ergoline and entacapone

The development of pharmacogenetic-based clinical practice guidelines for the use of anti-Parkinson's disease drugs requires, as a pre-requisite, the identification and validation of genetic biomarkers. These biomarkers are then used as surrogate endpoints. This review analyzes potential genetic biomarkers which can be used to improve anti-Parkinson's disease therapy.. The authors present an overview of current knowledge of pharmacogenetic implications of anti-Parkinson's disease drugs, including genes coding for the corresponding drug-metabolizing enzymes and drug targets. The gene/drug pairings with the strongest potential for pharmacogenetic recommendations include: CYP2C19/benztropine, COMT/levodopa and entacapone, CYP2B6/selegiline, UGT1A/entacapone, DRD2/ropinirole, pramipexole and cabergoline, and DRD3/ropinirole and pramipexole. Evidence supporting the effect of substrates, inhibitor or inducers for drug specific metabolizing enzymes in anti-Parkinson's disease drug response includes CYP1A2 in the response to ropinirole and rasagiline, and CYP3A4 in the response to bromocriptine, lisuride, pergolide and cabergoline. The authors present and discuss the current information on gene variations according to the 1000 genomes catalog and other databases with regards to anti-Parkinson's disease drugs. They also review and discuss the clinical implications of these variations.. The goal of pharmacogenomic testing for anti-Parkinson's disease drugs should be conservative and aimed at selecting determined drugs for determined patients. However, much additional research is still needed to obtain reliable pre-prescription tests.

Topics: Aryl Hydrocarbon Hydroxylases; Benzothiazoles; Benztropine; Bromocriptine; Cabergoline; Catechols; Cytochrome P-450 CYP1A2; Cytochrome P-450 CYP1A2 Inhibitors; Cytochrome P-450 CYP2B6; Cytochrome P-450 CYP2C19; Cytochrome P-450 CYP3A; Ergolines; Genetic Markers; Humans; Indans; Indoles; Levodopa; Lisuride; Nitriles; Parkinson Disease; Pergolide; Pharmacogenetics; Pramipexole; Receptors, Dopamine D2; Receptors, Dopamine D3; Reproducibility of Results; Selegiline

Although levodopa remains the most effective drug for the symptomatic treatment of Parkinson's disease (PD), there are significant limitations to its chronic use. Growing preclinical and clinical evidence suggests that the severity of motor fluctuations is influenced both by PD severity and pulsatile stimulation of striatal dopamine receptors. Current management of motor fluctuations is based primarily on strategies to prolong the effects of dopaminergic stimulation. This prolongation is accomplished either through the use of long-acting dopaminergic drugs or prolonging of the effects of levodopa. During the past decade, the armamentarium of dopamine agonists increased and agents that prolong the plasma half-life of levodopa became available. Furthermore, recent clinical trials provide evidence-based approaches to improve the management of motor fluctuations in patients with advanced and early PD.

Topics: Apomorphine; Benzophenones; Cabergoline; Catechol O-Methyltransferase Inhibitors; Catechols; Dopamine Agonists; Ergolines; Humans; Levodopa; Movement Disorders; Nitriles; Nitrophenols; Parkinson Disease; Tolcapone

To summarize the development, pharmacology, pharmacokinetics, efficacy, and safety of five investigational antiparkinsonian drugs that are in or have recently completed Phase III trials: three dopamine agonists, pramipexole, ropinirole, and cabergoline; and two catechol-O-methyltransferase (COMT) inhibitors, entacapone and tolcapone. The pathophysiology and the role of dopamine in Parkinson's disease are also reviewed.. A MEDLINE search of relevant English-language literature, clinical studies, abstracts, and review articles pertaining to Parkinson's disease was conducted. Manual searches of 1996/1997 meeting abstracts published by the American Academy of Neurology and the Movement Disorders Society were also performed. Manufacturers provided unpublished Phase III trial efficacy and pharmacokinetic data.. Clinical trial investigations selected for inclusion were limited to human subjects. Interim analyses after 6 months for long-term clinical studies in progress were included. Pharmacokinetic data from animals were cited if human data were unavailable. Statistical analyses for all studies were evaluated.. By selectivity targeting D2 receptors, the newer dopamine agonists (i.e., cabergoline, pramipexole, ropinirole) may delay the introduction of levodopa and thus the occurrence of levodopa-induced dyskinesias. In addition, they are efficacious as adjunctive therapies in patients with advanced Parkinson's disease. Unlike the currently available dopamine agonists, pramipexole and ropinirole are non-ergot derivatives and do not cause skin inflammation, paresthesias, pulmonary infiltrates, or pleural effusion. The COMT inhibitors, tolcapone and entacapone, improve the pharmacokinetics of levodopa by preventing its peripheral catabolism and increasing the concentration of brain dopamine; thus, these agents may reduce the incidence of "wearing-off" effects associated with the short half-life of levodopa and the progression of Parkinson's disease.. Interim 6-month analyses of pramipexole, ropinirole, and cabergoline for symptomatic treatment of early Parkinson's disease have shown these drugs to be efficacious and relatively well-tolerated when used as monotherapy. Their role in delaying the development of motor fluctuations and delaying the addition of levodopa is the subject of long-term clinical studies. In advanced stages of Parkinson's disease, these medications were also efficacious; however, the main adverse effects included dyskinesias, somnolence, and hallucinations. The COMT inhibitors, entacapone and tolcapone, have also demonstrated efficacy in improving on-time in patients with stable disease. Tolcapone has also demonstrated efficacy in patients with motor fluctuations. Both drugs are relatively well-tolerated, with the exception of dyskinesias that require reduction of the levodopa dosage and occasional diarrhea.

