ergoline and Parkinson-Disease

Treatment with dopamin agonists, particularly cabergoline, is the primary and preferred therapy for prolactinomas and symptomatic hyperprolactinaemia due to its effectiveness and tolerability. However, an association has been demonstrated between fibrotic heart valve disease and high-dose dopamin agonist use in patients with Parkinson's disease in several echocardiographic studies. Such observations have prompted a number of studies of valvular function in cabergoline-treated hyperprolactinaemia patients. These studies have failed to show an increased prevalence of clinically significant valvular regurgitation.

Topics: Antiparkinson Agents; Cabergoline; Dopamine Agonists; Ergolines; Heart Valve Diseases; Humans; Hyperprolactinemia; Parkinson Disease; Ultrasonography

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

Drug-induced valvular heart disease (DIVHD) was first described in the 1960s. Initially, associations with ergot derivatives used for migraine prevention, or with anorectic drugs, were described. Drugs used for the treatment of Parkinson's disease and endocrine diseases, like hyperprolactinemia, may also induce VHD. More recently, the use of 3,4-methylendioxymetamphetamine (MDMA, 'Ecstasy') and benfluorexhave been found to be associated with DIVHD. Although some of these drugs were withdrawn from the market, several cases of patients requiring valve surgery even years after the cessation of therapy have been reported. DIVHD is not infrequent, may be severe, and has been described in association with several drugs. Even after drug cessation, long-term implications of this type of VHD may persist. The present review underlines the need for a careful evaluation of the associated clinical and echocardiographic risk factors to allow early recognition so as not to delay appropriate management.

Topics: Dopamine Agonists; Ergolines; Global Health; Heart Valve Diseases; Humans; N-Methyl-3,4-methylenedioxyamphetamine; Parkinson Disease; Prevalence; Serotonin Agents

Parkinson's disease (PD) is a neurodegenerative condition characterized by progressive and profound loss of dopaminergic neurons in the substantia nigra pars compacta leading to the formation of eosinophillic, intracytoplamic, proteinacious inclusions termed as lewy bodies. L-dopa remains as a gold standard for the treatment of PD, and is often combined with carbidopa to reduce the dose-limiting side effects. Long-term levodopa treatment is associated with the development of motor fluctuations and peak dose dyskinesias. Dopamine Replacement Therapy (DRT) with dopamine agonists (DAs) (ropinirole and pramipexole) is used to manage complications of L-dopa treatment, however, has been associated with numerous pharmacovigilence reports. The present review attempts to narrate the multiple receptor interaction of DAs followed by the assessment of their side effects during the treatment of PD and possible remedial strategy for selective targeting of dopamine receptors to overcome these affects in therapy of Parkinson's disease.

Topics: Animals; Antiparkinson Agents; Apomorphine; Bromocriptine; Dopamine Agonists; Drug Delivery Systems; Ergolines; Humans; Parkinson Disease; Receptors, Dopamine

Valvular heart disease in patients being treated with ergot-derivative dopamine agonists (Ergot-DA) for Parkinson's disease has been reported to occur as a consequence of serotonine receptor stimulation. Goal of this analysis was to estimate the incidence of those changes from recently published studies and to determine its clinical relevance. Medline searches were performed to identify cross-sectional, echocardiographic studies comparing patients treated with dopamine agonists or controls, in terms of valvular changes. Observational studies of valve changes in Parkinsonian patients were used to estimate the incidence of severe valvulopathy. The results from 7 cross-sectional studies including 477 patients treated with Ergot-DA, 127 patients with non-Ergot-DA, and 364 control patients were analyzed. Moderate-to-severe valvular changes were detected in 26% of patients treated with Ergot-DA, 10% of patients treated with non-Ergot DA, and 10% of control patients. Severe valvulopathy was less than 1% both in cross-sectional and observational studies. The high rate of moderate valvular changes in patients treated with Ergot-DA suggests that close surveillance of the patients is required. Severe valvulopathy was less than 1% in the studies analyzed.

Topics: Antiparkinson Agents; Cabergoline; Cross-Sectional Studies; Dopamine Agonists; Drug Combinations; Echocardiography; Ergolines; Ergot Alkaloids; Heart Valve Diseases; Humans; Parkinson Disease; Pergolide; Product Surveillance, Postmarketing

Retroperitoneal and pleuropulmonary fibrosis are well known but rare complications of the treatment of Parkinson's disease with ergolinic dopamine agonists; however, until now, these complications have not substantially affected the routine clinical use of these drugs. The occurrence of restrictive valvular heart disease during treatment with pergolide and cabergoline caused concern about the safety of dopamine agonists in Parkinson's disease. Specifically, there is uncertainty whether fibrotic cardiac valvulopathy is due to exposure to these two ergolinic dopamine agonists or whether the abnormality is reversible. Changes in the heart valves can incur additional disability and worsen the clinical disorders of Parkinson's disease.. Population studies of patients with Parkinson's disease compared with non-parkinsonian controls have reported that pergolide and cabergoline have a similar risk of inducing fibrotic changes in cardiac valve leaflets. The fibrotic changes cause thickening, retraction, and stiffening of valves, which result in incomplete leaflet coaptation and clinically significant regurgitation, and have necessitated surgical valve replacement in some patients. Pergolide and cabergoline have high affinity for the 5-HT(2B) serotonin receptors, which are expressed in heart valves and might mediate mitogenesis and, in turn, the proliferation of fibroblasts. When analysed together, current population studies of similar designs and doses report 102 patients on cabergoline, 245 patients on pergolide, 181 patients on non-ergot agonists (pramipexole and ropinirole), and 177 non-parkinsonian controls. The frequency of moderate-to-severe regurgitation in at least one heart valve was higher in patients receiving cabergoline or pergolide than in patients taking non-ergot agonists or controls, and the incidence of new-onset valvulopathy was high in patients taking the ergot-derived drugs. WHERE NEXT?: Because of the routine prescription of pergolide and cabergoline, the switching of patients to different treatment regimens might be difficult. Moreover, whether the fibrotic changes are reversible is unknown. Finally, these adverse events do not occur in all patients, and no susceptibility factors are known. Prospective studies will assess the full effect of these abnormalities and help establish whether and when mitral valve tenting area abnormalities become clinically relevant during chronic treatment. The exact pathway leading to valvulopathy is unknown, although agonism of 5-HT(2B) receptors in the heart is implicated as a mediator in the process. Other ergolinic dopamine agonists, such as lisuride, and non-ergot dopamine agonists are devoid of 5-HT(2B) agonistic activity; therefore, their use might not induce fibrotic changes in heart valves. However, further prospective studies are needed. Such studies should also clarify the clinical relevance of mild-to-moderate echocardiographic changes and their natural history. Because of the clinical consequences of the adverse reactions, we suggest that affinity for 5-HT(2B) receptors is routinely tested in future drugs, in the laboratory or in animals, before they are given to patients.

Topics: Cabergoline; Dopamine Agonists; Ergolines; Heart Valve Diseases; Humans; Parkinson Disease; Pergolide

Parkinson's disease (PD) is a neurodegenerative, chronic and progressive disease whose evolutive course changed significantly after the introduction of levodopa. However, no antiparkinsonian drug has been able to stop the progression of PD. Thus, as the years have passed, greater drug doses have been necessary, either alone or in different combinations. Therefore, it is useful to have drugs with a wide threshold between effective dose and maximum tolerated dose. The concept of therapeutic reserve (TR) can be considered equivalent to therapeutic index or therapeutic window and could be defined as the difference between the dose needed to achieve an optimum therapeutic response at a given time and the dose that causes adverse events (maximum recommended dose or "ceiling dose"). This difference indicates the threshold that makes it possible to use higher doses as the disease advances to maintain an optimum clinical effect without the appearance of adverse events. This concept is important in the case of dopaminergic agonists whose efficacy seems to be similar in the daily clinical practice. Although there are no direct comparative studies, the analysis of the results of different studies suggests that the TR of ropinirole is superior to that of other dopaminergic agonists. The first effective dose, defined as an improvement superior to 30 % is observed with 9 mg/day in 75 % of the patients while the maximum recommended dose is 24 mg/day. This threshold is less with other dopamine agonists.

Topics: Benzothiazoles; Cabergoline; Dopamine; Dopamine Agonists; Dose-Response Relationship, Drug; Ergolines; Humans; Parkinson Disease; Pramipexole

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

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

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

Cabergoline is a synthetic ergoline dopamine agonist with a high affinity for dopamine D2 receptors and a long elimination half-life. This agent provides continuous dopaminergic stimulation with once-daily administration. Adjuvant oral cabergoline is usually well tolerated and effective in controlling symptoms in patients with advanced Parkinson's disease experiencing response fluctuations to long-term levodopa therapy. In patients with early Parkinson's disease, cabergoline (with or without levodopa) is well tolerated and effective in controlling disease symptoms, and may reduce the risk of developing drug-induced motor complications. Data from two pharmacoeconomic analyses suggest that cabergoline may be a cost-effective treatment option versus levodopa in patients with early Parkinson's disease, and highlight the need for further evaluation of the drug in this indication.

Topics: Antiparkinson Agents; Cabergoline; Clinical Trials as Topic; Dose-Response Relationship, Drug; Ergolines; Humans; Parkinson Disease

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

We report the case of a female patient with Parkinson's disease who experienced hair loss that appeared after the administration of cabergoline. Her hair re-grew after decreasing the dose of cabergoline, indicating that hair loss was induced by cabergoline. In reviewing the literature, there have been reports of hair loss after administration of various dopaminergic drugs that include levodopa and all types of dopamine receptor agonists. Although the pathophysiological mechanism underlying the hair loss is unclear, hair loss may be possibly overlooked, and should be noted as a possible side effect of the dopaminergic therapy.

Topics: Aged; Alopecia; Cabergoline; Dopamine Agonists; Ergolines; Female; Humans; Parkinson Disease

Topics: Cabergoline; Dopamine Agonists; Ergolines; Ergot Alkaloids; Humans; Parkinson Disease

Topics: Benzophenones; Bromocriptine; Cabergoline; Dopamine Agonists; Drug Therapy, Combination; Enzyme Inhibitors; Ergolines; Ergot Alkaloids; Humans; Levodopa; Lisuride; Nitrophenols; Parkinson Disease; Pergolide; Randomized Controlled Trials as Topic; Tolcapone

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

Cabergoline is an ergot-derived dopamine agonist used in the treatment of Parkinson's disease (PD). Both ergot and non-ergot-derived dopamine agonists directly stimulate dopamine receptors, unlike levodopa, which must undergo presynaptic breakdown to dopamine beforehand. Cabergoline has the longest half-life of the dopamine agonists currently available and is effective when given once-daily. It has been proposed that therapy with cabergoline may mimic physiological dopaminergic stimulation in PD by providing striatal intrasynaptic dopamine replacement. Its long half-life is likely to result in sustained rather than pulsatile dopaminergic stimulation, the preferred manner of treating PD. Placebo-controlled trials using cabergoline as an adjunctive therapy in PD have shown that it significantly reduces 'off' time, improves motor function and reduces levodopa requirements. Cabergoline has been shown to be as effective as other dopamine agonists in improving motor function as monotherapy in early PD, and a 5-year levodopa-controlled study indicates the superiority of cabergoline over levodopa in reducing dyskinesias. The efficacy of cabergoline in PD patients with nocturnal disabilities, restless leg syndrome and augmentation has also been demonstrated. Audits of the clinical efficacy of cabergoline indicate that it is well-tolerated and has an acceptable side effect profile.

Topics: Antiparkinson Agents; Cabergoline; Disease Models, Animal; Dopamine Agonists; Ergolines; Humans; Movement Disorders; Neuroprotective Agents; Parkinson Disease

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

Long term levodopa therapy in Parkinson's disease is associated with the development of motor complications including abnormal involuntary movements and a shortening response to each dose (wearing off phenomenon). It is thought that dopamine agonists can reduce the duration of immobile off periods and the need for levodopa therapy whilst maintaining or improving motor impairments and only minimally increasing dopaminergic adverse events.. To compare the efficacy and safety of adjuvant cabergoline therapy versus placebo in patients with Parkinson's disease, already established on levodopa and suffering from motor complications.. Electronic searches of MEDLINE, EMBASE and the Cochrane Controlled Trials Register. Handsearching of the neurology literature as part of the Cochrane Movement Disorders Group's strategy. Examination of the reference lists of identified studies and other reviews. Contact with Pharmacia Upjohn Limited.. Randomised controlled trials of cabergoline versus placebo in patients with a clinical diagnosis of idiopathic Parkinson's disease and long-term complications of levodopa therapy.. Data was abstracted independently by the authors and differences settled by discussion. The outcome measures used included Parkinson's disease rating scales, levodopa dosage, off time measurements and the frequency of withdrawals and adverse events.. Cabergoline has been compared with placebo in two phase II (6 - 12 weeks) and one phase III randomised controlled trials (24 weeks). These were double-blind, parallel group, multicentre studies including 268 patients with Parkinson's disease and motor complications. The reduction of 1.14 hours (WMD; 95% CI -0.06, 2.33; p = 0.06) in off time in favour of cabergoline was not statistically significant. Inadequate data on dyskinesia was collected either on rating scales or as adverse event reporting to allow a conclusion to be drawn. A small but statistically significant advantage of cabergoline over placebo was seen in one study for UPDRS ADL (part II) score and UPDRS motor score. No such advantage was seen in one other study due to small numbers of patients and the comparatively low doses of cabergoline used. No significant differences in Schwab and England scale were seen in two studies. Levodopa dose reduction was significantly greater with cabergoline (WMD 149.6 mg/d; 95% CI 94.1, 205.1; p < 0.00001). There was a trend towards more dopaminergic adverse events with cabergoline but this did not reach statistical significance at the p < 0.01 level. However, there was a trend towards fewer withdrawals from cabergoline.. In the management of the motor complications seen in Parkinson's disease, cabergoline can be used to reduce levodopa dose and modestly improve motor impairment and disability with an acceptable adverse event profile. These conclusions are based on, at best, medium term evidence.

Topics: Antiparkinson Agents; Cabergoline; Dopamine Agonists; Dyskinesia, Drug-Induced; Ergolines; Humans; Levodopa; Parkinson Disease; Randomized Controlled Trials as Topic

Long term levodopa therapy in Parkinson's disease is associated with the development of motor complications including abnormal involuntary movements and a shortening response to each dose (wearing off phenomenon). It is thought that dopamine agonists can reduce the duration of immobile off periods and the need for levodopa therapy whilst maintaining or improving motor impairments and only minimally increasing dopaminergic adverse events.. To compare the efficacy and safety of adjuvant cabergoline therapy versus bromocriptine in patients with Parkinson's disease, already established on levodopa and suffering from motor complications.. Electronic searches of MEDLINE, EMBASE and the Cochrane Controlled Trials Register. Handsearching of the neurology literature as part of the Cochrane Movement Disorders Group's strategy. Examination of the reference lists of identified studies and other reviews. Contact with Pharmacia Upjohn Limited.. Randomised controlled trials of cabergoline versus bromocriptine in patients with a clinical diagnosis of idiopathic Parkinson's disease and long-term complications of levodopa therapy.. Data were abstracted independently by the authors and differences settled by discussion. The outcome measures used included Parkinson's disease rating scales, levodopa dosage, off time measurements and the frequency of withdrawals and adverse events.. Cabergoline has been compared with bromocriptine in five randomised, double-blind, parallel group studies including 1071 patients. Only one of the phase II studies was medium term (36 weeks), the others all being short term (12 -15 weeks). The non-significant difference in off time reduction produced by cabergoline compared with bromocriptine was 0.29 hours/day in favour of the former (weighted mean difference; 95% CI -0.10, 0.68; p = 0.15). Dyskinesia reported as an adverse event was significantly increased with cabergoline compared with bromocriptine (Peto odds ratio 1.57; 95% CI 1.05, 2.35; p = 0.03). Motor impairment and disability were measured in four of the studies using the UPDRS rating scale but the small differences in UPDRS ADL (part II) and motor (part III) scores were not statistically significant in any study. Similarly, no significant difference in Schwab and England score was seen. The number of patients rated as much or very much improved on a clinician's global impression scale was similar with both agonists. Levodopa dose reduction was no different between cabergoline and bromocriptine. There was more confusion with cabergoline (Peto odds ratio 2.02; 95% CI 1.09, 3.76; p = 0.03). Otherwise, dopaminergic adverse events were comparable with these agonists and no significant difference in all cause withdrawal rate was found.. Cabergoline produces similar benefits to bromocriptine in off time reduction, motor impairment and disability ratings, and levodopa dose reduction over the first three months of therapy. Dyskinesia and confusion were increased with cabergoline but otherwise the frequency of adverse events and withdrawals from treatment were similar with the two agonists.

Topics: Antiparkinson Agents; Bromocriptine; Cabergoline; Dopamine Agonists; Dyskinesia, Drug-Induced; Ergolines; Humans; Levodopa; Parkinson Disease; Randomized Controlled Trials as Topic

The pharmacological effects of cabergoline, a novel ergot alkaloid, against parkinsonism were assessed by comparing its effects with those of bromocriptine and pergolide. The affinities of cabergoline and pergolide for the D2 receptor were about the same, about 7 times stronger than that of bromocriptine. The affinity of each compound for the D1 receptor was markedly lower than its affinity for the D2 receptor. However, other data suggest that cabergoline and pergolide would have D1-receptor agonist activity, whereas bromocriptine would act as a D1-receptor antagonist. In MPTP-lesioned parkinsonian monkeys, cabergoline improved motor disability, and its effect lasted longer than those of bromocriptine and pergolide. Moreover, cabergoline induced no behavioral abnormalities even though at the highest dose used, in contrast to bromocriptine and pergolide, both of which induced hyperactivity. This beneficial effect of cabergoline did not attenuate on prolonged administration. Combined treatment with a low dose of L-dopa and a low dose of cabergoline improved motor disability without inducing the hyperactivity and dyskinesia seen during treatment with L-dopa alone at high doses. From these results, we suggest that cabergoline promises to be a useful anti-parkinsonian agent with a long lasting effect that survives prolonged administration and without the side effects induced by L-dopa.

Topics: Animals; Antiparkinson Agents; Cabergoline; Dopamine Agonists; Ergolines; Haplorhini; Humans; Levodopa; Parkinson Disease; Receptors, Dopamine

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

While dopamine agonists are still traditionally used as adjunct medications to improve performance and smooth out motor response complications in advanced levodopa-treated Parkinson's disease, they are increasingly used in monotherapy or early in combination with levodopa particularly in patients under 65 years of age. Long-term studies using bromocriptine showed efficacy in lowering the cumulative levodopa dose and reducing the early incidence of levodopa-related motor response complications. New dopamine agonists have recently shown efficacy as adjunct medications in short-term trials. While we now have more options to fit our individual patients' needs and tolerance, it is important to view the new agonists in the light of the results obtained with ergot derivatives. In this article, the rationale for use and efficacy profile of the ergolines are briefly reviewed.

Topics: Animals; Antiparkinson Agents; Dopamine Agonists; Drug Therapy, Combination; Ergolines; Humans; Levodopa; Neuroprotective Agents; Parkinson Disease

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

The appearance of late motor complications is the major drawback of long term levodopa therapy in patients with Parkinson's disease. Although disease progression may be a factor in the aetiology of these complications, unfavourable properties of levodopa may promote their development. These include competition with amino acids for gastrointestinal absorption and passage through the blood-brain barrier; and a short duration of action with a rapid peak plasma concentration and rapid clearance, producing strong receptor stimulation that rapidly alternates with neurotransmitter vacancy and nonselective stimulation of all dopamine receptors. Moreover, advanced neurodegeneration results in loss of the anatomical substrate responsible for dopamine uptake and transport, whereas the postsynaptic dopamine receptors (the therapeutic target of dopamine agonists) are relatively spared. In theory, long-acting direct dopamine D2 receptor agonists that also stimulate the D1 receptor should provide a satisfactory alternative to levodopa without the above-mentioned drawbacks. Cabergoline possesses all the prerequisites for testing the hypothesis that steady stimulation of D2 receptors may be able to minimise the development of late motor complications in patients with Parkinson's disease. It has an appropriate receptor affinity profile, with potent and long-lasting dopaminergic stimulatory effects in 6-hydroxydopamine-lesioned rats and in MPTP (1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine)-lesioned primates; it has a consistent pharmacokinetic profile, with a very long mean plasma elimination half-life of 65 to 110 hours, and its absorption and excretion are unaffected by food, age or renal or hepatic disease; moreover, when given concomitantly, cabergoline does not influence levodopa pharmacokinetics. Initial clinical studies have demonstrated that the efficacy of cabergoline is comparable to that of levodopa in patients with Parkinson's disease. The preliminary results of a long term study of initiation of treatment with cabergoline or levodopa in patients with Parkinson's disease are in keeping with the hypothesis that steady receptor stimulation diminishes late motor complications.

Topics: Animals; Antiparkinson Agents; Area Under Curve; Cabergoline; Disease Progression; Dopamine Agonists; Ergolines; Female; Humans; Levodopa; Male; Parkinson Disease; Rats; Receptors, Dopamine D1; Receptors, Dopamine D2

The clinical efficacy of the long-acting dopamine agonist cabergoline as an adjunct to levodopa has been investigated in controlled and uncontrolled studies in > 1500 patients with advanced Parkinson's disease and motor complications. Four of these studies (including 2 comparisons with placebo and 2 with bromocriptine), which used similar methodology (including study design, blindness, selection criteria, treatment modalities and duration) and measurements of efficacy and safety, are reviewed. Compared with placebo, cabergoline 2 to 10 mg/day (median 5 mg/day) induced a significantly higher percentage decrease in the number of 'off' hours (18 vs 45%) in a preliminary phase II study that included 37 patients with severe motor fluctuations. This was not associated with an increase in dyskinesia in either treatment group. In a subsequent phase III placebo-controlled study (n = 188 patients with motor fluctuations), treatment with cabergoline 0.5 to 5 mg/day (median 3.5 mg/day) achieved a statistically significant decrease in levodopa dosage compared with placebo (18 vs 3%) and improved the Unified Parkinson's Disease Rating Scale scores for activities of daily living in a greater number of patients (23 vs 4%). Comparisons of cabergoline with bromocriptine have been conducted in 750 patients stabilised on levodopa therapy; one study was conducted in patients without, and the other in patients with, previous exposure to dopamine agonists. Cabergoline was administered once daily at doses ranging from 0.5 to 6 mg, and bromocriptine was given at a dosage of 5 to 40 mg/day divided into 3 administrations. A combined analysis of the response rates obtained in the 2 studies found cabergoline to be at least as effective and well tolerated as bromocriptine, with a trend in favour of cabergoline in terms of response rate and number of 'off' hours. The majority of adverse events in this patient population were those associated with levodopa therapy, as shown by the high frequency of adverse events in the placebo group (68%). Both cabergoline and bromocriptine showed a comparable incidence of adverse events, with CNS and gastrointestinal events being the most common. Thus, the potential advantages of cabergoline include improved patient compliance as a result of its once-daily administration, and an increased threshold for the development of dyskinesia as a result of the levodopa sparing effect of cabergoline.

Topics: Antiparkinson Agents; Bromocriptine; Cabergoline; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Drug Therapy, Combination; Ergolines; Female; Humans; Levodopa; Male; Middle Aged; Parkinson Disease; Randomized Controlled Trials as Topic

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

We have evaluated 5 DA agonists-bromocriptine, lergotrile, lisuride, pergolide, and mesulergine in studies encompassing 278 patients with advanced PD. In most of our patients the DA agonist was added to levodopa. Most of our patients were no longer satisfactorily responding to levodopa. Previous attempts at managing these patients by changing the dose of levodopa (increasing or decreasing it), the treatment schedule, or the ratio of levodopa to carbidopa or by temporarily discontinuing levodopa [drug holiday] were unsuccessful. The majority of our patients had diurnal fluctuations in performance, either "wearing off" or "on-off" phenomena. The addition of a DA agonist resulted in a decrease in parkinsonian disability in most patients and a decrease in the severity of the diurnal fluctuations in performance. Improvement in many patients was maintained for at least 2 years. Adverse effects included mental changes, dyskinesias, orthostatic hypotension, and nausea. All of the adverse effects were reversible when the agonist was decreased or discontinued. As a group the agonists behaved similarly but individual patients often responded better to one agonist than another. The main role of agonists is in combination with levodopa in the treatment of patients with early PD who have not yet developed dyskinesias or diurnal fluctuations in performance.

Topics: Aged; Aged, 80 and over; Antiparkinson Agents; Dopamine; Ergolines; Female; Humans; Male; Middle Aged; Parkinson Disease; Receptors, Dopamine; Receptors, Dopamine D1; Receptors, Dopamine D2

Since the initiation of bromocriptine therapy for Parkinson's disease several newer dopamine agonists have been developed. Pergolide has reached the stage of Phase 3 clinical trials and will probably be available for general use sometime in the foreseeable future. Lisuride shows most promise in its parenteral form for infusion therapy of patients with severe fluctuations. Mesulergine, another ergot-derivative and ciladopa, a new non-ergot agonist, have been withdrawn from further clinical use due to tumorogenesis in rats. It is questionable how applicable these findings are to the use of the drugs in elderly humans with parkinsonism. Recently a small number of drugs have been found to have postsynaptic dopamine agonist properties only in the setting of denervated supersensitive dopamine receptors. These agents may be particularly effective in the early treatment of patients with Parkinson's disease. This paper will review a number of the dopamine agonists which have been developed since the introduction of bromocriptine therapy. Several of these have shown beneficial effects in early clinical trials while others show promise in preclinical studies of animal models of parkinsonism.

Topics: Antiparkinson Agents; Bromocriptine; Dopamine; Ergolines; Humans; Parkinson Disease; Piperazines

Topics: Amantadine; Antiparkinson Agents; Atrophy; Brain; Bromocriptine; Cognition; Dementia; Dreams; Drug Interactions; Ergolines; Humans; Levodopa; Libido; Memory; Parasympatholytics; Parkinson Disease; Receptors, Dopamine; Sexual Behavior; Substance-Related Disorders; Visual Perception

The ability of MPTP to induce persistent parkinsonism in man may provide a vital clue to the cause of the idiopathic disease. However, the peripheral administration of MPTP to rodent species only produces losses in brain dopamine content and damage to the nigrostriatal system in high doses and no persistent motor deficits have been observed. In contrast, in primates, the administration of MPTP rapidly induces a persistent parkinsonian syndrome accompanied by evidence for selective damage to the nigro-striatal dopamine containing system. Other neurotransmitter systems appear unaffected by MPTP treatment. The MPTP-treated primate responds to the administration of L-DOPA and other antiparkinsonian drugs and may provide a useful test-bed for the development of novel antiparkinsonian medication. Administration of MPTP to primates causes an accumulation of MPP+ in a variety of brain areas. The accumulation of MPP+ and the neurotoxic actions of MPTP in primates can be prevented by the prior administration of monoamine oxidase inhibitors. The ability of monoamine oxidase inhibitors to prevent MPTP toxicity is related to the metabolism of MPTP by monoamine oxidase B, probably extraneuronally in glia, to produce MPDP+ and subsequently MPP+. In rodent synaptosomal preparations MPP+ is a substrate for the dopamine uptake mechanism and so would be selectively accumulated in brain dopamine neurones. Administration of MPTP to animals results in the production of a partial model of idiopathic Parkinson's disease as it occurs in man. MPTP treatment produces the major symptoms of Parkinson's disease in primates but the pathology is limited to the nigro-striatal system, whereas in Parkinson's disease pathology is more widespread. Biochemical changes induced by MPTP again seem primarily limited to those induced by damage to the nigro-striatal dopamine containing system. MPP+ (or another metabolite of MPTP) may be responsible for the neurotoxicity of MPTP but not all neurones which accumulate products of MPTP metabolism are damaged. The nigro-striatal system may be peculiarly sensitive to the effects of MPTP.

Topics: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; 2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine; Animals; Benzazepines; Callithrix; Corpus Striatum; Disease Models, Animal; Dopamine; Ergolines; Humans; Levodopa; Macaca mulatta; Neural Pathways; Pargyline; Parkinson Disease; Parkinson Disease, Secondary; Pyridines; Quinpirole; Rats; Saimiri; Selegiline; Species Specificity; Substantia Nigra

In the past decade, dopamine agonists have emerged as important treatment options for patients with Parkinson's disease. Originally, dopamine agonists were used only in patients with advanced disease in whom the response to levodopa had decreased (levodopa failures). The decreased response to levodopa, usually associated with diurnal oscillations in performance and the 'wearing-off' and 'on-off' phenomena, is secondary to disease progression with continued degeneration of the nigrostriatal neurons. In addition, chronic levodopa treatment itself may contribute to the decreased drug response and the diurnal oscillations in performance. Dopamine receptor agonists bypass the degenerating nigrostriatal neurons and directly stimulate the striatal dopamine receptors. Dopamine receptor agonists also permit a reduction in the dose of levodopa. Five ergoline dopamine agonists--bromocriptine, lergotrile, pergolide, lisuride, mesulergine, and the nonergoline agonist, ciladopa--have undergone clinical trials in Parkinson's disease. In 10 years, we treated a total of 278 patients with advanced Parkinson's disease, a declining response to levodopa, and diurnal oscillations in performance with five ergoline dopamine agonists (in addition to levodopa). The mean duration of treatment was one year (with a range of 1-60 months). Improvement was noted in 140 (50%) of our patients. Adverse effects necessitating discontinuation of the agonist occurred in 131 patients (46%). We compared our results with those of others who, unlike us, began treatment with a dopamine agonist earlier, using the agonist alone or adding it to levodopa before the response to levodopa had decreased. Many of the patients so treated had mild or moderate Parkinson's disease. A total of 1,599 patients were treated with ergoline dopamine agonists. Of these patients, 976 (61%) improved, while 407 (25%) experienced adverse effects. We believe that a greater number of these patients improved and fewer experienced adverse effects, in comparison to our patients, because the patients had less advanced disease.

Topics: Animals; Antiparkinson Agents; Dopamine; Ergolines; Humans; Parkinson Disease; Prognosis

Topics: Animals; Antiparkinson Agents; Ergolines; Humans; Parkinson Disease; Receptors, Dopamine

Topics: Bromocriptine; Corpus Striatum; Drug Therapy, Combination; Ergolines; Humans; Levodopa; Movement Disorders; Parkinson Disease; Pergolide; Receptors, Dopamine; Time Factors

Bromocriptine is an ergopeptine derivative and dopamine agonist that predominantly stimulates the striatal D2 non-adenyl cyclase-linked dopamine receptors. Bromocriptine, unlike other dopamine agonists, has mixed "agonist-antagonist" properties at these receptors. The striatal dopamine receptors exist in two different affinity states: a low and a high affinity state. Bromocriptine, unlike other dopamine agonists, does not differentiate between the low and the high affinity state of the D2 receptors, and bromocriptine does not induce a conformational change in these receptors. Bromocriptine, in low doses, is effective in patients with mild to moderate Parkinson's disease, while bromocriptine in higher doses is needed in patients with advanced disease. Both in low doses and in high doses, bromocriptine combined with levodopa is usually more effective than bromocriptine alone. The efficacy of low dose (5-30 mg/day) and high dose (31-100 mg/day) bromocriptine alone and with levodopa was examined in 27 studies encompassing 790 patients. Forty-six % of the studies were done in a double blind manner. In four studies of 79 patients, low dose bromocriptine (16 mg/day) without levodopa resulted in improvement in 58% of the patients. Only 9% of the patients experienced adverse effects. Most of the patients (63%) and mild or moderate Parkinson disease. In seven studies of 143 patients, high dose bromocriptine (56 mg/day) without levodopa resulted in improvement in 62% of patients, but with 27% having adverse effects. Most of these patients (77%) had mild or moderate disease. Diurnal oscillations in performance, the "wearing off" or "on-off" effect, were not seen during treatment with bromocriptine alone. In nine studies of 201 patients, low dose bromocriptine (23 mg/day) and levodopa resulted in improvement in 71% of patients with 26% having adverse effects. Most of these patients (66%) had advanced disease, and many had diurnal oscillations in performance. In seven studies of 367 patients, high dose bromocriptine (48 mg/day) and levodopa resulted in improvement in 58% with 37% having adverse effects. Most of these patients (85%) had advanced disease. The increased effectiveness of bromocriptine in combination with levodopa may be explained as follows. Bromocriptine by itself does not discriminate between the low and the high affinity states of the dopamine receptors.(ABSTRACT TRUNCATED AT 400 WORDS)

Topics: Aged; Animals; Bromocriptine; Drug Administration Schedule; Ergolines; Humans; Levodopa; Lisuride; Middle Aged; Parkinson Disease; Pergolide; Time Factors

Basic aspects and recent advances in the understanding of the pharmacological mechanism of action of the clinically most used antiparkinson drugs are reviewed. Recent human and animal biochemical investigations clearly confirm and extend previous findings indicating that benserazide is much more potent than carbidopa as peripheral decarboxylase inhibitor. L-DOPA in combination with benserazide or carbidopa constitutes the best available therapy for Parkinson's disease (PD). To reduce peaks and rapid fluctuations of L-DOPA plasma levels (possibly responsible for peak-dose dyskinesias and end-of-dose deterioration) a slow-release formulation of L-DOPA in combination with benserazide or with benserazide plus catechol-O-methyltransferase inhibitors should be developed. In parkinsonian patients under long-term L-DOPA therapy monoamine oxidase inhibitors type B (MAO-B) e.g. (-)deprenyl and direct dopamine receptor agonists (bromocriptine, lisuride, pergolide etc.), due to their L-DOPA-sparing effects, alleviate in some cases L-DOPA-induced side-effects e.g. dyskinesias and on-off phenomena. However, since (-)deprenyl, due to its metabolism to (-)methamphetamine and (-)amphetamine, seem to have indirect sympathomimetic activity, new selective MAO-B inhibitors devoid of indirect sympathomimetic effects should be tested clinically to assess the functional role of pure MAO-B inhibition in the therapy of PD. The auxiliary therapy with direct dopamine receptor agonists of the D-2 subtype represents another valid approach which should be further investigated in order to find novel dopamine agonists, less expensive than bromocriptine, and strictly selective for D-2 receptor sites.

Topics: Animals; Antiparkinson Agents; Aromatic Amino Acid Decarboxylase Inhibitors; Benserazide; Brain; Bromocriptine; Carbidopa; Corpus Striatum; Dopamine; Ergolines; Humans; Kidney; Kinetics; Levodopa; Lisuride; Liver; Methyldopa; Norepinephrine; Parkinson Disease; Pergolide; Receptors, Dopamine; Selegiline; Serotonin; Stereotyped Behavior; Substantia Nigra; Tyramine

Bromocriptine alters the motor behaviour of animals and improves the motor defect of parkinsonism. Changes in movement are accompanied by biochemical changes in the central nervous system, consistent with the idea that bromocriptine has a dopamine agonist action in the basal ganglia and also in the mesolimbic system and hypothalamus. The overall anti-parkinsonian effect of bromocriptine is similar to that of l-dopa alone or with benserazide (a decarboxylase inhibitor) when optimum doses are used, although individual patients may respond better to 1 drug than to the other.

Topics: Apomorphine; Bromocriptine; Catecholamines; Drug Interactions; Ergolines; Humans; Kinetics; Motor Activity; Movement Disorders; Parkinson Disease; Piribedil; Receptors, Drug; Stereotyped Behavior

Topics: Amantadine; Apomorphine; Bromocriptine; Dopamine; Ergolines; Extrapyramidal Tracts; Female; Humans; Levodopa; Male; Monoamine Oxidase Inhibitors; Neurotransmitter Agents; Parkinson Disease; Phosphodiesterase Inhibitors; Piribedil; Tremor

To evaluate the effects of levodopa and the dopamine D2 agonist cabergoline on striatal dopamine turnover estimated as the inverse of the effective dopamine distribution volume ratio (EDVR) measured by (18)F-dopa PET in de novo Parkinson disease (PD).. Single-center, parallel-group, randomized, observer-blinded study of cabergoline (3 mg/day) and levodopa (300 mg/day) over 12 weeks in patients with de novo PD. Primary efficacy measure was the change of the side-to-side averaged putaminal EDVR comparing baseline and end-of-maintenance period.. Thirty-five out of 39 randomized patients were assigned to the primary efficacy analysis (cabergoline, n = 17; levodopa, n = 18). At the end of treatment period, mean EDVRs were significantly lower compared to baseline solely in the levodopa group (relative change -1.0 ± 13.0% in cabergoline [p = 0.525 when compared to baseline], -8.3 ± 11.8% in levodopa group [p = 0.006]) with a nonsignificant trend between groups (mean relative difference: 7.3% (95% confidence interval -1.2% to 15.8%; p = 0.091). There was significant clinical improvement in both groups at 12 weeks compared to baseline, but no significant differences between groups in clinical and PET secondary outcome measures. Both pharmacologic treatments and PET scanning were well-tolerated and safe.. Putaminal dopamine turnover is increased by levodopa treatment in de novo PD. The nonsignificant trend toward a larger influence by levodopa compared to cabergoline is supported by ancillary statistical analyses. This augmentation of early compensatory events by levodopa might contribute not only to its symptomatic effects, but also to its induction of motor complications.

Topics: Adult; Aged; Aged, 80 and over; Antiparkinson Agents; Cabergoline; Corpus Striatum; Dopamine; Dopamine Agonists; Ergolines; Female; Humans; Levodopa; Male; Middle Aged; Parkinson Disease; Prospective Studies; Single-Blind Method; Treatment Outcome

The long-term use of levodopa to treat Parkinson's disease (PD) is often limited by the development of motor complications (e.g., levodopa-induced dyskinesia, LID). We hypothesized that a non-ergot dopamine agonist with strong affinity for D3) dopamine receptors (pramipexole) may improve LID in patients taking an ergot D1/D2 dopamine agonist.. Patients with PD and LID being treated with levodopa in addition to an ergot dopamine agonist were randomized to either a group in which pramipexole was added to current medications or a group in which the ergot dopamine agonist was switched to pramipexole. Dyskinesia was evaluated using Core Assessment Program for Surgical Interventional Therapies scores. The unified Parkinson's disease rating scale scores, modified Hoehn and Yahr stages (at 'on' time), Parkinson's disease questionnaire-39 scores and clinical global impression-improvement scores were also used for evaluation.. At 24 weeks, pramipexole alleviated LID with more efficiency in the switch group.. Pramipexole may be a therapeutic option for treating LID because its effects on D3 dopamine receptors may balance the D1 dopamine receptor supersensitivity associated with LID.

