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)

This paper reviews the preclinical study of the novel dopamine agonist pramipexole and its use in early Parkinson's disease (PD). Emphasis will be given to those properties distinguishing this drug from other dopamine agonists, the relevance of the preclinical data to clinical trial results in early PD, and the putative neuroprotective properties of the compound. The conventional dopamine agonists are ergot-derived compounds that are most widely used as adjunctive therapies in advancing Parkinson's disease (PD). Examples of conventional agonists are bromocriptine and pergolide. Pramipexole is an aminobenzothiazole compound, recently introduced for the treatment of both early and advanced PD. Its nonergot structure may reduce the risk of side-effects, considered unique to ergot drugs, such as membranous fibrosis. Pramipexole is a full dopamine agonist with high selectivity for the D2 dopamine receptor family. This family includes the D2, D3 and D4 receptor subtypes. Pramipexole has a 5- to 7-fold greater affinity for the D3 receptor subtype with lower affinities for the D2 and D4 receptor subtypes. The drug has only minimal alpha2-adrenoceptor activity and virtually no other receptor agonism or antagonism. The optimal dopamine receptor activation for the safe and effective treatment of PD is not known. Findings in animal models and clinical studies indicate that activation of the postsynaptic D2 receptor subtype provides the most robust symptomatic improvement in PD. Given its pharmacological profile, it is not surprising that pramipexole was found to be effective in ameliorating parkinsonian signs in animal models. This therapeutic effect has been confirmed in clinical trials in both early and advanced PD. In early disease, it provides a clear reduction in the chief motor manifestations of PD and improved activities of daily living. Perhaps most striking is the large number of clinical trial patients who have remained on pramipexole monotherapy for many months. The majority of these subjects have been maintained on pramipexole for an excess of 24 months without requiring additional symptomatic treatment with levodopa. This is in contrast to the general clinical experience with older conventional agonists. Pramipexole also has a favourable pharmacokinetic profile. It is rapidly absorbed with peak levels appearing in the bloodstream within 2 h of oral dosing. It has a high absolute bioavailability of > 90% and can be administered without regard to meals. It has no significant effects on other antiparkinson drugs such as levodopa or selegiline. Its excretion is primarily renal and, thus, has little or no impact on hepatic cytochrome P450 enzymes or other related metabolic pathways. Pramipexole has also been theorized to have 'neuroprotectant' properties. Oxyradical generation is posited as a cause or accelerant of brain nigral cell death in PD. Pramipexole stimulates brain dopamine autoreceptors and reduces dopamine synthesis and turnover which may minimize oxidative stress due to dopamine metabolism. Furthermore, the compound has a low oxidation potential that may serve as an oxyradical scavenger in the PD brain. In summary, pramipexole is a new antiparkinson medication found to have unique dopamine agonist characteristics and putative neuroprotective properties.
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PMID:Pre-clinical studies of pramipexole: clinical relevance. 1105 54

Pramipexole is a novel nonergoline dopamine agonist with a preference for the dopamine D3 receptor subtype. Its efficacy and safety in the treatment of advanced Parkinson's disease has been investigated in several clinical studies. This review provides a summary of the data currently available, particularly in reference to the recent results of the European clinical phase III study and the potential tremorlytic activity of pramipexole. Interim analysis of the open-label European clinical phase III study has provided evidence of long-term efficacy and safety of pramipexole. In another study pramipexole has been shown to be significantly superior to placebo with an improvement in tremor score by 48% (vs. 13% in the placebo group). In addition to its likely usefulness in the treatment of rest tremor in Parkinson's disease, data suggest that pramipexole is of interest due to its reported low frequency of cardiovascular and gastrointestinal side-effects. However, studies comparing pramipexole with other antiparkinsonian agents would be useful to further define its benefits in the treatment of tremor-dominant Parkinson's disease and to further document its favourable adverse event profile.
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PMID:Pramipexole in the treatment of advanced Parkinson's disease. 1105 55

