ergoline 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

Restless legs syndrome (RLS) is a common neurological disorder that might impair nocturnal rest causing decreased alertness, depressed mood, reduced job performance, and poor quality of life. In patients affected by severe RLS, a pharmacological treatment is mandatory.. The present review is based on a search using PubMed from 1994 to 2012. It is focused on the Absorption, Distribution, Metabolism, Elimination and Toxicology (ADMET) characteristics of the most used medications for RLS. In particular, the ADMET characteristics of dopaminergic agents, anticonvulsants able to improve neuropathic pain, and iron were discussed.. Clinical trials have showed that non-ergolic dopamine agonists are efficacious and safe for patients affected by moderate to severe idiopathic RLS. However, no head-to-head study has compared the long-term effects of the three dopamine agonists approved by the FDA for RLS (ropinirole, pramipexole, and rotigotine). Moreover, further studies should investigate the extended-release formulation of ropinirole and pramipexole in RLS patients affected by all day long distressing symptoms. A standardized treatment for symptomatic forms of RLS is lacking. Randomized, placebo-controlled trials should be performed at least in RLS patients with peripheral neuropathic and chronic kidney disease. Concerning RLS due to iron deficiency, a head-to-head study comparing efficacy, safety and compliance of oral iron versus intravenous one seems to be needed.

Topics: Amines; Anticonvulsants; Benzothiazoles; Carbamates; Cyclohexanecarboxylic Acids; Dopamine Agents; Dopamine Agonists; Ergolines; Gabapentin; gamma-Aminobutyric Acid; Humans; Indoles; Levodopa; Neuralgia; Pramipexole; Pregabalin; Randomized Controlled Trials as Topic; Restless Legs Syndrome; Tetrahydronaphthalenes; Thiophenes; Treatment Outcome

A systematic literature review and meta-analyses (where appropriate) were performed to update the previous AASM practice parameters on the treatments, both dopaminergic and other, of RLS and PLMD. A considerable amount of literature has been published since these previous reviews were performed, necessitating an update of the corresponding practice parameters. Therapies with a STANDARD level of recommendation include pramipexole and ropinirole. Therapies with a GUIDELINE level of recommendation include levodopa with dopa decarboxylase inhibitor, opioids, gabapentin enacarbil, and cabergoline (which has additional caveats for use). Therapies with an OPTION level of recommendation include carbamazepine, gabapentin, pregabalin, clonidine, and for patients with low ferritin levels, iron supplementation. The committee recommends a STANDARD AGAINST the use of pergolide because of the risks of heart valve damage. Therapies for RLS secondary to ESRD, neuropathy, and superficial venous insufficiency are discussed. Lastly, therapies for PLMD are reviewed. However, it should be mentioned that because PLMD therapy typically mimics RLS therapy, the primary focus of this review is therapy for idiopathic RLS.

Topics: Academies and Institutes; Benzothiazoles; Cabergoline; Carbamates; Dopamine Agents; Ergolines; Evidence-Based Medicine; gamma-Aminobutyric Acid; Humans; Indoles; Levodopa; Nocturnal Myoclonus Syndrome; Pergolide; Peripheral Nervous System Diseases; Pramipexole; Restless Legs Syndrome; Sleep Medicine Specialty; United States; Venous Insufficiency

Restless legs syndrome (RLS) is a common neurological disorder characterized by an urge to move the legs. The symptoms show a strong circadian rhythmicity, with onset or increase in the evening or at night; thus, sleep disturbances are the most frequent reason for patients seeking medical aid. The prevalence of the disorder increases strongly with age, with an estimated 9% to 20% of sufferers being among the elderly. Dopaminergic drugs are the first-line treatment option in RLS; opioids and anticonvulsants can also be used either as add-on or stand alone therapy options. Secondary forms of RLS and possible interaction with other medications require particular consideration in the elderly.

