entacapone and ropinirole

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

The year of 2007 was a turning point of the treatment of Parkinson's disease (PD) in Japan. Severe adverse effects of dopamine agonists including valvular heart disease induced by ergots and sudden onset of sleep attacks induced by non-ergots, were disclosed, and treatments with agonists were reassessed. Good news were marketing of ropinirole, a new non-ergot agonist, in December 2006 and entacapone, the first catechol-O-methyl transferase (COMT) inhibitor in Japan in April 2007. Having faced these new situations, Japanese Neurological Association has started revising "the Guideline 2002 for the treatment of Parkinson's disease". Clinical trials of translational gene therapy for Parkinson's disease with adeno-associated virus (AAV) vector are now going on in four approaches: restoring dopamine synthetic capacity, protecting against cell death with trophic factors, interfering with the aberrant protein aggregation, and converting the subthalamic nucleus into an inhibitory, rather than an excitatory, structure. In Japan, gene delivery of the dopamine synthesizing enzyme aromatic amino acid decarboxylase (AADC) to the striatum of PD patients is going on in Jichi Medical University. New findings of the causative genes, environmental factors and molecular mechanism of PD have provided with new tools for developing new treatments. The big success of induction of induced pluripotent stem (iPS) cells from fibroblast has given an impact on cell therapy research of PD.

Topics: Antiparkinson Agents; Aromatic-L-Amino-Acid Decarboxylases; Catechol O-Methyltransferase Inhibitors; Catechols; Cell- and Tissue-Based Therapy; Clinical Trials as Topic; Dependovirus; Dopamine Agonists; Enzyme Inhibitors; Gene Transfer Techniques; Genetic Therapy; Genetic Vectors; Humans; Indoles; Nitriles; Parkinson Disease; Pluripotent Stem Cells; Practice Guidelines as Topic

Topics: Amantadine; Benzophenones; Benzothiazoles; Brain Injuries; Catechols; Dopamine Agents; Humans; Indoles; Neuroprotective Agents; Nitriles; Nitrophenols; Patient Selection; Pramipexole; Selegiline; Thiazoles; 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

Several cases of syndrome of inappropriate antidiuresis induced by anti-Parkinson agents have been reported. Our previous study demonstrated that pergolide and pramipexole stimulated elevation of plasma arginine vasopressin (AVP) levels in some patients with Parkinson's disease (PD), but that levodopa/carbidopa (300/30 mg/day) did not affect plasma AVP levels in treatment-naïve PD patients. On the basis of the binding profile of ropinirole to monoamine receptors, we hypothesized that ropinirole does not stimulate AVP secretion. The aim of this study was to test this hypothesis.. Inclusion criteria were patients with probable PD suffering from a wearing-off phenomenon and who had been treated using levodopa/carbidopa with or without entacapone, but not with other classes of anti-Parkinson agents. Patients were excluded if they had at least one condition that could be associated with high AVP levels. Ropinirole was initiated at 0.5 mg 3 times daily, and daily dosages were increased by 1.5 mg/day on a biweekly basis up to 6 mg/day. Plasma AVP levels were determined every two weeks. Effects of escalating ropinirole dosage on plasma AVP levels were evaluated using a one-way analysis of variance for repeated measures, an a priori Dunnett multiple comparison test, and a regression analysis.. Of 16 patients enrolled, 11 patients (four males and seven females) completed the study. There was no statistically significant dose-response relationship between the ropinirole dosage and plasma AVP levels.. A minimal therapeutic dosage of ropinirole did not affect plasma AVP levels in patients with PD taking levodopa.

Topics: Aged; Arginine Vasopressin; Carbidopa; Catechols; Dopamine Agonists; Dose-Response Relationship, Drug; Drug Combinations; Drug Therapy, Combination; Female; Humans; Inappropriate ADH Syndrome; Indoles; Levodopa; Male; Middle Aged; Nitriles; Parkinson Disease

Psychotic features in patients with Parkinson's Disease usually present as visual hallucinations against a background of cognitive deterioration and dopaminomimetic therapy. Isolated delusions are rare. We report here 4 patients with Parkinson's Disease who developed a delusional syndrome resembling schizophreniform psychosis in the absence of changes in alertness, visual hallucinations or dementia. We suggest that this syndrome may be more common than previously recognized, and that it may be related to the use of dopaminergic medications and environmental triggers on a background of a susceptible individual. This syndrome suggests interesting parallels with the pathophysiology of amphetamine-induced psychosis and schizophrenia.

