Effects of 2-bromoterguride, a dopamine D2 receptor partial agonist, on cognitive dysfunction and social aversion in rats.

RATIONALE: 2-Bromoterguride, a dopamine D2 receptor partial agonist with antagonist properties at serotonin 5-HT2A receptors and α2C-adrenoceptors, meets the prerequisites of a putative atypical antipsychotic drug (APD). We recently showed that 2-bromoterguride is effective in tests of positive symptoms of schizophrenia in rats without inducing extrapyramidal side effects or metabolic changes. OBJECTIVE: In continuation of our recent work, we now investigated the effect of 2-bromoterguride on apomorphine and phencyclidine (PCP)-induced disruptions of prepulse inhibition (PPI) of the acoustic startle response, a measure of sensory gating. In addition, we used subchronic PCP treatment to produce cognitive deficits and social aversion, and assessed the effect of 2-bromoterguride on the performance in the novel object recognition (NOR) task (model for studying cognitive deficit symptoms of schizophrenia) and the social interaction test (model for studying negative symptoms of schizophrenia). Finally, we extended the side effect profile of 2-bromoterguride by measuring the prolactin response to systemic administration of the drug in rats. RESULTS: Treatment with 2-bromoterguride (0.1 and 0.3 mg/kg) reversed PPI deficits induced by apomorphine and PCP, respectively. Subchronic PCP induced impairments in object memory and social interaction behavior which were ameliorated by 2-bromoterguride but not by clozapine and aripiprazole, respectively. Prolactin concentration in blood serum was not elevated at 1, 2, or 4 h post-2-bromoterguride treatment, which further supports the safe and effective use of this drug. CONCLUSIONS: Our data support 2-bromoterguride as a promising APD candidate due to its beneficial effect on cognitive impairments and negative symptoms of schizophrenia.

Arreter la montee du lait

L' absence de stimulation des mamelons suffit generalement a stopper la lactation.En cas de douleur ; la prises de paracetamol est la premiere mesure a envisager

Lisuride, a dopamine receptor agonist with 5-HT2B receptor antagonist properties: absence of cardiac valvulopathy adverse drug reaction reports supports the concept of a crucial role for 5-HT2B receptor agonism in cardiac valvular fibrosis.

OBJECTIVES: The high incidence of fibrotic cardiac valvulopathies reported in association with the 8beta-ergoline dopamine (DA) agonist, pergolide, and also case reports for cabergoline and bromocriptine have made it necessary to review the theoretical basis and actual findings in the case of another DA agonist, the 8alpha-ergoline lisuride (used since the 1970s for migraine prophylaxis as well as since the 1980s for its prolactin-lowering and anti-Parkinson activity). METHODS: We have reviewed the pharmacology of lisuride in relation to other DA agonists, and we have performed a throughout literature search as well as a search of our own and other adverse drug reaction databases for a possible relationship of lisuride with cardiac valvulopathy or for any reports of fibrosis in other locations. RESULTS: Our review of the pharmacology and the literature strongly suggests that drug-induced cardiac valvulopathies are always related to a stimulatory drug effect on trophic 5-HT(2B) receptors. As lisuride is devoid of such an effect, but on the contrary is an extremely potent 5-HT(2B) antagonist, an association of lisuride therapy with cardiac valvulopathies seems to be highly unlikely. In agreement with this hypothesis, not a single report of a cardiac valvulopathy associated with lisuride therapy has been identified in any database so far.Furthermore, against a background of an estimated 360,000 patient years, we have found only a very small number of cases of any other form of fibrosis (1x retroperitoneal, 2x pleural, 2x pulmonary, 1x interstitial pulmonary changes), in part combined with other risk factors and confounding variables. This closely matches 4 reports available from WHO (1x retroperitoneal, 3x pleural fibrosis). In addition, only 5 other possibly related conditions (3x pleural effusion, 1x pleuritis, 1x pericarditis) were identified in the lisuride adverse drug reaction database of Schering, Berlin. CONCLUSIONS: No link has been found between lisuride use and fibrotic cardiac valvulopathy, in agreement with the 5-HT(2B) receptor antagonist effect of this drug. The very low incidence of spontaneous reports of any other fibrosis could be even compatible with an association by chance in the population exposed to lisuride. Although close monitoring for this kind of side effects is still to be recommended in the therapy with lisuride, our data do not support the concept of a class effect suggesting that all ergot-derived drugs and especially DA receptor agonists with some chemical similarity to the ergot structure will cause or facilitate cardiac valvulopathies as observed with pergolide.

