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)

Monoamine oxidase type B (MAO-B) is the predominant isoform responsible for the metabolic breakdown of dopamine in the brain. Selective inhibition of brain MAO-B results in elevation of synaptosomal dopamine concentrations. Data have been reported regarding the selective MAO-B inhibitors, rasagiline and selegiline, for the symptomatic treatment of Parkinson disease (PD). Selegiline has demonstrated efficacy as monotherapy in patients with early PD (Deprenyl and Tocopherol Antioxidative Therapy of Parkinsonism study), but evidence of selegiline efficacy as adjunctive treatment in levodopa-treated PD patients with motor fluctuations is equivocal. A new formulation of selegiline (Zydis selegiline) has been evaluated in 2 small, placebo-controlled studies as adjunctive therapy to levodopa. The Zydis formulation allows pregastric absorption of selegiline, minimizing first-pass metabolism, and thereby increasing selegiline bioavailability and reducing the concentration of amphetamine metabolites. Rasagiline is a selective, second-generation, irreversible MAO-B inhibitor, with at least 5 times the potency of selegiline in vitro and in animal models. Rasagiline has demonstrated efficacy in 1 large, randomized, double-blind, placebo-controlled trial (TVP-1012 in Early Monotherapy for Parkinson's Disease Outpatients) as initial monotherapy in patients with early PD, and in 2 large, controlled trials (Parkinson's Rasagiline: Efficacy and Safety in the Treatment of "Off," Lasting Effect in Adjunct Therapy With Rasagiline Given Once Daily) as adjunctive treatment in levodopa-treated PD patients with motor fluctuations. Unlike selegiline, rasagiline is an aminoindan derivative with no amphetamine metabolites. A randomized clinical trial is underway to confirm preclinical and preliminary clinical data suggesting rasagiline has disease-modifying effects.
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PMID:Monamine oxidase inhibitors: current and emerging agents for Parkinson disease. 1754 50

Parkinson's disease affects up to 1 million people in the US, most of them elderly. Motor and non-motor symptoms can be significantly disabling to the point of necessitating institutionalisation. Age-related changes in drug absorption, distribution, metabolism and excretion complicate the treatment of elderly patients with Parkinson's disease. General management principles include initiation of medication at low doses with gradual titration based on clinical effects, avoidance of certain classes of drugs (e.g. anticholinergics), and attention to polypharmacy and its risk for potentially toxic drug interactions. Levodopa remains the most efficacious anti-Parkinson's disease medication and should be the cornerstone of therapy in the elderly Parkinson's disease patient. Use of dopamine receptor agonists, amantadine and anticholinergic drugs in the elderly is limited by high risk for psychotoxicity. Catechol-O-methyltransferase inhibitors may be used to augment levodopa in the setting of 'wearing off' (i.e. motor fluctuations). Monoamine oxidase type B (MAO-B) inhibitors can be used across the spectrum of disease severity, but selegiline (deprenyl), the prototype in this class, is characterised by low and erratic bioavailability of the parent drug and conversion to amphetamine metabolites that may increase the risk of adverse events. A new orally disintegrating tablet formulation overcomes some of these limitations. Rasagiline is a new, selective, second-generation MAO-B inhibitor that is chemically and metabolically distinct from selegiline. The favourable safety profile of rasagiline in the elderly and its once-daily formulation may maximise drug adherence and improve outcomes.
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PMID:Community and long-term care management of Parkinson's disease in the elderly: focus on monoamine oxidase type B inhibitors. 1770 35

Symptomatic medical therapies for Parkinson's disease (PD) have been disease modifying and have led to improvement in daily function, quality of life, and survival. For 40 years, these therapies have been primarily dopaminergic, and currently include the dopamine (DA) precursor levodopa (LD), DA agonists, catechol-O-methyltransferase (COMT) inhibitors, and monoamine oxidase (MAO) inhibitors. The roles of all these classes of agents have evolved, with significant changes occurring since the early 2000s. This article reviews the current literature for each of these classes of drugs, with a focus on efficacy and place in the therapeutic scheme. Levodopa is no longer considered to be toxic and, thus, its early use is not only appropriate but recommended. Ergot agonists are no longer in use, and new agents administered in patch form or subcutaneous injections have been approved. The COMT inhibitor tolcapone, with its significant efficacy, has been reintroduced, and two new MAO inhibitors have been approved. Selected safety issues are discussed, including the incidence of melanoma in relation to LD; pathological gambling and DA agonists; hepatic toxicity of tolcapone; and the tyramine or so-called cheese reaction with MAO B inhibitors. The article closes with a discussion of future directions and new drugs under development.
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PMID:Current status of symptomatic medical therapy in Parkinson's disease. 1839 61