Topics: Aged; Antiparkinson Agents; Benzothiazoles; Bromocriptine; Cabergoline; Dopamine Agonists; Dyskinesia, Drug-Induced; Ergolines; Female; Humans; Levodopa; Male; Middle Aged; Parkinson Disease; Pergolide; Pramipexole; Receptors, Dopamine D1; Receptors, Dopamine D2; Receptors, Dopamine D3

Several international studies have suggested that treatment of early Parkinson's disease (PD) with a dopamine agonist instead of levodopa delays the occurrence of motor complications. This 5-year prospective, open, multicenter randomized study aimed to compare the effects of cabergoline on the onset of motor complications with those of levodopa in Japanese patients with early PD. Patients who had never been treated with dopamine agonists or levodopa were enrolled in this study. Four of 45 patients in the cabergoline group and 11 of 46 patients in the levodopa group developed motor complications. The estimated cumulative incidence of motor complications in the cabergoline and levodopa groups was 17% and 34% (hazard ratio, 0.57;95% confidence interval, 0.18-1.81; p = 0.347). Thirty-five adverse events (AEs) were reported in 24 patients in the cabergoline group, while 16 AEs were reported in 13 patients in the levodopa group. Patients in the cabergoline group showed fewer motor complications than did those in the levodopa group, although the difference was not statistically significant. However, the hazard ratio found in this study was similar to those in previous reports.

Topics: Adult; Aged; Antiparkinson Agents; Cabergoline; Dopamine Agonists; Ergolines; Female; Humans; Japan; Levodopa; Male; Middle Aged; Parkinson Disease; Prospective Studies; Time; Treatment Outcome

Tremor is one of the cardinal symptoms in Parkinson's disease, but only few clinical studies have focussed on its therapy as the primary endpoint. One reason is the substantial fluctuation of tremor severity over time, which is difficult to capture and may render momentary clinical assessments unreliable.. We evaluated the usefulness of a novel wrist-worn actigraph allowing long-term recordings of tremor in a pilot study, in which we assessed the therapeutic effect of cabergoline on tremor in 10 patients with tremor-dominant Parkinson's disease. Clinical data were obtained by using the Unified Parkinson's Disease Rating Scale (UPDRS Part III, item 20) and simultaneously a patient's tremor diary.. We found a significant reduction in UPDRS motor and tremor scores, in tremor duration and tremor amplitude by actigraphy and diaries. Furthermore, we found significant correlations between actigraphy measurements and patient ratings of tremor intensity and occurrence in diaries.. Long-term actigraphy is a reliable method to assess tremor occurrence and severity and may be used to document antitremor effects in clinical studies.

Topics: Aged; Antiparkinson Agents; Cabergoline; Ergolines; Female; Humans; Linear Models; Male; Monitoring, Ambulatory; Motor Activity; Parkinson Disease; Pilot Projects; Severity of Illness Index; Tremor

The aim of this study was to evaluate the safety and tolerability of overnight switching from ergot-derived dopamine agonists such as cabergoline to equivalent doses of pramipexole in patients with Parkinson's disease. The safety of overnight switching to pramipexole from cabergoline, which has a long plasma half-life and may cause dopaminergic excess after switchover, has not been established. Twenty-two consecutive patients with Parkinson's disease were included, 18 of them on cabergoline treatment. Patients were assessed with the Unified Parkinson's Disease Rating Scale (UPDRS) given just prior to switching as well as after 2, 4, 8, and 12 weeks of treatment. Eight patients (36.4%) experienced adverse events, of whom two were withdrawn from the study. Generally, however, significant improvement in the UPDRS was obtained after 2 weeks and improvement was maintained up to 12 weeks of treatment. Therefore, our study showed that overnight switching from ergot-derived dopamine agonists including cabergoline to dose-equivalent pramipexole was safe when associated with good patient compliance.

Topics: Benzothiazoles; Bromocriptine; Cabergoline; Dopamine Agonists; Dose-Response Relationship, Drug; Drug Administration Schedule; Ergolines; Humans; Japan; Outcome Assessment, Health Care; Parkinson Disease; Pergolide; Pramipexole; Severity of Illness Index; Time Factors; Treatment Outcome

To elucidate the association between treatment with ergot-derived dopamine agonists (EDDA) and valvular abnormalities amongst patients with idiopathic Parkinson's disease (IPD) and secondly, to analyse the yield of clinical screening for valvular heart disease.. A cross-sectional controlled study.. The cohort of IPD patients treated in the outpatient clinic, Department of Neurology, Aarhus University Hospital, Denmark.. A total of 138 IPD patients [median age 64 (39-87) years, 62% men] treated with either EDDA (n = 85) or non-EDDA (n = 53) for at least 6 months. Interventions. Patients were screened for valvular heart disease by clinical means and by examiner-blinded echocardiography. Main outcome measure was valvular regurgitation revealed by echocardiography.. Severe aortic regurgitation (n = 4) or moderate aortic (n = 12), mitral (n = 3) or tricuspidal valve regurgitation (n = 5) was found in 22 EDDA patients (25.9%). Two patients had coexistent moderate mitral and tricuspid valvular regurgitation. Two non-EDDA patients had moderate valve insufficiency (3.8%, P < 0.05). The adjusted relative risk for at least moderate valve insufficiency in the EDDA patients was 7.2% (P < 0.05). The sensitivity of detecting at least moderate valvular disease by cardiac murmur, dyspnoea, or the heart failure marker NT-proBNP (natriuretic peptide) was 62% for the neurologists and 93% for the cardiologist but with equally low specificity (30-35%).. EDDA was associated with a clinically important and statistically significant risk of at least moderate valve regurgitation. Clinical screening for valve disease was inadequate and it seems advisable to offer EDDA patients control with echocardiography.

Topics: Adult; Aged; Aged, 80 and over; Ambulatory Care Facilities; Cabergoline; Cross-Sectional Studies; Denmark; Dopamine Agonists; Electrocardiography; Ergolines; Ergot Alkaloids; Female; Heart Valve Diseases; Humans; Logistic Models; Male; Middle Aged; Parkinson Disease; Severity of Illness Index; Ultrasonography

To investigate the sleep-wake cycle and the effects of cabergoline monotherapy in a homogenous group of de novo Parkinson's Disease (PD) patients without confounding comorbid factors.. Twelve de novo patients affected by idiopathic PD underwent two ambulatory polysomnographic (APSG)monitoring sessions. The first was performed at baseline, and the second recording one-month after stable treatment with cabergoline monotherapy. Subjective daytime sleepiness was evaluated by means of the Epworth Sleepiness Scale.Data obtained in PD patients at baseline were compared with those obtained in 12 age- and sex-matched healthy subjects.. Diurnal sleep parameters did not show significant differences between controls and PD patients at baseline. In PD patients, no significant changes in diurnal sleep were observed between baseline and cabergoline treatment. Regarding nocturnal sleep, patients at baseline showed a significantly lower sleep efficiency and a significantly higher Wakefulness After Sleep Onset than controls. With respect to baseline, a significant increase in REM latency and a significant reduction in REM sleep were observed during cabergoline treatment.. In the early stage of PD, the neurodegenerative process does not seem to be directly responsible for daytime somnolence, but it may be directly involved in the alteration of nocturnal sleep. Cabergoline monotherapy does not affect daytime sleep propensity and, despite clinical improvement, it may have negative effects on REM sleep.

Topics: Aged; Antiparkinson Agents; Cabergoline; Case-Control Studies; Ergolines; Female; Humans; Male; Middle Aged; Outpatients; Parkinson Disease; Polysomnography; Severity of Illness Index; Sleep; Wakefulness

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

In this 12-wk, multi-center, randomized, open-label, rater-blinded study, efficacy and tolerability of Entacapone (ENT) or Cabergoline (CBG) in conjunction with levodopa were compared in 161 older Parkinson's disease patients with wearing-off. Patients received either ENT, 3 to 5 times daily, or CBG, titrated according to requirements to a maximum of 6 mg/d. A significant decrease of nearly 2 hours in the daily OFF-time (primary efficacy variable) was recorded in both treatment groups. The non-inferiority test failed despite a trend in favor of ENT. Reduction in OFF-time occurred faster in the ENT compared to the CBG treated patients. A decrease of approximately 20% was detected in parts II and III of the UPDRS, with no differences between the groups. Forty-three percent of the patients in the ENT group reported dyskinesias at baseline, and 35% at the final visit. The corresponding figures in the CBG group were 46% and 43%. Quality of life, measured by PDQ-39, increased substantially with both ENT and CBG. The mean daily dosage at the final visit was 698 mg for ENT (plus 447 mg levodopa) and 3.45 mg for CBG (plus 475 mg levodopa). Adverse events (AE), leading to discontinuation, were reported in 8.5% of the ENT and 13.9% of the CBG treated patients. Nausea was the most common AE in each group, corresponding figures being 7.3% with ENT and 25.3% with CBG (P=0.0024). A probable or possible causal relationship with ENT was reported in 41% and with CBG in 64% of the AE. Among these, only one serious AE (dehydration) was recorded with each treatment group. ENT and CBG reduced the patient's motor complications effectively and to a similar degree. The clinical benefit was more quickly apparent with ENT, which also showed a more favorable AE profile than CBG.

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

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

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

Cabergoline is used in the treatment of Parkinson's disease (PD). Clarithromycin is a potent inhibitor of CYP3A4 and P-glycoprotein and is often co-administered with cabergoline in usual clinical practice. We studied the effect of clarithromycin co-administration on the blood concentration of cabergoline in healthy male volunteers and in PD patients. Study 1: Ten healthy male volunteers were enrolled and were randomized to take a single oral dose of cabergoline (1 mg/day) for 6 days or a single oral dose of cabergoline plus clarithromycin (400 mg/day) for 6 days. Study 2: Seven PD patients receiving stable cabergoline doses were enrolled. They were evaluated for the plasma cabergoline concentration before and after the addition of clarithromycin 400 mg/day for 6 days, and again 1 month after discontinuation of clarithromycin. The dose and duration of clarithromycin were decided according to usual clinical practice. In healthy male volunteers, mean Cmax and AUC(0-10 h) of cabergoline increased to a similar degree during co-administration of clarithromycin. Mean plasma cabergoline concentration over 10 h post-dosing increased 2.6-fold with clarithromycin co-administration. In PD patients, plasma cabergoline concentration increased 1.7-fold during clarithromycin co-administration. Co-administration with clarithromycin may increase the blood concentration of cabergoline in healthy volunteers and in PD patients.

Topics: Adult; Aged; Aged, 80 and over; Animals; Anti-Bacterial Agents; ATP Binding Cassette Transporter, Subfamily B, Member 1; Cabergoline; Clarithromycin; Dopamine Agonists; Drug Interactions; Ergolines; Female; Humans; Male; Middle Aged; Parkinson Disease

Problems associated with long-term treatment of advanced Parkinson's disease (PD) include motor complications and psychotic and autonomic symptoms. We switched patients from bromocriptine (BR) or pergolide (PER) to cabergoline (CB) therapy and investigated CB's usefulness in alleviating such problems. Subjects were 30 patients (mean age 68.2 years; 13 receiving BR, 17 PER) with PD complicated by effects of long-term treatment but in whom their dose of dopamine (DA) agonist was contraindicated due to adverse reactions. Patients were switched to CB over a 2-4-week period. Hoehn-Yahr and Unified Parkinson Disease Rating Scale (UPDRS) I-IV "on" and "off" scores improved in both the BR and PER groups. CB was not discontinued due to adverse reactions in any patient. In conclusion, switching to CB is useful in patients in whom it is problematic to increase their dose of DA agonist due to motor complications or psychotic symptoms of advanced PD.

Topics: Aged; Antiparkinson Agents; Bromocriptine; Cabergoline; Ergolines; Humans; Parkinson Disease; Pergolide; Prospective Studies; Treatment Outcome

Cabergoline is an ergoline derivative with a very long half-life that allows once-daily administration and the potential for more continuous stimulation of dopaminergic receptors than is possible with other dopamine receptor agonists (DAs). The aim of this study was to evaluate whether the possible advantage resulting from a more sustained dopaminergic effect of cabergoline would translate into delayed onset of motor complications, compared with levodopa, in patients with newly diagnosed Parkinson's disease.. This study was a double-blind, multicentre trial that compared cabergoline and levodopa as initial therapy for Parkinson's disease. A total of 419 levodopa-, DA- and selegiline-naive patients with newly diagnosed Parkinson's disease were randomised to receive either cabergoline (n = 211) or levodopa (n = 209). Treatment was titrated to an optimal dose over a period of up to 24 weeks and then continued at this dose until the study endpoint (confirmed motor complications) or up to a maximum of 5 years. At years 1-5, the cabergoline group was receiving cabergoline at average daily doses ranging from 2.8-2.9 mg, with added levodopa at mean daily doses ranging from 322 mg at year 1 to 431 mg at year 5; over the same period, the levodopa group was receiving daily levodopa doses of 784 mg. Thus, patients in the cabergoline group received <50% levodopa than patients in the levodopa group.. Motor complications were significantly delayed (p = 0.0175) and occurred less frequently in cabergoline-treated patients than in levodopa-treated patients (22.3% vs 33.7%). Cox model proportional hazards regression analysis showed that the relative risk of developing such complications was >50% lower (0.46; p < 0.001) in the cabergoline group compared with the levodopa group. In particular, development of dyskinesias was markedly delayed in the cabergoline group and occurred in 9.5% of patients compared with 21.2% in the levodopa group (p < 0.001). Among patients not requiring supplemental levodopa, the frequency of motor complications was three times higher with levodopa (15.5% of 110 patients) than with cabergoline (5.3% of 76 patients). Among patients who did need supplemental levodopa, motor complications were more frequent in the levodopa arm (54.1% of 98 patients) than in the cabergoline arm (31.9% of 135 patients). Consistent improvements relative to baseline in average Unified Parkinson's Disease Rating Scale (UPDRS) daily living activities and motor function sections, and in Clinical Global Impression severity of illness and physician- and patient- rated global improvement scores, were seen in both treatment groups, with maximal effects occurring within 2 years. However, levodopa treatment was associated with a significantly (p < 0.001) greater improvement in motor disability (as measured by the UPDRS motor score) over time, with mean values of 13.8 versus 12.9 in the cabergoline versus levodopa arm recorded at 1 year, 18.6 versus 17.2 at 3 years and 19.2 versus 16.3 at 5 years, respectively. While the overall frequency of adverse events was similar in the two groups, the cabergoline-treated group experienced marginally, but not significantly, higher frequencies of nausea, vomiting, dyspepsia and gastritis (37.4% vs 32.2% in the levodopa group) and of dizziness and postural hypotension (31.3% vs 24% in the levodopa group). Cabergoline-treated patients also experienced a significantly higher frequency of peripheral oedema (16.1% vs 3.4%, respectively; p < 0.0001). The cabergoline and levodopa groups had similar rates of sleepiness (17.5% vs 18.3%, respectively) and hallucinations (4.8% vs 4.4%, respectively); in an elderly population subset, hallucinations were reported in 7.1% and 6.5% of patients taking cabergoline and levodopa, respectively. Adverse events generally occurred more frequently in female patients (with the exception of dyskinesias,. This study showed that, compared with levodopa, initial therapy with cabergoline in patients with Parkinson's disease is associated with a lower risk of response fluctuations at the cost of a marginally reduced symptomatic improvement and some tolerability disadvantages that are mostly limited to a significantly higher frequency of peripheral oedema.

Topics: Adult; Aged; Antiparkinson Agents; Cabergoline; Case-Control Studies; Double-Blind Method; Drug Therapy, Combination; Dyskinesia, Drug-Induced; Ergolines; Female; Humans; Levodopa; Longitudinal Studies; Male; Middle Aged; Motor Activity; Movement Disorders; Parkinson Disease; Risk Factors; Time Factors; Treatment Outcome

To investigate the effect of the dopamine D2 and D1 receptor agonist cabergoline on sleep, periodic leg movements (PLMs) in sleep, and early morning motor performance in patients with Parkinson's disease (PD). It was hypothesized that cabergoline had long-lasting beneficial effects on sleep and PLMs in sleep in patients with PD, after a single evening intake. A total of 15 patients with idiopathic PD underwent two nights of polysomnography and motor tests (UPDRS, tapping test) before and after 6-8 weeks of treatment with cabergoline (dosage: 3-6 mg/day). Additionally, patients completed a subjective sleep visual analog scale (VAS) before and during cabergoline treatment. Compared to baseline values, treatment with cabergoline did not change sleep efficiency or the amount of stage 1 and stage 2 sleep. The number of awakenings (22.4+/-10.1 vs 32.5+/-13.3, p<0.05) and stage shifts (119+/-42 vs 148+/-46, p<0.05) were increased during treatment with cabergoline, and PLMs in sleep were reduced (PLM index 34.9+/-44.9 vs 6.7+/-4.2 per hour, p<0.05). Cabergoline significantly improved early morning motor function, and in spite of increased phase shifts and awakenings, patients felt significantly more refreshed in the morning during cabergoline therapy. Cabergoline slightly fragmented sleep, without altering its total amount. The functional significance of this finding is uncertain. The subjective quality of sleep improved, and periodic limb movements in sleep decreased.

Topics: Activities of Daily Living; Aged; Antiparkinson Agents; Cabergoline; Dose-Response Relationship, Drug; Ergolines; Female; Humans; Male; Middle Aged; Motor Activity; Nocturnal Myoclonus Syndrome; Parkinson Disease; Polysomnography; Sleep; Treatment Outcome

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

The tetracyclic ergoline derivative cabergoline was investigated in three studies to test its efficacy in treating the motor symptoms of Parkinson's disease. In two studies, it was used as an add-on agent to the previous medication regimen that included other parkinsonian drugs, including levodopa. In the third study, cabergoline was switched from another dopamine agonist. All studies proved this drug's effectiveness in treating such motor symptoms as akinesia, dyskinesia, and nocturnal akinesia. Quality of life and disability in activities of daily living assessments were measured by PDQ 39 or UPDRS VI. Treatment with cabergoline showed higher efficacy and greater safety than other parkinsonian drugs.

Topics: Activities of Daily Living; Aged; Antiparkinson Agents; Cabergoline; Dopamine Agonists; Dyskinesias; Ergolines; Female; Humans; Male; Motor Activity; Parkinson Disease; Quality of Life; Sleep; Time

This multicentre randomised double-blind 3- to 5-year trial was designed to assess whether initial therapy with cabergoline alone or in combination with levodopa prevents or delays the occurrence of long term motor complications in patients with early Parkinson's disease. Patients eligible for study inclusion (n = 412) had early idiopathic Parkinson's disease (Hoehn and Yahr stages 1 to 3) and had received no previous treatment with levodopa, selegiline or dopamine agonists. Patients were randomised to receive either cabergoline (0.25 to 4 mg once daily) or levodopa (100 to 600 mg/day) titrated over a maximum period of 24 weeks. Once the optimum or maximum tolerated dose was achieved, it was maintained up to the end-point (development of motor complications confirmed at 2 consecutive 3-month visits) or up to a minimum of 3 years' treatment. Open labelled levodopa was added in both treatment arms when the improvement in motor disability [Unified Parkinson's Disease Rating Scale (UPDRS) factor III] decreased below 30% vs baseline. Both treatments improved motor disability, decreasing UPDRS factor III scores and factor II scores for activities of daily living. The development of motor complications (end-point) was significantly less frequent in patients treated with cabergoline than in levodopa recipients (22% vs 34%; p < 0.02). The relative risk of developing motor complications during treatment with cabergoline was more than 50% lower than with levodopa. Serious adverse events, either drug related or not, were slightly more frequent in cabergoline-treated patients (31%) than in those treated with levodopa (25%). The withdrawal rate in the cabergoline vs levodopa group was 16 vs 13%. In conclusion, the study shows that, in patients with early Parkinson's disease, cabergoline is effective either as monotherapy or combined with levodopa. Moreover, starting treatment with cabergoline significantly delays the development of motor complications.

Topics: Activities of Daily Living; Antiparkinson Agents; Cabergoline; Dopamine Agonists; Double-Blind Method; Ergolines; Female; Humans; Levodopa; Linear Models; Male; Middle Aged; Movement Disorders; Parkinson Disease; Time Factors

Cabergoline is a potent D2 receptor agonist with a half-life of 65 hours that may provide continuous dopaminergic stimulation administered once daily. In this study, we randomized de novo Parkinson's disease (PD) patients to treatment with increasing doses of cabergoline (0.25 to 4 mg/d) or levodopa (100 to 600 mg/d) up to the optimal or maximum tolerated dose. Decreases of > 30% in motor disability (Unified Parkinson's Disease Rating Scale Factor III) versus baseline were considered indicative of clinical improvement. If 30% improvement was not achieved, levodopa/ carbidopa could be added on an open basis. Of the 208 patients entered in the cabergoline group, 175 remained in the study for 1 year at a mean dose of 2.8 mg/d; in the levodopa group, 176 of the 205 patients entered were still on study after 1 year at a mean dose of 468 mg/d. The proportion of patients requiring additional levodopa/carbidopa increased in the cabergoline group from 18% at 6 months to 38% at 1 year versus 10% (p = 0.05) at 6 months and 18% (p < 0.01) at 1 year in the levodopa group. The proportion of patients showing clinical improvement did not differ significantly between the two groups, or between the subgroups on monotherapy, at any endpoint. Irrespective of levodopa/carbidopa addition, 81% of patients in the cabergoline group and 87% of patients in the levodopa group were clinically improved at 1 year (p = 0.189); the corresponding figures for the subgroup on monotherapy were 79% in the cabergoline-treated patients and 86% in the levodopa-treated patients (p = 0.199). The mean difference versus baseline in Unified Parkinson's Disease Rating Scale Factor III scores in patients who remained on monotherapy up to 1 year was 12.6 (95% confidence interval [CI]: 10.8, 14.3) in the cabergoline group and 16.4 (95% CI: 14.8, 18.0) in the levodopa group. Adverse events occurred in 76% of patients on cabergoline and in 66% of patients on levodopa. The severity profile for reported events was similar for the two agents. The results of this study indicate that cabergoline treatment for up to 1 year is only marginally less effective than levodopa in the proportion of patients who can be treated in monotherapy. More than 60% of de novo PD patients could be managed on cabergoline alone up to 1 year. In the patients in whom levodopa/carbidopa was needed, the combination therapy provided efficacy similar to that obtained with levodopa alone, with a relevant sparing of levodopa.

Topics: Aged; Antiparkinson Agents; Cabergoline; Double-Blind Method; Ergolines; Female; Humans; Levodopa; Male; Middle Aged; Parkinson Disease

Previous investigations on the mutual pharmacokinetic influence of L-dopa and dopamine agonists in Parkinson's disease (PD) have shown controversial results. Two studies of the possible clinical and pharmacokinetic interaction between L-dopa and cabergoline were performed in 10 patients with de novo PD and 12 patients with fluctuating PD. In the first study (de novo patients), cabergoline was administered at increasing dosages until the maximum dosage of 2 mg/day once a day for 8 weeks; subsequently L-dopa (250 mg/day) was added. Blood levels of cabergoline were assayed in two different days, before starting L-dopa, and 1 week thereafter. In the second 8-week study (fluctuating patients), cabergoline was added to the current L-dopa therapy (maximum dosage 4 mg/day once a day). Blood levels of L-dopa were measured in two different days, before cabergoline was added, and at the end of the study. In both studies motor performance was evaluated by means of the Unified Parkinson's Disease Rating Scale (motor examination) and the Clinical Global Impression Scale; on-off diaries of daily motor condition also were filled by fluctuating patients. In patients with de novo PD, cabergoline pharmacokinetic parameters were unmodified by the adjunct of L-dopa, except that the time to reach the peak concentration (Tmax) significantly increased after L-dopa. In patients with fluctuating PD, no modification of L-dopa pharmacokinetics was observed before and after cabergoline coadministration. Clinical evaluations confirmed that cabergoline is effective in the treatment of advanced PD as well as in the management of de novo patients.

Topics: Aged; Antiparkinson Agents; Cabergoline; Dose-Response Relationship, Drug; Drug Interactions; Drug Therapy, Combination; Ergolines; Female; Humans; Levodopa; Male; Middle Aged; Motor Activity; Parkinson Disease

The ergoline derivative FCE 23,884 acts as a dopamine D1 agonist in untreated parkinsonian animals and as a D2 antagonist in animals whose dopamine system is intact or levodopa treated. To evaluate whether this dual action might benefit patients with Parkinson's disease (PD) who have developed levodopa-induced dyskinesias, the motor effects of FCE 23,884 were examined in seven such individuals using a double-blind, placebo-controlled design. At doses up to the maximum tolerated dose (3.5 +/- 0.5 mg), FCE 23,884 monotherapy did not affect parkinsonian severity. On the other hand, coadministration of FCE 23,884 with a mildly dyskinetic dose of levodopa, infused intravenously under steady-state conditions, reduced the antiparkinson response by 54 +/- 19% and tended to diminish dyskinesia severity. The results thus fail to suggest any useful role for FCE 23,884 in the symptomatic treatment of PD. Although D2 receptor blockade provided by FCE 23,884 antagonizes both the antiparkinson and dyskinesigenic responses to levodopa, the degree of D1 receptor stimulation appears insufficient to ameliorate parkinsonian symptomatology.

Topics: Aged; Antiparkinson Agents; Carbidopa; Dopamine Agonists; Dopamine Antagonists; Dopamine D2 Receptor Antagonists; Double-Blind Method; Drug Therapy, Combination; Ergolines; Female; Humans; Levodopa; Male; Middle Aged; Neurologic Examination; Parkinson Disease; Receptors, Dopamine D1; Receptors, Dopamine D2; Treatment Outcome

Adjunctive cabergoline or placebo, in doses up to 5 mg daily, were administered to Parkinson's disease patients with short-duration levodopa responses in a 6-month double-blind trial. The 13 patients randomized to cabergoline and completing the study had significantly improved Unified Parkinson's Disease Rating Scale (UPDRS) motor scores and timed hand-tapping test scores. Serial measurements on test days documented improved scores: (a) before the first levodopa (and cabergoline) dose of the day, (b) at the time of the peak levodopa effect, and (c) at the end of the levodopa response cycle, 5 h after test doses. Continued testing verified that these therapeutic responses were sustained for at least 48 h after the last cabergoline dose. Patients randomized to placebo failed to improve on any of these measures. In a subsequent open-label dose-escalation phase, further improvement was documented as the dosage was gradually raised to 10 mg daily. As in the double-blind phase, levodopa reduction allowed the improvement to occur in the absence of significantly increased dyskinesias. Other side effects were more substantial with higher doses, however, including two of 11 patients with hallucinations and confusion. In summary, adjunctive single-daily-dose cabergoline therapy resulted in long-lasting, dose-related improvement in parkinsonism not seen in patients receiving placebo.

Topics: Adult; Aged; Antiparkinson Agents; Cabergoline; Dopamine Agonists; Dose-Response Relationship, Drug; Double-Blind Method; Drug Therapy, Combination; Ergolines; Humans; Levodopa; Male; Middle Aged; Movement Disorders; Parkinson Disease

Cabergoline is a dopaminergic agonist relatively specific for the D2 receptor and much longer-acting than other dopamine agonists. We conducted a randomized, placebo-controlled, double-blind study of cabergoline in 188 levodopa/carbidopa-treated patients with suboptimally controlled Parkinson's disease (PD). The cabergoline patients had significantly better Activities of Daily Living (p = 0.032) and Motor Examination (p = 0.031) scores at the conclusion of the trial compared with the placebo group. The daily levodopa dose for the cabergoline patients decreased 18% compared with a 3% reduction for the placebo group (p < 0.001). The amount of time in the "on" state increased more in the cabergoline group (p = 0.022). The side-effect was similar to that seen with other dopamine agonists, and cabergoline was generally well tolerated. We conclude that cabergoline is an effective adjunct to levodopa for the treatment of PD.

Topics: Activities of Daily Living; Adult; Aged; Aged, 80 and over; Cabergoline; Dopamine Agonists; Double-Blind Method; Drug Administration Schedule; Ergolines; Female; Humans; Levodopa; Male; Middle Aged; Movement; Parkinson Disease; Patient Dropouts; Placebos; Treatment Outcome

In the present study we compared the efficacy and safety of the new dopamine agonist cabergoline (CBG) with bromocriptine (BCR) in Parkinson's disease (PD). CBG has a very long half-life and can be administered as a single daily dose. Forty-four PD patients with uncontrolled motor fluctuations participated in the study. Patients were randomly and blindly assigned to equivalent doses of either CBG or BCR in addition to preexisting levodopa. Dosage was titrated to optimal, using up to 6 mg of CBG or 40 mg of BCR daily. CBG was given as a single morning dose whereas BCR was administered tid. Sixteen patients were followed for 1 year and 16 additional patients for 6 months. The mean follow-up duration was 9 +/- 5 months. The main effect of both drugs was observed on motor UPDRS scores, rigidity, bradykinesia items, and the percentage of awake hours spent during "on" and "off". In general, the effect of CBG was similar to that of BCR. The percentage of awake hours spent during "on" was higher with CBG as compared with BCR. Adverse events included dyskinesias, orthostatism, confusion, edema, and paresthesias in limbs. These effects were seen at similar frequencies with both drugs. The study shows that CBG given as a single morning dose is at least as efficacious as BCR given tid. CBG is a promising dopamine agonist for the treatment of motor fluctuations in PD.

Topics: Aged; Aged, 80 and over; Antiparkinson Agents; Bromocriptine; Cabergoline; Double-Blind Method; Ergolines; Female; Humans; Male; Middle Aged; Movement Disorders; Parkinson Disease

Topics: Aged; Cabergoline; Dopamine Agonists; Double-Blind Method; Drug Therapy, Combination; Ergolines; Female; Humans; Male; Middle Aged; Parkinson Disease; Placebos; Selective Serotonin Reuptake Inhibitors; Treatment Outcome

The use of a dopamine agonist with a long duration of action has theoretical advantages in attempting to reduce the motor fluctuations in Parkinson's disease. We report the results of a double-blind controlled study of adding cabergoline, an ergot derivative with potent long-lasting high affinity for the D2 receptor, to levodopa therapy in 37 patients with severe fluctuations in response to treatment. Increasing dosages of cabergoline (19 patients) or placebo (18 patients) were added to each patient's stable levodopa regime. The two patient groups were similar at baseline in terms of age, disease duration, duration of levodopa treatment, and average hours "off" per day. Following incremental dose titration, patients in the cabergoline group had a significant reduction in hours "off" per day from 5.0 (SD 2.1) to 3.0 (SD 2.5), but there was no change in this measure in the placebo group [4.0 (2.2) and 3.3 (2.3) respectively]. This was not at the expense of a significant increase in dyskinesia. However, there was no difference between the groups when comparing their average Hoehn and Yahr stage of disease, and Schwab and England activities of daily living index.

Topics: Adult; Aged; Blood Pressure; Cabergoline; Dose-Response Relationship, Drug; Double-Blind Method; Ergolines; Humans; Levodopa; Middle Aged; Movement; Parkinson Disease; Placebos; Severity of Illness Index; Time Factors

The addition of a dopamine agonist and of a monoamine oxidase type B inhibitor to I-dopa has been suggested in the therapy of Parkinson's disease. The plasma pharmacokinetics of both cabergoline and I-dopa have previously been shown to remain unaffected when the two drugs are given concomitantly. This study aimed at examining whether the plasma pharmacokinetic parameters of cabergoline and selegiline are modified when given in combination. Selegiline is hardly detectable in plasma. Therefore, the plasma levels of its metabolites amphetamine, methamphetamine and desmetylselegiline were used to assess the effect of cabergoline co-administration. Plasma levels of the selegiline metabolites were determined first after selegiline administration (10 mg/day) for 8 days, and then after administration of both drugs for 22 additional days (day 30). Cabergoline plasma levels were measured on day 30, and then after administration of cabergoline (1 mg/day) alone for further 22 days. No statistical difference was found between the Cmax.ss, tmax.ss, AUC0-24h.ss, C0h.ss, C24h.ss values of cabergoline and of the selegiline metabolites when the two drugs were given alone or in combination, indicating the absence of pharmacokinetic interaction between cabergoline and selegiline.

Topics: Aged; Amphetamine; Amphetamines; Antiparkinson Agents; Cabergoline; Dopamine Agonists; Drug Interactions; Ergolines; Female; Humans; Male; Methamphetamine; Middle Aged; Monoamine Oxidase Inhibitors; Parkinson Disease; Selegiline

Assessment of the very long-acting dopamine agonist medication cabergoline in the control of motor fluctuations in Parkinson's disease.. Open-label trial (13 weeks).. Referral centers (Mayo Clinic, Rochester, Minn, and Scottsdale, Ariz).. Volunteer sample of 41 patients with idiopathic Parkinson's disease who were experiencing motor fluctuations while receiving stable doses of carbidopa and levodopa.. Adjunctive oral cabergoline was incrementally administered once daily with the maintenance dose determined by the clinical response (maximum dose, 5 mg/d).. Standardized serial motor examinations were performed, beginning anywhere from 30 minutes before and continuing to 6 hours after test doses of medications were administered. Scores during adjunctive cabergoline therapy were compared with the prestudy baseline scores during therapy with carbidopa and levodopa without cabergoline.. Adjunctive cabergoline therapy significantly improved mean motor scores at the time of each standardized serial examination, from 30 minutes to 6 hours after the administration of test doses of medications. Significant motor score improvement was also measured 24 hours after the last cabergoline dose was administered, suggesting a very long-acting antiparkinsonian effect. Mean dyskinesia scores were slightly but nonsignificantly elevated. Diary card "off-time" was improved by 42%, whereas the levodopa dosage was reduced by 18%. Only three patients dropped out (7% of the total), which contrasts with much higher dropout rates owing to adverse events in previous clinical trials of other antiparkinsonian dopamine agonists.. Cabergoline improved motor control in patients with Parkinson's disease who were experiencing clinical fluctuations. Possible advantages of this medication include an extended clinical response (persisting to 24 hours), tolerability, and ease of use (once per day administration).

Topics: Adult; Aged; Cabergoline; Dopamine Agonists; Ergolines; Female; Humans; Male; Middle Aged; Movement Disorders; Parkinson Disease

Cabergoline, a new ergoline derivative with potent and long-lasting dopaminergic activity, is a promising drug for overcoming the akinetic episodes in L-Dopa-treated Parkinson's disease patients with motor fluctuations. Its long plasma half-life (65 h) allows a single daily dose administration. Seventeen patients with Parkinson's disease (mean age 66 years; mean disease duration 8.8 years; median Hoehn and Yahr stage, III) were included in an open-label study. All had persistent motor fluctuations while treated with L-Dopa plus carbidopa (mean dose, 660 mg + 66 mg). Cabergoline was added until a maximal dose was achieved (5 mg daily), while L-Dopa was slightly diminished. Eight patients completed 1 year of treatment. They showed significant improvement in their motor performance (Unified Parkinson's Disease Rating Scale) (bradykinesia score decreased from 8.2 to 4.2, p < 0.005), and in the proportion of "off" time spent during waking hours (32-23%, p < 0.05). Three patients abandoned the trial because of increasing severity of dyskinesias, hallucinations, and depression (one each), six were withdrawn because of poor compliance and refusal to continue the treatment. This study suggests that cabergoline may play an important role in the treatment of Parkinson's disease with motor fluctuations.

Topics: Aged; Antiparkinson Agents; Cabergoline; Dopamine Agonists; Ergolines; Female; Humans; Male; Middle Aged; Parkinson Disease; Receptors, Dopamine D2

We administered cabergoline, a potent, once-a-day dopamine against, to 61 patients with advanced Parkinson's disease (PD) and response fluctuations--"wearing-off" and "on-off" phenomena. The patients were on stable doses of levodopa/carbidopa. During the first 5 weeks, patients were randomized to allow equal numbers to end titration at each of five daily doses of cabergoline from 0.5 to 2.5 mg. We evaluated the patients using the Unified Parkinson's Disease Rating Scale (UPDRS) and diaries of motor performance. This part of the study was double-blinded. After 5 weeks, the mean Activities of Daily Living (ADL) score on the UPDRS decreased by 22% (p < 0.0001), the mean Motor Score in the "off" period decreased by 14% (p < 0.0001), and the mean Motor Score in the "on" period decreased by 22% (p < 0.0001). The mean percent "off" time decreased by 9.0%. Twenty-three patients (38%) achieved at least a 25% improvement in the combined ADL and motor examination of the UPDRS. Four patients dropped out because of adverse effects. We treated 37 patients, including some patients who had experienced a transient 25% improvement, for an additional 8 weeks in an open manner until they achieved a 25% improvement or reached a maximum of 5 mg/d. The other patients were continued in a double-blind manner on the dose of cabergoline they had achieved at the end of week 5. At the end of 13 weeks, the group of 37 patients achieved additional significant improvements in mean ADL and mean motor scores in the "on" and "off" periods. The percent time "off" decreased by 31%.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Aged; Cabergoline; Carbidopa; Dopamine Agents; Drug Combinations; Ergolines; Female; Humans; Levodopa; Male; Middle Aged; Motor Activity; Parkinson Disease; Receptors, Dopamine

Cabergoline, a new ergoline derivative, is a D2-specific dopaminergic agonist that is more potent and longer-acting than other agonist agents. We conducted a randomized, double-blind study of increasing doses of cabergoline taken once a day. Twenty-five patients with Parkinson's disease taking stable doses of levodopa began cabergoline at 0.5 mg. The dose was escalated at weekly intervals to 1.0 mg in 19 patients, 1.5 mg in 14 patients, 2.0 mg in nine patients, and 2.5 mg in four patients. Treatment continued for 8 weeks after titration. Unified Parkinson's Disease Rating Scale scores, Hoehn and Yahr stage of disease, and computerized measures of motor performance improved significantly with cabergoline treatment. Dose-response effects were not significant. No serious adverse experiences occurred during the 13-week trial, and the side-effect profile mirrored other dopaminergic agonists. Cabergoline appears to be a promising agent in the treatment of Parkinson's disease.

Topics: Adult; Aged; Cabergoline; Double-Blind Method; Ergolines; Female; Humans; Male; Middle Aged; Parkinson Disease

CQA 206-291, a mixed D1-D2 receptor agonist that also possesses dualistic dopamine antagonist-agonist properties, was investigated in a double-blind, placebo-controlled trial in individuals with Parkinson's disease of moderate severity. Significant improvement was noted in the treatment groups compared to the placebo group. Adverse effects were generally mild and transient. CQA appears to be an effective, well-tolerated agent in the treatment of Parkinson's disease. Nevertheless, because of laboratory-based toxicity concerns, CQA has been withdrawn from further human study and will not be developed clinically.