Topics: Aged, 80 and over; Benzothiazoles; Cabergoline; Circadian Rhythm; Cognition Disorders; Comorbidity; Diagnosis, Differential; Dopamine Agonists; Ergolines; Humans; Indoles; Polysomnography; Pramipexole; Prevalence; Restless Legs Syndrome; Sleep Wake Disorders

Dopamine agonists (DAs), which can be categorized as ergot derived and non-ergot derived, are used in the treatment of Parkinson's disease.. This review describes the pharmacologic and pharmacokinetic properties of selected DAs and relates these characteristics to clinical outcomes, with an emphasis on adverse events.. Relevant articles were identified through a search of MEDLINE (to May 2006) using the terms dopamine agonists (or each individual drug name) and pbarmacokinetics, metabolism, drug-drug interaction, interactions, CYP450, fibrosis, valvular heart disease, tremor, clinical trials, reviews, and meta-analyses. Abstracts from recent sessions of the International Congress of Parkinson's Disease and Movement Disorders were also examined. Clinical studies with <20 patients overall or <10 patients per treatment group in the final analysis were excluded. All DAs that were graded at least possibly useful with respect to at least 3 of 4 items connected to the treatment/prevention of motor symptoms/complications in the most recent evidence-based medical review update were included. This resulted in a focus on the ergot-derived DAs bromocriptine, cabergoline, and pergolide, and the non-ergot-derived DAs pramipexole and ropinirole.. Bromocriptine, cabergoline, pergolide, and ropinirole, but not pramipexole, have the potential for drug-drug interactions mediated by the cytochrome P450 (CYP) enzyme system. The occurrence of dyskinesia may be linked to stimulation of the dopamine D(1) receptor, for which cabergoline and pergolide have a similar and relatively high affinity; bromocriptine, pramipexole, and ropinirole have been associated with a lower risk of dyskinesias. The valvular heart disease (VHD) and pulmonary and retroperitoneal fibrosis seen with long-term use appear to represent a class effect of the ergot-derived DAs that may be related to stimulation of serotonin 5-HT(2B) (and possibly 5-HT(2A)) receptors. The incidence of valvular regurgitation was 31% to 47% with ergot-derived DAs, 10% with non-ergot-derived DAs, and 13% with controls.. As reflected in the results of the clinical trials included in this review, dyskinesia associated with DA therapy may be linked to stimulation of the D(1) receptor. Fibrosis (including VHD) seemed to be a class effect of the ergot-derived DAs. Each of the DAs except pramipexole has the potential to interact with other drugs via the CYP enzyme system.

Topics: Animals; Bromocriptine; Cabergoline; Dopamine Agonists; Drug Interactions; Dyskinesia, Drug-Induced; Ergolines; Heart Valve Diseases; Humans; Indoles; Pergolide; Pulmonary Fibrosis; Receptors, Dopamine

The objective of this study is to update a previous evidence-based medicine (EBM) review on Parkinson's disease (PD) treatments, adding January 2001 to January 2004 information. The Movement Disorder Society (MDS) Task Force prepared an EBM review of PD treatments covering data up to January 2001. The authors reviewed Level I (randomized clinical trials) reports of pharmacological and surgical interventions for PD, published as full articles in English (January 2001-January 2004). Inclusion criteria and ranking followed the original program and adhered to EBM methodology. For Efficacy Conclusions, treatments were designated Efficacious, Likely Efficacious, Non-Efficacious, or Insufficient Data. Four clinical indications were considered for each intervention: prevention of disease progression; treatment of Parkinsonism, as monotherapy and as adjuncts to levodopa where indicated; prevention of motor complications; treatment of motor complications. Twenty-seven new studies qualified for efficacy review, and others covered new safety issues. Apomorphine, piribedil, unilateral pallidotomy, and subthalamic nucleus stimulation moved upward in efficacy ratings. Rasagiline, was newly rated as Efficacious monotherapy for control of Parkinsonism. New Level I data moved human fetal nigral transplants, as performed to date, from Insufficient Data to Non- efficacious for the treatment of Parkinsonism, motor fluctuations, and dyskinesias. Selegiline was reassigned as Non-efficacious for the prevention of dyskinesias. Other designations did not change. In a field as active in clinical trials as PD, frequent updating of therapy-based reviews is essential. We consider a 3-year period a reasonable time frame for published updates and are working to establish a Web-based mechanism to update the report in an ongoing manner.

Topics: Amantadine; Antiparkinson Agents; Apomorphine; Benzophenones; Benzothiazoles; Bromocriptine; Cabergoline; Catechol O-Methyltransferase Inhibitors; Deep Brain Stimulation; Dihydroergocryptine; Ergolines; Fetal Tissue Transplantation; Globus Pallidus; Humans; Indans; Indoles; Levodopa; Lisuride; Mesencephalon; Monoamine Oxidase Inhibitors; Neurosurgical Procedures; Nitrophenols; Parkinson Disease; Pergolide; Piribedil; Pramipexole; Selegiline; Thiazoles; Tolcapone

