entacapone and Parkinsonian-Disorders

Levodopa remains the mainstay treatment for Parkinson's disease (PD). Chronic treatment is associated with motor complications (MC) that marred the clinical benefit of levodopa. These problems and experimental data in cell cultures indicating a neurotoxic effect of levodopa have led to the idea of delaying the introduction of levodopa treatment for as long as possible. We here review recent data regarding the mechanism of action of levodopa and its application in clinical practice on the light of the marketing of the combination levodopa-carbidopa- entacapone. Accumulated evidence indicates that MC are mainly the consequence of disease severity governing the degree of dopaminergic depletion and the "pulsatile" dopaminergic stimulation provided by levodopa short plasma half-life. There is no in vivo or clinical evidence of a relevant neurotoxic effect of levodopa. In fact, the recent ELLDOPA study may suggest a neuroprotective effect. Entacapone reduces homocysteine plasma levels which could provide a mechanism to reduce cell death in PD. Currently, the combination levodopa-carbidopa-entacapone is particularly indicated for the treatment of "wearing off" fluctuations. Experimental evidence suggests that early treatment with levodopa-carbidopa-entacapone may substantially ameliorate the incidence of MC. Such a clinical study in "de novo" patients is underway. At present, the combination levodopa-carbidopa-entacapone is indicated when levodopa is judged necessary.

Topics: Akathisia, Drug-Induced; Animals; Antiparkinson Agents; Carbidopa; Catechols; Clinical Trials as Topic; Dopamine; Drug Therapy, Combination; Humans; Hyperhomocysteinemia; Levodopa; MPTP Poisoning; Neuroprotective Agents; Nitriles; Parkinson Disease; Parkinsonian Disorders; Rats; Treatment Outcome

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

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

Topics: Antiparkinson Agents; Catechols; Female; Humans; Longitudinal Studies; Male; Nitriles; Parkinsonian Disorders; Proportional Hazards Models; Retrospective Studies

To study the effects of entacapone, a catechol-O-methyltransferase inhibitor, on colon motility and electrolyte transport in Parkinson's disease (PD) rats.. Distribution and expression of catechol-O-methyltransferase (COMT) were measured by immunohistochemistry and Western blotting methods. The colonic smooth muscle motility was examined in vitro by means of a muscle motility recording device. The mucosal electrolyte transport of PD rats was examined by using a short-circuit current (ISC ) technique and scanning ion-selective electrode technique (SIET). Intracellular detection of cAMP and cGMP was accomplished by radioimmunoassay testing.. COMT was expressed in the colons of both normal and PD rats, mainly on the apical membranes of villi and crypts in the colon. Compared to normal controls, PD rats expressed less COMT. The COMT inhibitor entacapone inhibited contraction of the PD rat longitudinal muscle in a dose-dependent manner. The β2 adrenoceptor antagonist ICI-118,551 blocked this inhibitory effect by approximately 67% (P < 0.01). Entacapone increased mucosal ISC in the colon of rats with PD. This induction was significantly inhibited by apical application of Cl(-) channel blocker diphenylamine-2, 2'-dicarboxylic acid, basolateral application of Na(+)-K(+)-2Cl(-)co-transporter antagonist bumetanide, elimination of Cl(-) from the extracellular fluid, as well as pretreatment using adenylate cyclase inhibitor MDL12330A. As an inhibitor of prostaglandin synthetase, indomethacin can inhibit entacapone-induced ISC by 45% (P < 0.01). When SIET was applied to measure Cl(-) flux changes, this provided similar results. Entacapone significantly increased intracellular cAMP content in the colonic mucosa, which was greatly inhibited by indomethacin.. COMT expression exists in rat colons. The β2 adrenoceptor is involved in the entacapone-induced inhibition of colon motility. Entacapone induces cAMP-dependent Cl(-) secretion in the PD rat.

Topics: Adenylyl Cyclase Inhibitors; Adrenergic beta-2 Receptor Antagonists; Animals; Antiparkinson Agents; Catechol O-Methyltransferase; Catechol O-Methyltransferase Inhibitors; Catechols; Chloride Channels; Chlorides; Colon; Cyclic AMP; Cyclooxygenase Inhibitors; Disease Models, Animal; Dose-Response Relationship, Drug; Gastrointestinal Motility; Intestinal Mucosa; Ion Transport; Male; Nitriles; Oxidopamine; Parkinsonian Disorders; Rats, Sprague-Dawley; Time Factors

