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)

Motor fluctuations often complicate chronic levodopa treatment of Parkinson's disease. Pharmacologically, these phenomena are characterized by a progressive shortening of the duration of action of levodopa and a gradual narrowing of the range of "optimally effective" doses, able to improve parkinsonian akinesia without inducing abnormal involuntary movements. The effects of a continuous intravenous infusion of levodopa lasting 9 +/- 0.3 days on these clinical-pharmacological indices have been studied in 12 parkinsonian patients. Continuous infusion therapy gradually ameliorated motor fluctuations by more than 40%, and this improvement lasted for at least 6 days after resuming standard oral therapy. Moreover, levodopa duration of action was prolonged by about 30%, and the range of "optimally effective" dose was widened by about 50%. The above data suggest the possibility of plastic modifications of the pathogenetic mechanisms underlying motor fluctuations in Parkinson's disease, and a potential deleterious effect of intermittent oral therapy. Consequently, continuous dopaminergic stimulation, when used in the early stages of the disease, might theoretically have a prophylactic role on the development or worsening of motor fluctuations.
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PMID:[Changes in the nigrostriatal dopamine receptor compartment after continuous dopaminergic infusions in Parkinson disease]. 181 72

Thirty-eight patients newly diagnosed as having Parkinson's disease (mean age, 57.3 years; mean Parkinson's disease duration, 2.7 years) in the earlier phase of the disease (mean Hoehn/Yahr stage, 2; mean motor scores, 11.4) were given selegiline (Deprenyl), 10 mg daily, and maintained on this drug alone until significant clinical worsening warranted the addition of low-dose levodopa (Sinemet, 25/100 three to four doses per day). Five of these patients were not yet receiving additional levodopa despite some worsening of motor scores. Of the 33 patients now taking combined therapy, seven have been followed up for 6 months or less. Twenty-four (92%) of the 26 patients taking combined therapy for a mean of 26 months (8.5 to 99 months) who have had Parkinson's disease for 6 years showed a dramatic improvement in their parkinsonism shortly after the addition of levodopa, with significant decreases in their rated motor scores, such improvement being maintained at their latest neurologic evaluation. Eighteen (75%) of these 24 patients responded to the combined selegiline/levodopa therapy with degrees of improvement equal to or greater than 50%, compared with their motor status at the start of combined therapy just before the addition of levodopa. This degree of "reversal" of parkinsonism on addition of levodopa (mean carbidopa/levodopa dose, 98/389 mg) was not observed in any of these same patients receiving selegiline alone for an average of 13.8 months. Four patients taking combined therapy developed mild, transient, abnormal involuntary movements, and end-of-dose pattern of response after more than 2 years of combined therapy (24.75 and 33.5 months, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Early combination of selegiline and low-dose levodopa as initial symptomatic therapy in Parkinson's disease. Experience in 26 patients receiving combined therapy for 26 months. 192 87

Long-term treatment of human Parkinson's disease with levodopa or dopamine agonists is often complicated by the appearance of abnormal involuntary movements (dyskinesias) that are extremely difficult to control. Little is known of the cause, pathophysiological mechanisms, or possible strategies for amelioration of this manifestation of dyskinesia. A hypothesis is set forth on the neural mechanisms that mediate levodopa- or dopamine agonist-induced dyskinesia (in particular chorea) as a side effect of the treatment of parkinsonism. Evidence is drawn from both clinical observations and experimental studies in a spectrum of movement disorders ranging from ballism through chorea to parkinsonism. It is proposed that (a) All forms of chorea, whatever their origin, share a common underlying neural mechanism. (b) Disordered activity of the subthalamic nucleus is central to the generation of choreic movements. In levodopa- or dopamine agonist-induced dyskinesia, (c) The site of action of dopaminergic agents in causing chorea is the putamen. (d) The specific pathophysiological state conducive to the appearance of chorea is brought about by the long-term exposure of the dopamine-depleted (parkinsonian) putamen to exogenous dopaminergic agents. (e) Long-term exposure to dopaminergic agents causes (either directly or indirectly) preferential inhibition of the subpopulation of putaminal neurones that project specifically to the lateral segment of the globus pallidus. This causes disinhibition of lateral pallidal neurones, which become overactive and physiologically inhibit the subthalamic nucleus. (f) The hypothesis suggests a number of possible strategies that might be useful for the alleviation of levodopa-induced dyskinesia.
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PMID:A hypothesis on the pathophysiological mechanisms that underlie levodopa- or dopamine agonist-induced dyskinesia in Parkinson's disease: implications for future strategies in treatment. 197 Jan 20