Transdermal lisuride: short-term efficacy and tolerability study in patients with severe restless legs syndrome.

BACKGROUND AND PURPOSE: Restless legs syndrome (RLS) patients suffer from symptoms not only at bedtime but also with variable circadian patterns. Transdermal application forms of dopamine agonists are expected to lead to a stable plasma concentration of the active drug which could ease treatment for RLS patients with daytime symptoms and avoid side effects of oral dopaminergic therapies. PATIENTS AND METHODS: In this controlled pilot study, 10 patients (six females, four males, mean age 58 years) with severe and long-lasting idiopathic RLS were treated during an initial open-label phase for 2 weeks either with one (n=3 patients) or, if required, two patches of lisuride every other day (dose per patch: 3mg lisuride, nominal effective release rate 7.0 microg lisuride/h). Patients were then randomized to double-blind treatment with lisuride (n=5) or placebo (n=4) for 1 week. RESULTS: Severity of RLS clearly improved during open-label and double-blind treatment with lisuride but became worse under placebo according to the International Restless Legs Syndrome Study Group Rating Scale (IRLS), RLS-6, and Clinical Global Impressions (CGIs) scales, and actigraphy assessments (periodic leg movement index) in the 1-week double-blind period. CONCLUSION: The explorative findings of this small controlled study suggest that lisuride patches might be an efficacious treatment for RLS patients without clinically relevant tolerability problems.

Prospective randomized trial of lisuride infusion versus oral levodopa in patients with Parkinson's disease.

Motor complications are a major source of disability for patients with advanced Parkinson's disease. Surgical therapies provide benefit to some, but these treatments are expensive and associated with adverse effects. Current research indicates that motor complications are associated with abnormal, intermittent, pulsatile stimulation of denervated dopamine receptors using short acting dopaminergic agents such as levodopa. Retrospective studies suggest that the use of longer-acting more continuous dopaminergic therapies can improve both motor fluctuations and dyskinesia. We performed a prospective, long-term (4-year) trial comparing patients randomized to receive subcutaneous infusion of the dopamine agonist lisuride versus conventional therapy with oral levodopa and dopamine agonists. We demonstrate that patients receiving lisuride infusions experienced a significant reduction in both motor fluctuations and dyskinesia compared with patients receiving standard dopaminergic therapies. Benefits persisted for the 4-year duration of the study. Mean Unified Parkinson's Disease Rating Scale scores in "ON" and "OFF" states did not significantly change between baseline and 4 years for patients in the lisuride group, but deteriorated in patients in the levodopa group. This study indicates that continuous lisuride infusion can be beneficial for patients with advanced Parkinson's disease and reverse established motor fluctuations and dyskinesia.

Lisuride, a dopamine D2 receptor agonist, and anticraving drug expectancy as modifiers of relapse in alcohol dependence.

Due to a central role of dopamine in mediating ethanol intake and dependence, the authors tested lisuride, a dopamine D2 receptor agonist, for relapse prevention in alcoholics. Psychological and neuroendocrine determinants of outcome were also assessed within the study. This double-blind, placebo-controlled randomized study comprised 120 alcoholics who were subjected to an intend-to-treat analysis (ITT). After hospital detoxification, patients received an outpatient rehabilitation program and either the study medication or placebo for 6 months and follow-up for another 6 months without medication. Pharmacological and psychological effects on relapse and times to first drink were assessed using survival analysis and multivariate analysis of variance (ANOVA). Neuroendocrine assessments were made using growth hormone (GH) response to stimulation with dopamine D2 receptor agonist apomorphine. In contrast to our hypothesis, the pharmacological effects of lisuride shortened (effect size: 0.51) and the expectation of receiving the drug (while being on medication) prolonged the latency of relapse (effect size: 0.47) in weaned alcoholics. Lisuride was associated with side effects like dizziness and hypotension. Dopaminergic responsivity to apomorphine stimulation was reduced under lisuride. This study supports the view that alcoholics may relapse due to decreased dopamine function, resulting from intake of dopamine D2 receptor agonists. In particular, our data do not support the use of lisuride for relapse prevention in alcoholics. The favorable impact of anticraving drug expectancy on outcome was unrelated to this effect.