Parkinson's disease (PD) is a progressive neurodegenerative, dopamine deficiency disorder. The main therapeutic strategies for PD treatment relies on dopamine precursors (levodopa), inhibition of dopamine metabolism (monoamine oxidase [MAO] B and catechol-O-methyl transferase inhibitors), and dopamine receptor agonists. Recently, a novel selective and irreversible MAO B propargylamine inhibitor rasagiline (N-propargyl-1-R-aminoindan, Azilect((R))) was approved for PD therapy. In contrast to selegiline, the prototype of MAO B inhibitors, rasagiline is not metabolized to potentially toxic amphetamine metabolites. The oral bioavailability of rasagiline is 35%, it reaches T(max) after 0.5-1 hours and its half-life is 1.5-3.5 hours. Rasagiline undergoes extensive hepatic metabolism primarily by cytochrome P450 type 1A2 (CYP1A2). Rasagiline is initiated at 1 mg once-daily dosage as monotherapy in early PD patients and at 0.5-1 mg once-daily as adjunctive to levodopa in advanced PD patients. Rasagiline treatment was not associated with "cheese effect" and up to 20 mg per day was well tolerated. In PD patients with hepatic impairment, rasagiline dosage should be carefully adjusted. Rasagiline should not be administered with other MAO inhibitors and co-administration with certain antidepressants and opioids should be avoided. Although further clinical evidence is needed on the neuroprotective effects of rasagiline in PD patients, this drug provides an additional tool for PD therapy.
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PMID:Rasagiline - a novel MAO B inhibitor in Parkinson's disease therapy. 1848 80

The addition of the neuropeptide carnosine (beta-alanyl-L-histidine) as a food additive to the basic protocol of Parkinson's disease treatment results in significant improvement of neurological symptoms, along with increase in red blood cell Cu/Zn-SOD and decrease in blood plasma protein carbonyls and lipid hydroperoxides, with no noticeable change in platelets MAO B activity. The combination of carnosine with basic therapy may be a useful way to increase efficiency of PD treatment.
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PMID:Carnosine [corrected] increases efficiency of DOPA therapy of Parkinson's disease: a pilot study. 1872 14

Dopamine (DA) supplementation therapy by l-dopa for Parkinson's disease (PD) was established around 1970. The dose of l-dopa can be reduced by the combined administration of inhibitors of peripheral l-amino acid decarboxylase (AADC), catechol O-methyltransferase (COMT), or monoamine oxidase B (MAO B). DA in the striatum may be produced from exogenously administered l-dopa by various AADC-containing cells, such as serotonin neurons. The long-term administration of l-dopa in PD patients may produce l-dopa-induced dyskinesia (LID), which may be due to chronic overstimulation of supersensitive DA D1 receptors. l-dopa may be used in combination with various new strategies such as gene therapy or transplantation in the future.
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PMID:L-dopa therapy for Parkinson's disease: past, present, and future. 1913 Oct 39

The first effective drugs for Parkinson's disease (PD) were anticholinergics, introduced at the end of 19.th century by Charcot. Since the introduction of levodopa in the sixties of the previous century, many new drugs have emerged for the treatment of Parkinson's disease: dopamine agonists (ergot as well as non-ergot, bromocriptine, pergolide, mirapexine, ropinirole), MAO B inhibitors (selegiline, rasagiline), amantadine, COMT inhibitors (entacapone, tolcapone). In all stages of the disease, levodopa remains the most effective drug for improving motor symptoms in PD. However, long term treatment with levodopa is accompanied by the development of motor fluctuations, dyskinesia, cognitive and neuropsychiatric adverse effects and increasingly diverse spectrum of drugs is needed to alleviate motor and nonmotor symptoms. Some of these drugs have caused considerable concern and controversies and were regarded at certain points as the 'bad guys' of Parkinson's disease pharmacological armamentarium. In the article, a short review of 'bad guys' including anticholinergics, selegiline, tolcapone and dopamine agonists, is given.
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PMID:'Bad guys' among the antiparkinsonian drugs. 1927 Jun 34