Topics: Aminoquinolines; Benzothiazoles; Bromocriptine; Cabergoline; Clinical Trials as Topic; Dopamine Agonists; Ergolines; Ergoloid Mesylates; Female; Humans; Hyperprolactinemia; Indoles; Pergolide; Pramipexole; Thiazoles

Dopamine agonists have been widely used as add-on to levodopa in the treatment of Parkinson's disease with motor fluctuations. However, the use of dopamine agonists in early Parkinson's disease and levodopa-naive patients is controversial. Although dopamine agonists have been compared with levodopa, no studies exist which directly compare one dopamine agonist with another. This evidence-based review compares the results of large published studies of early treatment of Parkinson's disease with dopamine agonists (cabergoline, ropinirole or pramipexole) with similar studies using levodopa. Because of their design, the common variables analysed in all studies were the proportion of patients who developed dyskinesia, those withdrawn from the trial and the mean change from baseline in Unified Parkinson's Disease Rating Scale (UPDRS) parts II and III scores. Cabergoline, pramipexole and ropinirole were similarly effective in reducing the risk for dyskinesia relative to levodopa (p < 0.01 for all three). The reduction in risk for dyskinesia was slightly more evident for pramipexole and ropinirole (p < 0.0001) than cabergoline (p = 0.0074). Odds ratios (95% confidence intervals [CI]) relative to levodopa were 0.38 (0.19-0.78) for cabergoline, 0.25 (0.13-0.47) for pramipexole and 0.31 (0.18-0.53) for ropinirole. The absolute risk reductions (95% CI) were, respectively, 8% (2.2-13.7), 20% (11.7-29.8) and 25% (13.6-36.7), ropinirole reducing the risk significantly more than cabergoline. The mean change from baseline UPDRS was similar for pramipexole and ropinirole (not evaluated for cabergoline). The proportion of withdrawn patients and the adverse effect profiles of the three agonists were similar to each other, with the exception of oedema, which was less prominent for ropinirole than for the other two agonists. Cabergoline, pramipexole and ropinirole are comparable choices for the delay of dyskinesia. Their adverse effect profiles are also similar, but they are less well tolerated than levodopa. The motor antiparkinsonian benefit of dopamine agonists is somewhat smaller than that of levodopa.

Topics: Age of Onset; Benzothiazoles; Cabergoline; Dopamine Agonists; Double-Blind Method; Ergolines; Evidence-Based Medicine; Humans; Indoles; Levodopa; Parkinson Disease; Pramipexole; Thiazoles

Topics: Antiparkinson Agents; Benzothiazoles; Bromocriptine; Cabergoline; Controlled Clinical Trials as Topic; Dopamine Agonists; Ergolines; Humans; Indoles; Lisuride; Parkinson Disease; Pergolide; Piribedil; Placebos; Pramipexole; Serotonin Receptor Agonists; Thiazoles; Time Factors

Levodopa is the gold-standard therapy for Parkinson's disease. However, long-term treatment leads to involuntary movements and response fluctuations which add to the complexities of later disease-management. In addition, preclinical evidence suggests that levodopa is toxic to dopaminergic neurons. These problems have led to a move away from levodopa towards initial monotherapy with a dopamine agonist.. Positron-emission tomography (PET) and single-photon emission computed tomography (SPECT) tracers have been developed which may be considered surrogate markers for remaining dopaminergic neurons. In a randomised controlled trial in patients with early Parkinson's disease, the Parkinson Study Group used 123I-beta-CIT SPECT (JAMA 2002; 287: 1653-61). Those patients given pramipexole had significantly reduced loss of striatal uptake at 46 months compared with those given levodopa (16.0% vs 25.5%). In a similar trial, Alan Whone and colleagues used 18F-DOPA PET (Neurology 2002; 58 [suppl 3]: A82-83). Patients given ropinirole had significantly reduced loss of striatal uptake at 24 months compared with those given levodopa (13% vs 20%). These studies suggest that agonist monotherapy may be neuroprotective and/or that levodopa is toxic. This work has been criticised as the SPECT results may have resulted from a differential effect of the agonist and levodopa on the regulation of the dopamine transporter, thereby influencing the imaging outcome measure. Other criticisms include insufficient data on the use of the potential neuroprotectant selegiline and patients on pramipexole in the SPECT study appear to have been clinically slow progressors. Single clinical trials with each of the four modern agonists compared with levodopa show that as monotherapy the agonists delay the onset of involuntary movements, although at the expense of poorer treatment of motor impairments and disability and more dopaminergic adverse events. The only health-related quality of life data show no difference between pramipexole and levodopa after 4 years. No information on health-economics measures is available but agonists cost two to three times as much as levodopa. WHERE NEXT? Young patients should be treated with agonist monotherapy since the trials included predominantly younger patients who have a higher incidence of motor complications. Those with significant co-morbidity, dementia, or a short life-expectancy should be treated with the lowest dose of levodopa required to maintain motor function. For the vast majority though, no clear guidance can be given. Further large-scale pragmatic trials in large numbers of patients over prolonged periods are urgently required.

