ergoline and Movement-Disorders

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 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

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

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

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

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

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

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

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

Transdihydrolisuride is an ergot derivative with mixed agonist and antagonist effects on central dopamine receptors. We gave the drug orally (1 mg daily) to 10 patients with Huntington's disease. In seven patients, the chorea improved with no adverse effects during the study.

Topics: Adolescent; Adult; Clinical Trials as Topic; Double-Blind Method; Ergolines; Female; Humans; Huntington Disease; Lisuride; Male; Mental Processes; Middle Aged; Movement Disorders; Neuropsychological Tests; Random Allocation; Receptors, Dopamine; Time Factors

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

Nine patients suffering from Parkinson's disease and 2 cases of Parkinsonian syndrome were treated with bromocriptine, for 41 to 117 days, with a daily dose of 20 to 40 mg. The results were very good in 4 cases, satisfactory in 6 and nil in one case. Improvement concerned akinesias, rigidity and tremor, and was more marked in patients with more advanced signs. In 2 patients, amantadine was stopped. The dose of L-dopa was decreased by 2/3 without any change in clinical condition and L-dopa could be withdrawn in 5 cases out of 8. Bromocriptine appears to be an interesting development in the treatment of Parkinson's disease.

Topics: Aged; Amantadine; Bromocriptine; Clinical Trials as Topic; Drug Evaluation; Ergolines; Female; Humans; Hypotension; Levodopa; Male; Movement Disorders; Nausea; Parkinson Disease, Secondary

Studies in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned monkeys and in parkinsonian patients show elevated preproenkephalin (PPE) mRNA levels, unaltered by chronic L-DOPA therapy, whereas preprotachykinin (PPT) mRNA levels are decreased by the lesion and corrected by L-DOPA. The relative contributions of the dopamine D1 and D2 receptors for PPE mRNA regulation were investigated in the present study and compared with those for PPT mRNA. In situ hybridization was used to measure peptide mRNA levels in the striatum of MPTP cynomolgus monkeys after chronic 1-month treatment with the D1 agonist SKF-82958, administered subcutaneously in pulsatile or continuous mode, compared with the long-acting D2 agonist cabergoline. Normal as well as untreated MPTP animals were also studied. PPE mRNA levels were elevated in the caudate nucleus and putamen of untreated MPTP monkeys compared with control animals with a more pronounced increase in the lateral as compared with the medial part of both structures. PPT mRNA levels showed a rostrocaudal gradient, with higher values in the middle of the caudate-putamen and more so in the medial versus the lateral parts. PPT mRNA levels were decreased in the caudate and putamen of untreated MPTP monkeys compared with control animals, and this was observed in the middle and posterior parts of these brain areas. Elevated PPE and decreased PPT mRNA levels observed after MPTP exposure were corrected after treatment with cabergoline (0.25 mg/kg, every other day), a dose that had antiparkinsonian effects and did not give sustained dyskinesia. In contrast, elevated PPE mRNA levels observed in untreated MPTP monkeys were markedly increased by pulsatile administration of SKF-82958 (1 mg/kg, three times daily) in two monkeys in which the parkinsonian symptoms were improved and dyskinesias developed, whereas it remained close to control values in a third one that did not display dyskinesias despite a sustained improvement in disability; a shorter duration of motor benefit (wearing off) over time was observed in these three animals. By contrast, pulsatile administration of SKF-82958 corrected the decreased PPT level observed in untreated MPTP monkeys. Continuous treatment with SKF-82958 (equivalent daily dose) produced no clear antiparkinsonian and dyskinetic responses and did not alter the denervation-induced elevation of PPE or decrease of PPT mRNA levels. The present data suggest an opposite contribution of the dopamine D1 rece

Topics: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Animals; Behavior, Animal; Benzazepines; Brain Chemistry; Cabergoline; Corpus Striatum; Denervation; Dopamine Agents; Dopamine Agonists; Enkephalins; Ergolines; Female; Gene Expression; Macaca fascicularis; Movement Disorders; Protein Precursors; Pulsatile Flow; Receptors, Dopamine D1; Receptors, Dopamine D2; RNA, Messenger; Tachykinins