Levodopa is the main medication used for the treatment of Parkinson's disease. However, dyskinesia and wearing-off appear after the administration of high-dose levodopa for a long period. To combat the dyskinesia and wearing-off, levodopa is used together with a dopamine (DA) receptor agonist, and the amount of levodopa is decreased. We have reported the monoamine oxidase (MAO)-B inhibitor selegiline to be effective for treating motor dysfunction in Parkinson's disease model rats. We analyzed the improvement in motor functions and catecholamine contents in various brain regions induced by a combination of the catechol-O-methyltransferase (COMT) inhibitor entacapone and a levodopa/dopadecarboxylase inhibitor (DDCI) in Japanese encephalitis virus (JEV) induced Parkinson's disease model rats. Entacapone (10 mg/kg) was administered via a single oral administration with levodopa/DDCI (10 mg/kg). The motor functions of the JEV model rats were significantly worsened, compared with those of the healthy control rats. The motor functions in the Parkinson's disease model rats were significantly recovered to the same levels as the healthy control rats by the combined administration of entacapone and levodopa/DDCI. A significant improvement in motor function was not demonstrated in the case of the administration of levodopa/DDCI alone. The striatal DA concentrations in the model rat brains were significantly increased by using levodopa/DDCI together with entacapone. Motor function was recovered by raising the striatum DA density in the model rats. Thus, COMT inhibitors are useful for decreasing the amount of levodopa administered to Parkinson's disease patients.

Topics: Administration, Oral; Animals; Antiparkinson Agents; Aromatic Amino Acid Decarboxylase Inhibitors; Basal Ganglia; Catechol O-Methyltransferase; Catechol O-Methyltransferase Inhibitors; Catechols; Corpus Striatum; Dopa Decarboxylase; Dopamine; Drug Combinations; Drug Synergism; Encephalitis Virus, Japanese; Encephalitis, Japanese; Enzyme Inhibitors; Levodopa; Nitriles; Parkinsonian Disorders; Rats; Rats, Inbred F344; Treatment Outcome

Coadministration of entacapone with levodopa attenuates motor complications in experimental models of Parkinson's disease. The mechanisms underlying entacapone effects are unknown. We investigated the effect of entacapone, on: long-duration response (LDR) to levodopa, levodopa-induced postsynaptic pharmacodynamic mechanisms and molecular changes in hemiparkinsonian rats. 6-Hydroxydopamine-unilaterally lesioned rats were treated with levodopa (25 mg/kg)+vehicle; levodopa+entacapone (30 mg/kg) or saline, twice daily for 22 days. The LDR and the apomorphine-induced rotations were measured. In situ hybridization was performed measuring the expression of striatal preproenkephalin, preprodynorphin and dopamine D-3 receptor mRNAs, subthalamic cytochrome oxidase mRNA and nigral glutamic acid decarboxylase mRNA. Entacapone potentiated the LDR but did not modify either the apomorphine-induced rotational behavior or the molecular changes. Our results suggest that the effects of entacapone on levodopa-induced motor response are not mediated by postsynaptic mechanisms and that administration of entacapone is not able to normalize the molecular alterations induced by levodopa in the basal ganglia.

Topics: Animals; Antiparkinson Agents; Apomorphine; Brain; Catechols; Corpus Striatum; Dynorphins; Electron Transport Complex IV; Enkephalins; Gene Expression; Glutamate Decarboxylase; Immunohistochemistry; In Situ Hybridization; Levodopa; Male; Motor Activity; Nitriles; Parkinsonian Disorders; Protein Precursors; Rats; Rats, Sprague-Dawley; Receptors, Dopamine D3; RNA, Messenger; Substantia Nigra; Subthalamus

Levodopa-induced dyskinesias (LIDs) have been associated with a sequence of events that includes pulsatile stimulation of dopamine receptors. The degree of nigrostriatal degeneration, the half-life of dopaminomimetic agents, and the dose of levodopa used to treat parkinsonian symptoms are factors directly correlated with the development of motor complications in Parkinson's disease patients. Long-acting agents producing continuous dopaminergic stimulation are less likely to prime for dyskinesia than short-acting drugs that produce pulsatile stimulation of dopamine receptors. Inhibition of the enzyme catechol-O-methyl transferase (COMT) by entacapone extends the half-life of levodopa and minimizes variability in plasma levodopa levels. The aim of the present study was to characterize the effect of the early administration of the COMT inhibitor entacapone in the recently described model of LIDs in rats with a nigrostriatal lesion induced by 6-hydroxydopamine (6-OHDA). Male Sprague-Dawley rats received a unilateral 6-OHDA administration in the nigrostriatal pathway. Animals were treated either with levodopa (6 mg/kg, twice at day, i.p.) plus entacapone (30 mg/kg per day, i.p.) or levodopa (6 mg/kg, twice at day, i.p.) plus vehicle for 22 consecutive days. Early administration of entacapone, in association with levodopa, induces a decrease in the severity of dyskinesia and delays their onset in hemiparkinsonian rats. All dyskinesia subtypes evaluated, such as axial, limb, and orofacial dyskinesias, have shown similar reductions. These results suggest that entacapone, by extending levodopa elimination half-life, might reduce its propensity to induce motor complications.

