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)

Although levodopa is the gold standard for treating motor symptoms of Parkinson's disease (PD), long-term therapy leads to levodopa-induced dyskinesia (LID). Dyskinesia refers to involuntary movements other than tremor and most commonly consists of chorea that occurs when levodopa-derived dopamine is peaking in the brain ("peak-dose dyskinesia"). However, dyskinesia can also consist of dystonia or myoclonus and occur during other parts of the levodopa dosing cycle. New validated rating scales and home diaries can better help the health care provider assess the timing and severity of dyskinesia. The exact etiology of LID is unknown, but there is evidence that abnormal pulsatile stimulation of dopamine receptors may be contributory. Treatment of LID includes adjustment of PD medications to maximize "on" time without troublesome dyskinesia. Amantadine is the only medication available with demonstrated ability to reduce the expression of established LID without reducing antiparkinsonian benefit. Other medications that are currently being studied to treat established LID include antiepileptics and serotonergic medications. Deep brain stimulation of the subthalamic nucleus is now the most commonly used surgical procedure for PD patients, and it is very effective in treating LID.
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PMID:Levodopa-induced dyskinesia in Parkinson's disease: epidemiology, etiology, and treatment. 1761 36

Parkinson's disease is a neurodegenerative disorder that affects approximately 1% of people over the age of 60 years. Levodopa is standard, and often initial, therapy for patients with this condition; however, with continued treatment and as the disease progresses, up to 80% of patients experience 'wearing-off' symptoms, dyskinesias and other motor complications. These levodopa-associated problems may become disabling and profoundly affect quality of life. Medications commonly used to manage these symptoms include monoamine oxidase type B (MAO-B) inhibitors, catechol-O-methyltransferase (COMT) inhibitors, the NMDA receptor antagonist amantadine and dopamine receptor agonists. Agents that block MAO-B, such as rasagiline and selegiline, are used as both initial and adjunctive therapy in patients with Parkinson's disease. These medications increase concentrations of dopamine in the brain by blocking its reuptake from the synaptic cleft, a mechanism that can slow motor decline, increase 'on' time and improve symptoms of Parkinson's disease. Adverse events with these agents can include confusion, hallucination and orthostatic hypotension. MAO-B inhibition may elicit drug-drug interactions if administered with TCAs, SSRIs or SNRIs. Conventional oral selegiline is associated with potentially harmful plasma concentrations of three major amphetamine metabolites, although metabolite concentrations are significantly lower with a new orally disintegrating tablet (ODT) selegiline formulation. Selegiline ODT is also absorbed more efficiently and shows less pharmacokinetic variability than conventional oral selegiline.COMT mediates peripheral catabolism of levodopa. Therefore, agents that block COMT, such as tolcapone and entacapone, increase the elimination half-life of levodopa. Given adjunctively with levodopa, COMT inhibitors can decrease 'off' time and increase 'on' time, as well as lower the daily levodopa dose. Although more potent than entacapone, tolcapone requires monitoring for hepatotoxicity. Amantadine is a noncompetitive NMDA receptor antagonist shown to lower dyskinesia scores and improve motor complications in patients with Parkinson's disease when given adjunctively with levodopa. Dopamine agonists, also used as initial and adjunctive therapy in Parkinson's disease, improve motor response and decrease 'off' time purportedly through direct stimulation of dopamine receptors. Current dopamine agonists include bromocriptine, pergolide, cabergoline, lisuride, apomorphine, pramipexole, ropinirole and rotigotine. Although effective, this class of medications can be associated with cardiovascular and psychiatric adverse effects that can limit their utility. All medications used to manage levodopa-associated motor complications in patients with Parkinson's disease have had differing degrees of success. Although head-to-head comparisons of drugs within classes are rare, some differences have emerged related to effects on motor fluctuations, dyskinesias and on/off times, as well as to adverse effects. When choosing a drug to treat levodopa-induced complications, it is important to consider the risks and benefits of the different classes and of the specific agents within each class, given the different efficacy and safety profiles of each.
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PMID:Medical management of levodopa-associated motor complications in patients with Parkinson's disease. 1763 Aug 19