Ten patients with Parkinson's disease (PD) with motor fluctuations that responded to a protein redistribution diet were studied. All 10 patients were receiving standard Sinemet (levodopa/carbidopa). Five randomly selected patients were changed from standard Sinemet to a controlled-release form of Sinemet. The other five patients continued to receive standard Sinemet. To maintain the same degree of control of PD in the five patients switched to the controlled-release form of Sinemet, the daily levodopa intake increased. While receiving optimal therapy (standard Sinemet or controlled-release Sinemet) and a protein redistribution diet, all 10 patients then underwent hourly videotaping and blood sampling (for plasma levodopa levels) during 2 consecutive days. Videotapes were blindly reviewed for PD disability, dyskinesia, and the time required to walk a measured distance. Comparing the two groups, standard Sinemet with controlled-release Sinemet, respectively, mean levodopa requirements were 505 and 1895 mg, plasma levodopa levels were 6.1 and 17.6 mumol/L, and abnormal involuntary movement scale scores were 14 and 26. Their mean PD disability scores did not differ statistically or clinically. Also no statistically significant differences were noted in either their mean walking times or their mean daily dose frequencies.
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PMID:Standard and controlled-release levodopa/carbidopa in patients with fluctuating Parkinson's disease on a protein redistribution diet. A preliminary report. 201 14

A 77-year-old woman with a 9 years history of Parkinson's disease was admitted to our hospital because of high fever, disturbance of consciousness, increased muscular rigidity and abnormal involuntary movements. She was continuously treated with levodopa + carbidopa (Menesit) 300 mg and amantadine 150 mg every day until admission. On admission, the pulse rate was 102 per minute, blood pressure 90/40 mmHg, body temperature 40.9 degrees C, and bloody stool was noticed. On laboratory examination, erythrocyte sedimentation rate was 6 mm/h, thrombocytes 8.1 X 10(4)/microliters, fibrinogen 91 mg/dl, FDP 40 mg/ml, suggesting DIC. According to her biochemical examination, serum GOT (167 u), GPT (119 u), CPK (847 IU/l), BUN (53.9 mg/dl) and myoglobin (10,370 ng/ml) were increased. These laboratory data indicated that she was suffering from neuroleptic malignant syndrome (NMS) with disseminated intravascular coagulation (DIC). On diagnosis of NMS associated with DIC, she was treated with dantrolene and FUT-175. Dantrolene was effective on the elevated COK level and FUT-175 was effective on the DIC, and symptoms of NMS and DIC were completely improved after a period of 14 days. Patients with Parkinson's disease have been suspected to have a low incidence of DIC, and this may be the first case report on successful treatment of levodopa-induced NMS with DIC in the patient with Parkinson's disease.
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PMID:[Successful treatment of levodopa-induced neuroleptic malignant syndrome (NMS) with disseminated intravascular coagulation (DIC) in a patient with Parkinson's disease]. 204 8

Intermittent treatment with L-dopa over a 2-year period induced abnormal involuntary movements in MPTP-treated squirrel monkeys. Dyskinesias included a choreic and dystonic component. Dose-response curves for chorea and dystonia revealed that the same dose of L-dopa (30 mg/kg) induced the highest score for both dyskinesias: however, the severity was much greater for chorea. Choreic movements were always most prevalent at the time of peak effect, whereas dystonia was apparent at the time of peak effect and at "end-of-dose", and was occasionally observed spontaneously. Our findings indicate that squirrel monkeys treated with MPTP develop L-dopa-induced dyskinesias which closely resemble those observed in Parkinson's disease. This species provides a valuable animal model to develop improved therapeutic agents.
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PMID:Characterisation of dyskinesias induced by L-dopa in MPTP-treated squirrel monkeys. 239 4