Topics: Activities of Daily Living; Aged; Dopamine Agents; Double-Blind Method; Drug Interactions; Ergolines; Humans; Levodopa; Middle Aged; Parkinson Disease

Topics: Aged; Dopamine Agents; Dose-Response Relationship, Drug; Drug Therapy, Combination; Ergolines; Female; Humans; Levodopa; Male; Middle Aged; Neurologic Examination; Parkinson Disease

The antiparkinsonian efficacy and tolerability of CQA 206-291, a novel ergoline derivative with potent dopamine agonist properties, were studied during 2 months of treatment in 72 parkinsonian patients. In 36 de novo patients (patients who have not previously been treated with levodopa or dopamine agonists), CQA 206-291 was studied in an open design, while in 36 levodopa-treated patients, CQA 206-291 was studied in a randomized, double-blind, parallel-group, placebo-controlled design. CQA 206-291 induced in both groups a significant antiparkinsonian effect with an effective dose range of 5-30 mg/day. The spectrum of adverse events was similar to what is commonly observed with dopamine agonists. Further studies are required to assess the putative therapeutic advantages of CQA 206-291 when compared to other antiparkinsonian drugs.

Topics: Aged; Antiparkinson Agents; Drug Therapy, Combination; Ergolines; Female; Humans; Levodopa; Male; Middle Aged; Parkinson Disease

Topics: Administration, Oral; Aged; Antiparkinson Agents; Cabergoline; Dose-Response Relationship, Drug; Drug Administration Schedule; Ergolines; Female; Humans; Male; Neurologic Examination; Parkinson Disease

In this study, the hemodynamic and neurochemical effects of lisuride, a dopamine agonist with serotoninergic properties, have been evaluated in de novo parkinsonian patients and in elderly subjects with mild cognitive impairment. Blood pressure (BP), heart rate (HR), and urinary catecholamine (CA) fluctuations throughout the 24-h cycle were monitored before and during lisuride therapy along with BP, HR, and plasma CA responses to the tilt-table test. Lisuride (1.2-2.4 mg/day) administered in an open-type 15-day study was capable of decreasing the urinary CA excretion and norepinephrine plasma levels in parkinsonian patients. In some cases, the cardiovascular response to standing was impaired. Lower doses of the drug (0.15 mg/day), administered to elderly patients in a double-blind parallel group vs. placebo study, did not induce any change in cardiopressor responses but decreased the 24-h urinary excretion of epinephrine. These results suggest the importance in both conditions of detecting early stages of alterations in cardiopressor homeostatic processes before therapy with DAergic drugs is initiated.

Topics: Aged; Aging; Blood Pressure; Catecholamines; Circadian Rhythm; Clinical Trials as Topic; Cognition Disorders; Double-Blind Method; Ergolines; Female; Heart Rate; Humans; Lisuride; Male; Middle Aged; Parkinson Disease; Posture; Time Factors

A randomized, prospective trial in 90 de novo parkinsonian patients showed that 4 years' treatment with lisuride resulted in significantly fewer end-of-dose disturbances and peak-dose dyskinesias, but also less improvement in parkinsonian disability, than with levodopa. Early combination of lisuride and a low dose of levodopa, during a 4-year follow-up, resulted in a therapeutic response equal to that achieved with high-dose levodopa alone, but significantly fewer end-of-dose failures and dyskinesias. Thus it seems advisable that treatment should begin in the early phase of the disease with a dopamine agonist such as lisuride combined with a low dose of levodopa.

Topics: Drug Therapy, Combination; Ergolines; Female; Humans; Levodopa; Lisuride; Male; Middle Aged; Parkinson Disease

At the first stage of a pilot study involving 14 parkinsonians with motor fluctuations, treatment with standard Madopar was substituted by a sustained-release form, Madopar HBS, which attenuated fluctuations in patients with end-of-dose impairment, but achieved only moderate improvement in patients with on-off phenomena. In a second phase of the trial, 4 parkinsonians exhibiting the most severe fluctuations of mobility and the poorest response to Madopar HBS (Hydrodynamically Balanced System) were selected for treatment with a combined regimen utilizing subcutaneous lisuride infusions as the additional component. The sequence of the trial was as follows: 1. standard Madopar, 2. Madopar HBS, 3. standard Madopar combined with lisuride infusions and 4. Madopar HBS combined with lisuride infusions. Steady improvement was observed along the lines of this schedule, but the best results were obtained when Madopar HBS was combined with lisuride infusions. Subsequently motor fluctuations were less marked or disappeared, early-morning Parkinson symptoms decreased and dystonia was not recorded any longer. Even better results could be accomplished in an extended trial attempting to establish the best dosage ratio of the combination, possibly admitting increased dosage. The tolerance of the combined regimen was excellent, except in one patient who transiently exhibited delusions and postural hypotension. The combination of sustained-release Madopar and continuous infusions of the dopaminergic agonist lisuride seems to prove a more physiological and effective regimen for the treatment of severe motor fluctuations.

Topics: Administration, Oral; Benserazide; Clinical Trials as Topic; Drug Administration Schedule; Drug Combinations; Drug Therapy, Combination; Drug Tolerance; Ergolines; Humans; Hydrazines; Infusion Pumps; Levodopa; Lisuride; Parkinson Disease; Severity of Illness Index

Terguride is an ergoline derivative with mixed agonistic/antagonistic dopaminergic activity. This led to a paradoxical suggestion that it is effective in the treatment of both schizophrenia and parkinsonism. A total of 65 in- or outpatients with parkinsonism mostly of vascular or idiopathic etiology were included in a 4-week, open, multicenter trial. Terguride was administered under an increasing dose schedule which was leveled off according to the clinical response. Mostly because of nausea, vomiting, and lack of improvement 25% of inpatients and 61% of outpatients were removed from the study. The average daily dose at the end of the trial was 4.2 mg, ranging from 1.0 to 5.5 mg. The average Simpson and Angus scale total score and performance in the Spiral Drawing Task improved significantly during the trial by 20% and 38% respectively. The following adverse effects were noted most frequently throughout the study (including those who withdrew): constipation (occurred in 42% of all ratings performed during the trial) drowsiness and nausea (16% each). Adverse circulatory effects were negligible. Psychotic symptoms, including depression, confusion, hallucinations, and paranoid syndrome, each occurred in 1 patient, i.e., at a lower rate than with other dopaminergic drugs. Scotopic electroretinograms in a subsample of 7 patients showed a significant transitory decrease in the B-wave amplitude at the end of the 1st week and a subsequent return to pretreatment values.

Topics: Adult; Aged; Aged, 80 and over; Clinical Trials as Topic; Ergolines; Female; Humans; Lisuride; Male; Middle Aged; Motor Skills; Neurologic Examination; Parkinson Disease

Lisuride at a mean daily dose of 3.2 mg was given to 15 untreated idiopathic Parkinson's disease patients. There were 10 dropouts, due mainly to inefficacy in the first months of therapy. The parkinsonian pattern in the patients who remained in the study for the full 4 years showed distinct improvement, which was maintained for less than 2 years. The patients did not develop "on-off" phenomena or abnormal involuntary movements during follow-up.

Topics: Adult; Aged; Clinical Trials as Topic; Ergolines; Female; Follow-Up Studies; Humans; Lisuride; Male; Middle Aged; Parkinson Disease; Time Factors

Topics: Adult; Aged; Brain; Clinical Trials as Topic; Disability Evaluation; Ergolines; Female; Humans; Lisuride; Male; Middle Aged; Motor Skills; Parkinson Disease; Receptors, Dopamine

The therapeutic effects of lisuride hydrogen maleate, a central dopamine agonist, were examined in 15 patients with advanced Parkinson's disease no longer satisfactorily responding to levodopa. A significant improvement (p less than 0.01) in the total Parkinson's disease disability score was obtained by the addition of lisuride to levodopa therapy. The clinical assessment in the follow-up was performed with 2 different disability scales that yielded a more precise evaluation of the efficacy of lisuride, an efficacy that, as with other dopaminergic drugs, showed a slight decrease in time after a mean of 3 months. No important adverse effects were noticed. The only limitation of the use of lisuride was the occurrence of reversible psychic disturbances. It is concluded from this study that lisuride is a valuable tool in the management of advanced Parkinson's disease that allows for a reduction of the side effects of levodopa therapy in the long-term treatment of the disease.

Topics: Aged; Clinical Trials as Topic; Ergolines; Female; Humans; Levodopa; Lisuride; Male; Middle Aged; Parkinson Disease; Time Factors

The efficacy and tolerance of treatment with an 8-alpha-amino-ergoline derivative CU32-o85, Mesulergine, were compared with levodopa/benserazide (Madopar) in a 3 month double-blind controlled trial in 31 patients with Parkinson's disease, not previously treated with levodopa. The two treatments were equally well tolerated, and neither dyskinesias nor dose-related fluctuations developed. In 90% of the patients treated with Mesulergine, Parkinsonian symptoms improved, and at the dose given the overall therapeutical response was two-thirds that of levodopa. During further 9 months of open study the beneficial effect was maintained equally well in both groups. Compared with other dopamine agonists Mesulergine has a considerable antiparkinsonian effect. Unfortunately, further clinical evaluation of the compound recently has been stopped owing to sex and species specific histological alterations in rats. It is suggested that Mesulergine derivatives might well be of value in future treatment of early Parkinson's disease and of late incompensated stages.

Topics: Aged; Antiparkinson Agents; Benserazide; Clinical Trials as Topic; Double-Blind Method; Drug Combinations; Ergolines; Female; Humans; Levodopa; Male; Middle Aged; Parkinson Disease; Random Allocation

Possible pergolide-induced cardiotoxicity has been reported in open trials. Over a 6-month period of observation, we prospectively analyzed ECGs and 24-hour ambulatory ECG in 23 patients with Parkinson's disease who were randomized in a double-blind fashion to pergolide or placebo treatments. Pergolide therapy was associated with a mild and transient bradycardiac effect, but no clinically significant cardiotoxicity.

Topics: Aged; Bradycardia; Clinical Trials as Topic; Double-Blind Method; Electrocardiography; Ergolines; Female; Heart; Heart Rate; Humans; Male; Middle Aged; Monitoring, Physiologic; Parkinson Disease; Pergolide; Prospective Studies

We used a new D2 dopamine agonist, mesulergine (8-alpha-amino-ergoline, CU 32-085), to treat 20 patients (12 men and 8 women), mean age 62.6 (SEM = 1.7) and mean duration of illness 5.9 (SEM = 1.0) years. Wearing-off effect was the principal indication for new therapy in 15 patients, and the others had inadequate response to levodopa. All continued on levodopa therapy, and 10 patients were studied in a double-blind controlled test. The mean motor disability decreased from 2.8 (SEM = 0.12) to 1.6 (SEM = 0.18) with mesulergine (p less than 0.0001) and increased to 1.9 (SEM = 0.20) with placebo (p less than 0.001). Tremor improved most, followed by rigidity, bradykinesia, gait, and postural instability. Side effects included dyskinesia, light-headedness, hallucinations, nausea, vomiting, drowsiness, and ankle edema, but, in general, mesulergine was tolerated well.

Topics: Aged; Antiparkinson Agents; Clinical Trials as Topic; Ergolines; Female; Humans; Male; Middle Aged; Parkinson Disease; Placebos

Pergolide mesylate, a dopamine agonist, was studied as adjunctive therapy in a 6-month double-blind trial in 20 patients with Parkinson's disease who were achieving less than optimal response from Sinemet. As pergolide or placebo was administered in increasing dosage, Sinemet was reduced if side effects developed. Both the pergolide and placebo groups improved significantly (p less than 0.05). The pergolide group improved 30% at the end of 24 weeks, and the placebo group 23%. There was no significant difference between drug and placebo groups, possibly due to a fortuitous support group and the side effects that may have burdened the pergolide group. Nevertheless, pergolide had a definite antiparkinsonian effect.

Topics: Aged; Carbidopa; Clinical Trials as Topic; Double-Blind Method; Drug Combinations; Ergolines; Female; Follow-Up Studies; Humans; Levodopa; Male; Middle Aged; Parkinson Disease; Pergolide

Nine patients with idiopathic Parkinson's disease were treated with pergolide to a daily maintenance dose of 2.2 +/- 0.9 mg (mean +/- SD) for 17.3 +/- 8.3 months. After 1 month, there was an average 68% increase in mobile on-time, but the improvement declined to 30% by 6 months, 23% by 1 year, and virtually disappeared by 18 months of therapy. Pergolide was discontinued in seven patients because of loss of efficacy (4 patients), confusion (1 patient), or myocardial infarction or ventricular ectopy (2 patients). Partial but temporary restoration of mobility was observed in seven patients who were switched to an alternate-day dosing schedule after 9.2 +/- 2.4 months. Two patients with advanced Shy-Drager syndrome were treated with pergolide without benefit.

Topics: Aged; Ambulatory Care; Antiparkinson Agents; Clinical Trials as Topic; Drug Administration Schedule; Ergolines; Female; Hospitalization; Humans; Male; Middle Aged; Parkinson Disease; Pergolide; Shy-Drager Syndrome; Time Factors

In a 12-month open-label trial, pergolide mesylate was administered in doses with antiparkinsonian efficacy to six patients with stable heart disease. Cardiac status did not worsen in any patient. Parkinson's disease improved in all patients. Pergolide is a safe and effective therapy for Parkinson's disease, even in patients with heart disease.

Topics: Aged; Clinical Trials as Topic; Electrocardiography; Ergolines; Female; Heart; Heart Diseases; Humans; Male; Middle Aged; Myocardial Contraction; Parkinson Disease; Pergolide

Twenty patients with Parkinson's disease were treated with the 8-alpha-ergoline derivative mesulergine. Participants were divided into two groups, and over a nine-week period, mesulergine dosage was increased to a maximum of either 10 or 20 mg daily. During this time levodopa-carbidopa (LD-CD) dosage was reduced and treatment was discontinued if possible. The dosage of LD-CD was reduced 75% in the 10 mg group and 74% in the 20 mg group. Patients in the low-dose group maintained their functional status and showed improvement in postural stability. Patients in the high-dose group showed improvement in each of the cardinal signs of parkinsonism. Adverse effects were generally mild and infrequent. Many adverse effects induced by LD-CD diminished or resolved. Our results suggest that mesulergine can be valuable in the management of Parkinson's disease, particularly in those individuals experiencing dose-limiting adverse effects from LD-CD.

Topics: Aged; Antiparkinson Agents; Clinical Trials as Topic; Double-Blind Method; Ergolines; Female; Humans; Male; Middle Aged; Parkinson Disease; Random Allocation

Previous studies with mesulergine (CU 32-085) demonstrated safety and efficacy in short-term observations of patients with Parkinson's disease. We compared mesulergine with bromocriptine in 20 patients with Parkinson's disease. Eighteen patients completed the randomized, double-blind, crossover study. Clinical assessments employed the UBC scale and "Mini-Mental State" examination; neurophysiologic measurements were undertaken on wrist rigidity and speed and accuracy of hand movement, and toxicity screening tests were compared. There were no significant differences between the effects of mesulergine (mean dosage, 27.4 mg/d) and bromocriptine (mean dosage, 40.8 mg/d).

Topics: Adult; Aged; Bromocriptine; Clinical Trials as Topic; Ergolines; Female; Humans; Male; Middle Aged; Movement; Nervous System; Parkinson Disease

A double-blind, placebo-controlled study was conducted of pergolide as an adjunctive treatment to levodopa in 17 patients with advanced Parkinson's disease. There was a significant improvement (p less than 0.05) in total disability score, in gait, and in "wearing off" and "on-off" phenomena. Pergolide is a useful drug in patients with advanced Parkinson's disease.

Topics: Adult; Aged; Clinical Trials as Topic; Double-Blind Method; Ergolines; Gait; Humans; Levodopa; Middle Aged; Motor Activity; Movement Disorders; Parkinson Disease; Pergolide; Random Allocation

24 levodopa pretreated patients with advanced parkinsonism were split into two equal groups receiving mesulergine or bromocriptine respectively as an adjuvant therapy. The trial was carried out under double blind conditions the first three months and then continued as an open trial for one year. Clinical benefit was similar in both groups with minor differences in regard to single symptoms. While bromocriptine showed a beginning decline in efficacy after one year, mesulergine showed no decline. The mean mesulergine-dose, necessary to achieve good clinical improvement, was about half of bromocriptine. Side-effects were similar, except orthostatic hypotension requiring vasopressor medication, which was less frequent in mesulergine treated patients. This advantage of mesulergine might be explained by its special pharmacological pattern with biphasic action on dopaminergic receptors.

Topics: Adult; Aged; Blood Pressure; Bromocriptine; Drug Administration Schedule; Ergolines; Female; Heart Rate; Humans; Levodopa; Male; Middle Aged; Parkinson Disease; Time Factors

We evaluated pergolide in 22 patients with Parkinson's disease and 3 with progressive supranuclear palsy (PSP). After achieving an optimal dose of pergolide and Sinemet, a matching placebo was substituted in double-blind manner. The mean dose of levodopa (in Sinemet) was reduced by 68%; in eight patients, pergolide completely replaced levodopa. In parkinsonian patients, the mean Hoehn-Yahr stage decreased from 3.2 to 1.6, and the mean total disability score decreased from 48.3 to 17.8. In 10 patients with on-off phenomenon, the time on increased 174% with pergolide. There was little effect in PSP. Postural light-headedness and reversible mental changes were seen.

Topics: Adult; Aged; Antiparkinson Agents; Bulbar Palsy, Progressive; Clinical Trials as Topic; Double-Blind Method; Ergolines; Female; Humans; Levodopa; Male; Middle Aged; Parkinson Disease; Pergolide; Placebos

Lisuride was administered to 63 patients with advanced Parkinson's disease (PD) who were no longer satisfactorily responding to levodopa. The group included 40 patients with 'on-off' phenomena. Lisuride alone (13 patients) or combined with levodopa (50 patients) resulted in a 34% decrease in PD disability as assessed in the 'on' period, a 16% decrease in disability as assessed in the 'off' period, and a 96% increase in the numbers of hours in which patients were 'on' (from 5.5 to 10.8 h). All of these changes were significant (p less than or equal to 0.001). 37 of the 63 patients (59%) improved at least one-stage on lisuride. The major adverse effect limiting the use of lisuride was the occurrence of an organic confusional syndrome. This was related, in part, to the presence of an underlying dementia and to the concurrent use of anticholinergic drugs.

Topics: Aged; Clinical Trials as Topic; Double-Blind Method; Drug Evaluation; Ergolines; Female; Humans; Lisuride; Male; Middle Aged; Parkinson Disease

Our study of 28 patients has shown lisuride to share a comparable profile of antiparkinsonian effects and adverse reactions to that found with bromocriptine. The similarity in clinical response to lisuride and bromocriptine in the same group of patients contrasts with the pharmacological differences that have been established between them in animal studies. There were considerable individual differences in the patients' preference of bromocriptine or lisuride. The daily intake requirements of each drug for optimal benefit also varied widely from one patient to another. The preliminary results of pharmacokinetic studies with lisuride suggest several explanations for the differences in daily dosage requirements. Although the mean optimal daily dose of lisuride was 4.5 mg, some patients required up to 10 mg. Eleven of the patients have continued on lisuride for more than 1 year. Our clinical impression is that problems with chronic levodopa therapy, such as dyskinesia and fluctuations in efficacy, are reduced in some patients taking either lisuride or bromocriptine.

Topics: Bromocriptine; Clinical Trials as Topic; Dose-Response Relationship, Drug; Double-Blind Method; Ergolines; Female; Humans; Lisuride; Male; Middle Aged; Parkinson Disease

Two alpha-aminoergolines with different dopaminergic effects in rats were tried in two groups of Parkinson patients. CQ 32-084 was given in increasing doses up to 10 mg a day for 4 weeks to 10 Parkinson patients, 6 untreated cases and 4 cases with long-term levodopa treatment problems. The patients were checked every week by the Webster rating scale. All patients improved more or less, the earlier untreated patients more than the levodopa-treated patients. Most patients stopped at a dose of 15 mg a day. The side effects were slight. Another group of 10 patients with long-term levodopa treatment problems or insufficient effect of actual treatment were treated in a double-blind crossover trial with another ergoline derivative, CU 32-085. The dose was increased as in the first experiment up to 20 mg a day. Seven of the patients improved during the active drug period. In three cases, the hyperkinesia was increased during the active period, and in two cases it improved. Three patients found an obvious antidepressive effect during the active drug period. Five patients indicated slight decrease of on/off phenomena during the active period of treatment. A more extensive examination of these drugs seems indicated.

Topics: Adult; Aged; Blood Pressure; Clinical Trials as Topic; Disability Evaluation; Ergolines; Female; Humans; Male; Middle Aged; Parkinson Disease; Pilot Projects

Topics: Clinical Trials as Topic; Disability Evaluation; Ergolines; Female; Humans; Levodopa; Male; Parkinson Disease; Pergolide; Sleep; Time Factors

Twenty-four parkinsonian patients compared pergolide and bromocriptine therapy in a randomized double-blind, two-period crossover study. Both drugs were adjusted to an optimal balance between benefits and side effects. The mean daily dose and dose range for pergolide and bromocriptine were 3.3 mg (0.7 to 7.2) and 42.7 mg (5.8 to 87.5), respectively. Adjunctive medications, which for most patients included levodopa (plus carbidopa), were not altered during the study. A similar spectrum of clinical effects was found with both drugs and with lisuride, which was used to treat 13 of the patients in a previous study. Despite neurochemical differences in the antiparkinsonian ergots, their clinical utility is quite similar. We draw attention to hepatotoxicity and pleural reactions that may occur rarely with these drugs.

Topics: Aged; Bromocriptine; Clinical Trials as Topic; Double-Blind Method; Ergolines; Female; Humans; Levodopa; Male; Middle Aged; Parkinson Disease; Pergolide

Bromocriptine (CB-154) and the 8-alpha-ergoline CU 32-085, two dopamine receptor agonists, were administered at different times to two series of 22 patients with Parkinson's disease, most of whom took levodopa (plus benserazide) at optimum dosage. The addition of bromocriptine (mean daily dose 32 mg; after 6 months 40 mg) led to a 38.5% reduction of levodopa, while CU 32-085 (mean daily dose 15.2 mg; after 6 months 17.5 mg) permitted a 33.7% reduction in levodopa. The mean dose in two patients on CU 32-085 monotherapy was 55 mg/day. A total of 15 patients tolerated adequate doses of bromocriptine (5-75 mg/day, mean duration of treatment 7.5 months) and 15 patients long-term treatment up to 14 months with CU 32-085 (dose range 1-60 mg/day; mean duration 8.8 months). Both groups showed a significant improvement of "total disability score' at 6 months by 56% and 67%, respectively, and after 6 months by 69% and 69.4%, respectively, with a significant decrease of all types of disability. All patients with fluctuations and "on-off' effects rapidly improved on both compounds. Bromocriptine and CU 32-085 were discontinued in seven patients each (32%) because of adverse effect including mental changes (for with bromocriptine, two with CU 32-085), nausea and vomiting (one and two, respectively), hypotension (one each) and increased tremor plus vomiting (one with CU 32-085). Although adverse effects were similar to those observed with levodopa, CU 32-085 in general showed less severe dyskinesia and mental changes but more frequent nausea than bromocriptine and levodopa. While the results of treatment with bromocriptine and CU 32-085 were comparable, the antitremor effect of the latter drug developed more rapidly, even at low dosage. Both compounds were useful in the management of patients with advanced Parkinson's disease, CU 32-085 having a stronger effect on tremor, bradykinesia, fluctuations and "on-off' effects than bromocriptine.

Topics: Aged; Bromocriptine; Clinical Trials as Topic; Dose-Response Relationship, Drug; Drug Therapy, Combination; Ergolines; Female; Humans; Levodopa; Male; Middle Aged; Parkinson Disease; Receptors, Dopamine

Twenty-six patients with late-stage Parkinson disease were given 0.4 to 15 mg of pergolide mesylate daily in addition to, or as replacement for, levodopa or bromocriptine therapy. Despite treatment with individually determined optimum doses of levodopa, bromocriptine, and anticholinergics, they had shown response failure or fluctuating response. Forty percent (11 patients) were unable to tolerate pergolide. Nausea and vomiting, somnolence, and psychiatric disturbances were the most frequent side effects. Eleven of the remaining patients improved on pergolide, 2 were unchanged, and 2 were slightly worse. Among the patients who benefited, pergolide improved dose-related response fluctuations more than non-dose-related fluctuations, with a reduction in number and duration of "off" periods and improvement in quality of sleep and early morning akinesia but little change in freezing episodes. Despite treatment failure in many cases, pergolide is at present the best available drug for specific late-stage management problems.

Topics: Bromocriptine; Clinical Trials as Topic; Double-Blind Method; Drug Therapy, Combination; Ergolines; Female; Humans; Levodopa; Male; Middle Aged; Parkinson Disease; Pergolide; Sleep Wake Disorders

Twenty-eight parkinsonian patients were studied in a double-blind, crossover comparison of lisuride and bromocriptine. All but two patients completed the study, with each drug adjusted to an optimal dose (mean daily intake of 4.5 mg for lisuride and 56.5 mg for bromocriptine). Treatment with each drug was given for 7 to 10 weeks; three assessments were made at biweekly intervals with optimal dose levels. Conventional antiparkinsonian medications, including levodopa, were not changed. Efficacy and adverse effects were assessed by objective and subjective techniques. The only significant difference was slightly better control of akinesia with bromocriptine. There was considerable variability in the optimal dose of each drug, though the clinical profile of lisuride was quite similar to that of bromocriptine.

Topics: Adult; Aged; Bromocriptine; Clinical Trials as Topic; Dose-Response Relationship, Drug; Double-Blind Method; Ergolines; Female; Humans; Lisuride; Male; Middle Aged; Parkinson Disease; Random Allocation

Topics: Clinical Trials as Topic; Ergolines; Female; Humans; Lisuride; Male; Parkinson Disease; Pergolide

The measurement of movement time provides a satisfactory objective measure of hypokinesia in parkinsonism. It is relatively constant in normal subjects, and it is often greatly prolonged in parkinsonism and correlates with clinical disability. The reaction time is only of limited value, because of small difference from normal values and wide individual variations.

Topics: Adult; Aged; Bromocriptine; Clinical Trials as Topic; Ergolines; Humans; Levodopa; Lisuride; Male; Middle Aged; Motor Activity; Movement; Parkinson Disease; Placebos; Posture; Time Factors

Lisuride hydrogen maleate, a semisynthetic ergoline and potent central dopamine and serotonin agonist, was tested in 10 patients with moderate to marked Parkinson disease whose response to levodopa had diminished. In the group of 10 patients, there was a significant reduction (p less than or equal to 0.05) in bradykinesia, gait disorder, and total Parkinson disease disability score when levodopa was replaced with lisuride. The mean dose of lisuride was 3.6 mg per day. Among the 10 patients, 5 were better on lisuride than on levodopa, and 4 continue on lisuride 1 year later. A decline in efficacy was noted in all four after a mean of 45 months. Adverse effects necessitating discontinuing the drug were mental changes in three patients and nausea in one patient. Lisuride, when used alone, has definite antiparkinsonian activity and is a promising new drug.

Topics: Aged; Clinical Trials as Topic; Double-Blind Method; Ergolines; Female; Humans; Levodopa; Lisuride; Male; Middle Aged; Parkinson Disease

Lisuride, a semisynthetic ergoline and potent central dopamine and serotonin agonist, was combined with levodopa in 20 patients with advanced Parkinson disease who were no longer responding satisfactorily to levodopa, including 14 patients with "on-off' phenomena. Every patient who completed the 8-week trial improved significantly (p greater than or equal to 0.01), with a decrease in all symptoms. The mean dose of lisuride was 2.4 mg per day. The dose of levodopa (mg of levodopa in Sinemet) was reduced from 1030 to 920 mg. Among the patients with "on-off' phenomena, there was a significant increase in the time in which they were 'on' (mobile) from 4.6 to 9.6 hours. In 5 of 10 patients who have been on lisuride for at least 1 year, there has been no decline in efficacy.

Topics: Adult; Aged; Clinical Trials as Topic; Double-Blind Method; Drug Therapy, Combination; Ergolines; Humans; Levodopa; Lisuride; Middle Aged; Parkinson Disease

Topics: Administration, Oral; Antiparkinson Agents; Bromocriptine; Clinical Trials as Topic; Drug Therapy, Combination; Ergolines; Humans; Lisuride; Parkinson Disease

Topics: Antiparkinson Agents; Clinical Trials as Topic; Drug Synergism; Drug Therapy, Combination; Ergolines; Humans; Levodopa; Lisuride; Parkinson Disease

The effects of bromocriptine and levodopa were compared in a blind trial in 18 patients with Parkinson's disease. Optimal doses of the two drugs were given in identical capsules: there was no significant difference between the therapeutic effects. There were wide individual differences in response to the two drugs. Side effects were more common with bromocriptine because of side effects.

Topics: Aged; Bromocriptine; Clinical Trials as Topic; Drug Evaluation; Ergolines; Humans; Individuality; Levodopa; Male; Middle Aged; Parkinson Disease

Lergotrile mesylate, an ergot alkaloid derivative and putative dopamine agonist, was effective in the majority of patients with Parkinson's disease who were showing signs of disease progression despite treatment with levodopa combined with a peripheral decarboxylase inhibitor (carbidopa). Among 20 patients completing a six-month trial, there was a significant (P less than .01) reduction in rigidity, tremor, bradykinesia, gait disturbance, and total score when lergotrile was added to levodopa plus carbidopa. Mean daily dose of lergotrile mesylate was 52 mg, and the mean daily dose of levodopa was reduced by 15%. Abnormal involuntary movements were decreased on addition of lergotrile and reduction in levodopa while mental changes and orthostatic hypotension were increased. Elevations in serum transaminase levels were noted in three patients. The ergot alkaloids promise to be an important new class of antiparkinsonian drugs.

Topics: Acetonitriles; Antiparkinson Agents; Bromocriptine; Carbidopa; Carboxy-Lyases; Clinical Trials as Topic; Drug Evaluation; Drug Therapy, Combination; Ergolines; Ergot Alkaloids; Female; Humans; Hypotension, Orthostatic; Levodopa; Male; Parkinson Disease

Bromocriptine, a dopamine receptor agonist, was administered to 20 patients with idiopathic parkinsonism taking levodopa (L-dopa) or "Sinemet" (levodopa combined with carbidopa in a 10/1 ratio) at optimum doses. In a double-blind randomised cross-over study lasting 6 months, the addition of bromocriptine (mean daily dose 79 mg) led to a significant (P less than 0.01) 74% reduction in the dose of sinemet and levodopa. "Total disability score" showed a significant (P less than 0.01) improvement at both low and high doses of bromocriptine. Tremor improved 50% (P less than 0.01), with significant improvements in gait, posture, writing, balance, rigidity, finger dexterity, and drooling. Adverse reactions were similar to those observed with sinemet and levodopa. Although both the cause and the cure of idiopathic parkinsonism remain elusive, bromocriptine appears to represent a therapeutic advance.

Topics: Aged; Bromocriptine; Carbidopa; Clinical Trials as Topic; Disability Evaluation; Dose-Response Relationship, Drug; Drug Combinations; Drug Evaluation; Ergolines; Female; Follow-Up Studies; Humans; Hydrazines; Levodopa; Male; Middle Aged; Parkinson Disease; Placebos; Time Factors

Caffeine was administered to six patients with idiopathic parkinsonism in an attempt to potentiate the therapeutic response of bromocriptine, a dopamine (DA) receptor agonist, by inhibition of phosphodiesterase. In a double-blind study at doses of 1,000 mg daily, caffeine failed to enhance the antiparkinsonian action of bromocriptine (40 mg daily) given concomitantly. Although effective in potentiating the action of levodopa and other agonists in animal models of parkinsonism, caffeine is inactive in parkinsonism in man.

Topics: Bromocriptine; Caffeine; Clinical Trials as Topic; Drug Synergism; Drug Therapy, Combination; Ergolines; Female; Humans; Male; Middle Aged; Parkinson Disease; Phosphodiesterase Inhibitors

Topics: 3',5'-Cyclic-AMP Phosphodiesterases; Bromocriptine; Clinical Trials as Topic; Ergolines; Humans; Levodopa; Parkinson Disease

Thirty-one patients with Parkinson's disease were treated with the ergot alkaloid bromocriptine, a drug which stimulates dopamine receptors. Bromocriptine had a slight therapeutic effect in patients on no other treatment and an additional effect in patients on levodopa. The mean optimum dosage of bromocriptine, established over a 12 week period, was 26 mg daily. In 20 patients bromocriptine was compared with placebo in a double-blind controlled trial. Active treatment caused a significant (P less than 0.02) reduction in total disability and akinesia scores. The least disabled patients showed the greatest response. Side-effects of bromocriptine--nausea, vomiting, hallucinations, and abnormal involuntary movements--were similar to nature to those of levodopa. In most normal subjects, bromocriptine causes an increase in plasma growth hormone concentration. This was determined in 20 patients with Parkinson's disease after 1-15 mg bromocriptine. Only a single patient showed an obvious increase up to 120 minutes after dosage. Bromocriptine was not effective treatment in two patients who had not previously responded to levodopa and replacement of this drug by bromocriptine in patients with end-of-dose akinesia after chronic levodopa treatment did not totally abolish response swings.

Topics: Aged; Clinical Trials as Topic; Dose-Response Relationship, Drug; Drug Evaluation; Ergolines; Female; Growth Hormone; Humans; Male; Middle Aged; Parkinson Disease

Twenty patients with paralysis agitans took part in a double-blind, cross-over investigation of CB 154 (2-bromo-alpha-ergocryptine) and Madopar (L-Dopa + benserazid (a peripheral decarboxylase inhibitor), dose ratio 4:1). Each treatment phase lasted for 8 weeks. Modapar was found to be significantly superior to CB 154 in the treatment of the Parkinson state as a whole (Webster total score) and the individual symptoms of hypokinesia, rigidity and tremor. Compared with pretreatment score, CB 154 had a weak, but significant effect on tremor, but not on the Webster total score, hypokinesia and rigidity. The effect of CB 154, however, varied: four patients preferred CB 154 to Madopar on account of its satisfactory therapeutic effect and fewer side-effects ("on-off" phenomena, hyperkinesia, psychiatric complications); other patients showed neither therapeutic effect nor side-effects of CB 154, which in some cases may be related to too low a dose-level of CB 154 (median 30 mg daily, range 20-60 mg). In the four cases first mentioned which showed a good effect of CB 154, the ratio between the dose of CB 154 and the dose of L-Dopa (in Madopar) was 3.5-10 mg/100 mg, i.e. in certain cases it must be assumed that the maximum dose of CB 154 lies around 120 mg daily.

Topics: Aged; Azides; Benserazide; Bromocriptine; Clinical Trials as Topic; Dose-Response Relationship, Drug; Drug Combinations; Ergolines; Female; Humans; Hydrazines; Hyperkinesis; Levodopa; Male; Middle Aged; Nausea; Parkinson Disease; Psychoses, Substance-Induced

A double-blind crossover study was performed in 12 patients with idiopathic parkinsonism to compare their response to bromocriptine with their response to previous optimal drug treatment, including levodopa. There was a 26 percent overall improvement with bromocriptine; rigidity, tremor, and facial expression showed the greatest response. Seven of eight patients who were taking levodopa at the beginning of the study was taken off the drug completely. Adverse reactions were transient and dose-dependent. Bromocriptine promises to be an effective new therapeutic agent in the treatment of idiopathic parkinsonism.

Topics: Aged; Bromocriptine; Clinical Trials as Topic; Drug Evaluation; Ergolines; Female; Humans; Levodopa; Male; Middle Aged; Muscle Rigidity; Parkinson Disease; Tremor

Topics: Aged; Amantadine; Bromocriptine; Chemical Phenomena; Chemistry; Clinical Trials as Topic; Dose-Response Relationship, Drug; Ergolines; Female; Humans; Levodopa; Male; Middle Aged; Parkinson Disease; Placebos; Trihexyphenidyl

Topics: Acromegaly; Bromocriptine; Clinical Trials as Topic; Ergolines; Female; Galactorrhea; Humans; Lactation; Parkinson Disease; Pregnancy

Topics: Bromocriptine; Clinical Trials as Topic; Drug Evaluation; Ergolines; Humans; Parkinson Disease

Topics: Bromocriptine; Drug Evaluation; Ergolines; Humans; Levodopa; Parkinson Disease

On June 2008, the European Medicines Agency (EMA) introduced changes to the Summary of Product Characteristics (SPC) for cabergoline and pergolide, to reduce the risk of cardiac valvulopathy in users of these drugs. To assess the effectiveness of EMA recommendations in Italian clinical practice, we retrospectively reviewed medical charts of patients with degenerative Parkinsonism treated with cabergoline in three large Italian clinics between January 2006 and June 2012. The prevalence and the severity of cardiac valve regurgitation were assessed in patients who stopped cabergoline therapy prior to June 2008 or continued therapy after that date. In addition, the proportion of patients undergoing echocardiographic examination in each cohort was evaluated. A total of 61 patients were available for evaluation. The proportion of patients who underwent a baseline echocardiographic examination increased from 64 % in the period before the 2008 SPC changes to 71 % among those who continued treatment after that date. However, only 18 and 29 % of patients underwent at least two echocardiographic examinations during the pre-SPC and cross-SPC change period, respectively. No severe cardiac valve regurgitation was documented in any of the study patients using cabergoline either prior or after 26th June 2008. Our findings show that the 2008 changes to the SPC resulted in an increase in physicians' awareness of cabergoline-induced valvulopathy risk in Italy. However, only a small percentage of patients underwent serial echocardiography. Further efforts are needed to achieve better compliance with the prescribing guidelines for cabergoline treated patients in clinical practice.

