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

Rasagiline is a MAO-B inhibitor that is currently registered for the symptomatic treatment of Parkinson disease. The ADAGIO trial studied the potential disease-modifying properties of rasagiline in 1100 patients with Parkinson disease, using an innovative 'delayed start' design. Patients were randomized to either immediate treatment or delayed treatment (after 9 months). Two doses of rasagiline were studied: 1 or 2 mg. Both doses relieved the symptoms. However, the group that immediately started on 1 mg showed an extra improvement at the end of follow-up. This could not be explained by the effect on the symptoms, but was possibly a disease-modifying effect. Surprisingly, the 2 mg group did not show this additional effect at the end of follow-up. Therefore no definite conclusions can be drawn with respect to the potential disease-modifying properties of rasagiline. Rasagiline should be prescribed only with the aim of symptomatic relief, but not to curb the progression of Parkinson disease.
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PMID:[Rasagiline is not for all Parkinson disease patients: the ADAGIO study]. 2097 89

Parkinson's disease is a complicated disease state that affects patients' quality of life. The first monoamine oxidase (MAO-B) inhibitor for PD, selegiline (Eldepryl), was approved by the Food and Drug Administration (FDA) in 1996, and rasagiline (Azilect) received FDA approval in 2006. At first, pharmacists may assume that rasagiline is just another me-too drug. There are three areas in which the two medications differ from each other: MAO type A inhibitors are found in high concentrations in the intestines, and MAO type B inhibitors are found mostly in the brain. If MAO-A inhibition occurs, the body cannot protect itself from exogenous amines such as tyramine. The absorbed tyramine can cause hypertensive crisis, also known as the cheese reaction. Selegiline's capsule product labeling includes a bolded warning that it "should not be used at daily doses exceeding 10 mg per day because of the risks associated with non-selective inhibition of MAO." It also says, "the selectivity of selegiline for MAO B may not be absolute, even at the recommended daily dose." The fact that rasagiline has the same effect has been challenged by two main-stream studies. Selegiline is a propargyl amphetamine derivative that undergoes extensive first-pass metabolism to L-methamphetamine and L-amphetamine. Rasagiline's major metabolite is amioindan, which has no amphetaminelike properties. Selegiline has been reviewed looking for neuroprotection, but studies have been unable to come to a definite positive neuroprotection conclusion. Proponents of rasagiline's neuroprotective effects also point to clinical studies in humans that demonstrate delayed and reduced need for future use of levodopa. In summary, selegiline and rasagiline look more and more like distant cousins instead of twins.
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PMID:Selegiline and rasagiline: twins or distant cousins? 2122 99

Cognitive impairment can occur at all stages of Parkinson's disease. Rasagiline is a selective monoamine oxidase type-B inhibitor that enhances central dopaminergic transmission. Dopamine is thought to be involved in certain cognitive processes such as working memory. We assessed the effects of rasagiline on cognitive deficits in cognitively impaired, nondemented patients with Parkinson's disease. This was a randomized, double-blind, placebo-controlled prospective study. Patients with Parkinson's disease receiving stable dopaminergic treatment were assigned to receive rasagiline 1 mg/day or placebo for 3 months. Patients were eligible if they had impairment in 2 of 4 cognitive domains (attention, executive functions, memory, visuospatial functions) in the screening neuropsychological tests, yet did not fulfill criteria for Parkinson's disease dementia. Fifty-five patients were randomized; 48 patients completed the study. Patients in the rasagiline group showed significant improvement in digit span-backward compared with the placebo group (P = .04), with trends favoring rasagiline in digit span total and digit-ordering tests. Verbal fluency total score showed a significant difference in favor of rasagiline (P = .038), with trends favoring rasagiline in semantic fluency test and Stroop spontaneous corrections. The composite cognitive domain Z scores revealed a significant difference in favor of rasagiline compared with placebo in the attentional Z score (P < .005). There were no significant differences between the 2 groups in the other cognitive tests or cognitive domain Z scores. The monoamine oxidase type-B inhibitor rasagiline may exert beneficial effects on certain aspects of attention and executive functions in nondemented patients with Parkinson's disease with cognitive impairment.
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PMID:The effects of rasagiline on cognitive deficits in Parkinson's disease patients without dementia: a randomized, double-blind, placebo-controlled, multicenter study. 2150 Feb 80