Ninety-three patients with idiopathic Parkinson's disease (PD) entered a 12 week open-label, baseline controlled, multicentre study. The study was designed to determine the levodopa sparing effect of pramipexole as add-on treatment in PD while maintaining an optimal clinical improvement in motor performance. The overall reduction in adjusted levodopa dose was the primary endpoint. Unified Parkinson's Disease Rating Scale (UPDRS) subscores as well as motor fluctuations, frequency and severity of dyskinesia (assessed by patient diaries) were secondary endpoints. Pramipexole permitted a median reduction of adjusted levodopa by 40% while maintaining or improving the UPDRS scores in 61 patients (per protocol [PP] analysis). The intent-to-treat (ITT) analysis (90 patients) similarly revealed a median reduction of 40%. An anticipated short-term levodopa dose reduction as substantiated by 95% confidence interval calculations lies within a range of 35% to 50%. If unadjusted levodopa doses were considered, a median reduction of 42% (PP) or 43% (ITT) was achieved. 47% patients (ITT) had a levodopa dose reduction (adjusted) of more than 40% while maintaining or improving their level of efficacy, and 72.2% had a reduction of at least 20%. Motor fluctuations improved compared to baseline according to patient diaries and UPDRS part IV. These findings suggest that pramipexole can markedly reduce the daily levodopa dosage without deterioration of motor response and support that this new selective D2/D3 receptor agonist also improves later levodopa-associated motor complications.
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PMID:An open-label, multicentre clinical trial to determine the levodopa dose-sparing capacity of pramipexole in patients with idiopathic Parkinson's disease. 1114 6

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

Objective: To assess the long-term safety and efficacy of pramipexole in advanced Parkinson's disease over a four year time period.Methods: This study is an open-label extension trial of pramipexole for Parkinson's disease open to patients completing a double-blind placebo controlled safety and efficacy trial of this drug. Three hundred and six patients entered the trial. These patients had moderate to severe PD (stage II-IV Hoehn and Yahr during off time) and were experiencing motor fluctuations. Patients were titrated over a six week period and then entered a maintenance phase which lasted up to 50 months. Patients were evaluated every 3 months using the Unified Parkinson's Disease Rating Scale (UPDRS II, III and IV) and modified Schwab and England scale (S/E).Results: Sixty-four percent (197) of the 306 patients who entered this study completed it. Patients showed steady improvement over the 6 week ascending dose interval when pramipexole was reintroduced into the trial as the open-label study medication. Over the duration of the trial patients slowly returned to their baseline levels. This was true for all measures evaluated except for the UPDRS part IV. On UPDRS part IV patients remained below their baseline score which indicated an improvement for the duration of the study. Patterns similar to the overall scores were seen when the individual components of the UPDRS scale part II for "on" and "off" periods and part III were evaluated. However tremor during "on" periods showed improvement over baseline for the duration of the trial. The most common adverse events secondary to pramipexole occurring in greater than 10% of patients included dyskinesias, asymptomatic orthostatic hypotension, dizziness, insomnia, and hallucinations.Conclusion: Pramipexole was well tolerated for up to 4 years. Pramipexole treatment appeared to show continued efficacy in the treatment of Parkinson's disease for 3 years in this open-label descriptive study. After 3 years there was a gradual return to baseline motor states perhaps suggesting progression of Parkinson's disease.
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PMID:The long-term safety and efficacy of pramipexole in advanced Parkinson's disease. 1124 92

Pramipexole is a non-ergot dopamine agonist recently approved for the treatment of early and advanced Parkinson's disease (PD). It has preferential affinity for the D(3) dopamine receptor, compared to previous dopamine agonists that have higher affinity for D(2) dopamine receptors. The ultimate question is whether its efficacy is linked to its action at the D(3) dopamine site or due to its binding to D(2) dopamine receptors. There is no direct experimental evidence available to answer this question. Based on a review of the pharmacological literature, it is likely that the motor benefits of pramipexole in PD patients are due to D(2) stimulation, whereas its putative effects on mood and apathy may be related to its D(3) agonist properties.
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PMID:The use of pramipexole in Parkinson's disease: are its actions D(3) mediated? 1133 Nov 91

