Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027497 (nausea)
 23,468 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

When peripheral decarboxylation is blocked by carbidopa or benserazide, the main metabolic pathway of levodopa is O-methylation by catechol-O-methyltransferase (COMT). Entacapone and tolcapone are new potent, selective and reversible nitrocatechol-type COMT inhibitors. Animal studies have demonstrated that entacapone mainly has a peripheral effect whereas tolcapone also inhibits O-methylation in the brain. In human volunteers, both entacapone and tolcapone dose-dependently inhibit the COMT activity in erythrocytes, improve the bioavailability and decrease the elimination of levodopa, and inhibit the formation of 3-O-methyldopa (3-OMD). Entacapone is administered with every scheduled dose of levodopa whereas tolcapone is administered 3 times daily. The different administration regimens for these agents are based on their different pharmacokinetic and pharmacodynamic profiles. Both entacapone and tolcapone enhance and extend the therapeutic effect of levodopa in patients with advanced and fluctuating Parkinson's disease. They prolong the duration of levodopa effect. Clinical studies show that they increase the daily ON time by an average 1 to 3 hours, improve the activities of daily living and allow daily levodopa dosage to be decreased. Correspondingly, they significantly reduce the daily OFF time. No comparative studies between entacapone and tolcapone have been performed. Tolcapone also appears to have a beneficial effect in patients with nonfluctuating Parkinson's disease. The main adverse effects of the COMT inhibitors are related to their dopaminergic and gastrointestinal effects. Enhancement of dopaminergic activity may cause an initial worsening of levodopa-induced adverse effects, such as dyskinesia, nausea, vomiting, orthostatic hypotension, sleep disorders and hallucinations. Levodopa dose adjustment is recommended to avoid these events. Tolcapone is associated with diarrhoea in about 16 to 18% of patients and entacapone in less than 10% of patients. Diarrhoea has led to discontinuation in 5 to 6% of patients treated with tolcapone and in 2.5% of those treated with entacapone. Urine discoloration to dark yellow or orange is related to the colour of COMT inhibitors and their metabolites. Elevated liver transaminase levels are reported in 1 to 3% of patients treated with tolcapone but very rarely, if at all, in patients treated with entacapone. The descriptions of acute, fatal fulminant hepatitis and potentially fatal neurological reactions, such as neuroleptic malignant syndrome and rhabdomyolysis, in association with tolcapone led to the suspension of its marketing authorisation in the European Community and Canada. In many other countries, the use of tolcapone is restricted to patients who are not responding satisfactorily to other therapies. Regular monitoring of liver enzymes is required if tolcapone is used. No such adverse reactions have so far been described for entacapone and no laboratory monitoring has been proposed. COMT inhibitors added to levodopa therapy are beneficial, particularly in patients with fluctuating disease. They may be combined with other antiparkinsonian drugs, such as dopamine agonists, selegiline and anticholinergics without adverse interactions. They provide a new treatment possibility in patients with Parkinson's disease who have problems with their present levodopa therapy.
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PMID:Clinical pharmacology, therapeutic use and potential of COMT inhibitors in Parkinson's disease. 1088 60

Entacapone increased the duration of action of carbidopa-levodopa and resulted in longer periods of symptomatic relief in a patient with restless legs syndrome. The only side effect was nausea.
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PMID:Entacapone in restless legs syndrome. 1192 Nov 39

(1) If patients with Parkinson's disease treated with levodopa develop end-of-dose motor fluctuations, the standard therapy is to add bromocriptine, a dopamine receptor agonist, to their ongoing treatment. (2) Evaluation data available in 1999 on entacapone, a catechol-o-methyltransferase (COMT) inhibitor, failed to show whether the balance of benefits versus harm was at least equivalent to that of bromocriptine. (3) Entacapone is now also available as a triple fixed-dose combination with levodopa + carbidopa. (4) Three double-blind trials have compared triple combinations of levodopa + carbidopa (or benserazide) + entacapone with levodopa + carbidopa (or benserazide) + placebo. Two of these trials showed an increase of about 1 hour in "on" phases during the day, together with a small reduction in the daily dose of levodopa. These results are consistent with earlier studies. (5) Entacapone has still not been compared with a dopamine agonist. (6) The fixed-dose combination of levodopa + carbidopa + entacapone has been compared with unfixed combinations in two unblinded trials only. (7) These two trials showed that efficacy was similar whether entacapone was used separately or included in a fixed-dose combination with levodopa + carbidopa. The only relevant trial (a non randomised cross-over trial) failed to show patient preference for the fixed-dose combination. (8) In France, a short-acting combination of levodopa and carbidopa is available, with a dose ratio of 10:1. This compares to a ratio of 4:1 for levodopa and carbidopa in the fixed-dose combination of levodopa + carbidopa + entacapone. The dose of carbidopa is therefore higher for a given dose of levodopa, provoking more dyskinesias and nausea. (9) Entacapone can cause drowsiness. Cases of cholestatic hepatitis have also been reported. Risks of liver toxicity, rhabdomyolysis and neuroleptic malignant syndrome remain to be determined. (10) In practice, bromocriptine remains the first-choice for adjunctive therapy when levodopa becomes ineffective.
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PMID:Levodopa + carbidopa + entacapone. Entacapone: a second look: new preparations. Parkinson's disease: a modest effect. 1587 40