Efficacy and tolerability of dopamine agonists in a parkinsonian population.

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.

Long-duration effect and the postsynaptic compartment: study using a dopamine agonist with a short half-life.

A possible reason why levodopa induces a sustained, stable motor benefit during the first months to years of therapy may be its long duration of action. This long-duration effect may be due either to a presynaptic storage mechanism or to postsynaptic pharmacodynamic changes. We previously reported that the dopamine agonist ropinirole induced a long-duration response (LDR) in levodopa-naive patients with Parkinson's disease. In this study, we investigated motor responses to the short half-life dopamine agonist lisuride in a group of levodopa naive parkinsonian patients. Once lisuride reached its maximum effect, it was substituted, in randomized order, with placebo. Neither investigators nor patients knew when the active drug was switched to placebo. When patients were switched from lisuride to placebo, their Unified Parkinson's Disease Rating Scale (UPDRS) motor scores and tapping test and screw scores declined to baseline values within a mean 9.0 +/- 1.9 days. The results confirmed that, like ropinirole and levodopa, the short-acting dopamine agonist lisuride induces a long-duration response, probably due to postsynaptic changes.

Five-year follow-up of early lisuride and levodopa combination therapy versus levodopa monotherapy in de novo Parkinson's disease. The French Lisuride Study Group.

The value of an early initial coadministration of levodopa (L-dopa) and lisuride in Parkinson's disease was the main goal of the present study. Eighty-two patients with recently diagnosed idiopathic Parkinson's disease were randomized into two groups for treatment with L-dopa alone or L-dopa + lisuride. The trial was double-blinded for the first year and open for the following 4 years. Selegiline (10 mg/day b.i.d.) was added in both groups at the end of the first year. Outcome measures were evolution of L-dopa dosage and Unified Parkinson's Disease Rating Scale scores and subscores, and incidence of motor complications. The dropout rate was higher in the L-dopa group (63.4%) than in the combination group. Motor improvement was better (p < 0.01) in the L-dopa + lisuride group. Expected motor complications were rare, moderate and equivalent in the two groups despite a difference in L-dopa dosage (446.7 vs. 387.5 mg/day). Long-term follow-up demonstrated the L-dopa-sparing effect of lisuride (average 1 mg/day), the beneficial effect of early combination therapy on motor status and the paucity of motor complications in both groups.

Sleep attacks and Parkinson's disease treatment.

Three patients with Parkinson's disease had so-called sleep attacks at the wheel while taking bromocryptine, lisuride pergolide, or piribedil. We believe that all dopamine agonists can induce sleep attacks.

Postpartum cerebral angiopathy with intracerebral hemorrhage in a patient receiving lisuride.

Postpartum cerebral angiopathy is a recognized but infrequent complication of ergot alkaloid derivatives. We describe a patient who experienced reversible cerebral vasoconstriction with intracerebral hemorrhage (ICH) after ingesting lisuride in the postpartum period. Lisuride is likely to cause postpartum cerebral angiopathy, and ICH must now be considered a possible cerebrovascular complication of postpartum cerebral angiopathy. Our observation calls for further study to verify these findings.

Ropinirole: new preparation. Wait for more convincing data.