In this workshop report, the N-methyl-D-aspartate (NMDA) receptor antagonists and the monoamine oxidase (MAO) type B inhibitors are discussed with respect to their role in the pharmacotherapy of Parkinson's Disease (PD). For the NMDA antagonist amantadine, studies demonstrated beneficial effects in various symptoms of the PD complex, while memantine seems to be beneficial in the treatment of cognitive deficits in PD-associated dementia. The MAO B inhibitors selegiline and rasagiline are in use for PD pharmacotherapy; for rasagiline, studies have demonstrated a possible disease-modifying effect. Although not supported by specific controlled studies, a "triple" early therapy is discussed which consists of a dopamine agonist, a MAO B inhibitor and amantadine, in order to try to delay the start of levodopa therapy.
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PMID:[On the role of MAO B inhibitors and NMDA antagonists in the therapy of Parkinson's disease]. 2019 40

Early treatment of Parkinson's disease (PD) affords an opportunity to forestall clinical progression. Levodopa is the most effective treatment for PD motor signs and symptoms, but its use is associated with the development of motor fluctuations and dyskinesias. Because of this, levodopa use is commonly withheld until the patient experiences functional disability. Other medications are available for the treatment of early PD and can be initiated at or near the time of diagnosis. Monoamine oxidase type B (MAO-B) inhibitors provide mild symptomatic benefit, delay the need for levodopa, are very well tolerated, and may provide long-term disease-modifying effects. Dopamine agonists provide moderate symptomatic benefit, delay the need for levodopa, and cause fewer motor complications than levodopa. Compared with levodopa, however, dopamine agonists cause more somnolence and sudden-onset sleep as well as impulse control disorders. The treatment of early PD depends in part on the individual patient's anticipated risk of side effects and the degree of motor improvement required. Physicians should also consider the early use of MAO-B inhibitors in light of their very good tolerability and the recent evidence suggesting long-term disease-modifying effects.
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PMID:Early pharmacologic treatment in Parkinson's disease. 2029 70

The main lesion in Parkinson disease (PD) is loss of substantia nigra dopaminergic neurons. Levodopa (L-DOPA) is the most widely used therapy, but it does not arrest disease progression. Some possible contributing factors to the continuing neuronal loss are oxidative stress, including oxidation of L-DOPA, and neurotoxins generated by locally activated microglia and astrocytes. A possible method of reducing these factors is to produce L-DOPA hybrid compounds that have antioxidant and antiinflammatory properties. Here we demonstrate the properties of four such L-DOPA hybrids based on coupling L-DOPA to four different hydrogen sulfide-donating compounds. The donors themselves were shown to be capable of conversion by isolated mitochondria to H(2)S or equivalent SH(-) ions. This capability was confirmed by in vivo results, showing a large increase in intracerebral dopamine and glutathione after iv administration in rats. When human microglia, astrocytes, and SH-SY5Y neuroblastoma cells were treated with these donating agents, they all accumulated H(2)S intracellularly as did their derivatives coupled to L-DOPA. The donating agents and the L-DOPA hybrids reduced the release of tumor necrosis factor-alpha, interleukin-6, and nitric oxide from stimulated microglia, astrocytes as well as the THP-1 and U373 cell lines. They also demonstrated a neuroprotective effect by reducing the toxicity of supernatants from these stimulated cells to SH-SY5Y cells. L-DOPA itself was without effect in any of these assays. The H(2)S-releasing L-DOPA hybrid molecules also inhibited MAO B activity. They may be useful for the treatment of PD because of their significant antiinflammatory, antioxidant, and neuroprotective properties.
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PMID:Effects of hydrogen sulfide-releasing L-DOPA derivatives on glial activation: potential for treating Parkinson disease. 2052


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