protein kinase C- and mitogen-activated protein kinase-dependent activation of alpha-secretase, and increases nerve growth factor, glial cell- derived neurotrophic factor (GDNF) and brain-derived neurotrophic factor (BDNF) expression and proteins. Thus, rasagiline may induce neuroprotection, neuroplasticity and long-term potentiation. Rasagiline has therefore been chosen by the National Institutes of Health (NIH) to study its neuroprotective effects in neurodegenerative diseases. Long-term studies are required to evaluate the drug's disease-modifying prospects in Parkinson's and Alzheimer's diseases.
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PMID:Neuropharmacological, neuroprotective and amyloid precursor processing properties of selective MAO-B inhibitor antiparkinsonian drug, rasagiline. 1611 Mar 45

Parkinson's disease (PD) is primarily a disease of elderly patients. This article reviews current knowledge and recent developments relating to drugs that can be used as alternatives to levodopa as initial treatment of PD. Synthetic orally acting dopamine agonists have found increasing favour as an option for early PD in relatively young patients. This strategy is based on evidence that this approach may delay the onset of motor fluctuations, at least during the first 5 years of treatment. Subcutaneous apomorphine infusions may attenuate motor fluctuations in late-stage disease, and transdermal rotigotine, a dopamine agonist in development, has also been shown to be efficacious. The greater proclivity for dopamine agonists to cause psychotoxicity has, however, limited their routine use in the elderly. Selective monoamine oxidase type B (MAO-B) inhibitors, used as monotherapy, delay the need for the introduction of levodopa by about 9 months. These agents appear to be less efficacious than dopamine agonists but are better tolerated. Concern has been expressed about the potential of the MAO-B inhibitor selegiline (deprenyl) to induce cardiovascular adverse effects (orthostatic hypotension), either directly or through its amphetamine catabolites. Rasagiline is a new MAO-B inhibitor that is not broken down to amphetamine derivatives and is indicated as both monotherapy in early PD and as adjunctive therapy in PD patients with motor fluctuations. Two older classes of agents have undergone a resurgence of interest in recent years. Amantadine, which enhances dopaminergic transmission and has antiglutamate activity, is occasionally used as monotherapy but has recently been widely used as an antidyskinetic agent in late-stage PD. Anticholinergic drugs, such as benztropine (benzatropine) and orphenadrine also provide control of symptoms when used as monotherapy, but their psychotoxic, cognitive and autonomic adverse events make them inappropriate for the treatment of the elderly. Effective therapy in PD should prevent disease progression and abolish motor and cognitive handicap. Currently, none of the existing drugs meets all these needs.
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PMID:Alternatives to levodopa in the initial treatment of early Parkinson's disease. 1615 77

Despite the current efficacious symptomatic approaches, the search is on for new therapies for Parkinson's disease that can control the cardinal symptoms of the disease (tremor, rigidity and bradykinesia), control/prevent motor complications induced by long-term levodopa, act on non-motor disease symptoms (dementia, dysautonomia, pain, insomnia, falls) and halt disease progression. Rasagiline is a monoamine oxidase-B inhibitor that has demonstrated efficacy against the cardinal symptoms of Parkinson's disease when used as monotherapy in early Parkinson's disease, and as an adjunct to levodopa in advanced disease stages. It reduces the duration and severity of poor symptom response episodes in fluctuating patients. Preliminary results allow discussion of putative effects of rasagiline on some non-motor signs and disease progression. This article outlines the evidence surrounding the efficacy and safety of rasagiline, and discusses its potential to address some of the currently unmet needs of Parkinson's disease therapy.
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PMID:Rasagiline in the pharmacotherapy of Parkinson's disease--a review. 1619 59

The objective of this study was to determine the effects of rasagiline as monotherapy on quality of life (QOL) in patients with early Parkinson's disease (PD). Rasagiline, a potent, second-generation, irreversible, selective monoamine oxidase B inhibitor improves PD symptoms in patients with early PD. Patients with early untreated PD were randomly assigned to once-daily rasagiline 1 mg/day, rasagiline 2 mg/day, or placebo in a 6-month, double-blind trial (n=404). At the end of 6 months, patients entered the preplanned, active-treatment phase in which those receiving 1 mg/day and 2 mg/day of rasagiline continued on their previously assigned dosages and those receiving placebo switched to rasagiline 2 mg/day, while maintaining blinding to treatment assignments. QOL was measured with the Parkinson's Disease Quality of Life questionnaire (PDQUALIF) at 0, 14, 26, and 52 weeks after randomization. Analysis of the change in PDQUALIF scores from baseline to 6 months showed adjusted treatment effects (with 95% confidence interval) favoring rasagiline over placebo of -2.91 units (-5.19, -0.64, P=0.01) for the 1 mg/day group and -2.74 units (-5.02, -0.45, P=0.02) for the 2 mg/day. Subscore analysis attributed most of this benefit to the self-image/sexuality domain. At 12 months (n=266), with all groups receiving rasagiline for at least 6 months, no significant differences in PDQUALIF scores were seen between groups. Rasagiline improved QOL compared with placebo. This QOL improvement appears to be accounted for primarily by the symptomatic benefit of rasagiline.
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PMID:Rasagiline improves quality of life in patients with early Parkinson's disease. 1645 Mar 40

Parkinson's disease (PD) is a therapy area with considerable unmet needs. The current key targets for PD treatment include the slowing of disease progression, improved control of motor fluctuations in advanced disease and the treatment of non-motor symptoms. In view of such major requirements, it is important to consider how new drug treatments fit into the context of PD therapy, and the practical advantages that they may offer in the management of PD in clinical practice. Rasagiline is a novel, second-generation, irreversible, selective monoamine oxidase type B inhibitor that is indicated for the treatment of idiopathic PD, either as initial monotherapy or as adjunct therapy (with levodopa) for patients experiencing end-of-dose motor fluctuations. This review assesses the outcome from several large-scale clinical studies that have investigated the use of rasagiline in early and advanced PD patient populations and discusses the role of rasagiline within the current scope of PD therapy.
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PMID:Rasagiline: defining the role of a novel therapy in the treatment of Parkinson's disease. 1645 Dec 81


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