entacapone and Parkinson-Disease--Secondary

Current concepts suggest that avoidance of pulsatile stimulation of dopamine receptors in Parkinson's disease (PD) can prevent the onset of dyskinesia. In MPTP-treated primates, repeated administration of levodopa or other short-acting dopamine agonist drugs leads to the onset of marked involuntary movements. In contrast, treatment with long-acting dopamine agonists leads to a much lower level of dyskinesia. Similar results have been obtained in PD patients, although the introduction of levodopa is a requirement in virtually all patients and this leads to further increases in motor complications. The concept of continuous dopaminergic stimulation should also apply to levodopa, such that reduced dyskinesia would be expected if it could be administered in a manner that avoids pulsatile receptor stimulation. In MPTP monkeys, administration of multiple small doses of levodopa in conjunction with the peripheral COMT inhibitor entacapone removes much of the pulsatility of motor function seen with standard levodopa treatment regimens and, at the same time, results in a lower incidence and intensity of dyskinesia. Furthermore, the addition of multiple small doses of levodopa plus entacapone to dopamine agonist treatment also avoids dyskinesia induction in MPTP-treated primates. These results suggest that administering of levodopa with entacapone as either initial or supplemental therapy for PD patients might reduce the risk for motor complications. Clinical trials to assess this hypothesis and determine if the results in MPTP monkeys can be duplicated in PD patients are warranted.

Topics: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Animals; Antiparkinson Agents; Catechols; Disease Models, Animal; Dopamine Agonists; Drug Administration Schedule; Drug Evaluation, Preclinical; Drug Therapy, Combination; Dyskinesia, Drug-Induced; Enzyme Inhibitors; Levodopa; Nitriles; Parkinson Disease, Secondary; Primates; Rats

The diagnosis of Parkinson's disease (PD) is clinical and is based on the identification of a combination of the cardinal motor signs of bradykinesia plus at least one of the following: rigidity, tremor or postural instability. There are many causes of parkinsonism such as drug induced parkinsonism, subcortical vascular disease, and multisystem atrophy. PD is a well characterised syndrome which represents only a part of the various causes of parkinsonism. A good response to dopaminergics is an important diagnostic criteria for PD. Pharmacotherapy for PD relies primarily on levodopa and dopamine agonists. Deep brain stimulation is increasingly used in the management of patients with severe dopa fluctuations and dyskinesias. Cholinesterase inhibitors are introduced for dementia in parkinsonism. Neuroprotective compounds, nerve growth factors such as GDNF and the implantation of dopaminergic cells are studied in clinical trials.

Topics: Aged; Amantadine; Antiparkinson Agents; Apomorphine; Botulinum Toxins; Catechols; Cholinesterase Inhibitors; Clinical Trials as Topic; Diagnosis, Differential; Dopamine Agents; Dopamine Agonists; Enzyme Inhibitors; Ergot Alkaloids; Family Practice; Female; Humans; Levodopa; Male; Nitriles; Parkinson Disease; Parkinson Disease, Secondary; Parkinsonian Disorders; Piperidines

Parkinson disease progression is associated with the development of levodopa short-duration responses and dyskinesias, as well as gait freezing. Levodopa dose adjustment and adjunctive treatment with dopamine agonists form the major therapeutic strategies. Catechol O-methyltransferase inhibitors are also appropriate considerations, whereas other drugs, including selegiline, amantadine, anticholinergic agents, and propranolol, have a more minor role.

Topics: Amantadine; Antiparkinson Agents; Benzophenones; Carbidopa; Catechol O-Methyltransferase Inhibitors; Catechols; Cholinergic Antagonists; Dopamine Agonists; Dose-Response Relationship, Drug; Drug Combinations; Dyskinesia, Drug-Induced; Enzyme Inhibitors; Humans; Levodopa; Nitriles; Nitrophenols; Parkinson Disease, Secondary; Propranolol; Randomized Controlled Trials as Topic; Selegiline; Tolcapone