Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0030567 (Parkinson's disease)
 63,064 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Recent information suggests that free radicals are closely involved in the pathogenesis and/or progression of Parkinson's disease (PD). High-dose levodopa therapy has been suggested to increase oxidative stress, thereby accelerating the progression of PD. Based on this viewpoint, free radical scavenging, antioxidant and neuroprotective agents which may prevent the progression of PD have recently attracted considerable attention. For example, ergot derivative dopamine (DA) agonists have been reported to scavenge free radicals in vitro and show a neuroprotective effect in vivo. Non-ergot DA agonists have also recently been used in the treatment of PD despite the lack of substantial evidence for any free radical scavenging activity or antioxidant activity. The present study was conducted to assess the in vitro free radical scavenging and antioxidant activities of ropinirole, a non-ergot DA agonist, as well as its glutathione (GSH), catalase and superoxide dismutase (SOD) activating effects and neuroprotective effect in vivo. Ropinirole scavenges free radicals and suppresses lipid peroxidation in vitro, but these activities are very weak, suggesting that the antioxidant effect of ropinirole observed in vitro may be a minor component of its neuroprotective effect in vivo. Administration of ropinirole for 7 days increased GSH, catalase and SOD activities in the striatum and protected striatal dopaminergic neurons against 6-hydroxydopamine (6-OHDA) in mice. Pre-treatment with sulpiride prevented ropinirole from enhancing striatal GSH, catalase and SOD activities and abolished the protection of dopaminergic neurons against 6-OHDA. Our findings indicate that activation of GSH, catalase and SOD mediated via DA D2 receptors may be the principal mechanism of neuroprotection by ropinirole.
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PMID:Dopamine D2 receptor-mediated antioxidant and neuroprotective effects of ropinirole, a dopamine agonist. 1044 16

Ropinirole and pramipexole are non-ergoline dopamine agonists which are relatively specific for the D2 family of dopamine receptors. They have side-effect profiles linked to peripheral and central dopaminergic stimulation, amenable to tolerance through a slow titration or the addition of domperidone in sensitive patients. They do not have the uncommon but problematic ergot-related side effects of bromocriptine and pergolide. Ropinirole and pramipexole have both been shown to be efficacious when used as monotherapy in early Parkinson's disease (PD), and have been suggested as being less likely than levodopa to lead to the early development of motor fluctuations and dyskinesias in this clinical setting. They have also been shown to be useful as adjunctive therapy to levodopa in advanced PD and to have a levodopa-sparing effect in these patients. Dose equivalents amongst the available dopamine agonists is difficult to know with certainty but has been estimated as follows: 30 mg of bromocriptine, 15 mg of ropinirole, 4.5 mg of pramipexole, and 3.0 mg of pergolide.
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PMID:Ropinirole and pramipexole, the new agonists. 1045 57

Ropinirole, 4-[2-(dipropylamino)ethyl]-1,3-dihydro-2H-indol-2-one, is a potent anti-Parkinson's disease drug developed by SmithKline Beecham Pharmaceuticals. Capillary liquid chromatography (CLC) was used for the separation and quantification of ropinirole and its five related impurities, potentially formed during its synthesis. A simultaneous optimization of three mobile phase parameters, i.e., pH, buffer concentration and acetonitrile content was performed employing an experimental design approach which proved a powerful tool in method development. The retention factors of the investigated substances in different mobile phases were determined. Baseline resolution of the six substances on a C18 reversed stationary phase was attained using a mobile phase with an optimized composition [acetonitrile-8.7 mM 2-(N-morpholino)ethanesulfonic acid adjusted to pH 6.0 (55:45, v/v)]. It was shown that CLC, operated in the isocratic mode under the mobile phase flow-rate of 4 microl/min, can determine the level of these impurities, down to a level of 0.06% of the main component within 25 min.
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PMID:Separation and quantification of ropinirole and some impurities using capillary liquid chromatography. 1051 66