Topics: Aged; Amantadine; Antiparkinson Agents; Benserazide; Benzothiazoles; Catechols; Clonazepam; Female; Humans; Indans; Indoles; Levodopa; Male; Middle Aged; Nitriles; Parkinson Disease; Pramipexole; Schizophrenia, Paranoid; Syndrome

More continuous delivery of l-3,4-dihydroxyphenylalanine (l-dopa) achieved by combination with the catechol-O-methyl transfer (COMT) inhibitor entacapone reduces the onset of dyskinesia in MPTP-treated common marmosets compared with pulsatile l-dopa regimens. We now investigate whether l-dopa delivery also influences dyskinesia induction when added to dopamine agonist treatment. Drug-naive 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride (MPTP)-treated common marmosets were treated with ropinirole twice daily (BID) for 14 days which reversed motor disability and increased locomotor activity with minimal dyskinesia. Ropinirole treatment was continued but some animals also received l-dopa BID or four times daily (QID) with and without entacapone or vehicle for a further 16 days. Continuing ropinirole treatment alone maintained a similar reversal of motor deficits and low levels of dyskinesia for the first 14 days and the second 16 days. The addition of l-dopa BID or QID without entacapone produced only a minor further reversal of motor deficits, but significantly increased the intensity of dyskinesia. In contrast, the addition of l-dopa BID or QID with entacapone also produced some further improvement in motor function with the combination of entacapone and l-dopa BID significantly improving motor disability compared to l-dopa alone, but no further increase in dyskinesia intensity was observed compared with ropinirole alone treatment. The results show that combined treatment with l-dopa and entacapone has a marked effect on dyskinesia induction even when therapy has been introduced with a dopamine agonist.

Topics: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Animals; Antiparkinson Agents; Callithrix; Catechols; Dopamine Agents; Dopamine Agonists; Drug Administration Schedule; Drug Synergism; Dyskinesia, Drug-Induced; Female; Indoles; Levodopa; Male; Motor Activity; Nitriles

Topics: Aged; Amantadine; Benzothiazoles; Catechols; Dopamine Agents; Dose-Response Relationship, Drug; Drug Interactions; Dyskinesia, Drug-Induced; Humans; Iatrogenic Disease; Indoles; Levodopa; Male; Middle Aged; Neurology; Neuropharmacology; Neurotoxicity Syndromes; Nitriles; Parkinson Disease; Pramipexole; Selegiline; Thiazoles; Treatment Outcome

Pathological hypersexuality developed in 13 patients with PD and two patients ultimately diagnosed clinically with MSA. Hypersexuality began within 8 months after starting dopamine agonist therapy in 14 of 15 cases, including four on agonist monotherapy. It resolved in the four cases where the agonist was stopped, despite continued levodopa therapy. This was not an isolated behavioral problem in most, with additional compulsive or addictive behaviors coinciding in nine patients (60%). A systematic literature review of pathological hypersexuality in PD revealed similar medication histories; combining these cases with our series, 26 of 29 patients (90%) were on adjuvant dopamine agonists.

Topics: Adult; Aged; Antiparkinson Agents; Benzothiazoles; Catechols; Databases, Factual; Dopamine Agonists; Humans; Indoles; Levodopa; Male; Mental Disorders; Middle Aged; Multiple System Atrophy; Nitriles; Parkinson Disease; Pramipexole; Sexual Dysfunctions, Psychological; Thiazoles

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

After levodopa, dopaminergic agonists are the most powerful agents in idiopathic Parkinson's disease treatment. Used in monotherapy or rather in early combination with levodopa, they allow a dramatic reduction of long-term motor side effects of the latter: onset and peak-dose dyskinesias, early morning dystonias. Their gastro-intestinal (nauseas) and moreover psychiatric (confusion and hallucinations) side effects limit their use, notably in geriatric populations. Superiority of so-called "second generation" agonists (ropinirole, pramipexole) on "first generation" agonists (bromocriptine, pergolide) remains to be proved.

Topics: Aged; Antiparkinson Agents; Apomorphine; Benzothiazoles; Biological Availability; Bromocriptine; Catechols; Dopamine Agonists; Drug Combinations; Drug Hypersensitivity; Humans; Hypotension, Orthostatic; Indoles; Levodopa; Metabolic Clearance Rate; Nitriles; Parkinson Disease; Pergolide; Pramipexole; Selegiline; Thiazoles

Topics: Antiparkinson Agents; Benzothiazoles; Catechol O-Methyltransferase Inhibitors; Catechols; Dopamine Agonists; Enzyme Inhibitors; Humans; Indoles; Levodopa; Nitriles; Parkinson Disease; Pramipexole; Thiazoles