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.
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PMID:The monoamine oxidase type B inhibitor rasagiline in the treatment of Parkinson disease: is tyramine a challenge? 2162

Monoamine oxidase (MAO) inhibitors were reported to have therapeutic value in several common neurodegenerative conditions owed to their diverse pharmacological functions in neuron survival. Rasagiline (N-propargyl-1-(R)-aminoindan) is a novel, highly potent irreversible MAO-B inhibitor in the treatment of Parkinson's disease (PD). It has been demonstrated to be neuroprotective in PD model systems by preventing the formation of reactive oxygen species derived from prevention of derived from oxidation of dopamine by MAO-B and via an antiapoptotic action, which appears to be independent of MAO-B inhibition and related to its embedded N-propargyl moiety. This review reflects on earlier and present evidence supporting a role for rasagiline as a neuroprotective molecule in the treatment of PD.
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PMID:Neuroprotective profile of the multitarget drug rasagiline in Parkinson's disease. 2197 Oct 6

It has long been recognized that monoamine oxidase (MAO) inhibitors have a role in the management of Parkinson's disease (PD). The MAO-B inhibitor rasagiline has neuroprotective effects in animal models, mediated partly by its antiapoptotic activity. Rasagiline has been shown to be effective as monotherapy for early PD and as an adjunct to dopaminergic therapy. Clinical trials have also shown putative disease-modifying effects, though rasagiline's potential to alter the long-term course of PD remains controversial. Given the demonstrated benefits of rasagiline, along with its safety and tolerability profile, it has an important role to play in PD therapy.
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PMID:Rasagiline in Parkinson's disease. 2197 Oct 7

The objective was to update previous evidence-based medicine reviews of treatments for motor symptoms of Parkinson's disease published between 2002 and 2005. Level I (randomized, controlled trial) reports of pharmacological, surgical, and nonpharmacological interventions for the motor symptoms of Parkinson's disease between January 2004 (2001 for nonpharmacological) and December 2010 were reviewed. Criteria for inclusion, clinical indications, ranking, efficacy conclusions, safety, and implications for clinical practice followed the original program outline and adhered to evidence-based medicine methodology. Sixty-eight new studies qualified for review. Piribedil, pramipexole, pramipexole extended release, ropinirole, rotigotine, cabergoline, and pergolide were all efficacious as symptomatic monotherapy; ropinirole prolonged release was likely efficacious. All were efficacious as a symptomatic adjunct except pramipexole extended release, for which there is insufficient evidence. For prevention/delay of motor fluctuations, pramipexole and cabergoline were efficacious, and for prevention/delay of dyskinesia, pramipexole, ropinirole, ropinirole prolonged release, and cabergoline were all efficacious, whereas pergolide was likely efficacious. Duodenal infusion of levodopa was likely efficacious in the treatment of motor complications, but the practice implication is investigational. Entacapone was nonefficacious as a symptomatic adjunct to levodopa in nonfluctuating patients and nonefficacious in the prevention/delay of motor complications. Rasagiline conclusions were revised to efficacious as a symptomatic adjunct, and as treatment for motor fluctuations. Clozapine was efficacious in dyskinesia, but because of safety issues, the practice implication is possibly useful. Bilateral subthalamic nucleus deep brain stimulation, bilateral globus pallidus stimulation, and unilateral pallidotomy were updated to efficacious for motor complications. Physical therapy was revised to likely efficacious as symptomatic adjunct therapy. This evidence-based medicine review updates the field and highlights gaps for research.
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PMID:The Movement Disorder Society Evidence-Based Medicine Review Update: Treatments for the motor symptoms of Parkinson's disease. 2202 Nov 73