Topics: Benzothiazoles; Cabergoline; Dopamine Agonists; Ergolines; Humans; Indoles; Levodopa; Middle Aged; Parkinson Disease; Pergolide; Pramipexole; Randomized Controlled Trials as Topic; Thiazoles; Tomography, Emission-Computed; Tomography, Emission-Computed, Single-Photon

With the availability of newer dopamine agonists selective for dopamine (D2) receptor subtypes, medical management of Parkinson's disease has progressed substantially. These agents can decrease the frequency of ergot-related side effects and dyskinesias. Also, when given as adjunctive therapy with levodopa, they can allow the levodopa maintenance dosage to be reduced without loss of symptom control. Based on early clinical experience, dopamine agonists can also be prescribed as initial monotherapy and can delay therapy with levodopa. Their therapeutic roles will be defined further by long-term studies.

Topics: Benzothiazoles; Cabergoline; Dopamine Agonists; Drug Interactions; Ergolines; Humans; Indoles; Parkinson Disease; Pramipexole; Thiazoles

Since the introduction of levodopa to treat Parkinson's disease (PD), several new therapies have been directed at improving symptom control, which can decline after a few years of levodopa therapy. Dopaminergic agents can serve as adjuncts or as alternatives to levodopa. In addition, a new class of drugs, catechol-O-methyltransferase inhibitors, can extend the duration of levodopa action. Although surgical options such as pallidotomy offer improvement of parkinsonism beyond the realm of pharmacologic treatment, judicious administration of drugs in combination can generally solve most problems of PD.

Topics: Antiparkinson Agents; Benzophenones; Benzothiazoles; Cabergoline; Catechol O-Methyltransferase Inhibitors; Dopamine Agonists; Drug Synergism; Enzyme Inhibitors; Ergolines; Humans; Indoles; Levodopa; Nitrophenols; Parkinson Disease; Pramipexole; Thiazoles; Tolcapone

The occurrence of side effects with long-term levodopa therapy, such as fluctuations in motor performance or abnormal movements, led to a search for new antiparkinsonian drugs. Dopamine agonists include ergot derivatives such as bromocriptine, lisuride, pergolide, and cabergoline and other agents which do not possess the ergot structure such as pramipexole and ropinirole. They all are powerful stimulators of the D2 dopamine receptor which probably underlies their therapeutic effects. The clinical consequences of their binding to other dopamine receptor subtypes (D1 or D3) remains unknown. They are usually prescribed in combination with levodopa when late side effects begin to occur. This review summarizes the available pharmacologic and clinical data to support the early use of dopamine agonists in Parkinson's disease. Several strategies can be used, such as monotherapy or "early" or "late" combination with levodopa. Results of recent well-performed, modern clinical trials show that early use of the new dopamine agonists is able to effectively control the clinical symptoms for more than 3 years thereby offering the possibility of delaying the occurrence of levodopa-induced late motor side effects.

Topics: Benzothiazoles; Bromocriptine; Cabergoline; Dopamine Agonists; Dose-Response Relationship, Drug; Drug Therapy, Combination; Ergolines; Humans; Indoles; Levodopa; Lisuride; Parkinson Disease; Pergolide; Pramipexole; Receptors, Dopamine D2; Thiazoles