Fatigue without coincident depression may accompany many neurological disorders, including multiple sclerosis, Parkinson's disease, motor neuron disease, stroke and post-polio syndrome, and is frequently reported by patients as a predominant complaint. The pathophysiology of fatigue is unknown. The role of various mechanisms has been suggested, including the effect of proinflammatory cytokines (TNF-alpha, IL-1beta and IL-6) on glutaminergic transmission, hypothalamo-pituitary-adrenal (HPA) axis dysfunction, disturbances of astroglia metabolism and decreased levels of the neurotransmitters noradrenaline and serotonin. The diagnosis of fatigue syndrome is based on exclusion of depression and additional organic conditions (anaemia, cardiovascular disorders, kidney diseases or hypothyroidism). The treatment of fatigue syndrome is complex. Physical activity, rehabilitation, psychotherapy and avoidance of factors which may increase fatigue, such as fever, anxiety, depression, pain, sleep disturbances, as well as some drugs like opioids and benzodiazepines, are important. Pharmacological treatment leads to slight improvement. Amantadine, modafinil and pemoline are administered to such patients.
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PMID:[Fatigue syndrome in chronic neurological disorders]. 1787 43

Punding, complex stereotyped behavior, sometimes occurs in patients with Parkinson's disease under dopaminergic replacement therapy. Reduction of dopaminergic drugs may reduce the problem but risks enhancing motor impairment. We report a patient with Parkinson's disease presenting disabling punding, which was reversed by amantadine without aggravating motor function. Amantadine may reduce punding by blocking NMDA receptors, in the same manner as in levodopa-induced dyskinesias.
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PMID:Amantadine may reverse punding in Parkinson's disease--observation in a patient. 1796 Aug 16

Amantadine is an effective drug for treatment of both, Parkinson's disease and viral infections. Side effects of amantadine include anemia, which may limit its therapeutic use. The cause of amantatine induced anemia is ill defined. At least in theory, the anemia could partially result from suicidal erythrocyte death or eryptosis, which accelerates the clearance of circulating erythrocytes. Eryptosis is characterized by cell shrinkage and cell membrane scrambling leading to phosphatidylserine exposure at the cell surface. Triggers of erythrocyte membrane scrambling include an increase of cytosolic Ca2+ concentration ([Ca2+]i) resulting from activation of Ca2+-permeable cation channels. The present study has been performed to test for an effect of amantadine on eryptosis. Erythrocytes from healthy volunteers were exposed to amantadine and annexin V binding (disclosing phosphatidylserine exposure), forward scatter (reflecting cell volume), and Fluo3-dependent fluorescence (reflecting [Ca2+]i) were determined by flow cytometry. Exposure of erythrocytes to amantadine (> or =0.2 microg/ml) increased [Ca2+]i and triggered annexin V binding, and increased forward scatter. The effect on annexin V binding was virtually abolished in the absence of extracellular Ca2+. The present observations disclose mechanisms presumably contributing to amantadine induced anemia.
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PMID:Stimulation of suicidal erythrocyte death by amantadine. 1820 39

Amantadine and dextromethorphan suppress levodopa (L-DOPA)-induced dyskinesia in Parkinson's disease patients and abnormal involuntary movements (AIMs) in the 6-hydroxydopamine (6-OHDA) rat model. These medications have been hypothesized to exert their therapeutic effects by a noncompetitive N-methyl-D-aspartate (NMDA) antagonist mechanism, but they also have known serotonin (5-HT) indirect agonist effects that could suppress AIMs. This raised the possibility that NMDA antagonists lacking 5-HTergic effects would not have the anti-dyskinetic action predicted by previous investigators. To test this hypothesis, we investigated MK-801, the most widely-studied NMDA antagonist. We found that chronic low-dose MK-801 (0.1 mg/kg) had no effect on development of AIMs or contraversive rotation. In addition, in L-DOPA-primed rats, low-dose MK-801 (0.1 mg/kg) had no effect on expression of AIMs, contraversive rotation, or sensorimotor function. Conversely, higher doses of MK-801 (0.2-0.3 mg/kg) suppressed expression of AIMs. However, as we show for the first time, anti-dyskinetic doses of MK-801 also suppressed L-DOPA-induced contralateral rotation and impaired sensorimotor function, likely due to non-specific interference of MK-801 with L-DOPA-induced behavior. We conclude that noncompetitive NMDA antagonists are unlikely to suppress dyskinesia clinically without worsening parkinsonism.
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PMID:MK-801 inhibits L-DOPA-induced abnormal involuntary movements only at doses that worsen parkinsonism. 2007 62