This study examined the effect of pramipexole (PPX), a selective dopamine (DA) D(3)/D(2) agonist, on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced damage to the nigrostriatal dopamine system in young (8-week-old) and aged (12-month-old) mice. Co-administration of PPX and MPTP to young or aged mice, followed by 2 or 14 days of additional PPX treatment, significantly attenuated MPTP-induced striatal DA loss. Pramipexole treatment also significantly attenuated the loss of tyrosine hydroxylase immunoreactive neurons (TH-IR) within the substantia nigra pars compacta (SNc) in both young and aged animals. Effects of PPX administration on dopaminergic cell survival were confirmed in Nissl-stained sections and by quantitation of retrogradely labeled Fluorogold-positive SNc neurons. Protective effects of PPX on striatal DA levels and SNc DA neuron survival were similar in young and aged animals, although the magnitude of these effects was significantly less in aged animals. These findings support the early initiation of PPX therapy in Parkinson's disease patients.
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PMID:Neuroprotective effects of pramipexole in young and aged MPTP-treated mice. 1142 78

Parkinson's disease (PD) is a common neurodegenerative disorder characterised by selective loss of dopaminergic neurones in the substantia nigra and resulting in progressive disability. Therapy has focused on replacing depleted dopamine (DA) via supplementation with levodopa or DA agonists. Pramipexole (Mirapex), Pharmacia Corp.) has recently been approved for the treatment of PD. Evidence from preclinical studies and clinical trials have proven the effectiveness of this agent in ameliorating the symptoms of PD. There is also non-human evidence that pramipexole may be neuroprotective and could therefore possibly slow disease progression; however, this has yet to be proven in humans. The use of pramipexole may be limited by its side effect profile compared to standard therapies and its relatively higher cost compared to levodopa. Despite these concerns, pramipexole does have a role in the treatment of PD in all stages of the illness and may arguably be the treatment of choice in early disease. In addition to its use in PD, pramipexole has shown some utility in the treatment of restless legs syndrome (RLS), depression and schizophrenia.
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PMID:A review of pramipexole and its clinical utility in Parkinson's disease. 1182 33

Levodopa should generally be avoided early in the course of Parkinson disease; dopamine agonists, particularly second-generation agents such as ropinirole (Requip) and pramipexole (Mirapex), carry a smaller long-term risk of dyskinesia and should be used instead. Deep brain stimulation is remarkably effective in refractory cases and may well usher in a new era in the treatment of chronic neurologic disease.
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PMID:Two advances in the management of Parkinson disease. 1218 72

Pramipexole is a novel, internationally available selective nonergot D2 dopamine agonist. The effectiveness, tolerability, and safety of pramipexole have been extensively proven in controlled trials in patients in the early and advanced stage of Parkinson's disease as monotherapy and in combination with L dopa. These trials indicated specific activity against tremor, anhedonia, and depression. Therefore, the present prospective, multicenter postmarketing surveillance study evaluated for the first time to what extent the results from the controlled pramipexole trials could be replicated under routine conditions in neurological practice and clinics. Modern scales were applied for the assessment of tremor and mood, i.e., the Short Parkinson's Evaluation Scale (SPES), the Tremor Impact Scale (TIS), and the German version of the Snaith-Hamilton Pleasure Scale (SHAPS-D). In 298 German Centers, 657 Parkinson's patients (365 men, 292 women) in advanced disease stages were treated with pramipexole in combination with levodopa. The average ages (+/- SD) were 67 (+/- 8.9) years for men and 69 (+/- 9.4) years for females. Motor functioning, especially tremor, motor complications, depression, and activities of daily living improved highly significantly (P < 0.0005), including self-rating by the patients. The dosage of levodopa could be reduced on average by 8% (P < 0.0001). This might contribute to a slowing of the disease progression in the long run. Dropouts due to side effects were observed only in 3.5% of the patients. Using new assessment scales suitable for routine application allowed confirmation of the results from controlled clinical trials with regard to tremor, anhedonia, and depression. The average daily dosage of pramipexole prescribed was 1.05 mg and thus was definitely lower than the average daily dosages of 2.35-2.66 mg used in controlled trials. This signifies that the option to adjust dosage according to effectiveness and tolerability under routine conditions yields a considerably lower incidence of adverse effects.
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PMID:[Pramipexole in Parkinson disease. Results of a treatment observation]. 1224 61


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