Oral levodopa is the most effective symptomatic treatment for Parkinson's disease. Dopamine agonists are useful adjuvants to levodopa in the pharmacotherapy of parkinsonian patients. Monotherapy with dopamine agonists in early Parkinson's disease has been advocated in order to delay the occurrence of complications associated with long term administration of levodopa. The use of dopamine agonists alone provides an adequate antiparkinsonian effect in only a minority of patients. In early stages of Parkinson's disease, dopamine agonists can produce a clinical response comparable with levodopa but, thereafter, their efficacy wanes. Early initiation of combination therapy with levodopa and dopamine agonists appears to reduce the severity and delay the appearance of the complications associated with long term administration of levodopa. Currently, dopamine agonists are most commonly used in combination with levodopa in patients in advanced stages of the disease who experience fluctuations of their motor symptoms. Despite their different pharmacodynamic and pharmacokinetic profiles, the ergot derivatives bromocriptine, lisuride and pergolide appear to be very similar in terms of their clinical efficacy. Continuous dopaminergic stimulation by parenteral infusion of water-soluble dopamine agonists such as apomorphine and lisuride can overcome motor fluctuations in advanced Parkinson's disease. Other dopamine agonists such as cabergoline, pramipexole and ropinirole are currently being studied. Further studies with these compounds will be required to determine their efficacy and adverse effects in comparison with the currently available orally active ergot agonists. It has been suggested that oxidative stress resulting from dopamine metabolism may be reduced by the administration of dopamine agonists. These drugs may therefore slow the rate of progression of Parkinson's disease. At present, however, there is no convincing clinical data to support a neuroprotective effect of dopamine agonists.

Topics: Animals; Antiparkinson Agents; Apomorphine; Benzothiazoles; Cabergoline; Dopamine Agonists; Ergolines; Ergot Alkaloids; Humans; Indoles; Neuroprotective Agents; Parkinson Disease; Pramipexole; Thiazoles

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

Topics: Antiparkinson Agents; Bromocriptine; Cabergoline; Dopamine Agonists; Ergolines; Humans; Indoles; Parkinson Disease

Dopamine agonists (DAGs) were first used in patients with moderate or advanced Parkinson's disease (PD). At that time, it was thought that DAGs could replace levodopa (LD) with fewer side effects. However, it soon became clear that while they could not replace LD, they did allow reduction of the dose of LD and diminished its side effects. Since the use of DAGs reduces response fluctuations as well as dyskinesias, there is a tendency to introduce them in the first stages of the disease, trying to delay motor fluctuations. While many DAGs have been developed, only four have been marketed and are used extensively for the treatment of Parkinson's disease: apomorphine, bromocriptine, lisuride and pergolide. In the present chapter, following a review of the "old" DAGs, the experience with three new promising DAGs is reported: cabergoline, ropinirole and pramipexole.

Topics: Antiparkinson Agents; Benzothiazoles; Cabergoline; Dopamine Agonists; Drugs, Investigational; Ergolines; Humans; Indoles; Parkinson Disease; Pramipexole; Thiazoles

Fibrotic valvular heart disease (VHD) has been reported in association with ergot dopamine agonists (DAs), but the current database is insufficient regarding clinical relevance and comparison to data on non-ergot DAs. We evaluated the effects of four DAs (pergolide, cabergoline, ropinirole, pramipexole) on morphology and function of heart valves in patients with Parkinson's disease (PD) to determine the frequency and clinical relevance of DA-induced VHD. A total of 85 patients treated with ergot or non-ergot DAs and 38 age-matched controls were evaluated by transthoracic echocardiography. Valvular pathology was assessed by established criteria of valvular regurgitation and a VHD scoring system. Both grading systems revealed increased frequency of VHD in ergot DA patients compared to both non-ergot DA patients and controls with 22% of ergot DA patients having moderate VHD versus 3% of non-ergot DA patients and none of controls (P = 0.001). We did not find correlations of echocardiographic findings with duration/cumulative dose of treatment, age, or vascular risk factors. Our data suggest that ergot DAs are associated with higher prevalence of VHD compared to non-ergot DAs and controls. Standard echocardiography seems sufficient to detect VHD in PD patients treated with DAs.

Topics: Benzothiazoles; Cabergoline; Dopamine Agonists; Double-Blind Method; Echocardiography; Ergolines; Female; Fibrosis; Heart Valve Diseases; Humans; Hypertrophy, Left Ventricular; Indoles; Male; Middle Aged; Mitral Valve Insufficiency; Parkinson Disease; Pergolide; Pramipexole; Severity of Illness Index; Tricuspid Valve Insufficiency