1. Monkeys with surgical unilateral ventromedial tegmental lesions of the brain stem served as models for investigating abnormalities in Parkinson's disease and Lesch-Nyhan syndrome. 2. The animals exhibited some neurological deficits which are similar to those observed in Parkinson's disease or Lesch-Nyhan syndrome. 3. In monkeys with unilateral ventrolateral tegmental lesions, the levels of dopamine and the activities of catecholamine-synthesizing enzymes were reduced on the lesion side of the striatum, and hypokinesia and tremor developed on the contralateral extremities. 4. Dopa or dopamine agonists relieve tremor and evoke abnormal involuntary movements which are similar to the responses observed in patients with Parkinson's disease. 5. The antitremor effect of Dopa is potentiated by catechol-O-methyltransferase inhibition, suggesting a therapeutic potential for these types of agents. 6. Evidence was obtained that stimulation of D2 dopamine receptors by selective dopamine agonists exerts antitremor activity and evokes abnormal involuntary movements. 7. Combined administration of D1 and D2 dopamine agonists seems to enhance the antitremor activity. 8. Partial dopamine agonists exert antitremor activity and produce less severe abnormal involuntary movements than full dopamine agonists. 9. In a group of monkeys with unilateral ventromedial tegmental lesions of the brain stem the administration of mixed D1/D2 dopamine agonists results in the occurrence of self-biting behavior of the forelimb digits and spasticity of the hindlimbs and these symptoms are similar to those observed in patients with Lesch-Nyhan syndrome. 10. The self-biting behavior seems to be associated with the stimulation of central D1 dopamine receptors and therefore the possible involvement of dopamine neuronal abnormalities in Lesch-Nyhan syndrome deserves further investigation.
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PMID:Monkeys with unilateral ventromedial tegmental lesions of the brain stem: models for Parkinson's disease and Lesch-Nyhan syndrome. 250 25

Levodopa combined with carbidopa (Sinemet) remains the most effective approach to the symptomatic relief of Parkinson's disease. Over time, however, an increasing number of parkinsonian patients evidence motor response complications, notably abnormal involuntary movements and motor fluctuations. Clinical pharmacologic studies suggest that these phenomena may arise as a consequence of factors reflecting both natural disease progression and levodopa toxicity. Simple wearing-off responses appear primarily related to advancing degenerative changes afflicting the dopamine system. The appearance of peak-dose dyskinesias and complex, random motor fluctuations of the on-off type, on the other hand, may signal secondary postjunctional changes arising as a consequence of chronic intermittent excitation of postsynaptic dopamine receptors that are normally tonically stimulated. Therapeutically, prompt correction of wearing-off fluctuations can ordinarily be achieved by measures that deliver dopaminomimetics continuously to the central nervous system. In contrast, fluctuations of the on-off type initially persist despite stable circulating levodopa levels. With continuous levodopa treatment, however, the threshold for dyskinesias begins to rise and the dose-response relation shifts to the right; clinically, the severity of both dyskinesias and on-off fluctuations tends to diminish. It is thus tempting to speculate that the early and continuing treatment of Parkinson's disease with compounds providing a relatively constant level of central dopamine stimulation will preclude wearing-off phenomena and mitigate on-off fluctuations and severe dyskinesias.
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PMID:Rationale for continuous dopaminomimetic therapy of Parkinson's disease. 268 53

The combination of carbidopa and levodopa (Sinemet) is a highly effective treatment for the symptoms of Parkinson's disease. However, side effects, such as abnormal involuntary movements, fluctuations in motor performance, and "wearing off" phenomena limit its long-term usefulness in some patients. Open-label studies show that controlled-release Sinemet CR is effective in reducing motor fluctuations. This report discusses the results of a 14-week double-blind crossover study comparing the efficacy and tolerability of standard Sinemet with controlled-release Sinemet CR. Overall, there were no statistically significant differences in efficacy between Sinemet CR and standard Sinemet on any of the major efficacy measures, suggesting a clinical equivalence in terms of treating the symptoms of Parkinson's disease. The study also supports the tolerability of Sinemet CR. In summary, Sinemet CR holds the promise of reducing some disturbing side effects of long-term levodopa therapy, thus achieving optimal control of parkinsonian symptoms.
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PMID:Double-blind comparison of standard Sinemet and Sinemet CR in patients with mild-to-moderate Parkinson's disease. 268 55

Fourteen patients with Parkinson's disease and motor fluctuations were given 125 mg of Madopar HBS or placebo twice a day in addition to their optimal standard Madopar treatment in a double-blind, cross-over study. Clinical response was evaluated by the King's College Hospital Parkinson's Disease Rating Scale, the Mobility in Bed Scale and self-scoring diaries. A significant improvement with the drug was found according to the rating scales, whereas evaluation by self-scoring diaries showed no significant changes. In three patients we observed worsening of abnormal involuntary movements. The present trial suggests that a low dose of Madopar HBS can be useful in addition to levodopa therapy in some patients on long-term treatment.
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PMID:A double-blind, cross-over trial with madopar HBS in patients with Parkinson's disease. 269 99


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