Topics: Aged; Antiparkinson Agents; Cabergoline; Cohort Studies; Echocardiography; Ergolines; Female; Guideline Adherence; Heart Valve Diseases; Heart Valves; Humans; Incidence; Italy; Male; Middle Aged; Parkinson Disease; Pergolide; Practice Guidelines as Topic; Prevalence; Retrospective Studies; Risk Factors; Supranuclear Palsy, Progressive

Topics: Adult; Antiparkinson Agents; Cabergoline; Chorea; Combined Modality Therapy; Deep Brain Stimulation; Equipment Failure; Ergolines; Female; Haloperidol; Humans; Magnetic Resonance Imaging; Parkinson Disease; Recurrence; Severity of Illness Index; Subthalamic Nucleus

In this study, we aimed to evaluate the impact of cabergoline use in patients with Parkinson's disease on valvular and biventricular functions.. In this observational cohort study, patients with Parkinson disease were divided into 2 groups as 34 patients (41.2% female, age; 57.4±15.3 years) using cabergoline (Group 1) and 42 patients (61.9% female, age; 53.7±7.1 years) not using cabergoline (Group 2). In addition to conventional echocardiography and diastolic functions, tissue Doppler imaging was used to evaluate both global and regional systolic - diastolic functions. Correlations were assessed using Pearson correlation coefficient for normally distributed variables.. In group 1 patients cabergoline was used for 7.7±5.1 years and mean and cumulative cabergoline dose were 3.3±1.1 mg and 9.8±7.0 g respectively. Left ventricular systolic functions and tissue Doppler measurements of septal and lateral mitral annulus and right ventricular systolic and diastolic velocities were similar between groups. Mitral valve tenting area was significantly higher in patients using cabergoline (p=0.007). The association between cumulative cabergoline dose and diastolic functions was also evaluated which revealed that among diastolic function parameters, Epeak (r=0.253, p=0.042), E/A (r=0.256, p=0.026) and DT (r=-0.382, p=0.001) were correlated with cumulative cabergoline dose. There was a positive correlation between cumulative cabergoline dose and duration of cabergoline therapy with composite regurgitation score (r=0.435, p<0.001; r=0.485, p<0.001, respectively).. Our findings indicated that despite the well known effects of cabergoline on valvular functions, we did not observe any alteration in systolic functions, but diastolic functions which was associated with cumulative cabergoline dose in patients with Parkinson's disease.

Topics: Cabergoline; Cohort Studies; Dopamine Agonists; Echocardiography; Ergolines; Female; Heart Valve Diseases; Humans; Male; Middle Aged; Parkinson Disease

Therapeutic options for Parkinson's disease mainly consist of L-dopa and dopamine agonists. However, in Japan, the product labeling of the ergot dopamine agonists, cabergoline and pergolide, was revised in April 2007 due to the risk of developing cardiac valvulopathy. Here, we describe the prescribing trends of anti-Parkinson drugs from 2005 through 2010 in Japan, and examined whether these trends changed after the drug safety measures in 2007.. We used medical claim data from January 2005 to December 2010 for Parkinson's disease patients older than 30 years who were prescribed anti-Parkinson drugs. We calculated the proportion of patients prescribed each drug for each year, and compared the proportions of first-line drugs prescribed before and after April 2007. We also examined the prescription variations of cabergoline/pergolide users one year before or after April 2007.. L-dopa was the most frequently prescribed drug for Parkinson's disease (2005, 58%; 2010, 51%). The proportion of patients prescribed ergot dopamine agonists markedly decreased and non-ergot dopamine agonists increased after 2007. Among first-line drugs, the proportion of non-ergot agents increased after April 2007. Among 54 cabergoline/pergolide users, 24 (44%) discontinued these drugs, nine of whom switched to non-ergot agents.. L-dopa was the mainstay of Parkinson's disease treatment between 2005 and 2010 in Japan. There was a decrease in ergot agents and an increase in non-ergot agents prescribed after the regulatory actions in 2007.

Topics: Aged; Antiparkinson Agents; Cabergoline; Dopamine Agonists; Drug Prescriptions; Ergolines; Female; Humans; Japan; Levodopa; Male; Middle Aged; Parkinson Disease; Pergolide

The patient was a 46-year-old woman requesting oral hygiene control. She had been treated for Parkinson's disease at the neurology department of another university hospital for 9 years. When the drugs were effective (drug efficacy), she could get out of bed and change clothes without assistance, albeit slowly. When the drugs were ineffective (no drug efficacy), however, she found it difficult to get out of bed, change clothes, or maintain posture during defecation without assistance. Occlusion was B-1 on the Eichner index, and neither dislocation of the temporomandibular joint nor mandibular tremor was observed. At her first visit, a medical history was taken and periodontal therapy commenced. Informed consent for bite splint therapy was obtained after examination of movement disorder. A bite splint was made for her, and any change in the grade of motor disorder using the bite splint evaluated. In addition, her grip strength was measured when wearing and not wearing the bite splint during periods of drug efficacy and no drug efficacy. The patient could get out of bed, change clothes, and maintain posture during defecation without assistance when wearing the bite splint, even during no drug efficacy. Grip strength in her left hand during drug efficacy and in both hands during no drug efficacy was greater when wearing the bite splint than without the bite splint. When this patient with Parkinson's disease wore a bite splint, her athletic ability and grip strength increased.

Topics: Activities of Daily Living; Antiparkinson Agents; Bromocriptine; Cabergoline; Clonidine; Dyskinesias; Ergolines; Female; Hand Strength; Humans; Levodopa; Middle Aged; Motor Skills; Occlusal Splints; Parkinson Disease; Posture

It has been suggested that ergoline dopamine agonists can cause ischemic complications. The effect of dopamine agonists in general on the prevalence of ischemic events in patients with Parkinson's disease (PD) has not been studied.. Our aim was to investigate the association between the use of dopamine agonists and hospitalization due to ischemic events in patients with PD.. We performed a nested case-control study using the PHARMO Institute for Drug Outcome Research database. All patients issued at least one prescription for levodopa after the age of 55 years between 1994 and 2006 were initially identified. Cases were patients who were hospitalized for the first time after November 1997 for an ischemic event and were matched to as many as four controls. Exposure to dopamine agonists during the year preceding the index date was identified.. The study population consisted of 542 cases and 2,155 controls. The mean effect of dopamine agonist use 1 year prior to the index date on ischemic events requiring hospitalization is shown with 95% probability in the 0.95-1.49 range. Stratified results according to the type of dopamine agonist showed no risk differences between ergoline and nonergoline agonists.. This study does not support an association between dopamine agonist use and an increased risk of ischemic events requiring hospitalization.

Topics: Aged; Aged, 80 and over; Antiparkinson Agents; Brain Ischemia; Case-Control Studies; Databases, Factual; Dopamine Agonists; Drug Prescriptions; Ergolines; Female; Hospitalization; Humans; Ischemia; Levodopa; Male; Myocardial Ischemia; Netherlands; Parkinson Disease; Practice Patterns, Physicians'; Prevalence; Raynaud Disease; Severity of Illness Index

Topics: Adult; Aged; Aged, 80 and over; Antiparkinson Agents; Cabergoline; Cohort Studies; Cross-Sectional Studies; Echocardiography; Ergolines; Female; Heart Valve Diseases; Humans; Male; Middle Aged; Odds Ratio; Parkinson Disease; Retrospective Studies; Risk Assessment

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

In a previous echocardiographic prevalence study we reported a significant increase in the frequency of heart valve regurgitation in patients with Parkinson's disease taking the ergot-derived dopamine agonists pergolide and cabergoline versus controls. We followed-up our original cohort of patients to ascertain whether valvulopathy regressed after discontinuation of treatment and/or its incidence increased over time.. Prospective follow-up of 101 patients treated with ergot-derived dopamine agonists included in the prevalence study: 53 given pergolide and 48 cabergoline (64% male; 66.4 ± 8.7 years of age, 11.5 ± 5.9 years of disease, 21.8 ± 5.9 months of follow-up); 55 stopped treatment while 46 continued. The main outcomes measures, were: echocardiographic quantification of regurgitant valve disease, abnormal leaflet, or cusp thickening and measurement of mitral valve tenting area.. Valve abnormalities regressed in about one third of patients with significant multivalvular and in about half of the patients with monovalvular regurgitation who withdrew; no progression was observed in remaining patients. Patients continuing ergot-derived dopamine agonists showed progression of cardiac valvulopathy: seven new cases with three to four regurgitation grade of any valve occurred during follow-up; this regarded also patients who had been on pergolide for many years.. Owing to the persistence of risk of heart valve damage over time and the lack of its mid-term reversibility in many patients, we believe that pergolide and cabergoline should be prescribed only when therapeutic alternatives with a better risk/benefit ratio are unavailable and the patient has access to echocardiography.

Topics: Adult; Aged; Antiparkinson Agents; Cabergoline; Dopamine Agonists; Ergolines; Female; Follow-Up Studies; Heart Valve Diseases; Humans; Italy; Male; Middle Aged; Parkinson Disease; Patient Selection; Pergolide; Prevalence; Prognosis; Prospective Studies; Risk Assessment; Risk Factors; Time Factors; Ultrasonography

Use of the ergot-derived dopamine receptor agonists (cabergoline and pergolide) is associated with an increased risk of cardiac valvulopathy. Pergolide was withdrawn from the US market in 2007 because of the risk of valvular heart disease, while the European Medicines Agency (EMA) required a reduction in the maximum daily dosage of cabergoline and pergolide from 6 mg/day to 3 mg/day in 2008. In Japan, the package inserts of both drugs were revised in April 2007 to request that physicians conduct periodic ultrasonic cardiography (UCG) examinations for patients taking cabergoline or pergolide. Also, through face-to-face communication with medical representatives of drug companies, physicians were informed that use of cabergoline and pergolide has increased the risk of valvulopathy. However, cabergoline and pergolide have remained in wide use, even following the regulatory actions.. The objective of this study was to assess the impact of actions, including the package insert revision in April 2007, to encourage periodic UCG.. Data on monthly claims (January 2005-October 2008) covering 330 000 patients were obtained from a Japanese database vendor. We selected patients ≥40 years of age with Parkinson's disease. The impact of the regulatory action on the proportion of patients with Parkinson's disease prescribed cabergoline or pergolide was assessed by segmented regression analysis and by a statistical model of the rates of UCG examination in patients taking/not taking cabergoline or pergolide before and after the action. We also compared the use of cabergoline and pergolide before and after the action with that of other antiparkinson drugs.. Of 574 patients with Parkinson's disease, the proportion of patients prescribed cabergoline or pergolide did not decrease but rather tended to increase after the action when analysed by segmented regression analysis (p = 0.13). Similarly, the proportion of the prevalent and incident users of cabergoline or pergolide did not change between two 19-month periods before and after the action. The adjusted rates of UCG examination per person-year before and after the action were both 0.02 in those not prescribed cabergoline or pergolide, but 0.02 before the action and 0.09 after the action in those taking either drug. The excess UCG examination rate of cabergoline or pergolide attributable to the action was 0.08 per person-year (95% CI 0.03, 0.11). While 1 of 49 (2%) patients taking cabergoline or pergolide had a UCG up to 19 months before the action, 9 of 36 (25%) patients taking cabergoline or pergolide had a UCG up to 19 months after the action. Annual sales from 2004 to 2008 were 195, 195, 170, 110 and 75 billion yen, respectively, and the number of valvulopathy events, including incompetence of aortic/mitral/tricuspid valves and cardiac valve disease, per annual sales from 2004 to 2008 were estimated at 0.23, 0.03, 0.08, 0.25 and 0.19 per billion yen, respectively.. Following the actions in April 2007, no decrease in the use of cabergoline or pergolide occurred, although more patients administered the drug underwent a UCG. However, those undergoing a UCG represented one-quarter of the total number prescribed cabergoline or pergolide. To mitigate the risk, additional risk management tools such as patient registration may be needed to secure careful clinical examination (including UCG examination, if necessary) for cardiac function.

Topics: Cabergoline; Databases, Factual; Dopamine Agonists; Drug Prescriptions; Drug Utilization Review; Ergolines; Government Regulation; Heart Valve Diseases; Humans; Insurance Claim Review; Japan; Legislation, Drug; Parkinson Disease; Pergolide; Regression Analysis; Ultrasonography

The ergot-derived dopamine agonists, cabergoline and pergolide, are associated with valvulopathy risk. In Japan, product labels were revised in April 2007 to recommend periodic echocardiography for patients taking these dopamine agonists, however, the compliance of physicians to follow through with this recommendation is unknown. This study assessed changes in echocardiography evaluation of patients with Parkinson's disease (PD) taking cabergoline or pergolide before and after the label revision and examined the factors related with echocardiography performance.. Medical claim data from January 2005 to December 2008 were used. Patients were divided into a C-P group (prescribed either cabergoline or pergolide) or reference group (prescribed other anti-PD drugs), and further classified based on whether they were prescribed these drugs "pre-revision" or "post-revision." The Cochran-Armitage trend test was used to compare the proportion of echocardiograms obtained amongst these groups before and after the revision. The frequencies of echocardiograms performed among the treatment groups for each period were compared by Fisher's exact test.. A total of 222 subjects (C-P, 73; reference, 149) were assessed. The proportion of C-P patients undergoing echocardiography increased from 4.8% to 27.9% after revision of product labels (p=0.001), which was higher than those in the reference group following label revisions (11.0%) (p=0.014). Prescription duration of C-P after the revision was longer in the patients with echocardiography than without echocardiography (p=0.026).. Although echocardiography evaluations increased, more than 70% of PD patients prescribed cabergoline or pergolide did not undergo such assessment despite the product label recommendation. Adherence to drug safety recommendations should be facilitated with more feasible and effective measures.

Topics: Adult; Aged; Cabergoline; Dopamine Agonists; Drug Labeling; Echocardiography; Ergolines; Female; Heart Valve Diseases; Humans; Incidence; Japan; Male; Middle Aged; Parkinson Disease; Pergolide; Retrospective Studies; Risk Factors

Topics: Antiparkinson Agents; Cabergoline; Echocardiography, Doppler, Color; Ergolines; Fibrosis; Heart Valve Diseases; Heart Valves; Humans; Male; Middle Aged; Parkinson Disease

Topics: Adult; Antiparkinson Agents; Benzothiazoles; Cabergoline; Clozapine; Ergolines; Female; Gambling; Humans; Male; Middle Aged; Parkinson Disease; Pramipexole; Selegiline; Serotonin Antagonists

An association between ergot-derived dopamine agonists and asymptomatic valvular heart disease in Parkinson's disease has been established. For safe use of these agonists, it is important to specify those at high risk for valvular heart disease among patients with Parkinson's disease. We performed a nested case-control study of 223 patients with Parkinson's disease. In results of multivariable logistic analyses, use of pergolide, use of cabergoline, age, male sex, and hypertension were independent significant risk factors for left-sided valvular regurgitation. In patients receiving cabergoline or pergolide, elderly (>or=70 years) hypertensive patients had a markedly high risk for valvular regurgitation (odds ratio 94.5) as compared to non-elderly (<70 years) patients without hypertension. The risk of valvular regurgitation caused by pergolide or cabergoline was found to be highly enhanced by comorbid hypertension or aging, suggesting that special attention should be paid when prescribing cabergoline or pergolide for those patients.

Topics: Age Factors; Aged; Benzothiazoles; Bromocriptine; Cabergoline; Case-Control Studies; Dopamine Agonists; Echocardiography; Ergolines; Female; Heart Valve Diseases; Humans; Hypertension; Male; Parkinson Disease; Pergolide; Pramipexole; Risk Factors

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

Topics: Cabergoline; Dopamine Agonists; Echocardiography; Ergolines; Heart Valve Diseases; Heart Valves; Humans; Hyperprolactinemia; Parkinson Disease; Pergolide; Tricuspid Valve Insufficiency

Cabergoline is a synthetic dopamine agonist used to treat Parkinson disease. The drug occasionally induces pleuropulmonary adverse effects, which manifest as pleural thickening or effusion, interstitial pneumonitis, pulmonary infiltrates, or fibrosis. We report a rare case of pleural effusion and severe pulmonary hypertension in a 79-year-old man with Parkinson disease who had been treated with cabergoline for 1 year. The symptoms disappeared 10 months after the drug was discontinued.

Topics: Aged; Antiparkinson Agents; Cabergoline; Ergolines; Humans; Hypertension, Pulmonary; Male; Parkinson Disease; Pleural Effusion

We present a PD patient in whom dopamine agonists awoke a hidden creativity that led to a gradual increase in painting productivity evolving to a disruptive impulsive behaviour that shared many features with punding. A dramatic change in painting style related to a more emotional experience during the process of creation developed after treatment onset. This case suggests that changes in creativity in PD seem to be related to dopaminergic imbalance in the limbic system.

Topics: Antiparkinson Agents; Arm; Art; Benzothiazoles; Brain; Cabergoline; Creativity; Depressive Disorder; Dopamine; Dopamine Agonists; Dose-Response Relationship, Drug; Drug Therapy, Combination; Ergolines; Humans; Levodopa; Male; Mental Disorders; Middle Aged; Motor Skills; Obsessive Behavior; Paintings; Parkinson Disease; Pramipexole

Topics: Antiparkinson Agents; Bromocriptine; Cabergoline; Case-Control Studies; Cross-Sectional Studies; Dopamine Agonists; Ergolines; Female; Heart Valve Diseases; Humans; Hyperprolactinemia; Male; Parkinson Disease; Pergolide; Prolactin; Serotonin 5-HT2 Receptor Agonists; Ultrasonography

Topics: Antiparkinson Agents; Aortic Valve Insufficiency; Cabergoline; Dopamine Agonists; Ergolines; Health Knowledge, Attitudes, Practice; Humans; Parkinson Disease; Pergolide

We experienced 2 patients of valvular heart disease in Parkinson's patients taking cabergoline. Patient 1 was a 79-year-old woman who began taking 4 mg cabergoline daily after being diagnosed with Parkinson's disease (PD) in June 2003. She presented with dyspnea in November 2005. The patient had cardiomegaly, pulmonary congestion, and pleural effusion, and an echocardiogram showed valvular heart disease in the form of aortic regurgitation (AR) (grade I), tricuspid regurgitation (TR) (grade I), and mitral regurgitation (MR) (grade III). Cabergoline was thought to have caused these phenomena, so it was replaced with pramipexole, and after administration of diuretics and angiotensin-converting enzyme inhibitors (ACEIs) the patient's symptoms gradually disappeared. MR, AR and TR also disappeared 3 months later. Patient 2 was a 74-year-old woman who presented with sluggish movement in April 2001 and subsequently developed Parkinson's. While being administered 700 mg levodopa (Menesit) and 4 mg cabergoline, the patient presented with shortness of breath in April 2005. An echocardiogram showed valvular heart disease in the form of MR (grade I) and TR (grade I). Heart function improved with the administration of diuretics. However, heart function again worsened in November 2005, and the patient presented with edema of the lungs and lower limbs. An echocardiogram in January 2006 showed worsening MR (grade III) and TR (grade II), and the patient also had pulmonary hypertension. ACEIs were administered along with diuretics and cabergoline was replaced with pramipexole, but the patient also developed malignant syndrome and disseminated intravascular coagulation (DIC) and later died. Patient 2 is the first case in Japan of death due to heart failure caused by the side effects of cabergoline. Caution is usually needed when treating a Parkinson's patient for valvular heart disease due to a dopamine agonist, and periodic checks for heart murmurs and echocardiography are crucial. When signs of heart failure develop during treatment with an ergot preparation of dopamine agonist, it is essential to immediately either stop the administration of the ergot preparation or change to a non-ergot preparation of dopamine agonist.

Topics: Aged; Antiparkinson Agents; Cabergoline; Ergolines; Fatal Outcome; Female; Heart Failure; Heart Valve Diseases; Humans; Parkinson Disease

Topics: Aged; Antiparkinson Agents; Cabergoline; Cardiovascular Diseases; Dopamine Agonists; Ergolines; Female; Humans; Male; Parkinson Disease; Pergolide; Treatment Outcome

Patients with Parkinson's disease (PD) tend to speak monotonously with minor modulation of pitch and intensity. The goal of this study was to find out whether these speech changes can be explained mainly by motor impairment, i.e. akinesia and rigidity of the articulatory apparatus, or whether alterations of emotional processing play an additional role. Sixteen patients with mild PD and 16 healthy controls (HC) were compared. Fundamental frequencies (pitch) and intensities (loudness) were determined as (1) maximal upper and lower values achieved in nonemotional speech (phonation capacity), (2) upper and lower values used when speaking "Anna" in emotional intonation (neutral, sad, happy) as requested (production task), or (3) when imitating a professional speaker (imitation task). Although groups did not significantly differ in their phonation capacity, patients showed a significantly smaller pitch and intensity range than HC in the production task. In the imitation task, however, ranges were again similar. These results suggest that alterations of emotional processing contribute to speech changes in PD, especially regarding emotional prosody, in addition to motor impairment.

Topics: Adult; Aged; Antiparkinson Agents; Articulation Disorders; Cabergoline; Emotions; Ergolines; Humans; Levodopa; Middle Aged; Parkinson Disease; Phonation; Speech

To investigate the frequency of cardiac valve regurgitation related with low dose dopamine agonists in patients with Parkinson's disease (PD), echocardiograms were analyzed in 527 consecutive PD patients (448 patients treated with dopamine agonists, 79 patients never treated with dopamine agonists as age-matched controls). The frequency of mild or above mild regurgitation of the aortic valve (AR) was significantly higher in the cabergoline group (13.7%, P < 0.05) compared with the controls (2.5%). Odds ratio adjusted by age and sex for AR was significantly higher in the cabergoline group (OR, 6.45; 95% CI, 1.46-28.60; P = 0.01): odds ratio was significantly higher in patients treated with higher daily doses (OR, 14.41; 95% CI, 3.08-67.38; P = 0.0007) and higher cumulative doses (OR, 15.29; 95% CI, 3.19-73.18; P = 0.0006). No statistical difference was identified in the frequency of the tricuspid and mitral regurgitation. None of the other dopamine agonist groups including pergolide gave higher frequency or higher odds ratio compared with the controls. None of our patients showed severe regurgitation or was operated for valvular heart disease. The question as to whether or not longer duration of low dose dopamine agonist treatment would yield the same results needs further studies.

Topics: Aged; Aortic Valve Insufficiency; Azepines; Benzothiazoles; Bromocriptine; Cabergoline; Dopamine Agonists; Ergolines; Female; Humans; Male; Mitral Valve Insufficiency; Parkinson Disease; Pergolide; Pramipexole; Prevalence

Case reports and echocardiographic studies suggest that the ergot-derived dopamine agonists pergolide and cabergoline, used in the treatment of Parkinson's disease and the restless legs syndrome, may increase the risk of cardiac-valve regurgitation.. We used data from the United Kingdom General Practice Research Database to identify a population-based cohort comprising 11,417 subjects 40 to 80 years of age who were prescribed antiparkinsonian drugs between 1988 and 2005. We conducted a nested case-control analysis within this cohort in which each patient with newly diagnosed cardiac-valve regurgitation was matched with up to 25 control subjects from the cohort, according to age, sex, and year of entry into the cohort. Incidence-rate ratios for cardiac-valve regurgitation with the use of different dopamine agonists were estimated by conditional logistic-regression analysis.. Of 31 case patients with newly diagnosed cardiac-valve regurgitation, 6 were currently exposed to pergolide, 6 were currently exposed to cabergoline, and 19 had not been exposed to any dopamine agonist within the previous year. The rate of cardiac-valve regurgitation was increased with current use of pergolide (incidence-rate ratio, 7.1; 95% confidence interval [CI], 2.3 to 22.3) and cabergoline (incidence-rate ratio, 4.9; 95% CI, 1.5 to 15.6), but not with current use of other dopamine agonists.. In this study, use of the dopamine agonists pergolide and cabergoline was associated with an increased risk of newly diagnosed cardiac-valve regurgitation.

Topics: Adult; Aged; Aged, 80 and over; Antiparkinson Agents; Cabergoline; Case-Control Studies; Cohort Studies; Dopamine Agonists; Ergolines; Female; Heart Valve Diseases; Humans; Logistic Models; Male; Middle Aged; Parkinson Disease; Pergolide; Serotonin 5-HT2 Receptor Agonists; Serotonin Receptor Agonists

Ergot-derived dopamine receptor agonists, often used in the treatment of Parkinson's disease, have been associated with an increased risk of valvular heart disease.. We performed an echocardiographic prevalence study in 155 patients taking dopamine agonists for Parkinson's disease (pergolide, 64 patients; cabergoline, 49; and non-ergot-derived dopamine agonists, 42) and 90 control subjects. Valve regurgitation was assessed according to American Society of Echocardiography recommendations. The mitral-valve tenting area was also measured and used as a quantitative index for leaflet stiffening and apical displacement of leaflet coaptation.. Clinically important regurgitation (moderate to severe, grade 3 to 4) in any valve was found with significantly greater frequency in patients taking pergolide (23.4%) or cabergoline (28.6%) but not in patients taking non-ergot-derived dopamine agonists (0%), as compared with control subjects (5.6%). The relative risk for moderate or severe valve regurgitation in the pergolide group was 6.3 for mitral regurgitation (P=0.008), 4.2 for aortic regurgitation (P=0.01), and 5.6 for tricuspid regurgitation (P=0.16); corresponding relative risks in the cabergoline group were 4.6 (P=0.09), 7.3 (P<0.001), and 5.5 (P=0.12). The mean mitral tenting area was significantly greater in ergot-treated patients and showed a linear relationship with the severity of mitral regurgitation. Patients treated with ergot derivatives who had grade 3 to 4 regurgitation of any valve had received a significantly higher mean cumulative dose of pergolide or cabergoline than had patients with lower grades.. The frequency of clinically important valve regurgitation was significantly increased in patients taking pergolide or cabergoline, but not in patients taking non-ergot-derived dopamine agonists, as compared with control subjects. These findings should be considered in evaluating the risk-benefit ratio of treatment with ergot derivatives.

Topics: Aged; Cabergoline; Case-Control Studies; Dopamine Agonists; Ergolines; Female; Heart Valve Diseases; Humans; Male; Middle Aged; Mitral Valve; Parkinson Disease; Pergolide; Regression Analysis; Risk; Serotonin 5-HT2 Receptor Agonists; Serotonin Receptor Agonists; Ultrasonography

To assess the effect of ergot derivatives on cardiac valves in patients with Parkinson's disease (PD).. Echocardiography was performed on 46 PD patients who used either pergolide or cabergoline (MonoPD) or both (MixPD) for a minimum of 1 year and 49 age-matched healthy controls. Valvular regurgitation was graded as mild, moderate and severe. MonoPD and MixPD groups were compared with regard to demographic features, drug profile and valvulopathy.. The PD group had a mean age of 63 years, agonist duration of 3.8 years and agonist equivalent dose of 3.5mg/day. Moderate regurgitation in all three valves was significantly more common in the PD group than the controls. Severe valvular regurgitation was not observed in either group, with the exception of one PD patient. The frequency of valvulopathy and doses of agonists did not differ between MixPD and MonoPD groups.. PD patients on dopamine ergot agonists are prone to moderate valvular regurgitation more than age-matched controls. However, the frequency of valvulopathy was similar in patients who used either one or more agonists.

Topics: Aged; Antiparkinson Agents; Aortic Valve Insufficiency; Cabergoline; Dopamine Agonists; Drug Therapy, Combination; Echocardiography; Ergolines; Female; Heart Valve Diseases; Humans; Male; Middle Aged; Parkinson Disease; Pergolide; Retrospective Studies; Tricuspid Valve Insufficiency

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

Topics: Antiparkinson Agents; Benzothiazoles; Cabergoline; Case-Control Studies; Dopamine Agonists; Ergolines; Female; Heart Valve Diseases; Humans; Male; Parkinson Disease; Patient Selection; Pergolide; Pramipexole; Research Design; Sex Factors

An 82-year-old man was referred to our hospital because of progressive heart failure. He had Parkinson's disease and had been treated with cabergoline during the preceding 4 years and 8 months. Echocardiography revealed severe mitral regurgitation through retracted mitral leaflets with incomplete coaptation. Heart failure persisted despite pharmacologic therapy, so the mitral valve was surgically replaced with a biological valve. Histologic analysis showed fibrous thickened mitral chordae with myxoid degeneration. These characteristics of the mitral valve of our patient are similar to the valvular heart disease described with the use of cabergoline. Clinicians must be care of valvular heart disease whenever they treat Parkinson's disease patients with cabergoline.

Topics: Aged, 80 and over; Antiparkinson Agents; Bioprosthesis; Cabergoline; Chordae Tendineae; Echocardiography; Ergolines; Heart Valve Prosthesis Implantation; Humans; Male; Mitral Valve; Mitral Valve Insufficiency; Parkinson Disease

Topics: Aged; Amyotrophic Lateral Sclerosis; Antiparkinson Agents; Cabergoline; Carbidopa; Dopamine Agents; Dopamine Agonists; Drug Therapy, Combination; Ergolines; Female; Humans; Levodopa; Neuroprotective Agents; Parkinson Disease; Riluzole; Time Factors; Tomography, X-Ray Computed

Topics: Antiparkinson Agents; Cabergoline; Carbidopa; Compulsive Behavior; Drug Combinations; Ergolines; Humans; Levodopa; Male; Middle Aged; Parkinson Disease; Selective Serotonin Reuptake Inhibitors; Severity of Illness Index; Sex Offenses

Topics: Aged; Cabergoline; Dopamine Agonists; Ergolines; Humans; Hyperprolactinemia; Male; Mitral Valve Insufficiency; Parkinson Disease

Long-term or high-dose L-DOPA therapy in patients with Parkinson's disease (PD) may accelerate degeneration of dopaminergic neurons, possibly by increasing oxidative stress. To investigate the effects of cabergoline on peroxynitrite-mediated oxidative damage caused by L-DOPA, the concentration of 3-nitrotyrosine in cerebrospinal fluid (CSF) of 18 PD patients was compared with that in 20 normal controls. The concentration of 3-nitrotyrosine in patients following L-DOPA therapy was significantly higher than in untreated PD patients and controls. On the other hand, the concentration in PD patients after cabergoline therapy was significantly lower than in PD patients after L-DOPA therapy alone. These data suggest that cabergoline scavenges peroxynitrite induced by L-DOPA in patients with PD.

Topics: Aged; Antiparkinson Agents; Cabergoline; Chromatography, High Pressure Liquid; Ergolines; Female; Free Radical Scavengers; Humans; Levodopa; Male; Oxidative Stress; Parkinson Disease; Peroxynitrous Acid; Tyrosine

Few studies focused on the effects of cabergoline on sleep-wake cycle in PD. Twelve patients affected by PD treated with levodopa as monotherapy underwent two 24-hour ambulatory polysomnographic (A-PSG) sessions twice: in baseline condition (levodopa as monotherapy) and after addition of cabergoline. In each condition, a subjective evaluation of sleep quality and daytime sleepiness was obtained by means of Parkinson's disease Sleep Scale (PDSS) and the Epworth Sleepiness Scale. The statistical analysis of sleep parameters revealed a significant increase of sleep efficiency and slow wave sleep under cabergoline. The PDSS total score showed a significant improvement of overall sleep quality after cabergoline. No significant changes in daytime sleepiness were observed. No patient referred and/or showed sleep attacks before and after addition of cabergoline. We hypothesize that the long-lasting effect of cabergoline may improve the objective quality of nocturnal sleep in PD patients complaining nocturnal motor disability without inducing daytime sleepiness.

Topics: Aged; Antiparkinson Agents; Cabergoline; Circadian Rhythm; Ergolines; Female; Humans; Levodopa; Male; Middle Aged; Parkinson Disease; Polysomnography; Sleep; Wakefulness

There are a large variety of dopamine agonists available. Especially de novo patients are treated with dopamine agonists to avoid dyskinesia. Dopamine agonists can be subdivided into ergoline and non-ergoline derivatives. This distinction raises the question whether there are differences in the effects to treat symptoms, not only in the side effects between the individual dopamine agonists but also between these two groups. Pergolide is now considered a second line drug because of its particularly high tendency towards valvular heart disease. Some authors claim that all ergoline-derivatives may cause this problem, while own results do not necessarily support this view. We recommend performing echocardiography on those patients being treated with an ergot-derivative. New data support the view that all dopaminergic drugs may cause somnolence and that there is no preference for non-ergots. It may be that the number of gamblers is slightly higher among patients treated with pramipexole than in others. Dopamine agonists with a high affinity to D3 receptors have a good anti-anhedonic potency. In cell culture all dopamine agonists studied so far show neuroprotective properties in cell culture. The introduction of a slow-release formulation for ropinirole and the rotigotine and lisuride patches have opened new ways of continuous dopamine receptor stimulation. Taken together, dopamine agonists show individual properties and there are differences between ergot and non-ergot derivatives.

Topics: Dopamine Agonists; Ergolines; Heart Valve Diseases; Humans; Parkinson Disease; Pulmonary Fibrosis; Retroperitoneal Fibrosis

Cardiac valvulopathy has been recently associated with the use of the ergot dopamine agonist (EDA) pergolide in Parkinson's disease (PD). Cabergoline a widely used, well-tolerated EDA which has also been recently implicated in relation to fibrotic side effects although the evidence base for this is not sound.. In PD patients on chronic cabergoline therapy, do symptoms suggestive of serosal/cardiac fibrosis imply underlying fibrotic lesions?. A retrospective data review of 234 PD cases from three UK centres, on chronic cabergoline monotherapy or adjunctive treatment to identify symptoms suggestive of pleuro-pulmonary, cardiac or retroperitoneal fibrosis. These causes were thereafter selectively examined by appropriate specialists with relevant investigations.. Out of 234 cases, 15 were identified with symptoms suggestive of respiratory, cardiac or abdominal systems involvement although subsequent investigations failed to reveal definite association with cabergoline except two cases with probable alveolitis and a possible association with cardiac murmur in one case. In spite of the deficiencies of a retrospective study, the results suggest a low risk of fibrotic side effects with cabergoline, particularly cardiac valvulopathy.

Topics: Adult; Aged; Aged, 80 and over; Antiparkinson Agents; Cabergoline; Ergolines; Female; Fibrosis; Heart Valve Diseases; Humans; Male; Middle Aged; Parkinson Disease; Pulmonary Fibrosis; Retroperitoneal Fibrosis; Retrospective Studies

Topics: Aged; Antiparkinson Agents; Cabergoline; Dopamine Agonists; Ergolines; Humans; Male; Mitral Valve; Mitral Valve Insufficiency; Parkinson Disease; Ultrasonography

Restrictive valvular heart disease has been reported in patients with Parkinson's disease treated with pergolide. However, few data are available on frequency, severity, dose dependency, and reversibility of pergolide-induced disease, nor on the pulmonary pressures of these patients. We aimed to clarify these characteristics in a large group of patients.. 78 patients with Parkinson's disease treated with pergolide and 18 never treated with an ergot-derived dopamine agonist (controls) were evaluated by echocardiography. A valvular scoring system was used, ranging from 1 (proven ergot-like restrictive valvular heart disease) to 4 (no disease). For the mitral valve, tenting areas and tenting distances were measured. Systolic pulmonary artery pressures were derived from the tricuspid regurgitant jet.. Restrictive valvular heart disease of any type was present in 26 (33%) patients in the pergolide group and none in controls (p=0.0025). Important disease (score 1 or 2) was present in 15 (19%) patients in the pergolide group and none in controls (p=0.066). Mean tenting distances and tenting areas of the mitral valve were 1.08 cm (range 0.55-2.66) and 2.39 cm2 (0.88-4.59) in the restrictive mitral valve group versus 0.63 cm (0.22-1.20) and 1.39 cm2 (0.39-3.23) in the non-restrictive group (p=0.003 and p<0.0001, respectively). Significant correlation was noted between cumulative doses of pergolide and tenting areas of the mitral valves (r=0.412, p=0.017). Mean systolic pulmonary artery pressures were 39.3 mm Hg (range 25-71) in the high-dose group versus 38.5 mm Hg (20-65) in the low-dose group (p=0.76) and 31 mm Hg (25-40) in controls (p=0.02 vs all patients given pergolide). In six patients, pergolide treatment was stopped because of restrictive valvular heart disease, in two of whom regression of disease was shown.. Restrictive valvular heart disease is not a rare finding in patients treated with pergolide. Clinicians should consider changing to a non-ergot drug if this disease is diagnosed.

Topics: Aged; Antiparkinson Agents; Dopamine Agonists; Echocardiography; Ergolines; Female; Heart Valve Diseases; Humans; Male; Middle Aged; Parkinson Disease; Pergolide

We report on 4 new cases of valvular heart disease in Parkinson's disease patients treated with the ergot derivative dopamine agonists pergolide and cabergoline. Noninflammatory fibrotic degeneration of cardiac valves has been reported to occur in patients with carcinoid syndrome and to occasionally complicate therapies with the anti-migraine ergot alkaloid ergotamine and methysergide and with the appetite suppressants fenfluramine and dexfenfluramine. In these cases, the pathogenesis is suspected to involve serotonin-mediated abnormal fibrogenesis by means of the 5-HT2B receptors, which are expressed in the fibroblasts of heart valves. Based on strikingly similar echocardiographic and histopathological features, we strongly suspect that ergot-derived dopamine agonists may cause a valvular heart disease nearly identical to that seen in those conditions. These cases add to a rapidly growing and worrying list of similar published reports, suggesting that we may well be facing a novel, yet unrecognized, complication of this class of agents, which are widely used not only in Parkinson's disease but also in restless legs syndrome and various common endocrine dysfunctions. Therefore, until more is known about the true prevalence of this side effect, we propose that an assessment of cardiac function be performed before and in the course of a long-term therapy with ergot derivative dopamine agonists.

Topics: Adult; Aged; Cabergoline; Carbidopa; Dopamine Agonists; Drug Combinations; Echocardiography, Transesophageal; Ergolines; Ergot Alkaloids; Female; Heart Valve Diseases; Humans; Levodopa; Male; Parkinson Disease; Pergolide

Topics: Antiparkinson Agents; Cabergoline; Cost-Benefit Analysis; Ergolines; Humans; Levodopa; Middle Aged; Parkinson Disease

Topics: Age Factors; Antiparkinson Agents; Cabergoline; Cost-Benefit Analysis; Decision Support Techniques; Ergolines; Humans; Levodopa; Middle Aged; Parkinson Disease; Prospective Studies; Surveys and Questionnaires

A 63 year old man with a six year history of Parkinson's disease presented with signs of right heart failure following a knee replacement. Constrictive pericarditis was diagnosed and a radical pericardectomy performed. Six months later, the patient remained unwell with raised inflammatory markers. An inflammatory fibrotic reaction caused by cabergoline was diagnosed. He improved after cessation of cabergoline.