Topics: Analysis of Variance; Animals; Antiparkinson Agents; Catechols; Disease Models, Animal; Drug Therapy, Combination; Dyskinesias; Levodopa; Male; Nitriles; Oxidopamine; Parkinsonian Disorders; Rats; Rats, Sprague-Dawley; Severity of Illness Index; Time Factors

The purpose of this study was to investigate the effect of the catechol-O-methyltransferase (COMT) inhibitor, entacapone, in the reversal and prevention of "wearing-off" phenomena in hemiparkinsonian rats. Catechol-O-methyltransferase (COMT) inhibitors increase the half-life and bioavailability of levodopa, providing more continuous dopamine receptor stimulation. This raises the possibility of using levodopa and a COMT inhibitor not only to treat motor complications, but also to prevent their development. Male Sprague-Dawley rats received a unilateral 6-hydroxydopamine (6-OHDA) administration in the nigrostriatal pathway. Two sets of experiments were performed. First, animals were treated with levodopa (50 mg/kg/day with benserazide 12.5 mg/kg/day, twice daily (b.i.d.), intraperitoneally (i.p.) for 22 days. On day 23, animals received either entacapone (30 mg/kg, i.p.) or vehicle with each levodopa dose. In the second set, animals were treated either with levodopa (50 mg/kg/day, i.p.) plus entacapone (30 mg/kg/day, i.p.) or levodopa (50 mg/kg/day, i.p.) plus vehicle, administered two or three times daily [b.i.d. or thrice daily (t.i.d.), respectively] for 22 consecutive days. Entacapone both reversed and prevented the shortening of the motor response duration that defines "wearing-off" motor fluctuations. Entacapone also decreased the frequency of failures to levodopa. The combination of levodopa and entacapone may reduce the likelihood of motor fluctuation development and may thus become a valuable approach to treat Parkinson disease whenever levodopa is needed.

Topics: Animals; Benserazide; Catechol O-Methyltransferase; Catechol O-Methyltransferase Inhibitors; Catechols; Disease Models, Animal; Drug Administration Schedule; Drug Interactions; Drug Therapy, Combination; Dyskinesia, Drug-Induced; Enzyme Inhibitors; Levodopa; Male; Nitriles; Oxidopamine; Parkinsonian Disorders; Rats; Rats, Sprague-Dawley; Treatment Outcome

Levodopa (L-dopa) consistently primes basal ganglia for the appearance of dyskinesia in parkinsonian patients and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride (MPTP) -treated primates. This finding may reflect its relatively short duration of effects resulting in pulsatile stimulation of postsynaptic dopamine receptors in the striatum. We have compared the relationship between L-dopa dose and frequency of administration on dyskinesia initiation in drug-naïve, MPTP-treated common marmosets. We have also studied the effect of increased brain exposure to pulsatile administration by combining a low-dose of L-dopa with the peripheral catechol-O-methyltransferase inhibitor (COMT-I), entacapone. Pulsatile administration of a low (dose range, 5.0-7.5 mg/kg p.o.) or a high (12.5 mg/kg) dose of L-dopa plus carbidopa b.i.d. produced a dose-related reversal of motor deficits. Repeated administration of low and high doses of L-dopa for 26 days to drug-naïve, MPTP-treated animals also caused a dose-related induction of peak-dose dyskinesia. Repeated administration of high-dose L-dopa b.i.d. compared to once daily caused a frequency-related improvement of motor symptoms, resulting in a more rapid and initially more intense appearance of peak-dose dyskinesia. Administration of low-dose L-dopa b.i.d. for 26 days in combination with entacapone enhanced the increase in locomotor activity and reversal of disability produced by L-dopa alone, but with no obvious change in duration of L-dopa's effect. However, combining entacapone with L-dopa resulted in the more rapid appearance of dyskinesia, which was initially more severe than occurred with L-dopa alone. Importantly, increasing pulsatile exposure of brain to L-dopa by preventing its peripheral breakdown also increases dyskinesia induction.

Topics: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Animals; Antiparkinson Agents; Callithrix; Carbidopa; Catechols; Dose-Response Relationship, Drug; Drug Synergism; Drug Therapy, Combination; Dyskinesia, Drug-Induced; Female; Levodopa; Locomotion; Male; Nitriles; Parkinsonian Disorders; Pulse Therapy, Drug; Substantia Nigra; Time Factors

Topics: Adult; Age Factors; Aged; Antiparkinson Agents; Catechols; Depressive Disorder; Diagnosis, Differential; Dopamine Agents; Dopamine Agonists; Follow-Up Studies; Humans; Indoles; Levodopa; Lewy Body Disease; Neuroprotective Agents; Nitriles; Parkinson Disease; Parkinsonian Disorders; Pergolide; Psychiatric Status Rating Scales; Psychotic Disorders; Time Factors

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