Amantadine (AMA) is an uncompetitive antagonist of the N-methyl-d-aspartate receptor, with clinical application, acting on treatment of influenza A virus and Parkinson's disease. It has been proposed that AMA can indirectly modulate dopaminergic transmission. In high doses, the central nervous system is its primary site of toxicity. To examine deleterious effects on CNS induced by AMA, this study evaluated possible neurobehavioral alterations induced by AMA such as stereotyped behavior, the effects on locomotion and memory and its possible genotoxic/mutagenic activities. Adult male CF-1 mice were treated with a systemic injection of AMA (15, 30 or 60 mg kg(-1) ) 20 min before behavioral tasks on open field and inhibitory avoidance. Higher AMA doses increased the latency to step-down inhibitory avoidance test in the training session in the inhibitory avoidance task. At 60 mg kg(-1) AMA induced impairing effects on locomotion and exploration and hence impaired habituation to a novel environment. Stereotyped behavior after each administration in a 3-day trial was observed, suggesting effects on dopaminergic system. Amantadine was not able to induce chromosomal mutagenesis or toxicity on bone marrow, as evaluated by the micronucleus assay. At the lowest dose tested, AMA did not induce DNA damage and it was unable to impair memory, locomotion, exploration or motivation in mice. However, higher AMA doses increased DNA damage in brain tissue, produced locomotor disturbances severe enough to preclude testing for learning and memory effects, and induced stereotypy, suggesting neurotoxicity.
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PMID:DNA damage in brain cells and behavioral deficits in mice after treatment with high doses of amantadine. 2057 81

To investigate the possible efficacy of amantadine in the control of pathological gambling (PG) associated with Parkinson disease (PD), 17 PD patients with PG were randomly selected for a double-blind crossover study with amantadine 200mg/day versus placebo and an open follow-up. Assessments included PG-specific scales (Yale-Brown Obsessive-Compulsive Scale for PG, Gambling-Symptom Assessment Scale, South Oaks Gambling Screen) and assessment of expenditures and time spent gambling. Amantadine abolished or reduced PG in all treated patients, as confirmed by scale score and daily expenditure reduction. Amantadine might be useful to treat PG. The effect of amantadine, acting as an antiglutamatergic agent, also opens new insights into the pathogenesis of PG.
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PMID:Pathological gambling in Parkinson disease is reduced by amantadine. 2128 95

Amantadine is becoming more commonly used for Parkinson's disease (PD), particularly for its efficacy in treating the drug-induced dyskinesias. Corneal edema is a known but unusual side effect of amantadine therapy, rarely reported in the neurological literature. We report amantadine-induced reversible corneal edema in a patient with advanced PD.
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PMID:Amantadine induced reversible corneal edema. 2116 53

The antiviral agent amantadine has been used to manage Parkinson's disease or levodopa-induced dyskinesias for nearly 5 decades. Amantadine is often associated with hallucinations as an adverse effect, but a long-term study reported no serious motor complications. We describe an unusual patient who had Parkinson's disease with dropped head syndrome (DHS) caused by amantadine. When the patient, who had DHS while receiving only 2 kinds of antiparkinsonian drugs, was rechallenged with amantadine, DHS developed, accompanied by increased muscle tone in the neck muscles on surface electromyogram. The DHS resolved after the withdrawal of amantadine. Moreover, an intravenous infusion of levodopa did not alter the DHS. These findings collectively suggest that the DHS in our patient was most likely caused directly by amantadine. Our findings suggest that amantadine may carry the risk of augmenting dystonic syndrome in humans.
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PMID:Dropped head associated with amantadine in Parkinson disease. 2124 45


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