Topics: Antiparkinson Agents; Cabergoline; Ergolines; Fibrosis; Humans; Male; Middle Aged; Parkinson Disease; Pericarditis, Constrictive; Pleura; Pulmonary Fibrosis

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

To quantitatively evaluate motor activity, its fluctuations, and drug effects in patients with Parkinson's disease (PD), the Lifecorder, a new monitoring device, was attached to a group of patients for several weeks. This enabled the continuous recording of motor activity in ten scaled magnitudes at two-minute intervals for 6 weeks.. Thirteen patients with PD who required dopamine receptor agonist therapy were monitored with Lifecorder, and seven healthy subjects served as the control group. The data obtained with this device correlated well with the Unified Parkinson's Disease Rating Scale (UPDRS) and Hoehn-Yahr grading. The dose of cabergoline, a D2-receptor agonist, was increased every 2 weeks, until optimum improvement was achieved.. By adding cabergoline, the mean UPDRS improved from 40.5 to 28.4, which was significant. In parallel, the mean daily walking count (WC) also increased from 2,459 to 3,315 steps (p < 0.01) and movement-related calorie consumption (MCC) increased from 56 to 74 kcal (p < 0.05). UPDRS thus correlated well with WC and MCC (p < 0.05) obtained with this device. The improvement ratio of WC and MCC of each individual patient was compared with that of UPDRS. WC, and MCC shifted in parallel with UPDRS with one exception. The daily time-dependent fluctuation of motor activity was clearly shown by the Excel-generated graphs to improve with D-agonist therapy. In contrast to enhanced daytime activities, nocturnal restfulness was also clearly documented with this device.. The unique properties of Lifecorder make this device a useful adjunct to the UPDRS for the objective evaluation of Parkinsonian motor activity. The device has a significant advantage over conventional clinical scales, as daytime as well as nocturnal motor activity can be objectively evaluated over long time periods ranging from one hour to one month, and the magnitude of motor activity is quantifiable in relation to the time-course.

Topics: Aged; Antiparkinson Agents; Cabergoline; Circadian Rhythm; Dopamine Agonists; Ergolines; Female; Humans; Male; Middle Aged; Monitoring, Ambulatory; Motor Activity; Parkinson Disease

A 79-year-old woman, with Parkinson's disease treated with cabergoline, was admitted to a hospital due to jaundice and weakness. She was found confused, absent minded, and died after 2 weeks. Autopsy showed an extrahepatic bile duct adenocarcinoma with spread to the gall bladder, the liver, and regional lymphnodes. While cleaning the hospital bed after her death, the nurses found several tablets hidden in the bed. Biological samples obtained at the autopsy were screened for common drugs and narcotics. Several drugs such as buprenorphine, codeine, paracetamol, and propranolol were detected in the blood at therapeutic levels. A method to determine cabergoline in whole blood and other forensic matrices was developed, and further investigations determined cabergoline concentrations in whole blood and liver tissue of 94 and 3100 microg/kg, respectively. The blood concentration was 100 times above the therapeutic level reported on cabergoline in plasma and in combination with her symptoms, suggest she took a fatal overdose of cabergoline.

Topics: Aged; Antiparkinson Agents; Cabergoline; Chromatography, Ion Exchange; Drug Overdose; Ergolines; Female; Gas Chromatography-Mass Spectrometry; Humans; Liver; Molecular Structure; Parkinson Disease; Spectrometry, Mass, Electrospray Ionization

Topics: Aortic Valve; Bromocriptine; Cabergoline; Dopamine Agonists; Ergolines; Fibrosis; Heart Valve Diseases; Humans; Parkinson Disease; Pergolide

Cabergoline (1-[(6-allelylergolin-8 beta-yl)carbonyl]-1-[3-(dimethylamino)propyl]-3-ethyl-urea) is a new agonist of the D2 dopaminergic receptors used in the treatment of Parkinson's disease. Cabergoline is characterized by unique pharmacologic properties, such as its long plasma half-life (about 68 hours), which allows for once a day administration. Cabergoline is well tolerated, as has been shown in several clinical trials. Based on the information available, we suggest that cabergoline produces an improvement in the symptoms of Parkinson's disease similar to those produced by other dopaminergic agonists. Cabergoline monotherapy, when used in previously untreated patients, is an appropriate option for the symptomatic treatment of Parkinson's disease. Cabergoline improves motor symptoms, delays the presentation of levodopa-induced motor complications, and diminishes the amount of levodopa required for the control of the symptoms. We suggest that cabergoline is an adequate adjuvant treatment for Parkinson' disease. There is improvement in motor symptoms (without substantially increased dyskinesias), reduced severity and duration of the wearing-off period, and diminished need for levodopa. Cabergoline can also be useful in the treatment of sleep disturbances associated with advanced Parkinson's disease such as nocturnal akinesia and dystonia. However, additional studies on cabergoline's effects in nocturnal disturbances associated with Parkinson's disease are still required. Cabergoline is a well tolerated drug. Its side effects are seen mainly in the digestive and nervous system (central and peripheral). The efficacy of cabergoline in comparison to other dopaminergic agonists should be tested in future clinical studies.

Topics: Antiparkinson Agents; Brain; Cabergoline; Drug Tolerance; Ergolines; Humans; Parkinson Disease; Randomized Controlled Trials as Topic

Psychosis characterized by hallucination or delusion, which occurs during drug therapy of parkinsonian patients, is one of the limiting factors for the control of motor symptoms or complications. In the present study, we encountered three patients with Parkinson's disease (PD) at advanced stages; all three patients had severe psychosis and severe wearing-off phenomenon and one had severe orthostatic hypotension. Their psychotic symptoms were successfully treated by administration of quetiapine, resulting in the favorable control of motor fluctuations and elevation of therapeutic levels unless any aggravation of parkinsonism occurs. Although the measure against drug-induced psychosis is principally a reduction of the doses or withdrawal of causative drugs, the effective use of antipsychotic drugs, such as quetiapine, is helpful to suppress psychosis and allow the patient to adjust to antiparkinsonian drugs for the control of symptoms other than psychosis.

Topics: Aged; Antiparkinson Agents; Antipsychotic Agents; Cabergoline; Dibenzothiazepines; Ergolines; Hallucinations; Humans; Levodopa; Male; Middle Aged; Parkinson Disease; Psychoses, Substance-Induced; Quetiapine Fumarate

We evaluated the incremental cost-effectiveness of cabergoline compared with levodopa monotherapy in patients with early Parkinson's disease (PD) in the German healthcare system. The study design was based on cost-effectiveness analysis using a Markov model with a 10-year time horizon. Model input data was based on a clinical trial "Early Treatment of PD with Cabergoline" as well as on cost data of a German hospital/office-based PD network. Direct and indirect medical and nonmedical costs were included. Outcomes were costs, disease stage, cumulative complication incidence, and mortality. An annual discount rate of 5% was applied and the societal perspective was chosen. The target population included patients in Hoehn and Yahr Stages I to III. It was found that the occurrence of motor complications was significantly lower in patients on cabergoline monotherapy. For patients aged >/=60 years of age, cabergoline monotherapy was cost effective when considering costs per decreased UPDRS score. Each point decrease in the UPDRS (I-IV) resulted in costs of euro;1,031. Incremental costs per additional motor complication-free patient were euro;104,400 for patients <60 years of age and euro;57,900 for patients >/=60 years of age. In conclusion, this decision-analytic model calculation for PD was based almost entirely on clinical and observed data with a limited number of assumptions. Although costs were higher in patients on cabergoline, the corresponding cost-effectiveness ratio for cabergoline was at least as favourable as the ratios for many commonly accepted therapies.

Topics: Antiparkinson Agents; Cabergoline; Cost-Benefit Analysis; Decision Making; Disease Progression; Ergolines; Female; Humans; Levodopa; Male; Markov Chains; Middle Aged; Parkinson Disease; Severity of Illness Index

Excessive daytime somnolence is a common adverse effect of dopamine-agonist treatment of Parkinson's disease (PD). Many factors, such as age and sleep disturbances, could be involved in the pathogenesis of this phenomenon. However, pharmacokinetic factors have never been considered. In this open, prospective, pilot study, nine consecutive non-demented PD patients in early disease stages on monotherapy treatment with dopamine agonists and with no significant sleep problems, were enrolled. They were selected based on the presence of excessive daytime sleepiness induced by the dopaminergic treatment. A fast switch-over from the dopamine agonist currently used to a single equivalent dose of cabergoline, a long-acting dopamine agonist, administered at bedtime was performed. All patients were evaluated by means of UPDRS and Epworth Sleepiness Scale (ESS). A significant 70% reduction of daytime sleepiness was observed during the 3-month study compared with baseline. Data from this study suggest that both pharmacodynamic and pharmacokinetic mechanisms are involved in the pathophysiology of dopamine agonist-induced sleepiness.

Topics: Aged; Antiparkinson Agents; Cabergoline; Disorders of Excessive Somnolence; Dopamine Agonists; Drug Administration Schedule; Drug Interactions; Ergolines; Female; Humans; Male; Mental Status Schedule; Middle Aged; Parkinson Disease; Pilot Projects; Prospective Studies; Psychomotor Performance; Time Factors

Levodopa continues to be the most effective agent for the symptomatic treatment of Parkinson's disease (PD). But over time, initial benefits decline in efficacy because of a rise in adverse effects such as dyskinesias. The pathophysiology of levodopa-induced dyskinesias (LID) is not completely understood, but it appears to result from deficient regulation by dopamine of corticostriatal glutamatergic inputs leading to a cascade of neurochemical changes in the striatum and the output pathways. In the present study, we examined if the addition of small doses of cabergoline (a long-acting D(2) receptor agonist) to levodopa could prevent LID. The major hypothesis is that sustained activation of postsynaptic D(2) receptors on medium spiny neurons even by small doses of cabergoline could prevent or reduce LID. The minor hypothesis, and the more controversial of the two, is that the long-acting stimulation by small doses of cabergoline could diminish the release of glutamate by the corticostriatal pathway and prevent LID. Eight MPTP-treated monkeys with a long-standing and stable parkinsonian syndrome and having never received dopaminergic agents were used. Two groups of four were treated for 1 month with levodopa/benserazide administered orally (100 mg/25 mg). The second group received in addition a threshold dose of cabergoline (dose ranging from 0.015 to 0.035 mg/kg, SC). During the treatment, we observed LID in the levodopa group but not in the group receiving levodopa+cabergoline. Furthermore, the combination produced a comparable antiparkinsonian effect in terms of quality but prolonged the duration (by 1 to 2 hours) and increased the locomotion (mean for 2 weeks congruent with 104%). Our data suggest that a small dose of a long-acting D(2) agonist combined with high doses of levodopa could be preventive of LID in patients with PD and could be an alternative to using antiglutamatergic agents for this purpose.

Topics: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Animals; Antiparkinson Agents; Behavior, Animal; Cabergoline; Disease Models, Animal; Dopamine Agonists; Drug Administration Schedule; Dyskinesia, Drug-Induced; Ergolines; Female; Locomotion; Macaca fascicularis; Parkinson Disease; Posture

An 80-year-old man was admitted to our hospital because of bradykinesia, muscle rigidity and respiratory dysfunction during sleep. Concerning bradykinesia and muscle rigidity, we diagnosed him as the early/moderate stage of Parkinson's disease without autonomic dysfunction. Polysomnography (PSG) showed a series of obstructive hypopneas and apneas. After administration of antiparkinsonian drugs, rigidity of the neck and trunk was diminished along with a drastic decrease in hypopnea on PSG. We consider that sleep hypopnea in this patient is caused by involvement of the striated musculature surrounding the upper-airway and/or rigidity in the trunk. These conditions are treatable with antiparkinsonian drugs.

Topics: Aged; Aged, 80 and over; Antiparkinson Agents; Benserazide; Cabergoline; Ergolines; Humans; Levodopa; Male; Parkinson Disease; Polysomnography; Sleep Apnea Syndromes

We investigated non-rapid eye movement (non-REM) sleep in patients with newly diagnosed Parkinson's disease (PD) who had never previously received dopaminergic medication. There were no significant differences in the conventional sleep parameters between de novo patients with PD and a healthy control group, but the length of stage 1 sleep and the number of awakenings increased significantly upon administration of dopaminergic drugs. Analyzing the quantitative electroencephalogram (EEG), we observed a significant reduction in the low-delta frequency range and a nonsignificant increase in the sigma frequency range in de novo patients with PD. The dopaminergic medication also nonsignificantly reduced the low-delta and sigma frequencies, the latter to the level of the controls. Possible mechanisms that may account for the observed differences are discussed. It is suggested that Parkinson's disease as well as the application of dopaminergic drugs exerts a desynchronizing effect on the sleep EEG that is reflected in a disruption of sleep continuity.

Topics: Aged; Brain; Cabergoline; Delta Rhythm; Dopamine Agonists; Drug Therapy, Combination; Electroencephalography; Electromyography; Ergolines; Female; Humans; Levodopa; Male; Middle Aged; Parkinson Disease; Polysomnography; Sleep, REM; Wakefulness

Topics: Adult; Aged; Cabergoline; Dopamine Agonists; Drug Administration Schedule; Drug Tolerance; Ergolines; Female; Humans; Male; Middle Aged; Parkinson Disease; Pergolide; Randomized Controlled Trials as Topic; Time

To study if cabergoline, a long-lasting specific dopamine D2 receptor agonist, has neuroprotective effects against oxidative stress, we exposed (3 h) SH-SY5Y human neuroblastoma cells to tert-butylhydroperoxide (t-BOOH; 500 microM). t-BOOH caused a 42+/-4% neuronal death, which was prevented by cabergoline (2 h before) in a concentration-dependent manner (EC(50): 1.24 microM). This effect was not antagonised by haloperidol (concentration up to 10 microM), and was associated with an increased availability of intracellular GSH contents (+30+/-11%) and a decrease in the membrane lipid peroxidation (-23+/-9%). Our data suggest that cabergoline has neuroprotective effects useful for Parkinson's disease therapy.

Topics: Cabergoline; Cell Death; Cell Survival; Dopamine Agonists; Dopamine Antagonists; Dopamine D2 Receptor Antagonists; Dose-Response Relationship, Drug; Ergolines; Free Radicals; Haloperidol; Humans; Lipid Peroxidation; Models, Neurological; Necrosis; Neurons; Neuroprotective Agents; Oxidative Stress; Parkinson Disease; Receptors, Dopamine D2; tert-Butylhydroperoxide; Tumor Cells, Cultured

We report on 2 patients with idiopathic Parkinson's disease who experienced marked improvement in symptoms following the addition of itraconazole to current cabergoline treatment. Plasma levels of cabergoline were analyzed in one of the patients and increased to approximately 300% during treatment with itraconazole, which paralleled major clinical improvement.

Topics: Adult; Aged; Antifungal Agents; Antiparkinson Agents; Cabergoline; Cytochrome P-450 CYP3A; Cytochrome P-450 Enzyme Inhibitors; Dose-Response Relationship, Drug; Drug Interactions; Drug Therapy, Combination; Ergolines; Female; Humans; Itraconazole; Male; Neurologic Examination; Onychomycosis; Parkinson Disease; Treatment Outcome

Topics: Aged; Alopecia; Antiparkinson Agents; Cabergoline; Dopamine Agonists; Ergolines; Humans; Male; Parkinson Disease

Topics: Aged; Animals; Antiparkinson Agents; Cabergoline; Dopamine Agonists; Ergolines; Humans; Libido; Male; Parkinson Disease; Penile Erection

To determine if therapy with an ergot and a non-ergot dopamine agonist and levodopa confers an increased risk of excessive daytime sleepiness and secondary "sleep attacks" in Parkinson's disease (PD).. Comparative study of three clinical groups taking, pramipexole (Group 1, n = 19, 8 monotherapy), cabergoline (Group 2, n = 22, 10 monotherapy), and levodopa monotherapy (Group 3, n = 14). Clinical and demographic characteristics, occurrence of "sleep attacks", and assessment of daytime sleepiness [using the Epworth Sleepiness Scale (ESS)], recorded.. No patients reported "sleep attacks". Mean ESS scores: Group 1 (pramipexole) 8.0 +/- 4.5 (range 0-16), Group 2 (cabergoline) 8.1 +/- 3.9 (range 0-19), Group 3 (levodopa), 8.1 +/- 5.5 (range 1-18). There was no significant difference between groups (p = 0.897). Scores of > or = 16 indicating excessive daytime sleepiness (EDS) were evenly distributed throughout treatment groups, particularly in older patients with more advanced disease.. a) EDS is not unique to pramipexole therapy and occurs with both cabergoline and levodopa. b) Increasing age, advanced disease, and higher treatment dose appear important predictors for EDS. c) Driving regulations should be reviewed accordingly.

Topics: Adult; Aged; Aged, 80 and over; Antiparkinson Agents; Benzothiazoles; Cabergoline; Disorders of Excessive Somnolence; Drug Therapy, Combination; Ergolines; Female; Humans; Levodopa; Male; Middle Aged; Parkinson Disease; Pramipexole; Retrospective Studies; 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

Generally, clinicians use rating scales or descriptive writing to characterize diurnal changes in motor signs and symptoms in Parkinson's disease (PD); however, these ratings are subjective and are not easily reproducible.. To examine the usefulness of actigraphy as an objective indicator of akinesia by long-term, continuous measurement of limb motor activity (MA), visualize 24-hour circadian profiles of akinesia, and quantitatively detect cabergoline (CBG) efficacy in both hospitalized patients and outpatients with Parkinson's disease.. MA was continuously recorded with a wrist-worn activity monitor (actigraph) in 29 hospitalized PD patients without tremor or abnormal involuntary movements. In another series consisting of 8 outpatients, the response duration of CBG was measured by using averaged actigraphy.. By averaging data gathered every 24 h over several days, it was possible to quantify the circadian patterns of akinesia. These cumulative evaluations of the patients' motor status determined 4 types of akinesia: (1) a wearing-off pattern seen in advanced efficacy stages, (2) stable response, (3) afternoon akinesia, and (4) morning akinesia. Following CBG therapy, the MA increased significantly throughout the daytime, i.e.: by 40% in the morning (8:00 a.m. to 12:00 noon), by 60% in the afternoon (12:00 noon to 6:00 p.m.), and by 60% in the next early morning (from time to get up until 8:00 a.m.).. In averaged motor activity, the charting of cumulative evaluations of motor status revealed the long-acting efficacy of CBG in ameliorating existing motor fluctuations throughout the daytime and even promoting sleep benefit in the next morning. Averaged actigraphy is considered to be useful in the quantitative detection of drug responses to parkinsonian akinesia and its circadian variations. This enables titration of the lowest dose of drugs needed to alleviate akinesia.

Topics: Aged; Antiparkinson Agents; Cabergoline; Circadian Rhythm; Electrophysiology; Ergolines; Female; Humans; Male; Middle Aged; Monitoring, Physiologic; Motor Activity; Parkinson Disease

This is the first report of a histologically confirmed pleuropulmonary fibrosis (PPF) associated with the dopamine agonist dihydroergocryptine.. A 67-year-old male patient with Parkinson's disease developed a severe restrictive pulmonary disorder with dyspnea and nonproductive cough after a daily intake of 45 mg dihydroergocryptine for 2 years. After changing the dopamine agonist to the non-ergoline substance pramipexole, marked improvement of the clinical symptoms of PPF occurred, while radiological signs showed only a moderate decrease.. PPF is a possibly fatal complication. Chest X-rays and specific pneumological diagnostics should be done if typical symptoms or nonspecific signs of PPF occur while a patient is on treatment with an ergoline dopamine agonist.

Topics: Aged; Antiparkinson Agents; Benzothiazoles; Cough; Dopamine Agonists; Dyspnea; Ergolines; Humans; Male; Parkinson Disease; Pramipexole; Pulmonary Fibrosis; Thiazoles

1. Chronic treatment for one month with the long-acting dopamine D2-like agonist cabergoline (0.25 mg/kg s.c. every 48 hours), had despite partial tolerance, sustained antiparkinsonian activity in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) Parkinsonian monkeys (Macaca fascicularis). 2. Cabergoline treatment decreased by half striatal D2 receptor binding density measured by [3H]spiperone autoradiography versus untreated MPTP monkeys. No change in D2 mRNA measured by in situ hybridization and D2 receptor immunostaining was observed. 3. No change in either D1 receptor binding density or D1 receptor mRNA levels was observed in cabergoline-treated MPTP-monkeys compared to untreated MPTP-monkeys, suggesting receptor subfamily specificity of cabergoline. 4. The present results suggest that the cabergoline-induced behavioral partial tolerance is accompanied by a decrease in D2 receptor binding but not due to alterations in the steady state of D2 mRNA levels.

Topics: Animals; Antiparkinson Agents; Binding Sites; Cabergoline; Disease Models, Animal; Ergolines; Female; In Situ Hybridization; Macaca fascicularis; Parkinson Disease; Receptors, Dopamine D1; Receptors, Dopamine D2

The involvement of abnormalities in nondopaminergic transmitter systems in Parkinson's disease is noteworthy because of the complications, such as dyskinesia, associated with long-term dopamine replacement therapy. The output regions of the basal ganglia, the substantia nigra pars reticulata, and the medial segment of the globus pallidus are overactive in Parkinson's disease but underactive in dyskinesia. 5-HT2C receptors are localized in these regions and are excitatory. A 5-HT2C receptor binding assay using [3H]-mesulergine and SB 200646A to define nonspecific binding was applied to postmortem tissue from patients with Parkinson's disease and from age-matched control patients. [3H]-mesulergine binding was increased in the substantia nigra pars reticulata by 108% in Parkinson's disease tissue as compared with control tissue. These data suggest abnormalities of 5-HT2C transmission in the basal ganglia of patients with Parkinson's disease.

Topics: Aged; Aged, 80 and over; Antiparkinson Agents; Autoradiography; Binding Sites; Brain; Dopamine Agonists; Dyskinesia, Drug-Induced; Ergolines; Female; Humans; Male; Parkinson Disease; Receptor, Serotonin, 5-HT2C; Receptors, Serotonin; Serotonin Antagonists; Substantia Nigra

Certain dopaminergic anti-Parkinson drugs (ergolines) have repeatedly been identified as a cause of pleuropulmonary disease with a focus on serosal cell damage. Recently, a pathogenetic link between ergolines and prior asbestos exposure was suggested, as regards the development of pleural pathology. This report describes a patient with idiopathic Parkinson's disease, who was on a multiple drug regimen including low dose cabergoline. The patient developed a febrile illness with widespread bilateral lung infiltrations nonresponsive to beta-lactam and macrolide antibiotics. Bronchoalveolar lavage and transbronchial lung biopsy showed a "hypersensitivity-like" interstitial lung disease, which cleared almost completely within 2 months after simple drug withdrawal. Circumstantial evidence suggests a so far undescribed adverse lung reaction to cabergoline, devoid of the more usual pleural changes.

Topics: Aged; Biopsy; Bronchoalveolar Lavage Fluid; Cabergoline; Diagnosis, Differential; Dopamine Agonists; Ergolines; Humans; Lung Diseases, Interstitial; Male; Parkinson Disease; Radiography, Thoracic; Tomography, X-Ray Computed

Topics: Antiparkinson Agents; Cabergoline; Dopamine Agonists; Ergolines; Humans; Parkinson Disease; Restless Legs Syndrome

Topics: Antiparkinson Agents; Cabergoline; Dopamine Agonists; Dose-Response Relationship, Drug; Ergolines; Humans; Parkinson Disease

Cabergoline is a long-acting D2 dopamine (DA) agonist. We conducted an open study to investigate the effectiveness and tolerability of cabergoline, administered once a day orally, in 50 consecutive patients with Parkinson's disease complicated by motor fluctuations and dyskinesias. In 15 patients cabergoline replaced another direct DA agonist. Evaluation after 6 months of treatment (also including patients who dropped out during this period), showed an improvement in off or on hours, or both, in excess of 50% in 27 patients, comprising 20 of the 35 patients (57%) previously untreated with DA agonists and seven of the 15 patients (47%) already on DA agonists when the study began. Of the 22 patients who received the treatment for 1 year, the improvement was maintained up to final evaluation in the patients not on DA agonists at admission (n = 16), whereas a slight deterioration in clinical condition was observed in the patients already on DA agonists at admission (n = 6). Only six patients showed a detectable increase in dyskinesias. The most common side effects were gastric upset (n = 12), orthostatic hypotension (n = 3), and ankle edema (n = 3), all mild; also observed were two cases of pleural effusion/pulmonary fibrosis. Twenty patients (40%) failed to complete the treatment; of these, five (10% of total) dropped out because of adverse effects. It is concluded that once-daily administrations of cabergoline are useful for treating patients with Parkinson's disease with motor fluctuations and may advantageously substitute other DA agonists. The side effects of the drug are generally mild, although two cases involving pleuropulmonary complications did emerge.

Topics: Aged; Cabergoline; Dopamine Agonists; Dose-Response Relationship, Drug; Dyskinesia, Drug-Induced; Ergolines; Humans; Middle Aged; Parkinson Disease; Receptors, Dopamine D2

We studied the characterization of cabergoline, a new ergot alkaloid derivative and a selective dopamine D2 receptor agonist, in comparison to bromocriptine and pergolide in reserpine-treated rodents. Cabergoline (0.25-1.0 mg/kg, s.c.) improved dose-dependently the reserpine-induced akinesia that was assessed on the locomotor activity, and the efficacy lasted longer than those of bromocriptine (1.25-5.0 mg/kg, s.c.) or pergolide (0.0625-0.5 mg/kg s.c.). Cabergoline (ED50 = 1.10 mg/kg, at 4 h after the administration of drugs) also reversed catalepsy, the failure to correct an externally imposed posture, and its efficacy was stronger and longer than bromocriptine (ED50 = 4.65 mg/kg, at 4 h). Further, reserpine-induced rigidity was improved equally by cabergoline (0.125-1.0 mg/kg, i.v) and bromocriptine (1.0 mg/kg, i.v.). When cabergoline was administered together with 3(3,4-dihydroxyphenyl)-L-alanine (L-DOPA), the effects were additive. Our results indicate that the long-lasting effects of cabergoline could be beneficial for treating Parkinson's disease.

Topics: Animals; Cabergoline; Dopamine Agonists; Ergolines; Levodopa; Male; Mice; Motor Activity; Parkinson Disease; Rats; Rats, Sprague-Dawley; Receptors, Dopamine D2; Reserpine

Topics: Cabergoline; Dopamine Agonists; Ergolines; Humans; Parkinson Disease

We had previously found that in animals with moderate nigro-striatal dopamine (DA) lesions (i.e. 45-65% residual neostriatal DA) the mixed D1/D2-agonist apomorphine induced ipsiversive rather than the usual contraversive turning found after more radical DA lesions. Since this result promised to provide a behavioral animal model for pre-clinical Parkinson's disease, we hoped to delineate the responsible receptor by challenging with selective D1- and D2-agonists. Thus, in the present study, the behavioral effects of the D1-agonist SKF38393 (5.0 mg/kg) and the D2-agonist LY171555 (0.5 mg/kg) were tested in drug-naive rats with unilateral 6-hydroxydopamine lesions of the nigro-striatal DA system. This analysis was performed dependent on the degree of the lesion, classified post-mortem with respect to the level of residual DA in the neostriatum: < 20%, 20-45%, 45-65%, and > 65% (as percentage of the intact hemisphere). The measures of turning, thigmotactic scanning and locomotion did not yield differences between animals treated with the D1-agonist and vehicle-treated rats. For example, animals with severe lesions (residual DA < 20%) showed ipsiversive asymmetries in turning and scanning, which were similar after vehicle or the D1-agonist, both with respect to degree and time-course. However, the analysis of grooming behavior, which was performed in a subset of animals with moderate lesions yielded differences between vehicle and the D1-agonist, since the duration of grooming was increased after SKF38393. In contrast to the D1-agonist, behavioral effects after the D2-agonist LY17155 were evident in all behavioral measures. The general response to this agonist could be characterized by a rapid decrease of behavioral activity including turning, scanning, locomotion and grooming. Although we failed to find significant behavioral asymmetries with either agonist, a micro-analysis showed evidence for selective effects after the D2-agonist, since a contraversive asymmetry in turning (and scanning) became apparent between 45 and 60 min after injection in animals with severe lesions (residual DA of about 10% or less), and since there was a weak ipsiversive turning asymmetry in animals with residual DA levels of 45-65%. Such asymmetries were not observed after vehicle or the D1-agonist. The possible physiological mechanisms of these effects, i.e. DA receptor mechanisms and DA availability, are discussed in the context of results from previous experiments using lesioned

Topics: 2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine; Animals; Behavior, Animal; Dopamine; Ergolines; Locomotion; Male; Nerve Degeneration; Oxidopamine; Parkinson Disease; Quinpirole; Rats; Rats, Wistar; Receptors, Dopamine D1; Receptors, Dopamine D2; Substantia Nigra; Time Factors

Methods for the assessment of akinesia in the unilateral rat Parkinson model have so far been lacking. The experiments reported here evaluate the usefulness of a new "stepping test" to monitor forelimb akinesia in rats with unilateral 6-hydroxydopamine (6-OHDA) lesions of the mesencephalic dopamine (DA) system, and to assess the ability of DA-receptor agonists and fetal DA neuron transplants to reverse these deficits. The 6-OHDA lesion induced marked and long-lasting impairments in the initiation of stepping movements with the contralateral paw. Systemic injections of low doses (chosen to be subthreshold for induction of rotation) of the mixed D1 and D2 receptor agonist apomorphine, the D1-selective agonist SKF 38393, and to a lesser extent also the D2-selective agonist quinpirole were effective in reversing these deficits. Similar effects was seen after a subrotational dose of L-dopa, whereas amphetamine had no effect. Fetal nigral transplants, implanted as multiple deposits in the ipsilateral caudate-putamen and substantia nigra, restored initiation of stepping to a similar degree as the DA agonists. Nigral grafts placed in substantia nigra alone were also effective, although the improvement was less pronounced. Apomorphine, at a dose effective in the lesion-only animals, had no additive effect in the grafted rats, whereas amphetamine appeared to further improve stepping in the rats with intranigral transplants. Identical experiments were performed on skilled forelimb use in the so-called staircase test. Interestingly, neither the DA agonist drugs nor the nigral transplants had any effects on the lesion induced deficits in this more complex task. The results show that forelimb stepping is a highly useful test to monitor lesion-/and transplant-induced changes in forelimb akinesia, a behavioral parameter that may be analogous to limb akinesia and gait problems seen in patients with Parkinson's disease.

Topics: 2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine; Analysis of Variance; Animals; Apomorphine; Brain Tissue Transplantation; Carbidopa; Dextroamphetamine; Disease Models, Animal; Dopamine; Dopamine Agonists; Ergolines; Female; Fetal Tissue Transplantation; Forelimb; Functional Laterality; Levodopa; Motor Activity; Movement Disorders; Norepinephrine; Oxidopamine; Parkinson Disease; Quinpirole; Rats; Rats, Sprague-Dawley; Rotation; Substantia Nigra; Transplantation, Heterotopic

We followed 4 patients with Parkinson's disease and severe, intermittent, drenching sweats. One patient was studied with serial plasma levodopa levels and simultaneous clinical examinations. She was observed during a severe sweating episode; this was associated with subtherapeutic plasma levodopa levels (low dopa state). All 4 patients' sweats responded favorably to the institution of agonist therapy. Drenching sweats should be considered part of the spectrum of off-period levodopa-related fluctuations in Parkinson's disease.

Topics: Aged; Bromocriptine; Cabergoline; Chorea; Dopamine Agonists; Ergolines; Female; Humans; Levodopa; Male; Middle Aged; Monitoring, Physiologic; Parkinson Disease; Pergolide; Sweating

Oxidant stress secondary to dopamine metabolism has been proposed as a pathogenic factor in the development of Parkinson's disease. Biochemical abnormalities extending beyond the central nervous system have been identified in patients with this condition. Previous investigators have found abnormally elevated concentrations of the lipid peroxidation product, malondialdehyde, in the plasma and serum of patients with Parkinson's disease. We attempted to replicate these findings but controlled for other factors that could influence malondialdehyde levels. We detected no significant elevations in mean serum malondialdehyde concentrations in either levodopa-treated or untreated patients with Parkinson's disease, compared to normal controls; similarly, no elevation was found in a group of patients with dementia of Alzheimer's type. On the other hand, a group of subjects with diabetes mellitus but no neurodegenerative disease had significantly elevated mean serum malondialdehyde levels, consistent with previous studies of diabetic patients. Autoxidation is one of the two major routes by which dopamine and dopa metabolism may generate oxygen free radicals. We analyzed the autoxidation product of dopa, 5-S-cysteinyl-dopa, in the plasma of these same groups of patients with neurodegenerative disease and normal controls; no significant differences were identified. Serum concentrations of two other antioxidant substances, alpha-tocopherol and uric acid, were also statistically similar in these groups. In conclusion, analysis of several blood products relevant to oxidant stress, including malondialdehyde, 5-S-cysteinyl-dopa, alpha-tocopherol, and uric acid, failed to distinguish patients with Parkinson's disease or dementia of Alzheimer's type from controls.

Topics: Aged; Alzheimer Disease; Antiparkinson Agents; Brain; Cabergoline; Carbidopa; Diabetes Mellitus; Ergolines; Female; Free Radicals; Humans; Levodopa; Lipid Peroxidation; Male; Malondialdehyde; Oxidative Stress; Parkinson Disease; Selegiline; Vitamin E

Motor fluctuations constitute a severe complication of chronic levodopa therapy. The addition of dopamine agonists may partially alleviate these responses; however, due to the short half-life of these drugs, several daily doses are required. Cabergoline is a new dopamine agonist with a long half-life and can be given in a single daily dose. Seventeen patients with severe fluctuations were treated with cabergoline, seven of them for > 1 year (up to 39 months). The motor status ameliorated and the percentage of "off" hours significantly decreased in the first year and did not increase significantly later during long-term follow-up. Cabergoline is a promising treatment for parkinsonian patients with motor fluctuations.

Topics: Aged; Cabergoline; Dopamine Agonists; Drug Tolerance; Dyskinesia, Drug-Induced; Edema; Ergolines; Female; Humans; Male; Middle Aged; Parkinson Disease

Studies on the influence of some dopamine agonists, particularly bromocriptine, on the pharmacokinetics of L-dopa have furnished contrasting results. Thus, any possible pharmacokinetic interaction should be taken into consideration when adding a new dopamine agonist to L-dopa treatment. In 12 Parkinson's disease (PD) patients with motor fluctuations, cabergoline was added in an 8-week study to their usual L-dopa/carbidopa therapy. Cabergoline was administered once a day at increasing doses of 0.5, 1, 2, and 3mg/day for a period of one week per dose, and 4mg/day for three weeks. Motor performance was assessed weekly evaluating the motor examination of the Unified Parkinson's Disease Rating Scale (UPDRS) and the patients' diaries of daily on-off time. Blood levels of both L-dopa and 3-O-methyldopa (3-OMD) were assayed by HPLC in two different days, over an 8-hour period, before initiating cabergoline and at the end of the study. The results of this study confirm that cabergoline is effective in the management of PD motor fluctuations without modifying L-dopa and 3-OMD pharmacokinetics.

Topics: Analysis of Variance; Antiparkinson Agents; Cabergoline; Dopamine Agonists; Dose-Response Relationship, Drug; Drug Therapy, Combination; Ergolines; Female; Humans; Levodopa; Male; Middle Aged; Movement Disorders; Parkinson Disease; Treatment Outcome

Cultured rat fetal mesencephalic dopaminergic neurons exhibit specific high-affinity uptake for [3H]dopamine (DA) and express DA D-2 autoreceptors, functionally coupled to the inhibition of depolarization evoked [3H]DA release. In this study, we examined the effect of short- and long-term sustained agonist exposure on the responsiveness of these DAD-2 receptors, expressed on cultured fetal mesencephalic dopaminergic neurons. Therefore, cultures were incubated in the absence or presence of the selective D-2 receptor agonist LY 171555 (Quinpirole, 1 microM) before the DA D-2 receptor-mediated inhibition of depolarization-induced [3H]DA release was determined. Short-term preincubation of cultures for 4 h did not lead to any change in the K(+)-evoked [3H]DA release nor to a change in the efficacy of LY 171555 (1 microM) to inhibit this release. Similar results were obtained after long-term agonist exposure for 6 days. Only after exposure for 12 consecutive days was a small reduction of the LY 171555 mediated inhibitory effect on DA release observed, while the IC50 value was slightly shifted to the right as compared to control cultures. Additionally, in pretreated cultures, a statistically significant increase was observed in the depolarization-induced release of [3H]DA in the absence of drugs. In the same model, activation of muscarinic acetylcholine (M-ACh) receptors was shown to potentiate the depolarization-induced release of [3H]DA. Preincubation for 4 h with the muscarinic agonist carbachol (100 microM) induced a strong reduction in the M-ACh receptor-mediated effect on [3H]DA release, indicative of a rapid desensitization of M-ACh receptors. It is concluded that, while no functional desensitization of DA D-2 autoreceptors is apparent, the depolarization-induced release of DA from cultured fetal dopaminergic neurons is enhanced upon long-term sustained activation of DA D-2 receptors.

Topics: Animals; Atropine; Brain Tissue Transplantation; Carbachol; Cells, Cultured; Dopamine; Dopamine Agents; Ergolines; Fetal Tissue Transplantation; Fetus; Mesencephalon; Neurons; Parkinson Disease; Potassium; Quinpirole; Rats; Receptors, Dopamine D2; Receptors, Muscarinic

Neural transplantation in experimental Parkinsonism has so far focused on the ectopic placement of fetal ventral mesencephalic (VM) neurons into the dopamine-denervated caudate-putamen. VM grafts are effective in restoring dopamine neurotransmission in the grafted caudate-putamen and in partial amelioration of behavioral deficits. Recent pharmacological and physiological data have provided strong evidence that dopamine released from dendrites of the substantia nigra pars compacta (SNc) neurons within the pars reticulata (SNr) plays an important role in the regulation of the basal ganglia output pathways. Using a novel microtransplantation approach, multiple small cell suspension grafts (250 nl) derived from the VM of E14 rat embryos were implanted into the SNr of unilaterally 6-hydroxydopamine-lesioned rats. Behavioral changes in drug-induced rotation asymmetry were monitored for up to 14 weeks postgrafting, followed by a quantitative assessment and correlation of tyrosine hydroxylase (TH)-positive cell survival. The reduction in rotational asymmetry caused by the intranigral VM grafts was 64% for SKF 38393 (D1 agonist), 54% for apomorphine (mixed D1 and D2 agonist), and 67% for quinpirole (D2 agonist) when compared to a control spinal cord graft group. By contrast, amphetamine-induced rotation was completely unaffected. The correlation between number of TH-positive cells and behavioral compensation was highest for the D1 agonist (R = -0.729), though clear-cut also for the mixed D1/D2 agonist apomorphine (R = -0.664) and the D2 agonist quinpirole (R = -0.642). Favorable morphological features of the VM micrografts included extensive migration of the dopaminergic neurons into the host SNr and the formation of dense patches of dendrite-like TH-positive terminal networks within the SNr. The results demonstrate a novel pattern of behavioral recovery induced by intranigral VM transplants in the rat Parkinson model. This may have important implications for the understanding of how the nigrostriatal dopamine system influences motor control in the basal ganglia as well as for the development of optimal transplantation strategies in Parkinson's disease.

