topiramate and Dyskinesia--Drug-Induced

Topics: Amantadine; Anticonvulsants; Antiparkinson Agents; Dose-Response Relationship, Drug; Double-Blind Method; Dyskinesia, Drug-Induced; Female; Follow-Up Studies; Humans; Male; Parkinson Disease; Seveso Accidental Release; Topiramate; Treatment Outcome

The antiepileptic drug topiramate reduces levodopa-induced dyskinesia without exacerbating parkinsonism in animal models. We report a randomized, double-blind, placebo-controlled crossover trial in patients with Parkinson's disease and levodopa-induced dyskinesia.. Fifteen patients with Parkinson's disease and stable levodopa-induced dyskinesia were enrolled into the study, of whom 13 were randomized to topiramate or placebo. The study medication was titrated to 100 mg/day over four weeks, and assessments were carried out after a further two weeks. Dyskinesia severity assessed by a blinded rater from video recordings was the primary outcome measure.. Seven patients (mean age 58.9 ± 12.8 years) completed the study. Patients taking topiramate vs. placebo showed a significant increase in dyskinesia severity compared to baseline (Wilcoxon signed rank test, P = 0.043). Five patients withdrew from the study whilst taking topiramate due to adverse effects.. Topiramate tended to worsen dyskinesia in patients with Parkinson's disease, and was poorly tolerated.

Topics: Adult; Aged; Anticonvulsants; Antiparkinson Agents; Cross-Over Studies; Double-Blind Method; Dyskinesia, Drug-Induced; Female; Fructose; Humans; Levodopa; Male; Middle Aged; Parkinson Disease; Topiramate

L-Dopa-induced dyskinesia in patients with Parkinson's disease can be alleviated by amantadine, an antagonist at N-methyl-D-aspartate glutamate receptors. The antiepileptic drug topiramate, which blocks α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors, has also been shown to reduce dyskinesia. The purpose of this study was to examine the behavioral pharmacology of topiramate alone and in combination with amantadine in animal models of PD and L-dopa-induced dyskinesia. The effects of topiramate (5-20 mg/kg) and amantadine (5-20 mg/kg) on abnormal involuntary movements (the rat homologue of dyskinesia) and Rotarod performance were assessed alone and in combination in the 6-hydroxydopamine-lesioned rat following chronic L-dopa treatment. Dyskinesia, parkinsonian disability, and "on-time" were assessed in the MPTP-lesioned nonhuman primate following administration of topiramate (5-20 mg/kg) and amantadine (0.1-1.0 mg/kg) alone and in combination. Topiramate and amantadine dose-dependently reduced dyskinesia in the 6-hydroxydopamine-lesioned rat, whereas topiramate reduced Rotarod performance; there was no effect on parkinsonian disability in the MPTP-lesioned nonhuman primate, in which both drugs reduced dyskinesia. Topiramate and amantadine exhibited differential antidyskinetic effects on dyskinesia elicited by the dopamine D1 receptor agonist SKF 38393 (2 mg/kg). Subthreshold doses of both drugs in combination had a synergistic effect on dyskinesia in the 6-hydroxydopamine-lesioned rat, with no worsening of motor performance; this effect was confirmed in the MPTP-lesioned nonhuman primate, with a selective reduction in "bad on-time." These data confirm the antidyskinetic potential of topiramate and suggest that combination with low-dose amantadine may allow better reduction of dyskinesia with no adverse motor effects.

Topics: Amantadine; Animals; Antiparkinson Agents; Behavior, Animal; Callithrix; Disease Models, Animal; Dopamine Agonists; Drug Synergism; Dyskinesia, Drug-Induced; Fructose; Levodopa; Male; MPTP Poisoning; Neuroprotective Agents; Parkinson Disease; Rats; Rats, Sprague-Dawley; Topiramate

Topics: Amino Acids, Branched-Chain; Anti-Obesity Agents; Dyskinesia, Drug-Induced; Fructose; Humans; Male; Middle Aged; Schizophrenia, Paranoid; Selective Serotonin Reuptake Inhibitors; Time Factors; Topiramate; Weight Loss

Overactive AMPA receptor-mediated transmission may be involved in the pathogenesis of levodopa-induced dyskinesia. The mechanism of action of the anticonvulsant drug topiramate involves attenuation of AMPA receptor-mediated transmission. In this study, the potential antidyskinetic action of topiramate was examined in the MPTP-lesioned marmoset model of Parkinson's disease and levodopa-induced dyskinesia. Topiramate significantly reduced levodopa-induced dyskinesia, without affecting the antiparkinsonian action of levodopa. Topiramate represents an exciting potential novel therapeutic approach to levodopa-induced dyskinesia in patients with Parkinson's disease.

Topics: Animals; Anticonvulsants; Antiparkinson Agents; Callithrix; Disease Models, Animal; Dyskinesia, Drug-Induced; Fructose; Levodopa; MPTP Poisoning; Parkinson Disease; Topiramate

Recently, we have described the antidyskinetic property of the GABA mimetic drug valproic acid on reserpine-induced oral dyskinesia, an animal model that has been related to tardive as well as acute dyskinesias, which are associated with important neuropathologies. The present study investigates the effects of different doses of the GABA mimetic anticonvulsant topiramate on the manifestation of reserpine-induced orofacial dyskinesia. Female EPM-M1 mice received two injections of control solution or of 0.5 mg/kg reserpine separated by 48 h. Twenty-four hours after the second reserpine or control solution injection, animals were acutely treated with control solution or topiramate (1, 3, 10 or 30 mg/kg) and were observed for quantification of oral dyskinesia or general activity in an open-field. In order to verify the effects of topiramate per se on oral dyskinesia or general activity, female EPM-M1 mice were acutely treated with control solution or 1, 3, 10 or 30 mg/kg topiramate and observed for quantification of oral dyskinesia and general activity. The highest dose of topiramate completely abolished the manifestation of reserpine-induced oral dyskinesia whereas the doses of 3 and 10 mg/kg significantly attenuated it. None of the doses of the anticonvulsant modified spontaneous locomotion frequency or oral movements, whereas spontaneous rearing frequency was decreased by 3, 10 and 30 mg/kg topiramate. The highest dose of topiramate did not modify general activity in reserpine-treated mice. These results support the potential therapeutic use of topiramate in the treatment of oral dyskinesias.

Topics: Adrenergic Uptake Inhibitors; Animals; Behavior, Animal; Disease Models, Animal; Dose-Response Relationship, Drug; Dyskinesia, Drug-Induced; Female; Fructose; Locomotion; Mastication; Maternal Behavior; Mice; Neuroprotective Agents; Reserpine; Topiramate

Topics: Acetates; Adult; Amines; Anticonvulsants; Antipsychotic Agents; Bipolar Disorder; Cyclohexanecarboxylic Acids; Dibenzothiazepines; Drug Therapy, Combination; Dyskinesia, Drug-Induced; Female; Fructose; Gabapentin; gamma-Aminobutyric Acid; Humans; Lithium; Quetiapine Fumarate; Topiramate