Continuous dopaminergic receptor stimulation is now considered as an interesting approach for the control of motor complications often seen in parkinsonian patients treated chronically with levodopa. Cabergoline, which is a long-acting dopamine D2-like receptor agonist, has been tried recently with good results as an adjunct in patients already on levodopa-therapy. Thus, the present study was designed to test the effects of repeated s.c. administration of cabergoline as sole therapeutic agent during a month in 3 drug-naive MPTP parkinsonian monkeys to see whether or not cabergoline, given every other day at 0.25 mg/kg, would have a sustained antiparkinsonian effect and would induce dyskinesias. The animals were rated to quantify the antiparkinsonian as well as the dyskinetic response and gross locomotor activity was monitored by photocells. The averaged locomotor response, initially greatly increased (approximately 9 times higher than after saline treatment in the same animals), decreased by approximately 50% after 2 weeks but was thereafter maintained at this level until the end of the study. The parkinsonian features were improved in a sustained manner in all monkeys and transient dyskinesias (week 1 and 2) were present in 2 of 3 monkeys. After sacrifice receptor binding assays were performed on striatal and pallidal tissues homogenates with tritiated selective ligands and compared with those of 3 normal and 3 MPTP-exposed monkeys otherwise untreated. A significant decrease in dopamine D2-like receptor density in the putamen (-36% on average vs. untreated MPTP-exposed monkeys) may be involved in the behavioral partial tolerance to antiparkinsonian effect of cabergoline and the disappearance of dyskinesias. A reversal of the supersensitivity of GABAA receptor in the internal segment of the globus pallidus (-15% on average vs. untreated MPTP-exposed monkeys) may also be implicated in this latter behavioral effect.

Topics: Animals; Antiparkinson Agents; Behavior, Animal; Cabergoline; Catecholamines; Dopamine Agonists; Ergolines; Female; Macaca fascicularis; Motor Activity; Movement Disorders; Putamen; Stereotyped Behavior

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

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

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

The regional distribution of high affinity [3H]5-HT recognition sites in the brain of several vertebrates (pigeon, rat, mouse, guinea-pig, cat, dog, monkey and human) was analyzed using in vitro autoradiography. The presence of subtypes of 5-HT1 binding sites was investigated by selective displacements with 8-OH-DPAT, mesulergine and (+/-)SDZ 21-009 at appropriate concentrations to block 5-HT1A, 5-HT1C and 5-HT1B sites respectively. In addition, 5-HT1A and 5-HT1C sites were directly visualized with the more selective radioligands [3H]8-OH-DPAT and [3H]mesulergine, respectively. In the pigeon brain, total [3H]5-HT binding sites were enriched in all telencephalic areas. Densely labelled regions were also present in the optic tectum and the brainstem. No binding was observed in the cerebellum. 8-OH-DPAT and mesulergine only displaced a small proportion of [3H]5-HT binding in most of the areas where high concentrations of 5-HT1 sites were found. (+/-)SDZ 21-009 did not affect [3H]5-HT binding in the regions examined. Taking into account our pharmacological studies, these results suggest that the majority of 5-HT1 sites belong to the 5-HT1D subtype in the pigeon brain. In the mammalian species investigated high levels of [3H]5-HT binding were found in the neo-cortex, hippocampal formation, basal ganglia and related structures (substantia nigra), raphe dorsalis, nucleus superior colliculus and choroid plexus. However, these brain areas were differentially enriched in subtypes of 5-HT1 recognition sites.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: 8-Hydroxy-2-(di-n-propylamino)tetralin; Aged; Animals; Autoradiography; Brain; Cats; Disease Models, Animal; Dogs; Ergolines; Female; Guinea Pigs; Humans; Macaca mulatta; Male; Mice; Movement Disorders; Receptors, Serotonin; Serotonin; Tetrahydronaphthalenes; Tritium

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

The right common carotid artery was surgically exposed under general anaesthesia in 6 cynomolgus monkeys and MPTP (0.5-2.2 mg/kg) directly infused. This produced a hemiparkinsonian syndrome in the contralateral limbs which responded to treatment with both levodopa and apomorphine. These drugs also precipitated dose-dependent contralateral rotation which reached a peak 2 weeks after MPTP infusion. A massive depletion of large, presumably dopaminergic cells was found from the ipsilateral substantia nigra pars compacta. Three animals receiving chronic therapy with apomorphine developed choreoathetoid movements of the limbs and the face contralateral to the infusion 2 weeks after the commencement of treatment. The severity of the dyskinesia gradually increased and after 4 weeks peak-dose hemiballistic movements were seen. Levodopa and the selective D-2 and D-1 dopamine agonists LY-171555 and SKF 38393 also reversed parkinsonian features and produced contralateral rotation and peak-dose dyskinesia. This unilateral model of parkinsonism in the primate will be of value in the elucidation of the mechanisms by which chronic levodopa or dopamine agonist therapy enhance involuntary movements in parkinsonism.