Topics: 2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine; Amphetamine; Animals; Behavior, Animal; Dopamine; Dopamine Agents; Ergolines; Female; Fetal Tissue Transplantation; Graft Survival; Mesencephalon; Neurons; Parkinson Disease; Quinpirole; Rats; Rats, Sprague-Dawley; Rotation; Stereotyped Behavior; Substantia Nigra

We treated 36 patients with motor fluctuations and dyskinesias on chronic levodopa therapy with cabergoline (CBG) once a day for a mean period of 14.2 +/- 5.8 months. There was a significant increase in the "on" hours and a reduction in "off-period" dystonia. Ten patients continued to show a marked improvement after 28.3 months of treatment (mean dose, 11.3 +/- 4.5 mg). In 23 patients, increased dyskinesias (daily CBG dose, 11 +/- 4.3 mg) had complicated the positive effect after 17.2 +/- 4.8 months. Three patients (daily CBG dose, 14.3 mg) were therapeutic failures, and administration of CBG was stopped. Side effects leading to CBG discontinuation were visual hallucinations (n = 5), heart failure (n = 5), and nausea and vomiting (n = 1). Plasma CBG levels, measured in seven patients taking 3, 5, or 7 mg daily (po), showed fairly stable concentrations throughout the 24 hours. We concluded that CBG is an efficient dopamine agonist that can provide continuous dopaminergic stimulation when taken orally once a day.

Topics: Adult; Aged; Cabergoline; Dopamine Agents; Drug Therapy, Combination; Ergolines; Female; Follow-Up Studies; Humans; Levodopa; Longitudinal Studies; Male; Middle Aged; Parkinson Disease; Treatment Outcome

The alleged selective, high efficacy dopamine D1 receptor agonist, SKF 81297 (0.05-0.3 mg/kg i.m.), induced rotational behaviour away from the lesion and stimulated use of the dominant right hand in unilaterally (left side) 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned rhesus monkeys (Macaca mulatta). The effects of SKF 81297 were completely blocked by the dopamine D1 receptor antagonist, SCH 23390 (0.05 mg/kg), but not by the dopamine D2 receptor antagonist, remoxipride (1 mg/kg), and were similar to those induced by the selective dopamine D2 agonist, LY 171555 (0.01 mg/kg). These results suggest a functional stimulatory role for the dopamine D1 receptor on motor behaviour in a non-human primate model of Parkinson's disease when stimulated with a high efficacy selective dopamine D1 receptor agonist.

Topics: Analysis of Variance; Animals; Benzazepines; Disease Models, Animal; Dopamine Agents; Ergolines; Macaca mulatta; Male; Motor Activity; MPTP Poisoning; Parkinson Disease; Quinpirole; Remoxipride

A patient with Parkinson's disease, initially treated with bromocriptine and subsequently with cabergoline, developed progressive pleuropulmonary abnormalities during the latter therapy. These lesions even worsened for some weeks after interruption of cabergoline, which may possibly be related to the prolonged action of this drug. Thus cabergoline may cause similar pleuropulmonary abnormalities to bromocriptine.

Topics: Bromocriptine; Cabergoline; Dopamine Agents; Ergolines; Humans; Lung Diseases; Male; Middle Aged; Parkinson Disease; Pleural Effusion

An antiserum against cabergoline, a powerful dopamine-agonist under clinical trials for the treatment of Parkinson's disease and hyperprolactinemia, has been raised in rabbits by immunization with an immunogen produced by conjugation of cabergoline to bovine serum albumin. The antiserum was able to bind a derivative of cabergoline labelled with tritium and was able to distinguish the drug molecule from some of its close related compounds and from other agents that could be simultaneously present in plasma from patients undergoing treatment with cabergoline. The antiserum and the tritium labelled hapten were used to develop a radioimmunoassay for cabergoline determination in human plasma and urine. A linear relationship between cabergoline added and % radioactivity bound was found in the range 1.9-500 pg/tube. The addition in the assay of 200 microliters human plasma or 25 microliters urine did not affect the specific and the non-specific binding of the radiolabelled hapten so enabling us to obtain a final sensitivity of about 12 pg/ml plasma and 120 pg/ml urine. The assay was validated in terms of reproducibility, precision and accuracy over the whole range of concentrations tested both in plasma and urine. The plasma concentrations at the steady state in a patient with Parkinson's disease who had received the drug at single oral daily doses of 3, 5 and 7 mg were determined using the assay.

Topics: Aged; Cabergoline; Cross Reactions; Dopamine Agents; Ergolines; Evaluation Studies as Topic; Humans; Male; Parkinson Disease; Radioimmunoassay; Reference Standards; Sensitivity and Specificity

Selective agonists for D1-like and D2-like dopamine receptors can interact synergistically to enhance each other's actions on locomotion and behavior in experimental animals. Clinically, the combination of the D2 agonist bromocriptine with L-dopa (which has pronounced D1 effects) is a highly effective treatment for Parkinson's disease. The mechanisms underlying this important receptor interaction are poorly understood and are the subject of intense study in vitro. In rats with unilateral 6-hydroxydopamine (6-OHDA) lesions of the nigrostriatal pathway, D1-selective (but not D2-selective) dopamine agonists produce a marked increase in expression of the immediate-early gene c-fos in the striatum ipsilateral to the 6-OHDA lesion. In the experiments reported here, we have used this in vivo model to explore the possibility that combinations of D1-selective and D2-selective agonists might have effects on c-fos transcription that are different from those exhibited by D1 or D2 agonists administered alone. We examined the effects of the D1-selective agonist SKF-38393 and the D2-selective agonist quinpirole (LY 171555) on the expression of Fos-like protein and c-fos mRNA in the caudoputamen and made parallel behavioral observations in the same animals. A low dose of SKF-38393 produced little contraversive rotation and little induction of Fos-like immunoreactivity in the striatum. A low dose of quinpirole elicited contralateral rotation but little or no induction of Fos-like immunoreactivity in the caudoputamen; there was, however, induction of Fos in the globus pallidus ipsilateral to the 6-OHDA lesion. Combination of the low dose of SKF-38393 and quinpirole produced a synergistic effect on rotation and elicited, in the dopamine-depleted caudoputamen, a striking pattern of Fos-like protein expression in which Fos-positive neurons were concentrated in striosomes and in the dorsolateral caudoputamen. Northern blot analysis showed that c-fos mRNA was expressed following combined agonist treatment but was not detectable after the single-agonist treatments. Both the contraversive rotation and the induction of Fos-like immunoreactivity were blocked by the preadministration of the D1-preferring antagonist SCH-23390 and the D2-selective antagonist raclopride in combination. Pretreatment with the glutamate NMDA receptor antagonist MK-801 also blocked the induction of Fos-like immunoreactivity, and it reversed the rotation. These findings suggest a D1/D2 synergistic mechanism

Topics: 2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine; Amino Acid Sequence; Animals; Behavior, Animal; Benzazepines; Corpus Striatum; Dizocilpine Maleate; Dopamine; Dopamine Agents; Ergolines; Male; Molecular Sequence Data; Oxidopamine; Parkinson Disease; Proto-Oncogene Proteins c-fos; Quinpirole; Rats; Receptors, Dopamine D1; Receptors, Dopamine D2

The hemodynamic and biochemical effects of cabergoline, a new ergoline derivative with selective, potent, and long-lasting dopamine (DA) agonistic properties, were evaluated in 19 parkinsonian patients, all previously identified as stable responders to levodopa plus L-Dopa decarboxylase inhibitor. The purpose of the study was to find markers capable of predicting the development of cardiopressor side effects during DA-agonistic therapy. Blood pressure (BP), heart rate, and plasma catecholamine responses to a standard meal and a tilt table test were evaluated before and during cabergoline therapy. Cabergoline (1.0 mg/day x os) in this open study significantly reduced the BP response to standing exclusively in the subgroup of patients who exhibited marked postprandial hypotension in baseline conditions. The patients subsequently experienced a partial recovery at day 7 of treatment. This finding indicates that postprandial hypotension is an early marker of autonomic failure in patients with Parkinson's disease (PD) and suggests the usefulness of evaluating cardiopressor response to a standard meal before starting new DA-agonist therapy in PD.

Topics: Aged; Blood Pressure; Cabergoline; Dopamine Agents; Ergolines; Female; Food; Heart Rate; Humans; Hypotension; Hypotension, Orthostatic; Male; Middle Aged; Parkinson Disease; Time Factors

Artificial dopamine agonists are widely employed for the treatment of idiopathic parkinsonism. Pleuropulmonary disease has previously been reported to occur with the use of bromocriptine and mesulergine. We report similar adverse effects induced by the newer agonists lisuride and cabergoline. All these agents are tetracyclic ergot derivatives. This suggests a causal link between ergot-derived dopamine agonists and pleuropulmonary disease.

Topics: Aged; Cabergoline; Dopamine Agents; Ergolines; Female; Humans; Lisuride; Lung Diseases; Male; Middle Aged; Parkinson Disease; Pleural Diseases; Radiography

Topics: Administration, Oral; Antiparkinson Agents; Cabergoline; Drug Evaluation; Drug Therapy, Combination; Ergolines; Humans; Levodopa; Parkinson Disease; Receptors, Dopamine

CQA 206-291, a new ergot derivative with a "biphasic" dopaminergic profile, was studied in 6 patients with longstanding Parkinson's disease suffering from pronounced fluctuations in hourly mobility. On alternate days, up to seven single doses, escalating from 0.2 to 20 mg, were given as replacement for the usual first morning dose of levodopa. At the most effective dosage, four of the six patients obtained as good a peak response to CQA (8-20 mg) as to L-dopa. Side effects were common and similar to other ergot derivatives, suggesting that the initial weak dopamine antagonist properties of the parent compound, documented in animals, may be of little clinical significance. However, comparative studies will be needed to confirm this suspicion. The addition of domperidone successfully reduced the incidence and severity of side effects. CQA 206-291 has potent anti-parkinsonian properties; further longer-term treatment trials are indicated.

Topics: Aged; Antiparkinson Agents; Ergolines; Female; Humans; Levodopa; Male; Middle Aged; Parkinson Disease; Psychomotor Performance

Topics: Antiparkinson Agents; Carbidopa; Drug Combinations; Drug Therapy, Combination; Ergolines; Humans; Levodopa; Lisuride; Parkinson Disease

The aim of this study was to assess whether or not continuous infusion of lisuride in combination with intermittent levodopa-carbidopa administration was associated with tolerance. Intravenous apomorphine was given to four patients before initiation of chronic treatment with subcutaneous lisuride infusion and oral levodopa. The study was repeated under identical conditions after a mean of 18 months of treatment. In no case was the motor response induced by apomorphine infusion reduced as compared to baseline assessment. Choreic dyskinesias accompanying the "on" state were enhanced in all patients. These findings suggest that chronic continuous infusion of a dopamine agonist like lisuride, associated with oral levodopa, is not accompanied by tolerance or down-regulation of striatal dopaminergic receptors.

Topics: Administration, Oral; Adult; Aged; Apomorphine; Drug Tolerance; Ergolines; Humans; Infusion Pumps; Levodopa; Lisuride; Middle Aged; Movement Disorders; Parkinson Disease

During 3 years' treatment of de novo parkinsonian patients with lisuride in combination with selegiline and levodopa the optimal therapeutic dose of levodopa was significantly lower than that when given alone or together with lisuride. The improvement in parkinsonian disability was equal in all these patient groups, but treatment with an early combination of lisuride and levodopa without or with selegiline resulted in significantly and equally reduced end-of-dose disturbances and dyskinesias than treatment with levodopa alone. This finding, together with the possible retardation of the progression of the disease with selegiline suggests that dopaminergic treatment in early Parkinson's disease should be initiated using a dopamine agonist such as lisuride in combination with selegiline and levodopa.

Topics: Drug Therapy, Combination; Ergolines; Female; Humans; Levodopa; Lisuride; Male; Middle Aged; Parkinson Disease; Phenethylamines; Selegiline

Serotonin-1 receptors were examined in post-mortem human brains, using quantitative in vitro autoradiography. [3H]Serotonin was used as a ligand. Serotonin-1 receptor subtypes were defined with 8-hydroxy-2-(di-n-propylamino)-tetralin and mesulergine. In the control human basal ganglia, the highest density of serotonin-1 binding sites was observed in both lateral and medial globus pallidus and substantia nigra reticulata. Lower densities were seen in the substantia nigra pars compacta, the nucleus accumbens, caudate and putamen. The majority of these serotonin-1 sites belonged to the serotonin-1D class. No significant alteration of the density and distribution of these sites was observed in Parkinson's disease brains. In contrast, a marked decrease in the density of the receptor binding was seen in the basal ganglia and the substantia nigra from patients dying with Huntington's disease. These results suggest that serotonin-1D receptors are expressed by cells intrinsic to the striatum which degenerate in Huntington's disease and project to the substantia nigra reticulata where these receptors are probably presynaptically localized. These observations in pathological human brains agree with the results of lesion studies in animal models and further support a role for serotoninergic mechanisms in movement control.

Topics: Aged; Basal Ganglia; Ergolines; Female; Humans; Huntington Disease; Male; Middle Aged; Parkinson Disease; Receptors, Serotonin

CQA 206-291, a new D2 dopamine receptor agonist with a biphasic dopaminergic profile, was given to six patients with idiopathic Parkinson's disease after overnight drug withdrawal. With incremental single oral doses of CQA, a dose-related, clinically significant, and prolonged antiparkinsonian effect was observed. Most subjects experienced drowsiness after the drug while a minority of subjects experienced nausea and/or vomiting or postural hypotension. Further study of this drug in humans is indicated.

Topics: Aged; Dopamine Agents; Dose-Response Relationship, Drug; Drug Evaluation; Ergolines; Female; Humans; Male; Middle Aged; Movement; Parkinson Disease; Receptors, Dopamine

The dopamine agonist, CQP 201-403, was administered to 10 patients in an open label fashion with rapid dosage escalation during hospitalization. Assessed over an average of 20 days, significant improvement occurred in bradykinesia, rigidity, and postural instability. Tremor did not occur in sufficient frequency in this group of patients to be accurately assessed. The most serious adverse effect encountered was prolonged confusion with psychosis. This study suggests that CQP 201-403 may be of value in the treatment of Parkinson's disease.

Topics: Aged; Dopamine Agents; Ergolines; Female; Humans; Male; Middle Aged; Parkinson Disease; Pilot Projects

Oral lisuride associated with the previous therapy (levodopa plus inhibitor) was given to 15 patients with complex fluctuations of mobility that were not controlled with usual therapy. In contrast with previous studies using this drug, in the present trial several lisuride doses (5-10 administrations) were distributed throughout the day. This therapeutic strategy permitted a greater control of the fluctuations, a significant reduction of the block hours and the disappearance or attenuation of biphasic dyskinesia and off dystonia. It is considered that the use of multiple doses of lisuride permits better therapeutic results than its usual administration schedule (3-4 times a day). Oral lisuride associated with levodopa may provide a definite improvement in motor function in patients with significant functional impairment. The general tolerance was very good using concomitant domperidone therapy.

Topics: Administration, Oral; Adult; Aged; Drug Administration Schedule; Drug Evaluation; Ergolines; Female; Humans; Lisuride; Male; Middle Aged; Movement Disorders; Parkinson Disease

1. A group of 14 fluctuating Parkinsonian patients underwent the subcutaneous Lisuride treatment, administered by an insulin delivery pump. Clinical response has been studied during a one year period. 2. Some patients (8 out of 14) were in combined therapy, assuming a relative small amount of oral L-Dopa together with subcutaneous Lisuride. 3. Lisuride confirmed, also by the subcutaneous route, its antiparkinsonian properties, without any loss of therapeutical efficacy during the 12 month period considered. 4. 7 patients dropped-out from the study, due to psychiatric or systemic side-effects and to "technical" management of the pump. 5. The only 2 patients assuming a 24 hour regimen of Lisuride infusion were among the withdrawn subjects. They were also the only to complain severe psychiatric disturbances.

Topics: Adult; Drug Therapy, Combination; Ergolines; Female; Humans; Infusion Pumps; Levodopa; Lisuride; Male; Middle Aged; Parkinson Disease

The cardiovascular effects of a continuous intravenous infusion of lisuride plus oral domperidone were studied in 16 fluctuating parkinsonian patients as compared to their usual oral therapy with levodopa plus carbidopa. The study was performed using a 24-h ambulatory recording and an automatic noninvasive device for blood pressure monitoring. During lisuride infusion, a significant increase of systolic blood pressure was observed; however, in three patients, a decrease of systolic-diastolic blood pressure occurred; furthermore, a mild increase of atrial arrhythmias and, in two patients, a short run of atrial fibrillation were noted. Asymptomatic orthostatic hypotension, observed in seven patients during levodopa therapy, disappeared during lisuride infusion. Paradoxical hypertensive effects and disappearance of orthostatic hypotension observed in our patients seem related to the concurrent administration of domperidone.

Topics: Adult; Blood Pressure; Domperidone; Drug Therapy, Combination; Electrocardiography; Ergolines; Female; Heart Rate; Hemodynamics; Humans; Infusions, Intravenous; Lisuride; Male; Middle Aged; Parkinson Disease

Topics: Adult; Aged; Drug Therapy, Combination; Ergolines; Humans; Levodopa; Middle Aged; Parkinson Disease; Pergolide; Retrospective Studies

28 patients with Parkinson's disease showing complex "on-off" fluctuations in response to chronic levodopa plus dopa decarboxylase inhibitor (po) were treated with subcutaneous lisuride using a portable infusion pump. All patients improved initially during the first weeks of treatment. Four patients abandoned the trial within the first few weeks as a consequence of psychiatric complications (2 cases), inability to understand how to use the pump (one case) and subcutaneous nodule formation plus psychological rejections to wearing a pump (one case). All other 24 patients were treated for a minimum periods of 3 months (mean 9.6 months, maximum 24 months). The average daily dose of lisuride was 2.80 mg. The levodopa dose was reduced by 37%, but total withdrawal was not possible in any patient. Among the 18 patients who continued treatment at present, about 50% are independent and capable of undertaking most daily life activities. Psychiatric side-effects were present in 9 patients leading to permanent withdrawal in five. Subcutaneous lisuride infusions added to oral levodopa are clearly effective in patients with severe motor fluctuations. Careful selection of suitable patients and close monitoring is mandatory in order to obtain the best therapeutic results while reducing the risk of psychiatric adverse effects.

Topics: Drug Eruptions; Dyskinesia, Drug-Induced; Equipment Failure; Ergolines; Female; Humans; Infusion Pumps; Injections, Subcutaneous; Lisuride; Male; Mental Disorders; Movement; Movement Disorders; Parkinson Disease; Platelet Aggregation

Thirteen patients with idiopathic Parkinson's disease and "on-off" fluctuations on oral levodopa plus dopa decarboxylase inhibitor (DDI) were treated with continuous (24 hour) subcutaneous lisuride infusions together with a reduced dose of levodopa (plus DDI). An improvement in motor performance was seen in 10 patients, with a mean increase in percentage of waking time spent "on" of 32 per cent (range 13-59 percent). However, adverse effects were common, especially psychiatric effects, leading to treatment withdrawal in 11 of 13 subjects after a mean of 40 days' treatment. Continuous lisuride infusion together with a small dose of levodopa (plus DDI) are effective treatment for "on-off" fluctuations in Parkinson's disease, but the frequency of adverse effects limits the number of patients who can be treated successfully with this technique.

Topics: Adult; Aged; Drug Eruptions; Dyskinesia, Drug-Induced; Ergolines; Female; Humans; Hypotension; Infusion Pumps; Lisuride; Male; Mental Disorders; Middle Aged; Movement; Parkinson Disease

Four patients with Parkinson's disease and severe fluctuating responses to levodopa and oral dopamine agonists were treated with continuous administration of lisuride infusions, administered by means of an externally worn pump. Levodopa dosage ranged from 300 to 687 mg/day and was kept stable throughout the study. In addition increasing doses of lisuride were injected subcutaneously in the abdomen. Lisuride doses ranged from 41 to 104 micrograms/h. A marked improvement in mobility was observed in every patient while severe biphasic dyskinesais almost remitted in one of them. The most common side-effect was the presence of subcutaneous nodules appearing at the injection site. Two cases had mild hemorrhagic complications and one initially had nausea. One patient developed acute psychiatric disturbances severe enough to be excluded from the study. Our findings suggest that lisuride subcutaneous infusions can be useful in severily handicapped parkinsonian patients, however local and psychiatric side-effects may be a serious threat in the long-term care.

Topics: Aged; Drug Eruptions; Drug Therapy, Combination; Ergolines; Female; Hematoma; Humans; Infusion Pumps; Levodopa; Lisuride; Male; Mental Disorders; Middle Aged; Movement Disorders; Parkinson Disease

Two patients, ages 66 and 72, with complications of chronic levodopa therapy (random fluctuations, end of dose deterioration and dyskinesias) who were treated with Lisuride by means of a portable subcutaneous infusion pump are reported. Results obtained show significant improvement in disability through a net increase in the number of hours spent "on". Dyskinesias remained unmodified. Limiting psychiatric side effects were observed in one of the patients. Practical and technical aspects of the management of this therapeutic method are discussed.

Topics: Aged; Drug Administration Schedule; Drug Eruptions; Drug Therapy, Combination; Dyskinesia, Drug-Induced; Ergolines; Humans; Levodopa; Lisuride; Mental Disorders; Parkinson Disease

In rats with a unilateral lesion of the nigrostriatal dopaminergic pathway, the ipsilateral rotation produced by the enhanced actions of endogenous dopamine (DA) on the nonlesioned side, induced by either the DA-releasing drug amphetamine or the DA uptake inhibitor GBR 13069, was blocked effectively by pretreatment with either the selective D1 DA receptor antagonist, SCH 23390, or the D2 selective antagonist, haloperidol. In contrast, contralateral rotation produced by apomorphine or I-dihydroxyphenylalanine, which lead to the preferential activation of D1 and D2 receptors on the lesioned side, was effectively prevented only when both receptor subtypes were inhibited. The results of these experiments demonstrate that the interaction between D1 and D2 receptors in the lesioned side differs from that in the nonlesioned side. Whereas the simultaneous stimulation of both DA receptor subtypes in the normally innervated basal ganglia is required for the production of turning behavior, the stimulation of either subtype alone in the dopaminergic denervated side can produce rotation. However, the concurrent administration of the D1 agonist, SKF 38393, with the D2 agonist, LY 171555, produced a synergistic effect on contralateral rotation. These results suggest that there is preservation of at least some functional interaction between D1 and D2 receptors in the lesioned basal ganglia but that there may be in addition a mechanism by which the two receptor subtypes can function independently of each other. The unilaterally lesioned rat appears to be a very good model in which to study the interaction between D1 and D2 receptors under conditions of both normal innervation and of DA denervation.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: 2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine; Animals; Basal Ganglia; Benzazepines; Corpus Striatum; Denervation; Dextroamphetamine; Ergolines; Female; Flunarizine; Functional Laterality; Haloperidol; Levodopa; Neural Pathways; Parkinson Disease; Quinpirole; Rats; Rats, Inbred Strains; Receptors, Dopamine; Receptors, Dopamine D1; Receptors, Dopamine D2; Rotation; Substantia Nigra

The continuous dopaminergic stimulation provided by infusion of dopamine agonist drugs, is a very effective strategy to control ON-OFF fluctuation in Parkinson's disease. Lisuride is a potent dopamine agonist drug, very soluble in water and can be administered subcutaneously. Many authors have shown that the subcutaneous infusion of lisuride can control fluctuations when applied in combination with oral levodopa as a 24 hour continuous infusion regimen. In this study, lisuride was given without any other antiparkinsonian medicament and using a 12 hour infusion regimen wherever possible. 13 fluctuating Parkinsonian patients were studied. 6 out of these 13 were satisfactory treated with lisuride alone and the remaining 7 with a combination of Lisuride + oral levodopa. Only in 3 out of 13 patients the 24 hour infusion regimen was required.

Topics: Administration, Oral; Adult; Drug Therapy, Combination; Ergolines; Female; Humans; Infusion Pumps; Levodopa; Lisuride; Male; Middle Aged; Parkinson Disease; Time Factors

On-off fluctuations in longstanding Parkinson's disease initially respond well to a combined drug regime of Levodopa with direct dopamine agonists and L-deprenyl. L-Dopa infusions are efficient, but not applicable for longer use. S.c.-Lisuride-infusions reduce markedly motor-response fluctuations, dystonias and hyperkinesias, but bear the risk of inducing confusion or even psychosis. In patients with coexisting response fluctuations and psychiatric disturbances a therapeutic approach is outlined to preserve still some favourable effects on motor performance avoiding severe psychosis. Side-effects and possible complications of that therapy are discussed as are some further indications for the clinical use of Lisuride in akinetic crisis, the neuroleptic malignant syndrome and in dyskinesias.

Topics: Aged; Dose-Response Relationship, Drug; Ergolines; Female; Humans; Infusion Pumps; Lisuride; Male; Mental Disorders; Middle Aged; Movement; Parkinson Disease

Six parkinsonian patients received a constant subcutaneous infusion of 60 micrograms lisuride per hour in the abdominal region for 2 hours. Plasma levels of the unchanged drug were measured by radio-immunoassay. During infusion, a steady state plasma level of 0.78 +/- 0.19 ng/ml was achieved. After discontinuation of the infusion, concentrations declined with a half-life of 1.4 +/- 0.4 hour. The total clearance of lisuride was 20 +/- 6 ml/min/kg. Due to the low interpatient variability of plasma levels, a good control of clinical effects is to be expected.

Topics: Administration, Oral; Biological Availability; Ergolines; Humans; Infusion Pumps; Infusions, Parenteral; Injections, Intramuscular; Injections, Intravenous; Lisuride; Parkinson Disease; Time Factors

Pleuropulmonary disease has been observed in eight patients with Parkinson's disease treated with bromocriptine or its related compound, mesulergine. The pleuropulmonary changes included pleural effusions, pleural thickening, and parenchymal lung disease. The patients developed symptoms from nine months to four years after starting treatment with bromocriptine that varied in dosage from 22 to 50 mg daily, while the patient receiving mesulergine was taking 6 mg daily. No other cause was found for the pleuropulmonary changes. In six patients the medication was discontinued with subsequent clinical, physiologic, and radiologic improvement. In two patients bromocriptine treatment was continued for one to two years, and in one patient there was further physiologic and radiologic progression of the pleuropulmonary changes. These findings suggest a causal relationship between bromocriptine treatment and pleuropulmonary disease. We recommend a chest roentgenogram and pulmonary function evaluation prior to bromocriptine treatment with follow-up studies if the patient develops respiratory symptoms. Physicians prescribing bromocriptine should be aware of this side effect to ensure early recognition and prompt withdrawal of bromocriptine therapy.

Topics: Aged; Antiparkinson Agents; Bromocriptine; Ergolines; Humans; Lung Diseases; Male; Middle Aged; Parkinson Disease; Pleural Diseases; Radiography

L-Dopa is still the most effective drug for the treatment of Parkinson's Disease, but after 5 years or more of therapy fluctuations in motor performance and abnormal involuntary movements commonly appear. Continuous intravenous infusions of L-Dopa abolish or strikingly reduce such fluctuations. Unfortunately, this is not suitable for daily treatment because of the low solubility of L-Dopa. Lisuride is a potent dopamine agonist and is very soluble in water. In this study the clinical effects of L-Dopa and lisuride continuous intravenous infusions were compared in a group of 20 fluctuating parkinsonian patients. L-Dopa controlled fluctuations in almost all the subjects, whereas only seven patients were continuously mobile while taking lisuride. Another seven patients showed a fluctuating response and the remaining six did not satisfactorily respond to lisuride. Dyskinesias were present in all patients during "on" phases, with both levodopa and lisuride treatment.

Topics: Adult; Drug Administration Schedule; Ergolines; Female; Humans; Infusions, Intravenous; Levodopa; Lisuride; Male; Middle Aged; Motor Skills; Parkinson Disease

Topics: Adult; Ergolines; Female; Humans; Infusions, Intravenous; Levodopa; Lisuride; Male; Middle Aged; Parkinson Disease

Lisuride at a mean daily dose of 3 mg was given to 48 patients with idiopathic Parkinson's disease. Twenty received lisuride alone (Group A) and 36 received lisuride + L-Dopa + peripheral decarboxylase inhibitors (Group B). Dropouts were due primarily to lack of efficacy in Group A patients and to mental side effects in Group B patients. The patients who remained in the study for the full 4 years showed distinct improvement, which was maintained. Group A patients did not have the on-off phenomenon or abnormal involuntary movements.

Topics: Adult; Aged; Ergolines; Female; Follow-Up Studies; Humans; Levodopa; Lisuride; Male; Middle Aged; Parkinson Disease; Time Factors

Topics: Antiparkinson Agents; Bromocriptine; Disability Evaluation; Drug Therapy, Combination; Ergolines; Humans; Levodopa; Lisuride; Long-Term Care; Parkinson Disease; Pergolide; Receptors, Dopamine

Lisuride, a semisynthetic dopaminergic ergot derivative, was administered in 34 patients with Parkinson's disease (mean age 67.5 years, average duration of illness 7.1 years, mostly stage IV) in an average oral dosage of 1.2 to 1.5 mg (range 0.4 to 3.0 mg) in addition to basic treatment with levodopa and decarboxylase inhibitor. Duration of combined treatment was 3 to 44 months. Daily dose of levodopa could be reduced by 13 to 34%. In the short-term group (3 months) the total disability score improved by 50%, and in the long-term group (up to 44 months) by 46%, with improvement of rigidity, tremor, speech and repeated movements, less of bradykinesia. Similar to treatment with dopamine agonists, after 18 to 24 months, despite increased dosage of levodopa, a slight increase of some clinical features of parkinsonism, particularly bradykinesia and gait disorders, were observed. Daily fluctuation and on-off symptoms often improved in intensity, but were eliminated only in a small number of patients. Discontinuation of lisuride due to adverse effects was necessary in 17.6%. Often, however, preexisting adverse effects of levodopa therapy, particularly psychiatric complications, responded favorably. Lisuride is a new effective agent in the combination treatment of advanced stages of parkinsonism.

Topics: Adult; Aged; Aged, 80 and over; Carboxy-Lyases; Drug Therapy, Combination; Ergolines; Female; Humans; Levodopa; Lisuride; Long-Term Care; Male; Middle Aged; Parkinson Disease

Quinpirole hydrochloride, a putative dopamine agonist, was investigated in animal models of central dopaminergic activity, to evaluate its possible role in the treatment of Parkinson's disease. The drug induced stereotyped sniffing in rats but, unlike apomorphine, did not produce a maximal behavioural response (stereotyped gnawing). Pretreatment with neuroleptics blocked the stereotypy induced by quinpirole. Quinpirole reversed the effects of reserpine and alpha-methyl-paratyrosine, caused dose-dependent contralateral rotations in rats with unilateral lesions of the substantia nigra induced by 6-hydroxydopamine and induced vomiting in dogs. Small doses of quinpirole decreased locomotor activity, an effect presumably mediated by pre-synaptic autoreceptors. Quinpirole bound to D2 dopamine receptors in the striatum of the rat. The chronic injection of both subthreshold and suprathreshold doses, failed to induce behavioral supersensitivity. These data indicate that quinpirole can stimulate central dopaminergic receptors, and that it is a partial agonist with direct-acting properties. Quinpirole differs from other dopaminergic drugs and may be useful for the therapy of Parkinson's disease.

Topics: Animals; Benzazepines; Corpus Striatum; Dogs; Dose-Response Relationship, Drug; Ergolines; Grooming; Haloperidol; Male; Motor Activity; Parkinson Disease; Quinpirole; Rats; Rats, Inbred Strains; Spiperone; Stereotyped Behavior; Sulpiride

The motor effects of direct agonists which act selectively on certain dopamine receptors were studied in monkeys rendered hemiparkinsonian by unilateral intracarotid injection of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). The D-2 dopamine agonist, LY 171555, but not the D-1 agonist, SKF 38393, reduced parkinsonian signs and induced rotation away from the side of the nigral lesion. When administered together, SKF 38393 diminished the LY 171555-induced turning in a dose-dependent manner. A selective D-1 antagonist, SCH 23390, induced mild and brief rotation when administered alone. These results suggest that D-2 receptor stimulation is necessary to ameliorate parkinsonism, but that pharmacologic manipulation of both D-1 and D-2 receptors may be required for an optimal therapeutic response.

Topics: 2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine; Animals; Benzazepines; Biomechanical Phenomena; Dopamine; Dose-Response Relationship, Drug; Ergolines; Female; Macaca fascicularis; Male; Movement Disorders; Parkinson Disease; Quinpirole; Rotation

Terguride, an analogue of lisuride, decreased locomotor activity, produced cataplexy, and blocked apomorphine-induced stereotypic behavior. It did not induce stereotypies in rodents or emesis in dogs. However, in rats with unilateral 6-hydroxydopamine lesions of the substantia nigra, terguride produced contralateral rotation. Terguride bound to D-2 striatal dopamine receptors. Terguride has both agonist and antagonist actions at striatal dopamine receptors, but chronic administration did not produce behavioral supersensitivity. These pharmacologic properties differ from those of other antiparkinsonian agents; terguride may be effective for the chronic treatment of Parkinson's disease.

Topics: Amphetamine; Animals; Apomorphine; Behavior, Animal; Brain; Disease Models, Animal; Ergolines; Levodopa; Lisuride; Male; Motor Activity; Parkinson Disease; Rats; Rats, Inbred Strains; Receptors, Dopamine; Stereotyped Behavior

Topics: Coronary Vasospasm; Electrocardiography; Ergolines; Humans; Injections, Intravenous; Lisuride; Male; Middle Aged; Parkinson Disease

Topics: Aged; Ergolines; Humans; Lisuride; Male; Middle Aged; Parkinson Disease

Seventeen hitherto untreated patients with mild Parkinson's disease were given the dopamine agonists mesulergine or pergolide. Of the 10 patients who received pergolide (mean dosage 3.7 mg/day) five failed to improve, four showed slight improvement and one gained moderate benefit. Of the seven patients who received mesulergine (mean dose 6.4 mg/day) three patients derived no benefit, two slight benefit and two moderate benefit. The incidence of adverse side-effects was high with both drugs despite the use of a peripheral dopamine receptor antagonist, domperidone, when required. These results are less encouraging than those reported from other centres both in respect of response rate and the severity of unwanted effects.

Topics: Aged; Antiparkinson Agents; Domperidone; Ergolines; Female; Humans; Male; Parkinson Disease; Pergolide

Lisuride was investigated for therapeutic effects in 19 patients with advanced Parkinson disease, no longer satisfactorily responding to routine L-Dopa therapy. The patients were treated with oral Lisuride (0.6-2.5 mg/die) and L-Dopa. The follow-up was at least 6 months. We noted a significant improvement on the Webster Rating Scale at 1st, 3rd and 6th months. Disability and on-off phenomen were reduced. Side effects were few. Lisuride is a valuable tool in this type of patient.

Topics: Adult; Aged; Dose-Response Relationship, Drug; Drug Therapy, Combination; Ergolines; Follow-Up Studies; Humans; Levodopa; Lisuride; Middle Aged; Parkinson Disease

The semisynthetic lisuride derivative transdihydrolisuride (terguride, TDHL) is an effective antiparkinsonian drug. In animals, TDHL appears to possess mixed dopamine agonist-antagonist effects, but this may not be the case in man. Single doses of TDHL were given to 21 subjects with parkinsonism. Overall, TDHL 0.25-0.5 mg caused dose-related improvement in parkinsonism for periods of up to 6 h, although 8 of 21 subjects showed no improvement or deterioration with TDHL 0.5-1 mg. In three patients with levodopa-induced psychosis, the addition of TDHL 0.75 mg daily for 5-10 days did not alter the psychotic state. In three subjects with levodopa-induced dyskinesias, the addition of TDHL 0.75 mg daily for 14 days resulted in a slight increase in the severity of involuntary movements. Side-effects of TDHL, sickness and hypotension, were similar to those observed with levodopa. Transdihydrolisuride caused prolonged inhibition of prolactin release, but unlike levodopa did not elevate plasma growth hormone levels. Additionally, TDHL did cause considerable sedation. These results may be due to combined effects of TDHL on nondopamine as well as dopamine neurotransmitter systems, rather than to partial or incomplete dopamine agonist effects.

Topics: Aged; Blood Pressure; Ergolines; Female; Humans; Levodopa; Lisuride; Male; Middle Aged; Movement Disorders; Nausea; Parkinson Disease; Psychoses, Substance-Induced

Topics: Adult; Aged; Ergolines; Female; Humans; Infusion Pumps; Infusions, Intravenous; Lisuride; Male; Middle Aged; Motor Skills; Parkinson Disease

Topics: Aged; Aged, 80 and over; Dose-Response Relationship, Drug; Ergolines; Female; Humans; Levodopa; Lisuride; Male; Middle Aged; Motor Skills; Parkinson Disease

In an open trial, 15 patients with PD (mostly stage V) were treated with the partial DA agonist, terguride, a derivative of lisuride. To the basic therapy, consisting of L-dopa plus benserazide and amantadine, a slowly increasing dosage of TDHL up to a maximum of 1.5 mg/day t.i.d. was added. There were 3 drop-outs; 12 patients completed the trial which lasted for 12 weeks. At this time a significant improvement in total score, bradykinesia, and functional score was seen, as well as a marked improvement in tremors score in the patients who showed this symptom (Columbia Rating Scale). As side-effects, dyskinesias occurred in two patients, psychotic symptoms in one, and marked orthostatic symptoms in one patient. No significant differences before and after 12 weeks TDHL treatment were found in the concentrations of noradrenaline, adrenaline, serotonin, and 5-hydroxy-indole-acetic-acid in plasma. It is concluded that TDHL is effective even in advanced stages of PD, and it is speculated that partial DA agonists may become important in the treatment of PD and might possibly have an advantage over "classical" DA agonists.