Dopamine agonists have been widely used as add-on to levodopa in the treatment of Parkinson's disease with motor fluctuations. However, the use of dopamine agonists in early Parkinson's disease and levodopa-naive patients is controversial. Although dopamine agonists have been compared with levodopa, no studies exist which directly compare one dopamine agonist with another. This evidence-based review compares the results of large published studies of early treatment of Parkinson's disease with dopamine agonists (cabergoline, ropinirole or pramipexole) with similar studies using levodopa. Because of their design, the common variables analysed in all studies were the proportion of patients who developed dyskinesia, those withdrawn from the trial and the mean change from baseline in Unified Parkinson's Disease Rating Scale (UPDRS) parts II and III scores. Cabergoline, pramipexole and ropinirole were similarly effective in reducing the risk for dyskinesia relative to levodopa (p < 0.01 for all three). The reduction in risk for dyskinesia was slightly more evident for pramipexole and ropinirole (p < 0.0001) than cabergoline (p = 0.0074). Odds ratios (95% confidence intervals [CI]) relative to levodopa were 0.38 (0.19-0.78) for cabergoline, 0.25 (0.13-0.47) for pramipexole and 0.31 (0.18-0.53) for ropinirole. The absolute risk reductions (95% CI) were, respectively, 8% (2.2-13.7), 20% (11.7-29.8) and 25% (13.6-36.7), ropinirole reducing the risk significantly more than cabergoline. The mean change from baseline UPDRS was similar for pramipexole and ropinirole (not evaluated for cabergoline). The proportion of withdrawn patients and the adverse effect profiles of the three agonists were similar to each other, with the exception of oedema, which was less prominent for ropinirole than for the other two agonists. Cabergoline, pramipexole and ropinirole are comparable choices for the delay of dyskinesia. Their adverse effect profiles are also similar, but they are less well tolerated than levodopa. The motor antiparkinsonian benefit of dopamine agonists is somewhat smaller than that of levodopa.

Topics: Age of Onset; Benzothiazoles; Cabergoline; Dopamine Agonists; Double-Blind Method; Ergolines; Evidence-Based Medicine; Humans; Indoles; Levodopa; Parkinson Disease; Pramipexole; Thiazoles

An alternative approach to the symptomatic treatment of parkinsonian patients with and without motor fluctuations is to use dual dopamine agonists. The aim of this study was to investigate the symptomatic effect of administrating a second dopamine agonist to parkinsonian patients already assuming pramipexole or ropinirole. As the second dopamine agonist we chose cabergoline, a drug with a long half life, whose pharmacological profile differs from that of the newer non-ergot-derived dopamine-receptor agonists. In this pilot study we enrolled 27 patients: 21 patients had motor fluctuations and were receiving levodopa plus a dopamine agonist, and 6 patients without motor fluctuations were receiving a dopamine agonist without levodopa. This open study shows that dual dopamine agonist therapy (cabergoline plus pramipexole or ropinirole) may be used in the symptomatic treatment of patients with Parkinson's disease receiving therapy with or without levodopa.

Topics: Aged; Antiparkinson Agents; Benzothiazoles; Cabergoline; Dopamine Agonists; Drug Therapy, Combination; Ergolines; Female; Humans; Indoles; Levodopa; Male; Middle Aged; Parkinson Disease; Pramipexole; Prospective Studies; Thiazoles; Treatment Outcome

Although 6-hydroxydopamine-induced (6-OHDA-induced) rats are a well-known Parkinson's disease model, the effects of dopamine D2 agonists in mice with 6-OHDA-induced lesions are not completely understood. We produced mice with 6-OHDA-induced lesions and measured their total locomotion counts following administration of several dopamine D2 agonists (pramipexole, ropinirole, cabergoline, rotigotine, apomorphine, talipexole, and quinelorane). Cabergoline showed the longest duration of drug action, which was in agreement with its long-lived anti-Parkinson effects in rats and humans. In contrast, pramipexole and ropinirole had notably short durations of drug action. We demonstrated that mice with 6-OHDA-induced lesions accompanied with significant lesions in the striatum may be reasonable models to predict the action duration of anti-Parkinson drug candidates in humans.

Topics: Animals; Antiparkinson Agents; Apomorphine; Azepines; Benzothiazoles; Cabergoline; Corpus Striatum; Disease Models, Animal; Dopamine Agonists; Ergolines; Indoles; Injections, Intraventricular; Male; Mice; Motor Activity; Oxidopamine; Parkinsonian Disorders; Pramipexole; Quinolines; Receptors, Dopamine D2; Tetrahydronaphthalenes; Thiophenes

Problems with impulse control and pathological gambling are known as possible side effects of dopaminergic therapy in patients with Parkinson's disease. We report 2 cases of pathological gambling induced by dopamine agonists in patients without Parkinson's disease. The first patient, a 46-year-old man, was treated with ropinirole for restless legs syndrome and had lost huge amounts of money in the context of internet-based poker game. Another 46-year-old male patient developed pathological gambling under treatment with cabergoline administered for prolactinoma. The two cases implicate pathological gambling as a possible consequence of dopaminergic treatment and support the increasing evidence regarding pathological gambling as an adverse drug reaction of dopaminergic treatment, also in patients who do not suffer from Parkinson's disease.