In previously untreated parkinsonian patients at an early stage of the disease, three comparative trials have shown that, during the first six months of treatment, the effect of ropinirole on motor symptoms almost equates to that of levodopa and is a little better than that of bromocriptine monotherapy. Until these trials have been completed (they are planned to last for 3 to 5 years), it will be impossible to know whether the postponement of dopatherapy with ropinirole administration influences the long-term outcome of Parkinson's disease. In patients already on levodopa who have mobility fluctuations, the only demonstrated effect in one trial was that the addition of ropinirole allowed the daily dose of levodopa to be reduced. However, this is a surrogate end point with no clinical relevance. A single comparative trial, versus another dopamine agonist, bromocriptine, is available, but its complex methodology makes it impossible to draw firm conclusions. The adverse effects of ropinirole are the same as those of other dopamine agonists. Again, this means that the assessment of ropinirole must continue to determine whether the drug carries an increased risk of dyskinesias or psychological effects.

[Parkinson disease--problems in long-term treatment. Dopamine agonists optimize L-dopa therapy]. / Morbus Parkinson--Probleme der Langzeitbehandlung. Dopaminagonisten optimieren die L-Dopa-Therapie.

In a 59-year-old male with a 10 year history of Parkinson's disease, progressive movement disorders occurred under medical treatment (end-of-dose akinesia and peak-dose dyskinesia). Thereupon his treatment was changed to a combination of L-dopa/ decarboxylase inhibitor administered during the day in 5 fractions, and additionally a slow-release dopa preparation given on retiring for the night. At the same time, the patient received the dopamine agonist lisuride. While the patient was hospitalized for surgery, his anti-parkinsonism regimen was initially stopped and then continued in changed form. In the following weeks he experienced a drastic impairment of mobility and, in particular, suffered pronounced nocturnal hypokinetic events. A second period of hospitalization became necessary, a complex medical therapeutic regimen similar to the previously successful combination was established. This resulted in satisfactory mobility, and the patient was able to go back to work.

Effects of terguride on anterior pituitary function in parkinsonian patients treated with L-dopa: a double-blind study versus placebo.

In a randomized double-blind study, 20 parkinsonian patients (suffering from the disease for 2-18 years), chronically treated with levodopa (500-750 mg/day for 0.5-12 years), received terguride (1 mg b.i.d.) or placebo for 4 weeks. Growth hormone (GH), prolactin (PRL), thyroid-stimulating hormone (TSH), and insulin-like growth factor (IGF-I) secretions were studied before and after the morning dose of levodopa (250 mg p.o.), both before and at the end of study period. At the beginning of the study, basal hormonal levels were within normal limits, and levodopa administration induced a significant suppression in PRL and TSH levels (both p < 0.01)) and a significant increase in GH (p < 0.01). The same results were observed at the end of the study period in the placebo group. Addition of terguride induced a significant suppression in basal PRL levels (p < 0.01), whereas levodopa-induced hormonal changes were unaffected. These data suggest that the hypothalamic dopaminergic function that controls anterior pituitary hormones is preserved in parkinsonian patients, regardless of both the duration of the disease and the long-term treatment with levodopa. The strong additional prolactin-lowering effect of terguride indicates long-lasting dopaminergic effects, as is already known from hyperprolactinemic conditions. The dopaminergic effects of levodopa on TSH, GH, and IGF-I secretion were unchanged by terguride treatment. The anti-dopaminergic effects of terguride observed in the motor system in animal studies, as well as in levodopa-induced dyskinesias in parkinsonian patients, could not be observed in the case of the dopaminergic control of anterior pituitary hormones under the conditions of this study.

A study on the effect and tolerance of lisuride on Parkinson's disease.

Seventeen idiopathic parkinsonian patients ranging between 47 and 75 years of age were included in this study to investigate the effect and tolerance of lisuride on PD. The duration of this simple clinical study, which had no control group was 12 weeks. There was 50% relief in disability scores and ADL in 13 patients in the first group in the combined therapy for 12 weeks with lisuride added to L-DOPA plus benserazide (p < 0.01). Optimal lisuride doses added to L-DOPA plus benserazide varied between 0.1 and 0.8 mg (mean 0.5 +/- 0.2 mg). With the addition of lisuride to treatment, the L-DOPA plus benserazide dose was reduced in 6 of 13 by 38%. Monotherapy with lisuride resulted in 56% to 57% improvement in disability scores and 47% in relief in ADL. Dry mouth, nausea, weakness, postural hypotension, and headache were the most frequently encountered side effects of lisuride. These adverse effects disappeared in 3 or 4 days, depending on a slight decrease and following increase in the dose of lisuride and/or the development of tolerance. Not only will such a combined therapy contribute to the reduction of the end-of-dose inadequacies, on-off phenomena, wearing off, peak-dose dyskinesias, and similar motor fluctuations, it may also play a prophylactic role in their prevention or delay.