Topics: Aged; Aged, 80 and over; Ergolines; Female; Humans; Lisuride; Male; Motor Skills; Parkinson Disease

Intravenous levodopa or lisuride infusions can successfully reduce daily motor fluctuations in Parkinson's disease, which indicates adequate striatal dopaminergic mechanisms even in severe cases. In 3 patients who received continuous subcutaneous administration of lisuride, by means of a portable mini-infusion pump, in addition to oral levodopa plus decarboxylase inhibitor, mobility improved considerably and "off" periods were reduced or abolished. This response was maintained for 4 to 7 months without toxic side-effects, but increased dyskinetic movements were observed. All 3 patients were discharged and have been able to live independently during the months on treatment. These results suggest that continuous dopaminergic stimulation with the use of a portable delivery system can be a practical therapeutic tool in parkinsonian patients with complicated motor fluctuations.

Topics: Ergolines; Female; Humans; Infusions, Parenteral; Injections, Subcutaneous; Lisuride; Male; Motor Activity; Movement Disorders; Parkinson Disease; Time Factors

Topics: Adult; Aged; Ergolines; Humans; Infusions, Parenteral; Lisuride; Male; Middle Aged; Parkinson Disease

Topics: Drug Administration Schedule; Drug Implants; Ergolines; Humans; Injections, Subcutaneous; Lisuride; Parkinson Disease

Topics: Adult; Dose-Response Relationship, Drug; Drug Evaluation; Drug Therapy, Combination; Ergolines; Female; Humans; Infusions, Parenteral; Levodopa; Lisuride; Male; Middle Aged; Parkinson Disease

Topics: Drug Therapy, Combination; Ergolines; Humans; Infusions, Parenteral; Levodopa; Lisuride; Parkinson Disease; Psychoses, Substance-Induced

Topics: Ergolines; Hallucinations; Humans; Lisuride; Paranoid Disorders; Parkinson Disease

Topics: 2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine; Animals; Benzazepines; Ergolines; Humans; Motor Activity; Parkinson Disease; Quinpirole; Receptors, Dopamine; Receptors, Dopamine D1; Receptors, Dopamine D2

Fluctuations in motor performances are the major problem in the longterm management of Parkinson's disease. In this study the clinical effects of L-dopa intravenous infusion were evaluated in 18 parkinsonian patients with fluctuations. 14 out of these were given Lisuride intravenous infusion in a following study. Lisuride is a potent dopamine agonist and it is highly soluble in water. The results obtained with L-dopa were very good and we found a close correlation between oral and intravenous dosage. The dosage of L-dopa infusion ranged between 360-1,250 mg for 12 hours. Lisuride proved to be able to give prolonged mobile state in 8 patients out of 14. The other 6 patients showed a different response to the drug. The dosage used ranged between 0.6 and 2.4 mg per day. No severe side-effects were observed during both studies except for nausea and vomiting occurring during Lisuride infusion.

Topics: Administration, Oral; Adult; Aged; Carbidopa; Domperidone; Ergolines; Female; Humans; Infusions, Intravenous; Levodopa; Lisuride; Male; Middle Aged; Movement Disorders; Parkinson Disease

Four patients with severe Parkinson's disease were given a trial of lisuride. Two patients responded well, but the other 2 developed psychiatric complications which seemed to be a major limiting factor in the use of the drug. Otherwise, lisuride could be useful in difficult Parkinsonian patients who have a diminished response to levodopa.

Topics: Adult; Ergolines; Female; Humans; Lisuride; Male; Middle Aged; Parkinson Disease

We report the clinical course of 35 patients with Parkinson's disease who experienced an initially favorable response to pergolide and who were taking the drug for at least 6 months. The duration of pergolide treatment was 6-50 (25 +/- 16 SD) months. Of the 14 patients who remained on pergolide for over 2 years, 12 remained less disabled for 26 +/- 17 SD months, seven enjoyed increased "on" time for 39 +/- 8 SD months, and nine had a lower Hoehn-Yahr stage for 25 +/- 17 SD months. Pergolide was discontinued after 5-39 months in eight patients; six patients then deteriorated. Pergolide can remain efficacious in the treatment of Parkinson's disease for up to 50 months.

Topics: Aged; Antiparkinson Agents; Ergolines; Female; Humans; Male; Middle Aged; Parkinson Disease; Pergolide; Time Factors

The long-term effects of mesulergine, a new drug with dopamine agonistic properties, were studied in 28 patients with Parkinson's disease. In 18 patients with late side effects of levodopa, the addition of mesulergine (10.9 mg/day) induced significant decreases in the global (-48%), rigidity (-62%), and akinesia (-37%) scores. The drug was found to be very effective on tremor (-71%). Mesulergine was useful in cases of inefficacy of levodopa alone or persistent intolerable side effects. The decrease in levodopa dose and the addition of mesulergine permitted a significant reduction in dyskinesia. Used as sole therapeutic agent (10.9 mg/day), mesulergine was found to be active on tremor and rigidity scores but not on akinesia or global scores. Mesulergine induced few side effects. These results show the antiparkinsonian properties of mesulergine that seem to be of significant therapeutic value in patients with tremor or in combination with levodopa.

Topics: Adult; Aged; Antiparkinson Agents; Drug Administration Schedule; Ergolines; Female; Humans; Levodopa; Male; Middle Aged; Movement Disorders; Parkinson Disease; Time Factors

Eleven patients who presented with predystonic syndrome later developed pure dystonic syndromes and later developed parkinsonism. This suggests that dystonic syndromes can be the precursor to a mixed syndrome including both dystonia and parkinsonism. While the parkinsonian features in such patients respond to either levodopa or direct-acting agonists, levodopa often exacerbates the underlying dystonia. Direct acting agonists appear to be less liable to do this.

Topics: Adult; Bromocriptine; Carbidopa; Dystonia; Ergolines; Humans; Levodopa; Meige Syndrome; Middle Aged; Parkinson Disease; Pergolide; Torticollis

Seventeen lisuride infusions were given to 12 patients with Parkinson's disease who showed daily oscillations in motor performance. The mean lisuride dose given in continuous intravenous infusion was 0.59 mg (range, 0.3 to 1.0 mg) during a mean period of 9.0 hours (range, 5 to 12 hours). A significant reduction in the number of hours "off" was obtained in all patients. Additional oral levodopa was necessary to maintain normal mobility throughout the infusions. Severe hypotension occurred in 2 patients which required termination of the infusions. Five patients experienced nausea, sweating, and malaise but this did not necessitate interruption of the infusions. Lisuride appears to be one of the best available dopamine agonists for continuous dopaminergic stimulation.

Topics: Adult; Aged; Domperidone; Drug Therapy, Combination; Dyskinesia, Drug-Induced; Ergolines; Female; Humans; Injections, Intravenous; Levodopa; Lisuride; Male; Middle Aged; Parkinson Disease

The activity of pergolide, a clavine ergolene, and mesulergine, an 8-alpha amino ergoline, were compared in 18 patients with advanced Parkinson's disease. All of the patients were no longer satisfactorily responding to levodopa, and 16 patients had diurnal oscillations in performance. Pergolide, mean dose 2.7 mg, when added to levodopa resulted in a significant (27%) decrease in Parkinson disability and a significant improvement in diurnal oscillations in performance (136% increase in hours 'on'). Twelve of the 18 patients (67%) improved. However, after 2 years pergolide was discontinued in all of the patients because of decreased efficacy, adverse effects, or both. At this time, mesulergine, mean dose 9.3 mg., when added to levodopa resulted in a significant (37%) decrease in Parkinson disability and a significant improvement in diurnal oscillations (61% increase in hours 'on'). Twelve of the 18 patients (67%) improved. Adverse effects (dyskinesias) were less with mesulergine than with pergolide. A declining response to one agonist does not preclude a successful response to another agonist of a different class.

Topics: Aged; Antiparkinson Agents; Drug Therapy, Combination; Dyskinesia, Drug-Induced; Ergolines; Humans; Levodopa; Middle Aged; Parkinson Disease; Pergolide

Topics: Aged; Bromocriptine; Dopamine; Ergolines; Humans; Levodopa; Lisuride; Parkinson Disease; Pergolide; Piribedil

Pergolide is thought to stimulate both D1 and D2 dopaminergic receptors. Its effects on Parkinson's disease were evaluated in an open trial, using clinical assessment scales and objective tests. Nine patients had previously been treated with L-dopa, but the drug had either gradually lost its effectiveness or produced invalidating side-effects. Pergolide in doses of 2 mg per day considerably and durably improved the parkinsonian symptoms and enabled the patients to reduce L-dopa dosage by about 50%. Dyskinesia and "on-off" phenomena partially regressed. Significant improvement was also observed in 3 of 4 patients with Parkinson's disease who had not previously received L-dopa. The side-effects of pergolide were fairly frequent in both groups, but they were relatively mild and reversible.

Topics: Aged; Antiparkinson Agents; Drug Therapy, Combination; Ergolines; Humans; Levodopa; Parkinson Disease; Pergolide

Topics: Adult; Aged; Drug Evaluation; Ergolines; Female; Humans; Lisuride; Male; Middle Aged; Parkinson Disease; Time Factors

Topics: Ergolines; Humans; Levodopa; Parasympatholytics; Parkinson Disease; Phenethylamines; Selegiline

We treated 12 patients with Parkinson's disease with an 8-alpha-amino-ergoline derivative, CU 32-085. The daily dosage was increased slowly to 7 mg over 9 weeks, held constant for 8 weeks, then replaced by placebo for 4 weeks. We found statistically significant benefit over placebo or pretreatment disability. The effect was seen at daily dosages of 3 mg or more. Its magnitude was dose related. There was no further improvement on prolonged treatment with 7 mg daily. Side effects were mild and did not require interruption of treatment.

Topics: Adult; Aged; Ergolines; Female; Humans; Male; Middle Aged; Neurologic Examination; Parkinson Disease; Psychomotor Performance

In 18 patients with Parkinson's disease, the effects of pergolide after 28 months of treatment were compared with the response after the initial 10-week therapy. At a mean 3.2-mg daily dose of pergolide, the daily dose of levodopa was still 33% lower than at the onset of pergolide therapy. The mean motor disability score, which decreased by 65% during the first 10 weeks of pergolide, was still decreased by 42% after 28 months. In the 12 patients with on-off effect, the percent time on increased 117% during the first phase of the study and was still increased 63% after more than 2 years of pergolide therapy. Sudden freezing episodes became the most disabling problem in the majority of patients. "Down-regulation" of dopamine receptors may contribute, but it is not the only cause of loss of responsiveness to pergolide.

Topics: Adult; Aged; Disability Evaluation; Ergolines; Female; Follow-Up Studies; Humans; Levodopa; Male; Middle Aged; Parkinson Disease; Pergolide; Time Factors

In a previous study, the sleep pattern in Parkinson's disease patients was found to be altered. The disturbance consisted of a "light fragmented sleep pattern" with increased muscle activity. Using a combined polysomnographic and electromyographic recording technique, we found that a reversal of the light fragmented sleep pattern and normalization of muscle activity during sleep occurred after clinical improvement with dopaminergic treatment. The effect of dopaminergic treatment on sleep disturbance was analyzed. There is an intimate relationship between sleep pattern and the normalization of sleep muscle activity produced by dopaminergic agents.

Topics: Aged; Carbidopa; Drug Combinations; Ergolines; Female; Humans; Levodopa; Male; Middle Aged; Parkinson Disease; Pergolide; Receptors, Dopamine; Sleep Wake Disorders; Sleep, REM

We used pergolide to treat 10 patients with idiopathic Parkinson's disease who had first responded to, and then failed, bromocriptine therapy. At the end of 5 years, patients had improved when compared with study entry. Peak efficacy, equal with both drugs, was seen at 12 months. After a mean treatment of 29 months, bromocriptine was no longer effective, but pergolide was still beneficial.

Topics: Aged; Antiparkinson Agents; Bromocriptine; Drug Therapy, Combination; Dyskinesia, Drug-Induced; Dystonia; Ergolines; Female; Hallucinations; Humans; Levodopa; Male; Middle Aged; Nausea; Outcome and Process Assessment, Health Care; Parkinson Disease; Pergolide; Time Factors

In 15 patients (8 men, 7 women), aged 44-81 years, with idiopathic parkinsonism, the effects of mesulergine (CU 32-085) were observed for up to 3 years. Of these patients, four had been without previous levodopa treatment, five had been on levodopa/decarboxylase inhibitor for 6.4 years and six patients had been on levodopa/decarboxylase inhibitor and bromocriptine for a period of 7.5 years. Mesulergine proved to be effective in all three groups of patients and for each main symptom of the disease. Rigidity and tremor showed a better response than akinesia. A decline in efficacy could be observed after 18 months of treatment. By increasing the levodopa dosage, the worsening of the symptomatology could be reduced again and after 3 years patients were slightly better off than before the introduction of mesulergine. Fine motor performance showed a longer-lasting improvement than walking, which was affected by an increase of freezing. Mesulergine was not fully sufficient when given in monotherapy and the levodopa saving effect was only temporary. Parallel with the decline in the therapeutic response as assessed by the rating scales, there was a worsening in the on/off symptomatology. The on/off symptoms, evaluated by patients themselves, had shown very small or no improvement at the beginning of mesulergine administration, contrasting with the findings reflected in the assessment scales. The most frequent side-effects were hallucinations and dyskinesias. Orthostatic hypotension did not prove a problem. Dyskinesias were not seen during monotherapy with mesulergine in de novo patients.

Topics: Adult; Aged; Antiparkinson Agents; Bromocriptine; Drug Therapy, Combination; Ergolines; Female; Humans; Levodopa; Male; Middle Aged; Parkinson Disease

Pergolide, an experimental dopamine agonist, was administered to 56 patients with advanced Parkinson disease who were no longer satisfactorily responding to levodopa, including 45 patients with diurnal oscillations in performance: "on-off" phenomena. Lisuride, an experimental dopamine agonist was administered to 63 patients with advanced Parkinson disease. Pergolide or lisuride, when added to levodopa, resulted in a significant decrease in disability in both the "on" and the "off" period, and an increase in the number of hours in which patients were "on". Forty-one of 56 patients (73%) improved on Pergolide. Thirty-seven of 63 patients (59%) improved on lisuride. Mean dose of pergolide was 2.5 mg. (range 0.2 to 10.0 mg.). Mean dose of lisuride was 2.6 mg. (range 0.2 to 5.0 mg.). Pergolide was discontinued in 18 patients because of adverse effects, including an organic confusional syndrome (six patients), dyskinesias (four patients) and cardiovascular abnormalities (three patients). Lisuride was discontinued in 26 patients because of adverse effects, including an organic confusional syndrome (15 patients), dyskinesias (five patients) and vasospasm (two patients). Pergolide was discontinued in nine patients and lisuride in 12 because of a lack of effect or a declining effect. Both drugs are equally useful in patients with advanced Parkinson disease.

Topics: Adult; Aged; Alanine Transaminase; Antiparkinson Agents; Aspartate Aminotransferases; Cognition Disorders; Dopamine; Drug Evaluation; Ergolines; Female; Humans; Lisuride; Male; Middle Aged; Nausea; Neurologic Examination; Parkinson Disease; Pergolide; Vasculitis

The blink reflex presents a tendency to habituation (a gradual diminution of the amplitude of the response during repetitive stimulation). Electromyographic analysis of this reflex makes it possible to quantify this phenomenon. A lack of the habituation of the blink reflex is a typical feature of Parkinson disease. L-Dopa and amantadine, but not anticholinergic drugs, are able to partly reverse these abnormalities in blink reflex habituation to a normal pattern. Lisuride, a dopamine agonist with serotoninergic activity, has been recently proposed as antiparkinsonian agent. In our study we observed that lisuride has a positive effect on blink reflex habituation in Parkinson disease. A good correlation between the improvement of this electrophysiological parameter and clinical akinesia was seen. Mechanisms underlying the therapeutic effect of lisuride are complex, but this drug usually has a postsynaptic effect on D2 receptors. Our data suggest that these receptors play an important role in blink reflex habituation.

Topics: Adult; Aged; Amantadine; Blinking; Electrophysiology; Ergolines; Habituation, Psychophysiologic; Humans; Levodopa; Lisuride; Male; Middle Aged; Parkinson Disease

Topics: Adult; Aged; Bromocriptine; Drug Evaluation; Drug Therapy, Combination; Dyskinesia, Drug-Induced; Ergolines; Female; Humans; Levodopa; Lisuride; Male; Middle Aged; Parkinson Disease

Topics: Animals; Antiparkinson Agents; Corpus Striatum; Ergolines; In Vitro Techniques; Male; Parkinson Disease; Pergolide; Radioligand Assay; Rats; Rats, Inbred Strains; Receptors, Dopamine

Terguride, a mixed agonist-antagonist of central dopamine receptors, was administered to eight patients with Parkinson's Disease. The clinical symptomatology of all patients improved significantly. The maximum neurological effect of terguride was noted at the highest daily dose (1.2 mg) after 21 days of treatment in all subjects, with a statistically significant average of 50.6% neurological improvement on the Webster scale in respect to admission. All single scores of the Webster scale decreased significantly: swing of the arms, facial expression, bradikinesia, rigidity and gait, particularly. No significant adverse reactions were observed during treatment. Our study in drug-free parkinsonian patients demonstrated that terguride is able to improve the neurological symptoms similar to DA agonists, but without their typical side effects.

Topics: Aged; Disability Evaluation; Dopamine; Drug Evaluation; Ergolines; Female; Humans; Lisuride; Male; Middle Aged; Nervous System; Parkinson Disease

The therapeutic use of dopamine agonists for Parkinson's disease, clinical guidelines for their introduction into antiparkinson regimens, and their range of adverse effects are reviewed. The role played by the dopaminomimetic ergots in elucidating dopamine receptor function, and laboratory methods that identify dopamine agonists, are also examined.

Topics: Antiparkinson Agents; Apomorphine; Brain; Bromocriptine; Ergolines; Ergot Alkaloids; Humans; Levodopa; Lisuride; Neurons; Parkinson Disease; Pergolide; Piribedil; Receptors, Dopamine

Dopamine agonists have yielded two important advances to our understanding of the basal ganglia--they have facilitated the subdivision of different classes of dopamine receptors, and they have established the fact that important dopaminergic effects can be achieved by activation of dopamine receptors in a manner that is unrelated to anoxal impulse traffic in dopaminergic neurons--a phenomenon similar in its diffuse, slow, characteristics to an endocrine effect. The tangible clinical benefit of dopamine agonists has been evident in patients with prominent dyskinesia or wearing off reactions. It is possible that earlier use of agonists, in low doses combined with similarly low doses of levodopa, may improve the long term treatment of Parkinson's disease, but as yet there is no firm evidence. In the future, we can expect to see agonists with more prolonged effects, deriving from the formation of active metabolites. We can also hope to gain further insight into the correlations between the various animal models of dopaminomimetic activity, and specific aspects of drug efficacy and toxicity in parkinsonian patients. Such information should allow the design of improved pharmacotherapy.

Topics: Bromocriptine; Dopamine; Drug Therapy, Combination; Ergolines; Ergot Alkaloids; Humans; Levodopa; Lisuride; Parkinson Disease; Pergolide; Receptors, Dopamine; Receptors, Dopamine D1; Receptors, Dopamine D2

Topics: Antiparkinson Agents; Ergolines; Humans; Levodopa; Parasympatholytics; Parkinson Disease

A total of 26 patients were treated with pergolide mesylate, a semi-synthetic ergot derivative with the property of direct dopamine activity. Of these patients, 18 suffered from late failure of L-dopa, while the remaining 8 had never before been treated with L-dopa. The aim of the trial was to study the activity of pergolide, either by giving it to untreated patients or by reducing as much as possible the L-dopa given in patients with parkinsonism. Adverse effects and failure rate were reduced by slowly increasing the daily dosage, by giving considerable dose flexibility whenever side-effects were manifest, and by the use of relatively low doses (mean of 3.8 mg in the L-dopa-group and 2.9 in the other group). At present, from 26 patients, 13 (50%) still remain in the study for an average treatment period of 16 months (3 weeks to 25 months for the group as a whole). All patients experienced a beneficial effect from pergolide, especially during the first months of treatment, in selfcare, rigidity, gait and automatic movements. Slight or no improvement was seen in tremor, speech and posture. The most frequent side-effects were nausea and vomiting (in the initial phase of the treatment), insomnia and psychotoxic reactions (mostly periods of confusion accompanied by visual hallucinations and paranoid illusions). The study indicated that pergolide mesylate is a useful additive for treatment of parkinsonism, but special attention should be paid to the important psychotoxic adverse effects that may appear, even at a low dose.

Topics: Aged; Ergolines; Female; Humans; Levodopa; Male; Middle Aged; Parkinson Disease; Pergolide

Pergolide mesylate, a long-acting dopamine agonist, is effective in treating Parkinson's disease. Behavioral change is said to be one adverse effect. We therefore studied 19 parkinsonian patients with neuropsychological tests before and after initiating pergolide therapy. Intellectual and behavioral changes were also monitored clinically for up to 2 years. There was no decline in performance on the neuropsychological tests. Six patients had transient psychiatric or intellectual changes that were controlled by reducing drug dosage. These changes were similar to those seen with other dopamine agonists.

Topics: Adult; Aged; Behavior; Ergolines; Female; Humans; Male; Middle Aged; Nervous System; Parkinson Disease; Pergolide; Psychological Tests

We studied the effect of pergolide (combined with levodopa) in 17 patients with Parkinson's disease, including 15 with "wearing off" or on-off phenomena, who had been taking pergolide for at least 2 years. Mean duration of the study was 27.8 months. All 17 patients improved initially, but the improvement later faded. Mean disability score, which decreased initially by 60% (significant), was decreased only by 20% after 2 years (not significant). Wearing off and on-off phenomena, which improved initially, became prominent again. Four patients lost all the improvement, nine patients lost much of the improvement, and four maintained much of the improvement. Mean dose of pergolide was 2.2 mg (range, 0.8 to 5.0 mg).

Topics: Aged; Dose-Response Relationship, Drug; Drug Therapy, Combination; Ergolines; Female; Humans; Levodopa; Male; Middle Aged; Parkinson Disease; Pergolide; Time Factors

Topics: Bromocriptine; Ergolines; Humans; Parkinson Disease; Pergolide

Pergolide, a long-acting central dopamine agonist, was used as monotherapy in 16 parkinsonian patients. A mean daily dose of 6.3 mg resulted in 73% improvement of parkinsonian disability. Clinical improvement after acute administration of one dose of pergolide was similar to that observed after levodopa plus a peripheral decarboxylase inhibitor but at a dose 100 times lower (2.2 mg and 200 mg, respectively). The effect lasted twice as long (5 1/2 hours and 2 1/4 hours, respectively).

Topics: Adult; Aged; Carbidopa; Ergolines; Female; Humans; Levodopa; Male; Middle Aged; Parkinson Disease; Pergolide

Topics: Ergolines; Female; Humans; Male; Middle Aged; Parkinson Disease

Refractory response to dopamine (DA) agonists is a common problem in the treatment of Parkinson's disease. In rats with unilateral lesions of the substantia nigra, denervation induced significant increases in striatal 3(H)-spiperone binding sites ipsilateral to the lesion. Chronic treatment with levodopa or with pergolide mesylate significantly decreased the number of 3(H)-spiperone striatal binding sites. Agonist-induced decreases were approximately equivalent in intact and denervated striata and did not appear to be affected by lesions. These results suggest that the poor response to DA agonist in certain parkinsonian patients with chronic drug exposure may be mediated by drug-induced DA receptor down-regulation.

Topics: Animals; Corpus Striatum; Denervation; Ergolines; Levodopa; Male; Parkinson Disease; Pergolide; Rats; Rats, Inbred Strains; Receptors, Dopamine

Topics: Aged; Antiparkinson Agents; Ergolines; Female; Humans; Hypotension; Male; Middle Aged; Nausea; Pain; Parkinson Disease; Pergolide; Spasm

In a retrospective study, treatment with lisuride was compared to pergolide in 25 patients with advanced PD in whom the response to levodopa had diminished. Sixteen patients had wearing off and/or ON-OFF phenomena. Lisuride or pergolide, when added to levodopa, resulted in comparable and significant decreases in disability in both ON and OFF periods; pergolide resulted in a greater increase in the number of hours in which patients were ON. Adverse reactions were comparable on both drugs. However, patients who developed an adverse reaction on one drug did not necessarily develop the same reaction on the other drug. Both lisuride and pergolide are effective anti-Parkinson drugs.

Topics: Aged; Antiparkinson Agents; Ergolines; Humans; Lisuride; Middle Aged; Parkinson Disease; Pergolide; Retrospective Studies

Topics: Antiparkinson Agents; Domperidone; Ergolines; Humans; Levodopa; Mental Disorders; Parkinson Disease; Parkinson Disease, Postencephalitic; Pergolide

Topics: Adult; Aged; Ergolines; Female; Humans; Hypotension; Lisuride; Male; Mental Disorders; Middle Aged; Nausea; Parkinson Disease; Sleep Wake Disorders; Vertigo; Vomiting

Topics: Aged; Antiparkinson Agents; Bromocriptine; Drug Therapy, Combination; Ergolines; Female; Humans; Levodopa; Male; Middle Aged; Parkinson Disease

Topics: Adult; Aged; Bromocriptine; Carboxy-Lyases; Drug Therapy, Combination; Ergolines; Female; Humans; Levodopa; Lisuride; Male; Middle Aged; Parkinson Disease

Topics: Animals; Basal Ganglia Diseases; Chorea; Corpus Striatum; Dystonia; Ergolines; Female; Humans; Lisuride; Male; Middle Aged; Parkinson Disease; Rats; Syndrome; Torticollis

Topics: Athetosis; Carbidopa; Chorea; Drug Combinations; Drug Evaluation; Drug Therapy, Combination; Ergolines; Humans; Hypotension; Levodopa; Male; Middle Aged; Parkinson Disease; Pergolide

The single and multiple oral dose plasma kinetics of lisuride were followed by a recently developed radioimmunoassay method in 11 patients with Parkinson's disease. A very wide range of plasma drug concentrations resulted from a single dose of 300 micrograms, as reflected in large interindividual differences in peak concentration (0.27 to 3.30 ng/ml) and AUC after the initial dose (43.1 to 617 ng X min/ml). Absorption was rapid, with a mean time to peak of 39 min. Only 0.05% of the dose was excreted unchanged in urine in 24 hr. There was a 110% increase in apparent oral clearance after 2 to 4 wk of treatment.

Topics: Administration, Oral; Aged; Biological Availability; Ergolines; Female; Humans; Kinetics; Lisuride; Male; Middle Aged; Parkinson Disease; Radioimmunoassay

A 71 year old retired printer developed idiopathic Parkinson's disease over a period of 3 years. On account of his worsening condition he was admitted to hospital. Following the interruption of his medication the patient developed an akinetic crisis. A 48 hour polysomnogram recording, repeated five times during hospitalization, showed severe sleep deprivation. Treatment with Pergolide alone was then started; and sleep monitoring showed suppression of REM rebound, REM only appearing when the dose of the drug was reduced. It is suggested that REM rebound phenomena produced by sleep deprivation in a Parkinson's disease patient are suppressed by the effect of the dopaminergic agent Pergolide.

Topics: Aged; Antiparkinson Agents; Electroencephalography; Ergolines; Humans; Male; Parkinson Disease; Pergolide; Sleep Deprivation; Sleep, REM

The antiparkinsonian activity of several dopamine agonists was investigated in an animal model and clinically in parkinsonian patients. The semisynthetic ergoline, pergolide, the partial ergoline, LY 141865 and the 8-alpha-aminoergoline, CU 32-085 were found to be effective antitremor agents in monkeys with ventromedial tegmental lesions. The administration of pergolide or LY 141865 results in a relief of tremor with a concomitant occurrence of severe abnormal involuntary movements, while the administration of CU 32-085 results in a relief of tremor with the occurrence of only minor abnormal involuntary movements. Clinical studies have revealed that pergolide is an effective drug in patients with advanced Parkinson's disease, and it reduces the "on-off" phenomena. The possible regulation of dopamine neurotransmission by the norepinephrine neuronal systems was reviewed. Preliminary data suggest that clonidine may interact with presynaptic dopamine receptors.

Topics: Adrenergic alpha-Agonists; Animals; Dopamine; Ergolines; Haplorhini; Humans; Neurons; Norepinephrine; Parkinson Disease; Pergolide; Quinpirole; Rats

Twenty patients with advanced progressing Parkinson's disease have been treated with the 8-alpha-ergoline CU 32-085 in combination therapy for 3 months. With a mean daily dose of 12.65 mg, CU 32-085 together with levodopa plus a decarboxylase inhibitor produced a significant reduction in akinesia, rigor and tremor. Adverse reactions were rare and mild; in one case the drug was discontinued because of dyskinetic movements. Many of the pre-existing side effects were reduced or eliminated, particularly the involuntary movements and the levodopa response swings. The compound was considered useful in the treatment of advanced, progressing Parkinson's disease.

Topics: Adult; Aged; Amantadine; Antiparkinson Agents; Bromocriptine; Carboxy-Lyases; Drug Therapy, Combination; Ergolines; Female; Humans; Levodopa; Male; Middle Aged; Parasympatholytics; Parkinson Disease

Clinical responses to bromocriptine and three new ergoline derivatives, CM 29-712, CQ 32-084, and CU 32-085, in the treatment of Parkinson's disease were studied in new, non-levodopa-treated parkinsonian patients. All compounds elicited a significant but mostly only mild or moderate antiparkinsonian efficacy which seems to be less than that of levodopa. The therapeutic profile of the dopaminergic agonists studied was similar, and the improvement in tremor was considerably better than that in rigidity and hypokinesia. All of the compounds elicited clinical side effects typical of dopaminergic agonists but differed both quantitatively and qualitatively in certain respects. Fewer side effects, especially reduced blood pressure or the occurrence of postural hypotension, developed during treatment with CU 32-085. It is evident that more effective, specific, and tolerable dopaminergic agonists are needed before they can be considered a primary treatment of Parkinson's disease. At present, the main indications for dopaminergic agonists seem to be a deteriorating response to levodopa and daily fluctuations in performance.

Topics: Blood Pressure; Bromocriptine; Disability Evaluation; Domperidone; Dopamine; Ergolines; Follow-Up Studies; Humans; Levodopa; Parkinson Disease; Pleural Effusion; Receptors, Neurotransmitter; Time Factors

According to the classification scheme of Kebabian and Calne, there are two types of dopamine (DA) receptors: D1 (activation of which causes increased cyclic AMP formation) and D2 (activation of which causes no increment in cyclic AMP). It is not clear what role the different receptors play in mediating motor behavior. Using drugs that act selectively at only one receptor site, we studied the effects of D1 and D2 receptor activation in two different models of parkinsonism--the rotating rat and the reserpinized mouse. Neither the D1 agonist nor the D2 agonist, given alone, could overcome reserpine akinesia, but together they restored locomotor activity. In rats with unilateral nigrostriatal lesions, both drugs induced a rotational response, each with a distinct temporal pattern. Pretreatment with alpha-methyl-paratyrosine (an inhibitor of DA synthesis) led to decrements in the rotational response induced by D2 agonists, but not that induced by D1 agonists. The mechanism by which these DA agonists induce motor activity is different; activation of both types of DA receptors seems to be necessary for normal motor behavior.

Topics: 2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine; Animals; Benzazepines; Disease Models, Animal; Ergolines; Female; Locomotion; Mice; Mice, Inbred Strains; Parkinson Disease; Quinpirole; Rats; Rats, Inbred Strains; Receptors, Dopamine; Reserpine

Topics: Ergolines; Humans; Infusions, Parenteral; Lisuride; Parkinson Disease

Twenty-two patients received pergolide mesylate for Parkinson's disease for one year. Improvement was maximal at six months, but average functional scores were still better at 12 months than at pretreatment evaluation. On-off fluctuations were reduced in severity, and two of 18 patients experienced full resolution. Pergolide is an effective and safe ongoing medication for Parkinson's disease.

Topics: Aged; Ergolines; Female; Humans; Male; Middle Aged; Parkinson Disease; Pergolide

8-alpha-amino-ergoline (CU 32-085) is a dopamine receptor agonist that should have fewer side effects than most other dopamine agonists. We studied the effect of this drug in 19 parkinsonian patients. In untreated or levodopa-treated patients, there was considerable improvement of akinesia, rigidity, and tremor; on-off symptoms also improved in the levodopa-treated patients. In patients pretreated with levodopa/bromocriptine, about half the dose of CU 32-085 was necessary to obtain the same therapeutic results, but there was no further improvement of on-off symptoms. Side effects were less pronounced than with bromocriptine; no circulatory disturbances and no psychotic episodes were observed.

Topics: Activities of Daily Living; Adult; Aged; Antiparkinson Agents; Bromocriptine; Drug Therapy, Combination; Ergolines; Female; Humans; Hypotension, Orthostatic; Levodopa; Male; Middle Aged; Nausea; Parkinson Disease; Psychomotor Performance; Receptors, Dopamine

We used four disability scales to evaluate eight patients with Parkinson's disease who were treated with pergolide mesylate for 1 year. Disability was rated on all four scales by the same neurologist at each of 11 visits. Prior ratings were not available to the examiner, who did not know that the scales themselves were an object of study. Disability scores, converted to percentage improvement relative to baseline, varied considerably between scales; for instance, at 5 months, one showed 13% improvement and another 58%. At 9 months, one showed worsening of 6% and another showed improvement of 34%. The four disability scales clearly measure different aspects of parkinsonism, and comparing results of different studies may not be valid if the disability scales are not the same.

Topics: Drug Evaluation; Ergolines; Humans; Parkinson Disease; Pergolide

Lisuride was compared with bromocriptine in 25 parkinsonian patients in whom the response to levodopa had diminished; 19 had "wearing off," "on-off" phenomena, or both. At the time bromocriptine was added to levodopa, the mean age of the patients was 62.7 years and mean disease duration was 8.9 years. Disability decreased by 34% in the on period and by 20% in the off period, and the number of hours the patients were on increased from 9.6 to 12.8. All these changes were significant (p less than or equal to 0.01 to 0.05). Bromocriptine, however, had to be discontinued in 11 patients because of adverse effects. In the remaining 14 patients, bromocriptine was eventually discontinued because of decreased efficacy. Mean dose of bromocriptine was 55 mg (range, 20 to 100 mg). At the time lisuride was added to levodopa the patients were older (65.4 years), had had the disease longer (11.4 years), and were more disabled. Nonetheless, disability decreased in the on period by 33% and in the off period by 17%, and the number of hours the patients were on increased from 3.9 to 8.9. All these changes were significant (p less than or equal to 0.01 to 0.05). The mean dose of lisuride was 2.8 mg (range, 0.6 to 5.0 mg). Lisuride was discontinued in 8 patients because of adverse effects. Both bromocriptine and lisuride are useful in managing patients with advanced Parkinson disease whose response to levodopa has diminished. While it is presently not possible to state which of the drugs is more effective, ultimately their usage will probably be determined by their relative cost.

Topics: Aged; Bromocriptine; Carbidopa; Drug Therapy, Combination; Ergolines; Humans; Levodopa; Lisuride; Middle Aged; Parkinson Disease

Among 415 patients with parkinsonism, 16 (3.9%) had findings of progressive supranuclear palsy (PSP). This report reviews the clinical features and response to drug therapy in those 16 patients. Anticholinergic drugs failed to benefit any of the 5 patients treated, while presynaptic dopaminergic drugs (Sinemet or amantadine) were beneficial in only 5 of 22 patient trials. Alternatively, dopamine agonists (bromocriptine and pergolide) caused improvement in 9 of 14 patient trials despite the fact that all but 1 of these patients had previously failed to respond to presynaptic dopaminergic drugs. Dopamine agonists such as bromocriptine and pergolide may be useful in some patients with PSP.

Topics: Aged; Bromocriptine; Bulbar Palsy, Progressive; Ergolines; Female; Follow-Up Studies; Humans; Male; Middle Aged; Parkinson Disease; Pergolide

Topics: Aged; Antiparkinson Agents; Drug Evaluation; Drug Resistance; Ergolines; Female; Humans; Levodopa; Lisuride; Male; Middle Aged; Parkinson Disease

Topics: Aged; Disability Evaluation; Dose-Response Relationship, Drug; Ergolines; Humans; Lisuride; Middle Aged; Parkinson Disease; Pergolide; Sleep

The effect of pergolide, a semisynthetic ergot alkaloid, on the cardiovascular system of 40 patients with Parkinson's disease (PD) was evaluated. The mean daily dose of pergolide was 2.4 mg (range, 0.1 to 10 mg). The mean duration of follow-up was 6 months (range, 2 weeks to 20 months). The 40 patients were selected only on the basis of severe PD. All 13 patients in the first part of the study underwent 1 to 5 days of Holter monitoring before starting pergolide. Monitoring was then carried out for an additional period of between 2 and 10 weeks while the patients were on pergolide. Seven of the 13 patients manifested repetitive ventricular rhythms. These were isolated and unassociated with increases in premature ventricular contractions. The dose at which the RVRs occurred was a function of the presence or absence of heart disease. The changes occurred below 3 mg/day in patients with heart disease and above 3 mg/day in patients without heart disease. Pergolide was discontinued in three of the patients with heart disease. It was concluded that pergolide may, in the diseased heart, predispose to RVRs. In the second part of the study, Holter monitoring was carried out only at the discretion of the cardiologist, and five patients were so monitored. None of these patients was rejected from the study. Only one patient (with heart disease) of the 27 patients in the second part of the study experienced an arrhythmia. This consisted of an increase in PVCs on 4 mg/day of pergolide. Pergolide was discontinued. Eight of the 40 patients in these early dose-ranging studies experienced orthostasis, two with syncope, immediately on addition of pergolide (0.1 to 0.4 mg) to levodopa. The orthostasis could be eliminated in all but two patients by reducing or discontinuing levodopa.