Topics: Antiparkinson Agents; Cabergoline; Dopamine Agonists; Ergolines; Gambling; Humans; Indoles; International Classification of Diseases; Male; Middle Aged; Pituitary Neoplasms; Prolactinoma; Restless Legs Syndrome

Dopaminergic agents are commonly used and effective treatments for restless legs syndrome (RLS), a disabling sensorimotor disorder. Less known are some of the potentially disabling side effects of these treatments, particularly iatrogenic gambling addiction, as is described here. Here the authors present a 62-year-old man, with a 20-year history of RLS, who developed gambling addiction while on dopaminergic treatment. He was not forewarned of this side effect, nor was he ever screened for gambling behaviours prior to or during treatment. Eight months after discontinuation of dopaminergic treatment and after 10 sessions of cognitive-behavioural therapy for gambling addiction, his gambling behaviours have partially resolved. To our knowledge, this is the first ever first person account of this condition. To prevent the devastating consequences of gambling addiction or to minimise its impact by early intervention, the authors call for clinicians involved in treatment of RLS to follow these simple measures: screen patients for gambling behaviours prior to the onset and during dopaminergic treatment; forewarn patients of this potential side effect; and if patients screen positive, refer them to specialist gambling treatment services, in addition to making necessary changes to their medication regime.

Topics: Cabergoline; Carbidopa; Cognitive Behavioral Therapy; Dopamine Agonists; Drug Combinations; Ergolines; Gambling; Humans; Indoles; Levodopa; Male; Middle Aged; Restless Legs Syndrome; Tetrahydronaphthalenes; Thiophenes

There is growing evidence that the ergot-derived dopamine agonists cabergoline and pergolide can cause fibrotic cardiac valvulopathy. Data on other fibrotic reactions and nonergot-derived dopamine agonists are sparse. Aim of this study was to investigate whether there are signals that dopamine agonists are related to cardiac and other fibrotic reactions. We identified all reports of fibrotic reactions at the heart, lung, and retroperitoneal space associated with dopamine agonists within the US Adverse Event Reporting System database. Disproportionality analyses were used to calculate adjusted reporting odds ratios (RORs). For ergot-derived dopamine agonists (bromocriptine, cabergoline, pergolide), the RORs of all reactions under study were increased, whereas no such increases were observed for nonergot-derived drugs (apomorphine, pramipexole, ropinirole, rotigotine). Fibrotic reactions due to ergot-derived dopamine agonists may not be limited to heart valves. For nonergot-derived dopamine agonists, no drug safety signals were evident.

Topics: Aged; Aged, 80 and over; Apomorphine; Benzothiazoles; Bromocriptine; Cabergoline; Databases, Factual; Dopamine Agonists; Endomyocardial Fibrosis; Ergolines; Female; Fibrosis; Heart Valve Diseases; Humans; Indoles; Male; Middle Aged; Pergolide; Pericarditis; Pleural Diseases; Pramipexole; Pulmonary Fibrosis; Retroperitoneal Fibrosis; Tetrahydronaphthalenes; Thiophenes; United States

Simple and reproducible spectrophotometric methods have been developed for determination of dopaminergic drugs used for Parkinson's disease, cabergoline (CAB) and ropinirole hydrochloride (ROP), in pharmaceutical preparations. The methods are based on the reactions between the studied drug substances and ion-pair agents [methyl orange (MO), bromocresol green (BCG) and bromophenol blue (BPB)] producing yellow colored ion-pair complexes in acidic buffers, after extracting in dichloromethane, which are spectrophotometrically determined at the appropriate wavelength of ion-pair complexes. Beer's law was obeyed within the concentration range from 1.0 to 35 microg ml(-1). The developed methods were applied successfully for the determination of these drugs in tablets.

Topics: Cabergoline; Dopamine Agents; Ergolines; Humans; Hydrogen-Ion Concentration; Indoles; Parkinson Disease; Pharmaceutical Preparations; Reproducibility of Results; Sensitivity and Specificity

Of 99 patients on ergot-derived dopamine agonists informed about possible long-term side effects, switching to a nonergot was undertaken in 88 (89%). There were adverse events in 26%. After 11 months, 82% were on their switch agonist and 93% were on any agonist. Switching dopamine agonists is feasible in this population.

