nitrophenols and Parkinsonian-Disorders

Recent prospective, double-blind, placebo-controlled trials have examined the long-term effects of the catechol-O-methyl transferase (COMT) inhibitors entacapone and tolcapone as adjuncts to levodopa in PD patients with wearing-off motor fluctuations. These studies demonstrate that both tolcapone and entacapone provide PD patients who suffer motor fluctuations with increased "on" time, decreased "off" time, and improved motor scores in comparison to placebo-treated patients. The improvement was observed rapidly, often being evident within days of initiating the intervention. Benefits persisted throughout the duration of the study. Increased dopaminergic side effects were observed with both drugs, but these were generally readily controlled by a concomitant reduction in levodopa dose. Tolcapone was associated with some instances of explosive diarrhea and liver enzyme elevation so that periodic monitoring of liver function was recommended. These did not occur with entacapone, and monitoring of liver function was not required. This report reviews the results of the multi-center trials of entacapone, and tolcapone.

Topics: Benzophenones; Catechol O-Methyltransferase Inhibitors; Catechols; Female; Humans; Levodopa; Male; Middle Aged; Nitriles; Nitrophenols; Parkinsonian Disorders; Tolcapone

The development of reliable biological markers of nigrostriatal degeneration has important implications from both experimental and clinical viewpoints, since such biomarkers could be used for diagnostic and monitoring purposes in models of parkinsonism as well as in Parkinson's disease patients. In this study, levels of the dopamine metabolite 3,4-dihydroxyphenylacetic acid (DOPAC) were measured in the cerebrospinal fluid (CSF) of normal and parkinsonian squirrel monkeys in order to assess their reliability as indicators of nigrostriatal injury. In particular, we tested the hypothesis that these measurements may become more accurate by inhibiting catecholamine-O-methyltransferase (COMT) activity and therefore blocking the conversion of DOPAC to homovanillic acid. Oral administration of the COMT inhibitor tolcapone (2 doses of 15 mg/kg each with a 4-h interval) significantly reduced enzyme activity in the monkey brain. Tolcapone treatment enhanced CSF DOPAC concentrations in unlesioned animals (by approximately four times) as well as monkeys rendered parkinsonian after severe nigrostriatal dopaminergic injury caused by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Importantly, however, COMT inhibition greatly magnified the differences in CSF DOPAC levels between control and parkinsonian monkeys, since MPTP-induced DOPAC depletion was 35% in the absence vs >60% in the presence of tolcapone. Thus, tolcapone administration enhances the detection of DOPAC in the CSF and, by doing so, improves the reliability of CSF DOPAC as a marker of nigrostriatal degeneration.

Topics: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; 3,4-Dihydroxyphenylacetic Acid; Animals; Antiparkinson Agents; Benzophenones; Biomarkers; Catechol O-Methyltransferase; Corpus Striatum; Disease Models, Animal; Dopamine; Enzyme Activation; Female; Homovanillic Acid; Male; Neurodegenerative Diseases; Nitrophenols; Parkinsonian Disorders; Predictive Value of Tests; Putamen; Saimiri; Substantia Nigra; Tolcapone

Inhibition of catechol catechol-O-methyltransferase (COMT) in the brains of subjects treated with L-DOPA (L-3,4-dihydroxylphenylalanine) and an aromatic amino acid decarboxylase (AADC) inhibitor is suggested to cause an increase of L-DOPA, which might lead to oxidative damage through enhanced formation of free radicals. To investigate this hypothesis, the acute effects of two doses of the systemically administered COMT inhibitors entacapone (peripheral) and tolcapone (peripheral and central) on the extracellular formation of hydroxyl radicals in vivo following treatment with L-DOPA and the AADC inhibitor carbidopa were examined. The formation of extracellular hydroxyl radicals were determined by the measurement of 2,3-dihydroxybenzoic acid (2,3-DHBA), a reaction product of hydroxyl radicals with sodium salicylate, using microdialysis in the striatum of anesthetised rats. The COMT inhibitors were administered together with 50 mg/kg i.p. carbidopa as 5% gum arabic suspensions intraperitoneally (i.p.) at doses of 0, 1.0, and 10 mg/kg body weight to a total of 36 male HAN-Wistars rats. L-DOPA was injected i.p. 40 min after drugs of interest. Microdialysis samples were collected every 20 min for 400 min at a perfusion rate of 1 microl/min. Systemically administered 10 mg/kg tolcapone, but not entacapone, induced an increase in hydroxyl radical formation in the striatum of anesthetised rats following treatment with L-DOPA/carbidopa. The increase in hydroxyl radical formation was reflected by higher extracellular concentrations of the hydroxylate product of salicylate, 2,3-DHBA, peaking at 192% of baseline at the end of the observation period. Similar results were also found using the AUC (area under the curve) value estimated for the observation period. We conclude that the increase in hydroxyl radical formation is likely to result from an increased rate of monoamine oxidase-mediated and non-enzymatic (autoxidation) dopamine metabolism following increased central availability caused by reduction in COMT-mediated metabolism. We cannot, however, exclude the possibility that hydroxyl radicals are produced by tolcapone as a result of uncoupling mitochondrial oxidative phosphorylation.

Topics: 3,4-Dihydroxyphenylacetic Acid; Animals; Antiparkinson Agents; Benzophenones; Carbidopa; Catechol O-Methyltransferase Inhibitors; Catechols; Corpus Striatum; Dopamine; Dose-Response Relationship, Drug; Hydroxyl Radical; Levodopa; Male; Microdialysis; Nitriles; Nitrophenols; Oxidative Stress; Parkinsonian Disorders; Rats; Rats, Wistar; Tolcapone