Playing a pivotal role in the metabolism of neurotransmitters in the central nervous system, the mitochondrial enzymes monoamine oxidases A and B (MAO A and B) have been for long studied as drug targets for neurodegenerative and neurological diseases. MAO inhibitors (MAOIs) are clinically used to treat Parkinson's disease and depression by blocking the degradation of neuroactive catecholamines and providing a symptomatic relief in the patients. More recent is the idea that the neuroprotective effect of MAOIs may result from the prevention of oxidative stress produced by the MAO reaction rather than being simply related to the inhibition of neurotransmitters degradation. Tranylcypromine and phenelzine are among the first developed MAOI drugs and have been used for years to treat depression. Their usage is now limited to cases of refractory depression because of their negative side effects, which are due to both the lack of MAO A/MAO B selectivity and the inhibition of other enzymes such as the drug-metabolizing cytochromes P450. Although the multi-target action of these MAOIs determines negative implications, the most newly developed compounds have improved properties not only for their specificity relatively to MAO A/MAO B selectivity but also because they function through multiple mechanisms that produce beneficial effects. In particular, safinamide, a MAO B selective inhibitor in clinical trials for Parkinson's disease, is neuroprotective by blocking the voltage-dependent Na+ and Ca2+ channels and the Ca2+-mediated glutamate release processes. Rasagiline is a drug used in combination with L-dopa in the treatment of parkinsonian patients and the metabolic products of its degradation exert neuroprotective effects. Moreover, rasagiline scaffold is used to design analogs by addition of pharmacophores that act on other neurological targets. This multi-target approach may prove successful in order to find new and more effective therapies for the complexity of neurodegenerative diseases.
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PMID:Lights and shadows on monoamine oxidase inhibition in neuroprotective pharmacological therapies. 2203 78

Monoamine oxidase inhibitors (MAO-I) belong to the earliest drugs tried in Parkinson's disease (PD). They have been used with or without levodopa (L-DOPA). Non-selective MAO-I due to their side-effect/adverse reaction profile, like tranylcypromine have limited use in the treatment of depression in PD, while selective, reversible MAO-A inhibitors are recommended due to their easier clinical handling. For the treatment of akinesia and motor fluctuations selective irreversible MAO-B inhibitors selegiline and rasagiline are recommended. They are safe and well tolerated at the recommended daily doses. Their main differences are related to (1) metabolism, (2) interaction with CYP-enzymes and (3) quantitative properties at the molecular biological/genetic level. Rasagiline is more potent in clinical practise and has a hypothesis driven more favourable side effect/adverse reaction profile due to its metabolism to aminoindan. Both selegiline and rasagiline have a neuroprotective and neurorestaurative potential. A head-to head clinical trial would be of utmost interest from both the clinical outcome and a hypothesis-driven point of view. Selegiline is available as tablet and melting tablet for PD and as transdermal selegiline for depression, while rasagiline is marketed as tablet for PD. In general, the clinical use of MAO-I nowadays is underestimated. There should be more efforts to evaluate their clinical potency as antidepressants and antidementive drugs in addition to the final proof of their disease-modifying potential. In line with this are recent innovative developments of MAO-I plus inhibition of acetylcholine esterase for Alzheimer's disease as well as combined MAO-I and iron chelation for PD.
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PMID:MAO-inhibitors in Parkinson's Disease. 2211 Mar 57

Parkinson's disease (PD) is characterized by loss of dopamine neurons in the substantia nigra of the brain. Since there are limited treatment options for PD, neuroprotective agents are currently being tested as a means to slow disease progression. Agents targeting oxidative stress, mitochondrial dysfunction, and inflammation are prime candidates for neuroprotection. This review identifies Rasagiline, Minocycline, and creatine, as the most promising neuroprotective agents for PD, and they are all currently in phase III trials. Other agents possessing protective characteristics in delaying PD include stimulants, vitamins, supplements, and other drugs. Additionally, combination therapies also show benefits in slowing PD progression. The identification of neuroprotective agents for PD provides us with therapeutic opportunities for modifying the course of disease progression and, perhaps, reducing the risk of onset when preclinical biomarkers become available.
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PMID:The promise of neuroprotective agents in Parkinson's disease. 2212 48


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