Topics: Adult; Adverse Drug Reaction Reporting Systems; Antiparkinson Agents; Benzothiazoles; Bromocriptine; Cabergoline; Domperidone; Dopamine Agonists; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Therapy, Combination; Ergolines; Ergot Alkaloids; Feasibility Studies; Female; Follow-Up Studies; Humans; Indoles; Levodopa; Male; Middle Aged; Parkinson Disease; Pergolide; Pramipexole; Therapeutic Equivalency; Thiazoles

With respect to the ongoing discussion of "sleep attacks" in Parkinson's disease (PD), we sought to estimate the prevalence of sudden onset of sleep (SOS) with and without preceding sleepiness in PD, to identify associated factors, and to define the role of antiparkinsonian medication in SOS. We sent a questionnaire about SOS, sleep behaviour, and medication to 12,000 PD patients. The response rate was 63%, from which 6,620 complete data sets could be analysed. A total of 42.9% of our population reported SOS, 10% of whom never experienced sleepiness before the appearance of SOS (4.3% of all), and we identified the administration of all dopaminergic drugs as a risk factor for SOS. However, SOS occurred earlier after introduction of nonergoline dopamine agonists (DA) and was more strongly associated with nonergoline DA in younger patients (below 70 years) with a shorter disease duration (up to 7 years) but, actually, medication was less efficient in predicting SOS than most other factors considered such as higher age, male sex, longer disease duration, and the report of sleep disturbances. This survey strongly suggests that SOS is a multifactorial phenomenon. Some subgroups are at particular risk of experiencing SOS under nonergoline DA, especially at the beginning of this therapy. Our results support the current notion that SOS, in part, can be attributed to PD-specific pathology because disease duration and subjective disease severity have been shown to be predictors of SOS. We recommend the development of a standardised question to recognise SOS and to facilitate the comparison of prevalence estimates.

Topics: Aged; Antiparkinson Agents; Benzothiazoles; Comorbidity; Cross-Sectional Studies; Dopamine Agonists; Drug Therapy, Combination; Ergolines; Female; Humans; Indoles; Levodopa; Male; Middle Aged; Narcolepsy; Parkinson Disease; Pramipexole; Risk Factors; Surveys and Questionnaires; Thiazoles

A clinical retrospective study was carried out in a population of 366 Parkinson's disease (PD) outpatients, to analyse the efficacy and tolerability of nonergoline and ergoline dopamine agonist (DA), in monotherapy or in combination with L-dopa. Safety was comparable in both groups except for higher occurrence of gastrointestinal symptoms in ergoline group and somnolence in nonergoline group. No significant difference concerning efficacy and tolerability was found during DA monotherapy. Mean age at PD onset was slightly higher in patients withdrawing DA monotherapy for adverse events comparing to patients who needed the addition of L-dopa (60.36 +/- 7.53 versus 54.88 +/- 10.75; p<0.05), suggesting that older age at the onset of the disease increases the risk for adverse events during DA monotherapy. The follow-up of the remaining patients still in monotherapy with DA will allow a better evaluation of these aspects.

Topics: Age of Onset; Aged; Aging; Benzothiazoles; Bromocriptine; Dopamine Agonists; Drug Administration Schedule; Drug Interactions; Drug Therapy, Combination; Drug Tolerance; Ergolines; Female; Follow-Up Studies; Humans; Indoles; Levodopa; Lisuride; Male; Middle Aged; Parkinson Disease; Pergolide; Pramipexole; Retrospective Studies; Thiazoles; Treatment Outcome

A paucity of studies are available concerning the comparative therapeutic effectiveness of presently available dopamine agonist agents in the control of Parkinson symptoms. To provide a basis for resolving this issue, we measured the circling response in unilaterally nigrotomized (6-OHDA) rats following the administration of ropinirole, pramipexole, pergolide, bromocriptine, and cabergoline. Cabergoline, and to a lesser extent pergolide, produced the most vigorous and longest lasting circling response. This response was sustained with administration of these agents over a nine day period. Bromocriptine, pramipexole and ropinirole were all less effective. These results suggest that dopamine agonists whose effect is primarily on D1 and D2 receptors are more effective than those whose actions do not include D1 activation.

Topics: Animals; Benzothiazoles; Brain; Bromocriptine; Cabergoline; Dopamine Agonists; Drug Administration Schedule; Ergolines; Indoles; Male; Motor Activity; Oxidopamine; Parkinsonian Disorders; Pergolide; Pramipexole; Rats; Rats, Sprague-Dawley; Reaction Time; Receptors, Dopamine D1; Receptors, Dopamine D2; Thiazoles