Topics: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Animals; Apomorphine; Dose-Response Relationship, Drug; Ergolines; Injections, Intravenous; Levodopa; Macaca fascicularis; Movement Disorders; Parkinson Disease, Secondary; Pyridines; Quinpirole; Stereotyped Behavior

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

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

Selective D1 and D2 dopamine (DA) antagonists and agonists were given to 4 Cebus monkeys who had previously received haloperidol treatment for 4 years. SCH 23390 (a selective D1 antagonist) and raclopride (a selective D2 antagonist) induced identical syndromes consisting of dystonia and oral dyskinesia. Biperiden (an anticholinergic drug) and LY 171555 (a selective D2 agonist) completely antagonized the dystonia and dyskinesia induced by SCH 23390 as well as raclopride. The combined treatment with LY 171555 and SCH 23390 (but not LY 171555 and raclopride) caused pronounced sedation. LY 171555 induced repetitive movements of head, legs and trunk, but no oral dyskinesia. SKF 38393 (a partial D1 agonist) caused slight sedation, minimal oral dyskinesia and a significant reduction in D2 agonist-induced repetitive movements.

Topics: 2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine; Animals; Antipsychotic Agents; Benzazepines; Biperiden; Cebus; Dystonia; Ergolines; Haloperidol; Male; Movement Disorders; Quinpirole; Raclopride; Receptors, Dopamine; Salicylamides; Stereotyped Behavior

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

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

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

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

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

Lisuride antagonized L-5-hydroxytryptophan (5-HTP)-induced head twitches at doses lower than those sufficient to induce the serotonin (5-HT) syndrome. Among several other 5-HT agonists tested, only LSD and 1-(m-trifluoromethylphenyl)-piperazine (TFMPP) shared this paradoxical profile. Assessment of various dopamine (DA) agonists revealed a lack of correlation between DA-mediated stereotyped behavior (indicative of postsynaptic DA agonism) and blockade of 5-HTP-induced head twitches. Lisuride displaced specific ligand binding from putative S1a, S1b and S2 receptors at nanomolar concentrations, and other drugs that blocked 5-HTP-induced head twitches also displaced binding at S2 sites. It is proposed that lisuride may have agonist properties at S1a receptors mediating the 5-HT syndrome but antagonist properties at S2 receptors mediating 5-HTP-induced head twitching.

Topics: 5-Hydroxytryptophan; Animals; Dopamine; Ergolines; Fenfluramine; Lisuride; Lysergic Acid Diethylamide; Male; Movement Disorders; Rats; Receptors, Dopamine; Serotonin Antagonists; Stereotyped Behavior; Synaptic Transmission

In this study the effects of an acute injection of lisuride and apomorphine in 12 subjects affected by dystonic-dyskinetic syndromes of different aetiology are evaluated: 3 patients with spasmodic torticollis, 4 with tardive dyskinesia and 5 Parkinson patients suffering from "on-off" attacks with prominent dyskinesias during the mobile phase. In the last group drugs were administered during the "on" phase. In 11 out of 12 patients both lisuride and apomorphine induced a marked improvement of the abnormal involuntary movements. In Parkinson and torticollis patients both drugs also reduced the rigidity. In comparison to apomorphine, lisuride showed a more effective and long-lasting action. Only in one Parkinson patient did the drugs fail in showing any change.

Topics: Apomorphine; Dystonia; Ergolines; Evaluation Studies as Topic; Female; Humans; Lisuride; Male; Middle Aged; Movement Disorders

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

Neurochemical and neuropharmacological investigations with four ergot derivatives reveal differential pharmacodynamic effects of these compounds. Bromocriptine and CM 29-712 showed actions typical of postsynaptic dopamine receptor stimulants, in particular in the extrapyramidal system. CM 29-712 proved to be more potent than bromocriptine, with an early onset of action. CF 25-397 and dihydroergotoxine, while not showing all actions typical of central dopamine agonists, appeared to exert some of their effects by means of a stimulation of central serotoninergic sites. In the rat sleep-wakefulness cycles and in reserpine-induced ponto-geniculooccipital waves in the cat, they mimicked the effects of 5-hydroxytryptophan. In the latter test, CF 25-397 proved to be particularly potent. In addition, bromocriptine, dihydroergotoxine and CM 29-712 showed neurochemical effects consistent with central alpha-adrenergic blockade or an enhanced impulse flow in central noradrenergic neurons.

Topics: Animals; Behavior, Animal; Brain; Bromocriptine; Catecholamines; Chemical Phenomena; Chemistry; Dihydroergotoxine; Electroencephalography; Ergolines; Humans; Locomotion; Male; Mice; Morphine; Movement Disorders; Rabbits; Rats; Receptors, Dopamine; Reserpine; Sleep; Stereotyped Behavior

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 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