Topics: Adult; Aged; Cardiovascular System; Ergolines; Female; Heart Diseases; Heart Ventricles; Humans; Hypotension, Orthostatic; Male; Middle Aged; Myocardial Contraction; Parkinson Disease; Pergolide; Pulse; Sick Sinus Syndrome

Topics: Adult; Aged; Ergolines; Female; Humans; Levodopa; Male; Middle Aged; Parkinson Disease; Pergolide; Respiration Disorders

Treatment with pergolide was compared with bromocriptine in 25 patients, all of whom were also receiving levodopa and in all of whom the response to levodopa had diminished. All 25 patients had "on-off" phenomena. At the time bromocriptine was added to levodopa, the mean age of the patients was 61.8 years, mean duration of disease was 9.0 years, and mean duration of levodopa treatment was 6.1 years. For the group as a whole, disability as determined in the "on" period decreased by 36%, from 28.7 to 18.5; and 11 patients improved at least one stage. Disability as determined in the "off" period decreased by 25%, from 59.5 to 44.4. The number of hours in which patients were "on" increased by 62%, from 7.1 to 11.5. All of these changes were significant (p less than or equal to 0.05). Bromocriptine had to be discontinued in nine patients (eight because of mental changes). In the remaining 16 patients, bromocriptine was eventually discontinued because of diminishing efficacy. Mean dose of bromocriptine was 50 mg (range, 10-100 mg), and mean duration of treatment was 23 months (range, 2-65 months). At the time of their treatment with pergolide, the patients were older, 65.5 years, had the disease longer, 12.7 years, and were more disabled. Nonetheless, for the group as a whole, disability score as determined in the "on" period decreased significantly by 40%, from 43.5 to 26.3, and 14 patients improved at least one stage. Disability as determined in the "off" period decreased significantly by 21%, from 69.0 to 54.8. The number of hours in which patients were "on" increased significantly by 224%, from 3.4 to 11.0 hr. The mean dose of pergolide was 2.1 mg (range, 0.1-10.0 mg), and the mean duration of treatment was 6.2 months (range, 0.5-20 months). Pergolide was discontinued in eight patients: three because of asymptomatic tachyarrhythmias of unknown clinical significance (detected only by Holter monitoring); two because of orthostatic hypotension; and two because of mental changes. Although pergolide appears to be more potent than bromocriptine because of its greater effect in a larger number of patients at a more advanced stage of their disease, both drugs are useful, and both enhance our ability to manage patients with PD.

Topics: Aged; Bromocriptine; Disability Evaluation; Drug Evaluation; Ergolines; Humans; Levodopa; Middle Aged; Parkinson Disease; Pergolide; Time Factors

Topics: Antiparkinson Agents; Bromocriptine; Carbidopa; Ergolines; Humans; Male; Middle Aged; Paraphilic Disorders; Parkinson Disease; Pergolide

Topics: Aged; Bromocriptine; Drug Tolerance; Ergolines; Humans; Lisuride; Male; Middle Aged; Parkinson Disease

Lisuride is a new effective antiparkinson agent that is useful in the management of patients in an advanced stage of parkinsonism where levodopa therapy is no longer sufficient and/or limited by 'wearing off' reactions. Patients with these problems usually respond favorably to 1.5-4.5 mg of lisuride daily provided the daily dose is built up gradually over a period of 4-8 weeks. All the clinical features of parkinsonism may be improved and the daily dose of levodopa may be reduced by 30-40%. In some instances it may be possible to give lisuride as a replacement for levodopa. Less established, however, is the potential role of lisuride in treating patients in the early stages of parkinsonism and the long-term effects of lisuride. And, as with other ergots, caution should be exercised in using lisuride if patients have a history of hypotension, hepatic dysfunction, cardiac arrhythmias, and dementia. Finally, lisuride, unlike other drugs, is highly water soluble with a nearly immediate outset of antiparkinsonian action when given intravenously and may therefore be of considerable value in the emergency treatment of severe parkinsonism.

Topics: Administration, Oral; Aged; Dose-Response Relationship, Drug; Ergolines; Female; Humans; Injections, Intravenous; Lisuride; Male; Middle Aged; Parkinson Disease; Receptors, Dopamine

Topics: Antiparkinson Agents; Bromocriptine; Carbidopa; Ergolines; Female; gamma-Aminobutyric Acid; Humans; Levodopa; Male; Middle Aged; Parkinson Disease; Prognosis; Radioligand Assay

In rats with a unilateral 6-hydroxydopamine lesion of the nigrostriatal system we compared the behavioral effects of pergolide with those of L-dopa, bromocriptine, and lergotrile. In this animal model of parkinsonism, doses of 0.25 mg per kilogram pergolide (free base) induced vigorous circling for 24 hours. Pergolide was more potent than bromocriptine or lergotrile. Pretreatment with alpha-methylparatyrosine nearly abolished the effects of bromocriptine, markedly diminished the effects of lergotrile, and only partially diminished the effects of pergolide. These findings suggest that pergolide should be more effective than bromocriptine in the treatment of parkinsonism.

Topics: Animals; Behavior, Animal; Brain Diseases; Bromocriptine; Ergolines; Female; Hydroxydopamines; Oxidopamine; Parkinson Disease; Pergolide; Rats; Rats, Inbred Strains

We studied the effects of pergolide mesylate in an open trial of 23 patients with idiopathic Parkinson disease (PD). All had suffered from loss of efficacy or dose-limiting side effects on current antiparkinsonian regimens. On pergolide therapy, improvement, which was maintained for 6 months, was noted in some parkinsonian features in all 23 patients. All patients suffering from on-off phenomenon were helped by pergolide. Significant side effects were not encountered. Pergolide is useful in the treatment of PD.

Topics: Adolescent; Adult; Carbidopa; Child; Child, Preschool; Drug Combinations; Drug Therapy, Combination; Ergolines; Female; Humans; Levodopa; Male; Parkinson Disease; Pergolide

Pergolide was administered to 56 patients with advanced Parkinson disease who were no longer satisfactorily responding to levodopa. The group included 45 patients with on-off phenomena. Pergolide, when combined with levodopa, resulted in a 44% decrease in disability as assessed in the on period, a 15% decrease in disability as assessed in the off period, and a 148% increase in the number of hours in which patients were on (from 4.6 +/- 0.3 hours to 11.4 +/- 0.6 hours). All these changes were significant at 1%. Forty-one of the 56 patients (59%) improved when pergolide was added to levodopa. Mean dose of pergolide was 2.5 mg (range, 0.2 to 10.0 mg). Mean duration of the study was 13 months (range, 1 day to 34 months). Maximum improvement occurred within 2 months and began to decline, usually after 6 months. The major adverse effects necessitating discontinuing pergolide were the occurrence of an organic confusional syndrome (six patients), increased dyskinesias (four patients), and cardiovascular abnormalities (three patients). Nine patients discontinued pergolide because of a lack of effect or declining effect.

Topics: Adult; Aged; Carbidopa; Confusion; Drug Combinations; Drug Therapy, Combination; Ergolines; Female; Humans; Levodopa; Male; Middle Aged; Parkinson Disease; Pergolide

Topics: Antiparkinson Agents; Arrhythmias, Cardiac; Ergolines; Humans; Levodopa; Parkinson Disease; Pergolide

Pergolide, a semisynthetic ergoline and a potent long-acting adenylcyclase-linked dopamine agonist, was given to 40 patients with advanced Parkinson's disease whose response to levodopa had diminished considerably. The group included 31 patients with marked diurnal oscillations in performance ("wearing off" and/or "on-off" phenomena). Pergolide alone (7 patients) or combined with levodopa (33 patients), resulted in a reduction in disability (P less than or equal to 0.01) as assessed in both the patients' "on" and "off" periods. Pergolide also resulted in an increase (P less than or equal to 0.001) in the number of hours in which patients were on from 3.8 (+/-0.4) to 11.9 (+/-0.9). The mean daily dose of pergolide was 2.4 mg (range 0.1 to 10.0). The mean duration of the study was 12 mo (range 1 to 24). Pergolide is effective in Parkinson's disease and will change the management of patients whose response to levodopa has diminished.

Topics: Adult; Aged; Antiparkinson Agents; Double-Blind Method; Drug Evaluation; Drug Synergism; Drug Therapy, Combination; Ergolines; Female; Humans; Levodopa; Male; Middle Aged; Parkinson Disease; Pergolide; Random Allocation; Time Factors

Seven patients with progressive supranuclear palsy were treated with lisuride. Mean age was 62 years (range, 52 to 68 years), and duration of disease was 4.4 years (range, 1 to 7 years). All seven had been treated with levodopa/carbidopa and three with bromocriptine; four had, at one time, shown a partial response to levodopa. One patient had also shown a partial response to bromocriptine. Lisuride was used alone in four patients, and combined with levodopa/carbidopa in three patients. Mean dose of lisuride was 2.5 mg (range, 1.5 to 5.0 mg). Mean duration of treatment was 4 months (range, 1 to 10 months). While two patients showed a reduction in rigidity, one in tremor and two in bradykinesia, in only one of them was there an overall improvement. It is postulated that the relative lack of response to lisuride may be due to a loss of both the dopaminergic and serotonergic receptors in progressive supranuclear palsy.

Topics: Aged; Bulbar Palsy, Progressive; Ergolines; Female; Humans; Lisuride; Male; Middle Aged; Parkinson Disease

Topics: Aged; Ergolines; Female; Humans; Levodopa; Lisuride; Male; Middle Aged; Parkinson Disease; Psychoses, Substance-Induced

We studied the actions of lisuride, a dopaminergic ergot derivative, in 20 parkinsonian patients. When the dose was increased gradually, most patients tolerated up to 5 mg daily. Clinical assessment and objective, computer-assisted evaluation revealed improvement in akinesia, rigidity and tremor. Adverse reactions were similar to those seen with levodopa and bromocriptine, but somnolence tended to occur more often with lisuride.

Topics: Adult; Aged; Bromocriptine; Double-Blind Method; Ergolines; Humans; Lisuride; Middle Aged; Movement; Parkinson Disease; Placebos; Reaction Time; Receptors, Serotonin; Sleep

Pergolide mesylate, a semisynthetic ergoline and a potent, long-acting central dopamine agonist, was tested in 13 patients with advanced Parkinson disease and diurnal oscillations in performance ("wearing-off" or "on-off" phenomena or both) whose response to levodopa had diminished considerably. Among all nine patients who completed the initial clinical trial, pergolide alone (two patients) or combined with levodopa (seven patients) had a marked antiparkinson effect. There was a significant reduction (p less than 0.05) in rigidity, bradykinesia, gait disorder and total Parkinson disease disability score. Pergolide had a marked effect in all the patients with "wearing-off" or "on-off" phenomena or both, resulting in a significant increase (p less than 0.01) in the duration of the time patients were "on." the number of hours in which patients were "on" increased from 3.8 +/- 0.5 (SEM) to 11.4 +/0 ).8 (SEM). The main daily dose of pergolide was 2.4 mg (range, 2 to 5 mg). Ten months later, all nine patients are doing well. Pergolide is an effective drug in patients with advanced Parkinson disease and reduces "on-off" phenomena.

Topics: Aged; Arrhythmias, Cardiac; Brain; Dopamine; Double-Blind Method; Ergolines; Humans; Levodopa; Middle Aged; Neurons; Parkinson Disease; Pergolide; Random Allocation

Lisuride is a soluble ergolene derivative with endocrine effects similar to but more potent than those of bromocriptine. In nine subjects with idiopathic, postencephalitic, or drug-induced parkinsonism, lisuride at a dosage of 0.05 to 0.15 mg intravenously caused an immediate improvement in tremor, rigidity, akinesia, and postural deformity, but also caused chorea and orofacial dyskinesia. Improvement lasted 2 to 3 hours. Lisuride had little or no effect in a single patient with progressively supranuclear palsy. Oral lisuride therapy, 0.8 to 4.8 mg daily, had similar effects but occasionally caused reduced awareness and hallucinations.

Topics: Administration, Oral; Aged; Benzimidazoles; Chorea; Domperidone; Dose-Response Relationship, Drug; Drug Therapy, Combination; Dyskinesia, Drug-Induced; Ergolines; Female; Growth Hormone; Humans; Injections, Intravenous; Lisuride; Male; Middle Aged; Paralysis; Parkinson Disease; Parkinson Disease, Postencephalitic; Parkinson Disease, Secondary; Piperidines; Prolactin

Topics: Antiparkinson Agents; Ergolines; Humans; Lisuride; Parkinson Disease; Pergolide

1. When initially given to patients with idiopathic parkinsonism, lergotrile induced marked supine arterial hypotension. Tolerance to this hypotensive effect developed and larger doses of lergotrile were administered without this adverse effect. 2. Cross tolerance occurred between lergotrile and a structurally related ergot derivative, bromocriptine. A high dose of lergotrile given to patients who had been on long term bromocriptine therapy did not induce any significant hypotension when compared to placebo whereas hypotension still occurred when lergotrile was given after previous treatment with levodopa.

Topics: Aged; Blood Pressure; Bromocriptine; Drug Tolerance; Ergolines; Heart Rate; Humans; Levodopa; Male; Middle Aged; Parkinson Disease

Topics: Aged; Bromocriptine; Cognition Disorders; Confusion; Dose-Response Relationship, Drug; Electroencephalography; Ergolines; Female; Humans; Male; Mental Disorders; Middle Aged; Parkinson Disease; Personality Disorders; Psychoses, Substance-Induced; Schizophrenia

Topics: Aromatic Amino Acid Decarboxylase Inhibitors; Bromocriptine; Dopamine Antagonists; Ergolines; Humans; Monoamine Oxidase Inhibitors; Parkinson Disease; Receptors, Dopamine

Topics: Aged; Carbidopa; Dystonia; Ergolines; Female; Hepatolenticular Degeneration; Humans; Huntington Disease; Levodopa; Male; Middle Aged; Movement Disorders; Parkinson Disease

The effect of a new synthetic ergot alkaloid, pergolide mesylate, on the inhibition of PRL during 24-h periods was evaluated in four rhesus monkeys and three patients with Parkinson's disease. In the monkeys, the mean PRL level during the 24-h period fell to 24% of control in response to 50 micrograms. With 1000 micrograms pergolide daily and to 6.6% of control with 200 micrograms pergolide daily, PRL was unmeasurable in the great majority of samples over 24 h. In addition, the marked episodic fluctuation in PRL occurring in controls was not observed in treated animals. In three patients with Parkinson's disease, treatment with pergolide also resulted in uniform 24-h suppression of PRL. In one patient on pergolide (100 micrograms/day), the mean 24-h PRL level fell to 18% of control, and in two other patients on 200 and 600 micrograms pergolide, respectively, whose mean PRL levels were 4.1 and 7.4 ng/ml, respectively, before treatment, no PRL was detected in any of the blood samples obtained during the 24-h periods. These data provide evidence that pergolide is a potent inhibitor of PRL in rhesus monkeys and in patients with Parkinson's disease; the effect is iniform over 24-h periods.

Topics: Animals; Circadian Rhythm; Ergolines; Female; Haplorhini; Humans; Macaca mulatta; Parkinson Disease; Pergolide; Prolactin

Lisuride 1.2-4.8 mg daily was given to 10 patients with severe Parkinsonism for up to 9 months. All had been taking bromocriptine and eight had been taking levodopa combined with carbidopa. Total replacement of bromocriptine by lisuride was achieved in every case, but partial or total levodopa replacement was possible only in five patients. Lisuride 1 mg has approximately the same antiparkinsonian activity as bromocriptine 15 mg or levodopa 250-500 mg combined with carbidopa, but the duration of action of each dose is short, and gastro-intestinal and neuropsychiatric side effects are common. However, lisuride i.v. may be of considerable value in the emergency treatment of severe Parkinsonism.

Topics: Administration, Oral; Aged; Bromocriptine; Drug Therapy, Combination; Ergolines; Humans; Injections, Intravenous; Levodopa; Lisuride; Middle Aged; Parkinson Disease

Increased serum activities of the enzymes alanine aminotransferase (ALT) and aspartate aminotransferase (AST) occurred in 12 out of 19 patients with idiopathic parkinsonism when they were treated with the ergot derivative lergotrile at an oral dose varying from 50 to 150 mg daily. Hepatocellular injury was confirmed by microscopic examination of liver biopsies obtained from 3 of these patients when the serum activities of ALT and AST were appreciably elevated. Light microscopy revealed features of mild acute hepatocellular injury, and electron microscopy showed proliferation of the smooth endoplasmic reticulum and apparently unique mitochondrial changes in hepatocytes. This is the first report of pathological changes in the liver associated with the therapeutic use of an ergot derivative. The presence of a potentially reactive cyanide group in the lergotrile molecule could be causally related to the observed hepatocellular injury. It is suggested that serum ALT and AST activities should be monitored carefully when the therapeutic potential of any new ergot derivative is assessed.

Topics: Adolescent; Adult; Aged; Alanine Transaminase; Aspartate Aminotransferases; Chemical and Drug Induced Liver Injury; Child; Ergolines; Female; Humans; Liver; Male; Middle Aged; Mitochondria, Liver; Parkinson Disease

Lergotrile was administered to 53 patients with advanced Parkinson disease (PD), who had increasing disability despite optimal treatment with levodopa/carbidopa (Sinemet). Thirty-nine patients who could tolerate at least 20 mg per day lergotrile (thus considered "adequately treated") had significant descreases in rigidity, tremor, bradykinesia, gait disturbance, and total score without increased involuntary movements. Twenty-one of these 39 patients improved by at least one stage. Among the 39 patients, 23 had "on-off" effects, and in 13 of these the "on-off" effects decreased on lergotrile. The mean daily dose of lergotrile in adequately treated patients was 49 mg, permitting a 10 percent reduction in the dose of levodopa. Lergotrile was discontinued in 33 of the 53 patients because of adverse effects, including hepatotoxicity (11 patients), mental changes (12 patients) and orthostatic hypotension (8 patients). Although lergotrile, when added to levodopa, has a definite antiparkinsonian effect, the incidence of adverse effects, particularly hepatotoxicity, makes it unlikely that this ergot alkaloid will become widely available for the treatment of PD. Analogues of lergotrile have been synthesized, and it is hoped that they will duplicate the antiparkinsonian effect of this drug without its toxicity.

Topics: Aged; Bromocriptine; Chemical Phenomena; Chemistry; Dopa Decarboxylase; Ergolines; Humans; Levodopa; Middle Aged; Parkinson Disease

Topics: Animals; Antiparkinson Agents; Ergolines; Guinea Pigs; Parkinson Disease; Pergolide; Rats

Topics: Acetonitriles; Animals; Bromocriptine; Corpus Striatum; Ergolines; Ergot Alkaloids; Haplorhini; Humans; Levodopa; Parkinson Disease; Receptors, Dopamine; Spiperone; Substantia Nigra; Synaptosomes; Tremor; Tyrosine 3-Monooxygenase

Topics: Aged; Bromocriptine; Confusion; Depression; Ergolines; Female; Hallucinations; Humans; Male; Mental Disorders; Middle Aged; Neurocognitive Disorders; Parkinson Disease; Schizophrenia, Paranoid

The response of Parkinsonism to three ergot derivatives which modify dopaminergic transmission was studied. CF 25-397 behaved more as an antagonist than an agonist. Lergotrile was an agonist with therapeutic properties marred by prominent hepatotoxicity. Bromocriptine is an effective anti-Parkinsonian agent, particularly useful in patients with prominent dyskinesia or "on-off" reactions to levodopa; in most patients optimal results have been obtained by combining from 40 to 90 mg of bromocriptine daily with approximately 60% of the previous maximal dose of levodopa. Unfortunately, only some 50% of patients tolerate long-term bromocriptine therapy, but all adverse reactions have been dose dependent and reversible.

Topics: Bromocriptine; Ergolines; Humans; Parkinson Disease; Pyridines

Plasma PRL was measured at 20-min intervals in six patients with Parkinson's disease under various treatment protocols. In addition, 24-h mean GH levels were measured. The results of these studies showed that two untreated patients with Parkinson's disease had normal 24-h mean PRL levels with the normal increase during sleep. During chronic treatment with L-dopa-carbidopa (Sinemet), the 24-h PRL level was 12.8 +/- 4.9 ng/ml (mean +/- SD) and there was persistence of augmented PRL secretion during sleep. The 24-h mean GH level ranged from 1.5-4.4 ng/ml, with a mean of 2.5 ng/ml. The addition of a dopamine agonist (Lergotrile mesylate) resulted in a significant (P less than 0.01) suppression of the 24-h mean PRL levels and abolition of the normal sleep augmentation after 2 weeks of therapy. This suppression was maintained in one patient who was restudied 4 months after the addition of dopamine agonist therapy to L-dopa-carbidopa. The 24-h mean GH levels did not change significantly after the addition of the dopamine agonist when compared to L-dopa-carbidopa alone. These results suggest a dichotomy between the PRL and GH responses to combined L-dopa-carbidopa and dopamine agonist therapy. In addition, the preservation of normal PRL regulation in the two untreated patients with Parkinson's disease suggests that dopaminergic neurons are not universally affected in this disorder.

Topics: Adult; Aged; Carbidopa; Circadian Rhythm; Drug Combinations; Drug Therapy, Combination; Ergolines; Female; Growth Hormone; Humans; Levodopa; Male; Middle Aged; Parkinson Disease; Prolactin; Sleep

Lergotrile mesylate, a direct-acting dopamine agonist, was administered for up to 10 months to 25 patients with Parkinson disease. Of six patients not receiving levodopa concurrently, five showed definite improvement in parkinsonian signs and symptoms. These results are the first clear indication that lergotrile is efficacious, independently of any interaction with levodopa, in the treatment of Parkinson disease. The drug was also effective in relieving some complications of long-term levodopa therapy. Lergotrile was more effective in alleviating on-off problems than in reversing loss of levodopa efficacy. Side effects of lergotrile included exacerbation of hallucinations, dyskinesias, hypotension, and alterations in liver function tests.

Topics: Acetonitriles; Drug Evaluation; Ergolines; Humans; Liver Function Tests; Parkinson Disease

Lergotrile, an ergot alkaloid, has been shown to be effective in treating disorders associated with elevated serum prolactin levels (e.g., galactorrhea-amenorrhea). Lergotrile has also been found to be a potent dopaminergic agonist and thus to be effective in Parkinson's disease. This study describes the physiologic disposition of lergotrile after administration to human volunteers. N-14CH3-lergotrile was rapidly absorbed from the gastrointestinal tract. Lergotrile was detected at low concentrations in plasma when subjects received large doses over extended periods of time. The major portion of radioactivity in plasma was attributed to the presence of circulating metabolites of lergotrile. Lergotrile metabolities were eliminated in the feces (ca. 60%), urine (ca. 20%), and breath (ca. 7% as 14CO2). A metabolite in feces was identified as 13-OH-lergotrile (up to 30% of the dose). A metabolite in urine was formed by conversion of the C8-acetonitrile group of lergotrile to a carboxyl group (about 10% of the dose). The presence of 14CO2 in the expired air after administering N-14C-methyl-lergotrile indicated that the drug was N-demethylated to form norlergotrile.

Topics: Acetonitriles; Adult; Blood Proteins; Chromatography, Gas; Chromatography, High Pressure Liquid; Chromatography, Thin Layer; Dealkylation; Ergolines; Humans; Male; Middle Aged; Parkinson Disease; Protein Binding

Topics: Acetonitriles; Animals; Bromocriptine; Disease Models, Animal; Ergolines; Humans; Liver; Parkinson Disease; Pyridines; Structure-Activity Relationship

The therapeutic and adverse effects of two ergot derivatives, bromocriptine and lergotrile, were compared in idiopathic parkinsonism. At both low (50 mg daily) and high (150 mg daily) dosage there was a similar but not identical profile of response. Initially, lergotrile tended to induce more severe but always transient hypotension. At higher doses, bromocriptine caused more dyskinesia. Neurological deficits improved with increasing doses up to an average daily level of 80 to 150 mg of ergot derivatives combined with levodopa, 450 to 1,150 mg, and carbidopa, 45 to 115 mg. However, efficacy often declined at the highest doses of antiparkinsonian agents. Adverse effects caused by ergot derivatives are more common with dosages greater than 100 mg per day. In general, the best overall therapeutic results with bromocriptine and lergotrile were obtained in the dose range of 50 to 100 mg daily for each. It is concluded that bromocriptine and lergotrile are similar in their therapeutic properties and that both are comparable in efficacy to levodopa plus carbidopa (though optimal results are commonly obtained by combining submaximal doses of levodopa with ergot derivatives). The role for each drug in the treatment of parkinsonism is likely to be determined by factors such as cost (bromocriptine) and hepatotoxicity (lergotrile).

Topics: Acetonitriles; Adult; Aged; Bromocriptine; Carbidopa; Chemical Phenomena; Chemistry; Ergolines; Female; Humans; Levodopa; Male; Middle Aged; Parkinson Disease; Receptors, Dopamine

A patient with the classical stigmata of parkinsonism was treated on three separate occasions with levodopa, a combination of levodopa and carbidopa, and lergotrile mesylate, a direct-acting dopamine-receptor agonist. All three treatment regimens resulted in dose-related increases in parkinsonian features. To our knowledge, this response has not been previously described. Lergotrile did not alter CSF homovanillic acid concentration. It is suggested that this rare paradoxical motor response to dopaminergic agents may be associated with dysfunction of the postsynaptic dopamine receptor site.

Topics: Acetonitriles; Aged; Carbidopa; Ergolines; Homovanillic Acid; Humans; Hydrazines; Levodopa; Male; Parkinson Disease; Receptors, Dopamine

Topics: Animals; Bromocriptine; Cyclic AMP; Ergolines; Female; Humans; Huntington Disease; Male; Middle Aged; Motor Activity; Nervous System Diseases; Parkinson Disease; Rats; Schizophrenia; Stereotyped Behavior; Synapses

Studies on rats with unilateral nigral lesions suggest that a new ergoline, CF 25-397, is a dopaminergic agonist that might improve parkinsonism. CF 25-397 induces less stereotyped behavior than other dopaminergic agents in rats, and might therefore cause less dyskinesia than levodopa in man. We investigated the clinical actions of CF 25-397 in nine patients. During treatment, severe deterioration resulted in hypokinesia and rigidity; five patients showed marked dysphagia and dysphonia. There was statistically significant deterioration in four timed tests. Mild improvement, not statistically significant, was noted in tremor. These results indicate that clinical implication of the response to potential therapeutic agents in rodent models of parkinsonism must be interpreted with caution.

Topics: Aged; Animals; Corpus Striatum; Deglutition Disorders; Disease Models, Animal; Dopamine; Drug Evaluation; Drug Evaluation, Preclinical; Ergolines; Female; Humans; Male; Middle Aged; Movement Disorders; Parkinson Disease; Rats; Species Specificity; Stereotyped Behavior; Tremor

The present investigation examined the biochemical interaction of bromocriptine and levodopa with respect to monoamine and gamma-aminobutyric acid metabolism in the brain. Rats were treated with levodopa, 250 mg per kilogram of body weight intraperitoneally, with or without carbidopa, 25 mg per kilogram, 1 or 2 hours before sacrifice. Some were also given bromocriptine, 5.0 mg per kilogram, 4 hours before sacrifice. Rats were killed 1 and 2 hours after levodopa and brain levels of gamma-aminobutyric acid and monoamines, and their metabolites were measured. Dopamine levels and metabolism were not markedly altered when bromocriptine was added to levodopa treatment. The level of serotonin, which was reduced 25 to 40 percent by levodopa alone, was close to normal with the combination treatment. Serotonin metabolism was also enhanced by the addition of bromocriptine as shown by increased levels of 5-hydroxyindoleacetic acid. The results suggest that bromocriptine not only may improve the motor disorder of parkinsonism but also may reduce some side effects of levodopa therapy, such as depression, which could be due to serotonin depletion.

Topics: Animals; Brain; Bromocriptine; Carbidopa; Dopamine; Drug Interactions; Ergolines; gamma-Aminobutyric Acid; Hydroxyindoleacetic Acid; Levodopa; Male; Parkinson Disease; Rats; Serotonin

Topics: Bromocriptine; Ergolines; Humans; Levodopa; Parkinson Disease

Topics: Acromegaly; Bromocriptine; Ergolines; Female; Galactorrhea; Humans; Lactation Disorders; Parkinson Disease; Pregnancy

In the course of a clinical trial with 2alpha-bromoergocryptin in Parkinson's disease, the serum levels of several pituitary hormones have been studied in the assumption that the drug active on nigro-striatal dopaminergic system might also interfere with hypothalamus-protuberantial neurotransmission, and have effects on the function of the pituitary. No changes in serum levels of FSH, LH, STH and TSH were detected for every dose of the drug employed. Only prolactin serum levels diminished since the beginning of the treatment, the decrease being significant (p less than 0.05 and p less than 0.01). This effect on prolactin does not change in the dose range considered. Clinical improvement was observed for doses of drugs above 15 mg/day, whereas the effect on prolactin secretion occurred with the dose of 7.5 mg/day.

Topics: Aged; Bromocriptine; Ergolines; Female; Gonadotropins, Pituitary; Growth Hormone; Humans; Male; Middle Aged; Parkinson Disease; Pituitary Hormones, Anterior; Thyrotropin

Topics: Aromatic Amino Acid Decarboxylase Inhibitors; Bromocriptine; Carbidopa; Dopamine; Drug Therapy, Combination; Ergolines; Humans; Levodopa; Parkinson Disease; Receptors, Dopamine

Topics: Bromocriptine; Ergolines; Growth Hormone; Humans; Parkinson Disease

Topics: Acetonitriles; Antiparkinson Agents; Drug Evaluation; Ergolines; Humans; Parkinson Disease

Topics: Bromocriptine; Ergolines; Growth Hormone; Homovanillic Acid; Humans; Huntington Disease; Hydroxyindoleacetic Acid; Parkinson Disease; Prolactin

The antiparkinsonian activity of bromocriptine, a presumed dopaminergic receptor agonist, was investigated in monkeys with surgically induced tremor and in a group of parkinsonian patients. A single administration of bromocriptine resulted in a dose-dependent relief of tremor in monkeys. Repeated administration enhanced this effect. Only mild abnormal involuntary movements were observed and only after repeated administration. Eleven patients with Parkinson's disease were treated with bromocriptine (mean dose, 26.4 mg a day). Clinically obvious improvement was noted in one or more of the cardinal signs of the disease in six patients (responders). No obvious improvement in any of the cardinal signs was noted in the remaining five patients (nonresponders). Clinically, the responders were older and more severely affected and had been on a higher dose of levodopa. However, they had had the disease for a shorter period. It is suggested that failure to respond to bromocriptine may be related to a decrease in the sensitivity of postsynaptic dopaminergic receptors.

Topics: Age Factors; Animals; Dose-Response Relationship, Drug; Ergolines; Haplorhini; Humans; Movement Disorders; Parkinson Disease; Time Factors; Tremor

A dopaminergic agonist, bromocriptine, has been studied in patients with idiopathic parkinsonism complicated by severe "on-off" phenomena induced by levodopa. In a "blind" self-evaluating within-patient comparison, fluctuations in clinical state still occurred when levodopa (with or without carbidopa) was replaced with bromocriptine, but they were significantly reduced in frequency. The observation that on-off phenomena can be induced by bromocriptine complicates interpretation of these episodes in terms of pharmacokinetics of levodopa. There may be variations in receptor sensitivity or alterations in the influence of unidentified neurophysiologic mechanisms that modulate striatal output.

Topics: Bromocriptine; Drug Evaluation; Drug Therapy, Combination; Ergolines; Female; Humans; Levodopa; Male; Middle Aged; Parkinson Disease

Topics: Acromegaly; Bromocriptine; Ergolines; Female; Humans; Hypogonadism; Lactation; Lactation Disorders; Male; Parkinson Disease; Pregnancy

Topics: Blood Coagulation; Bromocriptine; Ergolines; Female; Fibrinolysis; Humans; Male; Parkinson Disease; Platelet Aggregation

Topics: Bromocriptine; Ergolines; Humans; Levodopa; Parkinson Disease; Reflex

Bromocriptine in high doses (up to 100 mg per day) was administered to 14 patients with advanced Parkinson's disease whose disorder was progressing despite optimum treatment with levodopa combined with a peripheral dopa decarboxylase inhibitor (carbidopa). In 10, bromocriptine (mean dose, 57 mg) induced a statistically significant (P less than 0.01) improvement in rigidity, tremor, bradykinesia, gait disturbance and total score. In seven patients levodopa with carbidopa was completely replaced by bromocriptine (mean dose, 70 mg), with improvement in four. Adverse effects were similar to those observed with levodopa and carbidopa, except that in individual patients abnormal involuntary movements and diurnal oscillations in performance (on-off effect) were decreased whereas orthostatic hypotension and mental changes were increased. Bromocriptine appears to be a major new agent in Parkinson's disease that is especially promising in patients no longer responding to levodopa.

Topics: Aged; Bromocriptine; Delusions; Dopa Decarboxylase; Drug Evaluation; Ergolines; Female; Humans; Hypotension, Orthostatic; Levodopa; Male; Middle Aged; Parkinson Disease

Topics: Antiparkinson Agents; Bromocriptine; Drug Synergism; Ergolines; Humans; Parkinson Disease

Topics: Aged; Carboxy-Lyases; Drug Evaluation; Drug Synergism; Drug Therapy, Combination; Enzyme Inhibitors; Ergolines; Female; Humans; Levodopa; Male; Middle Aged; Parkinson Disease; Receptors, Dopamine

On the basis of a reassessment of the aetiopathogenetic problem and the neuroendocrine implications, the therapeutic effectiveness of a prolactin inhibitor, 2-alpha-Br-ergocryptine (CB 154), in Parkinson's disease is assessed. Five patients were treated for a total of two weeks using doses between 10 and 15 mg/die. CB 154 was found to act as a dopaminergic receptor agonist at nigro-striatal level, considerably improving tremor and rigidity and to a lesser extent bradykinesia and total disability.

Topics: Aged; Bromocriptine; Drug Evaluation; Ergolines; Female; Humans; Middle Aged; Parkinson Disease; Prolactin

Topics: Acromegaly; Aged; Bromocriptine; Ergolines; Female; Humans; Infertility, Female; Parkinson Disease; Pituitary Neoplasms; Receptors, Dopamine

Thirty-seven patients with Parkinsonism were treated with bromocriptine 2.5-300 mg daily. Bromocriptine, alone or combined with levodopa, caused a 20-30% reduction in disability scores in 11 patients treated for one year. Tolerance did not develop during this period. Bromocriptine treatment was not of value in six patients who had previously not responded or who had lost their response to levodopa. However, in four of five patients with response swings on levodopa due to rapid changes in plasma dopa levels, the addition of bromocriptine caused a more stable response. Dose response curves to bromocriptine 12.5, 25, 50, and 100 mg and to levodopa 250, 500, 1000, and 2000 mg were studied in seven patients. Levodopa 2 g had a greater therapeutic effect and caused a greater rise in plasma growth hormone concentration than bromocriptine 100 mg. Levodopa caused emesis more commonly and hallucinations less commonly than bromocriptine. Bromocriptine appears to be a less potent stimulant than dopamine, and has both pre- and post-synaptic effects. Metoclopramide 60 mg oral was given 30 minutes before bromocriptine or levodopa to establish whether this caused dopamine-receptor blockade. Metoclopramide acted as a competitive antagonist to the anti-Parkinsonism and growth hormone effect of both drugs and in individual cases prevented emesis and hallucinations. The fall in blood pressure due to bromocriptine or levodopa was not antagonised by metoclopramide. Central and peripheral vascular dopamine receptors may be different in nature.

Topics: Aged; Bromocriptine; Dose-Response Relationship, Drug; Drug Evaluation; Drug Therapy, Combination; Dyskinesia, Drug-Induced; Ergolines; Female; Follow-Up Studies; Growth Hormone; Humans; Levodopa; Male; Metoclopramide; Middle Aged; Parkinson Disease; Receptors, Dopamine

Topics: Aged; Bromocriptine; Drug Evaluation; Ergolines; Female; Humans; Male; Middle Aged; Parkinson Disease

Topics: Bromocriptine; Drug Evaluation; Ergolines; Humans; Parkinson Disease

Topics: Aged; Bromocriptine; Drug Evaluation; Ergolines; Female; Humans; Male; Middle Aged; Parkinson Disease

Topics: Acromegaly; Bromocriptine; Depression, Chemical; Ergolines; Female; Humans; Lactation; Parkinson Disease; Pregnancy; Prolactin

The antiparkinsonian activity of lergotrile mesylate, a presumed dopaminergic receptor stimulating agent, was investigating in monkeys with surgically induced tremor and in parkinsonian patients. The administration of lergotrile resulted in a dose-dependent reduction in the intensity of tremor in the monkeys. In 13 patients with Parkinson's disease treated with lergotrile (up to 12 mg a day), overall improvement was observed in five. Tremor was the main clinical feature to benefit, and the improvement reached statistical significance. In a subgroup of four patients treated with a higher dose of lergotrile (up to 20 mg a day), further improvement in rigidity and bradykinesia was noted, but again, only improvement in tremor was statistically significant. Adverse effects included orthostatic hypotension, behavioral alterations, and nausea and vomiting. These were severe enough to result in drug withdrawal in three patients.

Topics: Acetonitriles; Aged; Animals; Disease Models, Animal; Dopamine; Dose-Response Relationship, Drug; Drug Evaluation; Drug Evaluation, Preclinical; Ergolines; Female; Gait; Haplorhini; Humans; Male; Mesylates; Middle Aged; Muscle Rigidity; Parkinson Disease; Prolactin; Receptors, Drug; Tremor

Topics: Bromocriptine; Drug Evaluation; Drug Therapy, Combination; Ergolines; Humans; Levodopa; Parkinson Disease

Topics: Adult; Aged; Benzocycloheptenes; Dihydroxyphenylalanine; Ergolines; Female; Histamine H1 Antagonists; Humans; Male; Middle Aged; Parkinson Disease; Piperidines; Promethazine; Thiophenes; Tremor; Trihexyphenidyl

Topics: Adult; Aged; Amantadine; Ergolines; Female; Humans; Male; Middle Aged; Parkinson Disease; Promethazine; Tremor; Trihexyphenidyl

Topics: Brain; Brain Chemistry; Dihydroxyphenylalanine; Electrophysiology; Ergolines; Globus Pallidus; Hippocampus; Humans; Mesencephalon; Motor Activity; Parasympatholytics; Parkinson Disease; Psychological Tests; Thalamic Nuclei; Thinking