Levodopa, a dopamine precursor administered with a decarboxylase inhibitor, is the principal therapy for treating the symptoms of Parkinson's disease. Unfortunately, after approximately 2-5 years, it frequently loses its beneficial effects as evidenced by motor fluctuations. Entacapone (Comtan) is a selective, reversible catechol-O-methyltransferase inhibitor that dose-dependently increases the peripheral bioavailability of levodopa and prolongs its duration of action. Early studies confirmed that treatment with entacapone resulted in increased striatal uptake of levodopa after iv. administration of [18F] levodopa. Preclinical studies confirmed decreased formation of COMT-dependent metabolites, including 3-O methyldopa and homovanillic acid. Clinical studies performed in patients with motor fluctuations have shown that entacapone prolonged the duration of motor response by an average of 1-1.3 h. Parkinsonian patients receiving therapeutic doses of dopamine agonists and selegiline also experienced an incremental improvement in 'on' time when entacapone was added to their drug regimen. At present, there are no published safety studies beyond six to twelve months in duration, or studies in nonfluctuating patients. Based on the clinical trial data available, entacapone is well-tolerated in the majority of patients. Dopaminergic-related adverse effects include dyskinesias, nausea and dizziness. Non-dopaminergic adverse effects include diarrhoea, abdominal discomfort and discoloration of urine. Diarrhoea is occasionally severe and may require discontinuation of therapy. Of 406 entacapone-treated subjects, there was one incidence of elevated liver transaminases, although this was attributed to an underlying disorder. In the US, Phase III trials have been completed and a New Drug Application (NDA) has been filed. In Europe, the drug received a favourable review and is currently available.
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PMID:Entacapone, a catechol-O-methyltransferase inhibitor for treating Parkinson's disease: review and current status. 1599 91

In this 12-wk, multi-center, randomized, open-label, rater-blinded study, efficacy and tolerability of Entacapone (ENT) or Cabergoline (CBG) in conjunction with levodopa were compared in 161 older Parkinson's disease patients with wearing-off. Patients received either ENT, 3 to 5 times daily, or CBG, titrated according to requirements to a maximum of 6 mg/d. A significant decrease of nearly 2 hours in the daily OFF-time (primary efficacy variable) was recorded in both treatment groups. The non-inferiority test failed despite a trend in favor of ENT. Reduction in OFF-time occurred faster in the ENT compared to the CBG treated patients. A decrease of approximately 20% was detected in parts II and III of the UPDRS, with no differences between the groups. Forty-three percent of the patients in the ENT group reported dyskinesias at baseline, and 35% at the final visit. The corresponding figures in the CBG group were 46% and 43%. Quality of life, measured by PDQ-39, increased substantially with both ENT and CBG. The mean daily dosage at the final visit was 698 mg for ENT (plus 447 mg levodopa) and 3.45 mg for CBG (plus 475 mg levodopa). Adverse events (AE), leading to discontinuation, were reported in 8.5% of the ENT and 13.9% of the CBG treated patients. Nausea was the most common AE in each group, corresponding figures being 7.3% with ENT and 25.3% with CBG (P=0.0024). A probable or possible causal relationship with ENT was reported in 41% and with CBG in 64% of the AE. Among these, only one serious AE (dehydration) was recorded with each treatment group. ENT and CBG reduced the patient's motor complications effectively and to a similar degree. The clinical benefit was more quickly apparent with ENT, which also showed a more favorable AE profile than CBG.
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PMID:Efficacy and tolerability of Entacapone versus Cabergoline in parkinsonian patients suffering from wearing-off. 1751 84

We investigated clinical response and pharmacokinetics of levodopa when entacapone, a catechol O-methyltransferase (COMT) inhibitor, was administered concomitantly with either a standard (Std) or a controlled-release (CR) levodopa/carbidopa preparation to 12 patients with Parkinson's disease. An open cross-over study consisted of the initial study day without entacapone followed by two 10-day treatment periods with a study day at the end of each period. The patients who received entacapone (200 mg t.i.d. or q.i.d.) concomitantly with Std levodopa/carbidopa (200/50 mg t.i.d. or q.i.d.) during the first period received subsequently entacapone with CR levodopa/carbidopa (200/50 mg t.i.d. or q.i.d.), and vice versa. On the study days, the patients took the medication at 8 a.m. and the second dose 6 h later. We evaluated the disability before drug administration and then 1-h intervals for 8 h. Repeated blood samples were taken for analysis of plasma levodopa, 3-O-methyldopa (3-OMD), dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), carbidopa, and entacapone. Entacapone decreased significantly the clinical disability with both Std and CR levodopa, slightly more with Std levodopa. The clinical response started earlier with Std levodopa whereas the "on"-time increased by about 1 h, equally with both levodopa preparations. Std levodopa produced 23% higher area under the curve (AUC) of levodopa than the CR preparation, but entacapone increased the AUC approximately equally, 33% with Std and 36% with CR levodopa. Entacapone slightly decreased Cmax of levodopa in combination with Std levodopa, whereas it increased that with CR levodopa. The AUC of 3-OMD was about 20% smaller after Std than after CR levodopa. Entacapone decreased the AUC of 3-OMD by 38-40% with both levodopa preparations. Entacapone did not modify the AUC levels of carbidopa although its bioavailability was less from CR levodopa than from Std levodopa. In three patients levodopa dosage was reduced when on Std levodopa because of nausea. Otherwise, the treatments were well tolerated. The study shows that entacapone is an effective COMT inhibitor when combined with either Std levodopa or CR levodopa.
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PMID:Entacapone in combination with standard or controlled-release levodopa/carbidopa: a clinical and pharmacokinetic study in patients with Parkinson's disease. 2428 86