Ropinirole (4-[2-(dipropylamino)ethyl]-2-indolinone monohydrochloride) a nonergoline dopamine receptor agonist with high affinity for native dopamine D(2)-like receptors in human caudate tissue, was tested with respect to the stimulation of postsynaptic brain dopamine receptors in standard preclinical models of Parkinson's disease. Additionally, in these animal models the antiparkinsonian activity of ropinirole was compared to that of bromocriptine. The ED(50)s (95% confidence limits) of ropinirole and bromocriptine on the turning behavior in 6-OHDA-lesioned rats were 20.17 mg/kg (14.27-26.88 mg/kg) and 11.99 mg/kg (9.37-14.17 mg/kg), respectively. The ED(50)s (95% confidence limits) of ropinirole and bromocriptine on the catalepsy induced by reserpine were 18.55 mg/kg (15.29-22.99 mg/kg) and 12.56 mg/kg (10.25-14.64 mg/kg), respectively. Ropinirole and bromocriptine had no effect on the tremors induced by oxotremorine in mice, whereas atropine markedly suppressed the tremors. The ED(50)s (95% confidence limits) of ropinirole and bromocriptine on the tremors in VMT-lesioned monkeys were 0.18 mg/kg (0.12-0.29 mg/kg) and 2.63 mg/kg (1.06-6.45 mg/kg), respectively. In rodent parkinsonian models, bromocriptine was more potent than ropinirole; however, in the nonhuman primate parkinsonian model, ropinirole was a more potent inhibitor of parkinsonian activity than bromocriptine. This study suggests that ropinirole is a dopamine D(2)-like receptor agonistic drug of potential use in the treatment of Parkinson's disease.
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PMID:Effects of ropinirole on various parkinsonian models in mice, rats, and cynomolgus monkeys. 1068 91

The objectives of this study were to measure the pharmacokinetics of ropinirole at steady state when the drug is used as an adjunct to L-dopa and evaluate the long-term tolerability of ropinirole in this indication. Twenty-four patients who were taking L-dopa for Parkinson's disease and experiencing a lack of symptomatic control were recruited. Patients received open-label adjunctive treatment with ropinirole for up to 2 years. The starting dose was 0.5 mg bid, which could be titrated to a maximum of 6.0 mg tid. Ropinirole demonstrated approximately dose-linear pharmacokinetics at steady state; corresponding values were higher during tid than bid dosing. A reduction in mean L-dopa dose was maintained throughout the trial. The combination of L-dopa and ropinirole was generally well tolerated, with only 1 patient withdrawing from treatment because of adverse events. Thus, ropinirole shows approximately linear steady-state pharmacokinetics and a good safety profile when administered with L-dopa.
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PMID:Linear pharmacokinetic behavior of ropinirole during multiple dosing in patients with Parkinson's disease. 1086 15

The dopamine receptor agonist ropinirole (SKF-101468) is used to treat Parkinson's disease. Ropinirole is metabolized by two routes to a series of different metabolites although the predominant pathway is species-dependent. It is unknown whether any of the metabolites contribute to its antiparkinsonian activity and whether D3 or D2 receptor agonist activity plays a preferential role. Therefore ropinirole and its primary metabolites, SKF-104557, SKF-97930 and SKF-96990, and the rat metabolite, SKF-89124 were tested in the 6-hydroxydopamine lesion model of Parkinson's disease. SKF-89124 and SKF-96990 were also assayed in radioligand binding and microphysiometer functional assays at cloned human dopamine D2 and D3. Ropinirole and SKF-89124 were equipotent in-vivo, and produced dose-related increases in circling at 0.05-0.8 mg kg(-1), s.c. (ropinirole) and 0.05-0.75 mg kg(-1), s.c. (SKF-89124). Neither SKF-96990 or SKF-97930, at doses up to 15 mg kg(-1), increased the circling rate. Some circling was observed with 15 mg kg(-1) SKF-104557 but the response was less than half that produced by ropinirole (0.8 mgkg(-1)). SKF-104557 was 150-fold less potent than ropinirole. SKF-89124 possessed-30-fold higher affinity for D3 over D2 receptors in radioligand binding studies, but was not selective in the functional microphysiometer assay. SKF-96990 was 10-fold selective for D3 over D2 receptors in the radioligand binding assay. Ropinirole and SKF-104557 are 20-fold selective for D3 over D2 receptors in radioligand binding assays whereas in microphysiometry, selectivity is 10-fold. SKF-97930 is inactive in radioligand binding and microphysiometer assays. Primary metabolites of ropinirole did not contribute significantly to its activity in this model of Parkinson's disease. The lack of dopamine D3/D2 receptor selectivity for ropinirole rules out the possibility of attributing the degree of either D2 or D3 receptor activity to the behavioural efficacy of ropinirole.
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PMID:Comparative pharmacological study of ropinirole (SKF-101468) and its metabolites in rats. 1104 94