Topics: Benzophenones; Benzothiazoles; Cabergoline; Catechol O-Methyltransferase Inhibitors; Catechols; Dopamine Agonists; Enzyme Inhibitors; Ergolines; Humans; Indoles; Nitriles; Nitrophenols; Parkinson Disease; Pramipexole; Receptors, Dopamine D2; Thiazoles; Tolcapone

New medications recently developed for treating Parkinson's disease include two inhibitors of catechol-O-methyltransferase (COMT), entacapone and tolcapone, which, by decreasing the elimination of levodopa, extend the duration of its effects. Increased 'on' time and less 'wearing-off' symptomatology can be expected with the use of these COMT inhibitors. Two non-ergot dopaminergic agonists (pramipexole and ropinirole) and a long-acting ergoline (cabergoline) are also being introduced. These dopaminergic agonists, like the ergot derivatives currently available (bromocriptine, lisuride, and pergolide), are useful as adjuncts to levodopa, and are also efficacious as monotherapies.

Topics: Antiparkinson Agents; Benzophenones; Benzothiazoles; Cabergoline; Catechol O-Methyltransferase; Catechol O-Methyltransferase Inhibitors; Catechols; Enzyme Inhibitors; Ergolines; Guidelines as Topic; Humans; Indoles; Nitriles; Nitrophenols; Parkinson Disease; Pramipexole; Thiazoles; Tolcapone; Treatment Outcome

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.

Topics: Aged; Analysis of Variance; Antiparkinson Agents; Cabergoline; Catechols; Double-Blind Method; Drug Administration Schedule; Drug Tolerance; Dyskinesias; Ergolines; Female; Humans; Male; Medical Records; Middle Aged; Nitriles; Parkinson Disease; Psychiatric Status Rating Scales; Surveys and Questionnaires

To assess the efficacy and safety of high-dose (up to 20 mg/day) cabergoline in Parkinson's disease (PD) patients with motor fluctuations and/or dyskinesias.. Thirty-four PD patients had cabergoline up-titrated and their levodopa (L-dopa) reduced over a maximum of 20 weeks, followed by at least 6 weeks steady cabergoline dosing. Primary endpoint was change in mean hyperkinesia intensity at the final visit (week 26).. Mean (+/- SD) cabergoline was increased from 6.43 +/- 2.66 to 12.78 +/- 5.67 mg/day and mean L-dopa reduced from 606.6 +/- 263.9 to 370.6 +/- 192.5 mg/day. A significant reduction (P < 0.001) in mean hyperkinesia intensity occurred from baseline (day 0) to week 26. Improvements in 'on with dyskinesias', mean dystonia intensity (P < 0.05), time spent in 'severe off' condition, severity of 'off' periods as well as clinical/patient global impression, and health-related quality of life were observed. Twenty-four drug-related adverse events were recorded of which four were regarded as serious.. High-dose cabergoline was well tolerated and provided significant improvements in the Parkinson symptomatology and a reduced requirement for L-dopa.

Topics: Adolescent; Adult; Aged; Amantadine; Antiparkinson Agents; Cabergoline; Catechols; Drug Therapy, Combination; Dyskinesia, Drug-Induced; Dystonia; Ergolines; Humans; Levodopa; Middle Aged; Nitriles; Parkinson Disease; Piperidines; Prospective Studies; Quality of Life; Selegiline; Severity of Illness Index; Treatment Outcome

Topics: 5-alpha Reductase Inhibitors; Aged; Antiparkinson Agents; Benzothiazoles; Cabergoline; Carbidopa; Catechols; Drug Combinations; Drug Monitoring; Drug Therapy, Combination; Ergolines; Finasteride; Gambling; Humans; Levodopa; Male; Middle Aged; Nitriles; Parkinson Disease; Pramipexole; Treatment Outcome; Video Games

Topics: Aged; Antiparkinson Agents; Azepines; Benzothiazoles; Cabergoline; Carbidopa; Catatonia; Catechols; Drug Therapy, Combination; Electroconvulsive Therapy; Ergolines; Female; Humans; Levodopa; Nitriles; Parkinson Disease; Pramipexole