[Clinical aspects and follow-up of dopamine-induced psychoses in continuous dopaminergic therapy and their implications for the dopamine hypothesis of schizophrenic symptoms]. / Klinik und Verlauf dopamininduzierter Psychosen unter kontinuierlicher dopaminerger Therapie und ihre Implikationen für die Dopaminhypothese schizophrener Symptomatik.

We present the case reports of 11 Parkinsonian patients who developed acute psychosis under continuous dopaminergic stimulation. Psychopathologically, two of the patients mainly suffered from organic hallucinosis, while nine patients showed the clinical symptoms of delirium. The clinical course and psychopathological findings in these patients did not differ from other acute organic psychoses. However, the symptoms of these dopaminergically induced psychoses varied significantly from the psychopathological findings of paranoid schizophrenic patients who were regularly treated and evaluated in our clinic. These differences in symptoms and clinical course of dopamine-induced and schizophrenic psychosis do not support the hypothesis that the pathogenesis of schizophrenic symptoms can be explained only by a hyperfunction of dopaminergic transmission. Instead, the involvement of other neurotransmitter system must be considered in order to explain the pathogenesis of schizophrenic symptoms on a neurobiological level.

[Is dopaminergic therapy immunologically rejuvinating? Increased interferon-gamma production with the dopaminergic agent lisuride]. / Macht dopaminerge Therapie immunologisch jung? Erhöhte Interferon-gamma-Produktion unter dem Dopaminergikum Lisurid.

Eighteen patients with advanced Parkinson's disease (n = 13) or dopamine-sensitive dystonia (n = 5) were treated with the dopaminergic agent, lisuride, applied as a long-term subcutaneous infusion. The results were compared with those obtained in a group of younger, and a group of older, healthy volunteers. The liberation of gamma-interferon (gamma-IFN) following mitogenic stimulation of whole blood with phytohemagglutinin (PHA) was highly significantly elevated in comparison with the group of older healthy volunteers, and clearly, but not significantly, elevated in comparison with the younger group. There was no difference between patients with dystonia and those with Parkinson's disease. The effect observed is thus probably due to lisuride. This effect might explain the longer life expectancy and reduced proclivity for infection shown by patients with Parkinson's disease. It needs to be determined whether, on the basis of these initial data, a therapeutic principle for the treatment of diseases that can be directly influenced by gamma-IFN can be derived.

[Inhibition of lactation with lisuride. CLinical evaluation]. / Inhibición de la lactancia con lisurida. Evaluación clínica.

Lactation in humans requires the collaboration of neural and endocrine systems. During pregnancy and after parturition prolactin and also sex steroids, corticoids, growth hormone and human placental lactogen are necessary for lactogenesis. In an open, simple and prospective study, 50 women with normal delivery or cesarean section, between 34 and 41 weeks of gestation, were treated with lisuride, 0.2 mg t.i.d. for 14 days in order to inhibit lactation. The arrest of lactation was mandatory for medical reasons and the results were evaluated by changes in breast related with shape, volume, symmetry, coloring, temperature, turgescence, venous appearance, nipple condition, colostrum and lymph nodes increase. Lactation that was already present in 87% of patients in the first exploration 24 hours after delivery was satisfactorily suppressed and also breast pain, engorgement and discomfort caused by milk leakage. None had rebound lactation. 5 patients had light nausea. The dopamine agonist lisuride can be used for primary arrest of lactation with clinical effectiveness and without potential dangerous side effects of hormonal compounds.