Ropinirole is a selective non-ergoline dopamine D2 receptor agonist indicated for use in treating Parkinson's disease. When taken as oral tablets, ropinirole is rapidly and almost completely absorbed, and it is extensively distributed from the vascular compartment. The bioavailability is approximately 50%. Ropinirole shows low plasma protein binding. The drug is inactivated by metabolism in the liver, and none of the major circulating metabolites have pharmacological activity. The principal metabolic enzyme is the cytochrome P450 (CYP) isoenzyme CYP1A2. Ropinirole shows approximately linear pharmacokinetics when given as single or repeated doses, and is eliminated with a half-life of approximately 6 hours. Population pharmacokinetics have demonstrated that gender, mild or moderate renal impairment, Parkinson's disease stage and concomitant illnesses or the use of several common concomitant medications have no effect on the pharmacokinetics of ropinirole. Clearance is slower for patients older than 65 years compared with those who are younger, and in women taking hormone replacement therapy compared with those who are not. The CYP1A2 inhibitor ciprofloxacin produced increases in the plasma concentrations of ropinirole when these 2 drugs were coadministered, but no interaction was seen with theophylline which, like ropinirole, is also a substrate for CYP1A2. There is no obvious plasma concentration-effect relationship for ropinirole.
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PMID:Clinical pharmacokinetics of ropinirole. 1106 11

The effects of ropinirole (4-[2-(dipropylamino)ethyl]-2-indolinone monohydrochloride), a nonergoline dopamine receptor agonist with a high affinity for native dopamine D(2)-like receptors, on Parkinsonism induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), 2.5 mg/animal in common marmosets were examined and compared to the effects of bromocriptine. Ropinirole (0.1-3 mg/kg, PO) increased motor activity dose dependently and reversed akinesia or uncoordinated movement in MPTP-treated marmosets. The activities for ropinirole were very similar to those of bromocriptine. Ropinirole had, however, several properties that differed from those of bromocriptine. Ropinirole caused a more rapid onset of anti-Parkinsonian activity compared to bromocriptine, and had a potency more than five times greater than that of bromocriptine in the improvement of motor deficits. The combination of ropinirole and L-DOPA increased the effectiveness of ropinirole or L-DOPA alone, and produced a more marked additive effect on motor activity than did bromocriptine and L-DOPA. Chronic administration of ropinirole for 21 days produced a statistically significant increase in motor activity compared to the initial administration, and akinesia scores, measured through rating the quality of movements, were also improved without obvious dyskinesia. This study suggests that ropinirole is a dopamine D(2)-like receptor agonistic drug of potential use in the treatment of Parkinson's disease.
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PMID:Effects of ropinirole on motor behavior in MPTP-treated common marmosets. 1111 91

To compare the efficacy and tolerability of three dopamine agonists--pergolide (PRG), pramipexole (PRX), and ropinirole (ROP)-and two catechol-O-methyltranferase (COMT) inhibitors-tolcapone (TOL) and entacapone (ENT)-as add-on therapies to levodopa (L-Dopa) in Parkinson's disease, we analyzed randomized, double-blind, placebo-controlled, multicenter studies. To our knowledge, they had not yet been evaluated in comparison with each other. Statistical analyses used odds ratios, numbers needed to harm, and Fisher's inverse chi2 method. Seven studies meeting the inclusion criteria included treatment of 1,756 patients. The common efficacy measures were the reduction of L-Dopa dose and "off' duration. The reported reduction in L-Dopa dose was significant for all drugs in relation to placebo, but was most significant for PRX and ENT (p < 0.0001). The most significant reduction in "off' duration was with PRG, PRX, and ENT (p < 0.001). The common tolerability measures were the percentage of patients withdrawn because of side effects, because of any reason, and because of the development of dyskinesias. Ropinirole, PRX, and ENT caused fewer withdrawals related to side effects. Pergolide was better than other analyzed drugs concerning withdrawals for any reason. All drugs caused more dyskinesias than placebo (p < 0.0001), with overlapping confidence intervals, except for TOL 600 mg, which caused more dyskinesias than dopamine agonists and ENT. Pramipexole and ENT had the best efficacy and tolerability profile in this analysis.
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PMID:A comparison of dopamine agonists and catechol-O-methyltransferase inhibitors in Parkinson's disease. 1115 93

Ropinirole is effective as mono- and combination therapy in PD. Previous studies have used a maximal dose of 24 mg/day; the present study assesses the effect of higher doses (up to 36 mg/day) on patients with motor fluctuations. Outcome measures were changes in the motor function score of the Unified Parkinson's Disease Rating Scale, the duration of dyskinesias and reductions in levodopa dose. 21/22 patients completed the study. The mean daily ropinirole dose at endpoint was 26.2 mg (SD, 4.43 mg, range 20-36 mg). Improvements in motor function (29%) and the duration of dyskinesias (45%) from baseline to endpoint were significant (p < 0.01 and p < 0.05, respectively). The mean levodopa dose fell by 32% during the study (from 599 mg to 409 mg; p = 0.007). Side effects were mild. High-dose ropinirole (20-36 mg/day) was well tolerated and conferred significant clinical benefit on patients with motor fluctuations.
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PMID:High-dose therapy with ropinirole in patients with Parkinson's disease. 1176 29


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