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PubMed1997

Cabergoline in the treatment of early Parkinson's disease: results of the first year of treatment in a double-blind comparison of cabergoline and levodopa. The PKDS009 Collaborative Study Group.

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.

Aged↗
PubMed1994

A comparison of cabergoline and bromocriptine in the treatment of hyperprolactinemic amenorrhea. Cabergoline Comparative Study Group.

BACKGROUND: Cabergoline is a long-acting dopamine-agonist drug that suppresses prolactin secretion and restores gonadal function in women with hyperprolactinemic amenorrhea. We designed a study to compare its safety and efficacy with those of bromocriptine, which has been the standard therapy. METHODS: A total of 459 women with hyperprolactinemic amenorrhea were treated with either cabergoline (0.5 to 1.0 mg twice weekly) or bromocriptine (2.5 to 5.0 mg twice daily), administered in a double-blind fashion for 8 weeks and subsequently in an open fashion for 16 weeks, during which adjustments in the dose were made according to the response. Of the 459 women, 279 had microprolactinomas, 3 had macroprolactinomas, 1 had a craniopharyngioma, 167 had idiopathic hyperprolactinemia, and the remainder had an empty sella. Clinical and biochemical status was assessed at 2-week intervals for 8 weeks and monthly thereafter for a total of 6 months, with an additional assessment at 14 weeks. RESULTS: Stable normoprolactinemia was achieved in 186 of the 223 women treated with cabergoline (83 percent) and 138 of the 236 women treated with bromocriptine (59 percent, P < 0.001). Seventy-two percent of the women treated with cabergoline and 52 percent of those treated with bromocriptine had ovulatory cycles or became pregnant during treatment (P < 0.001). Amenorrhea persisted in 7 percent of the cabergoline-treated women and 16 percent of the bromocriptine-treated women. Adverse effects were recorded in 68 percent of the women taking cabergoline and 78 percent of those taking bromocriptine (P = 0.03); 3 percent discontinued taking cabergoline, and 12 percent stopped taking bromocriptine (P < 0.001) because of drug intolerance. Gastrointestinal symptoms were significantly less frequent, less severe, and shorter-lived in the women treated with cabergoline. CONCLUSIONS: Cabergoline is more effective and better tolerated than bromocriptine in women with hyperprolactinemic amenorrhea.

Adolescent↗
PubMed1992

Dose-dependent suppression of serum prolactin by cabergoline in hyperprolactinaemia: a placebo controlled, double blind, multicentre study. European Multicentre Cabergoline Dose-finding Study Group.

OBJECTIVE: Dopamine agonists have a well established place in the treatment of hyperprolactinaemic disorders but their use is associated with a high incidence of adverse effects. We have investigated the biochemical efficacy and side-effect profile of a range of doses of the novel, long-acting dopamine agonist, cabergoline, in suppressing prolactin (PRL) in hyperprolactinaemic women. DESIGN: Multicentre, prospective, randomized, placebo controlled and double blind. PATIENTS: One hundred and eighty-eight women with hyperprolactinaemia secondary to microprolactinoma (n = 113), idiopathic disease (n = 67), empty sella syndrome (n = 7) or following failed surgery for a macroprolactinoma (n = 1). MEASUREMENTS: Weekly assessment of adverse symptoms, blood pressure and pulse, serum PRL, blood count, liver and renal function. RESULTS: Patients received either placebo (n = 20) or cabergoline 0.125 (n = 43), 0.5 (n = 42), 0.75 (n = 42) or 1.0 mg (n = 41) twice weekly for 4 weeks. The five treatment groups were comparable in age (mean 31.8, range 16-46 years), diagnosis, previous therapy, and pretreatment serum PRL. PRL was suppressed to below half the pretreatment level in 5, 60, 90, 95 and 98% and normalized in 0, 30, 74, 74 and 95% of patients taking placebo or cabergoline 0.125, 0.5, 0.75 or 1.0 mg twice weekly respectively (Armitage's test, chi 2 = 39.3, P < 0.01). Cabergoline therapy (all doses) restored menses in 82% of the amenorrhoeic women not previously treated with dopamine agonists. Adverse events were recorded in 45% of patients in the placebo group and in 44, 50, 50 and 58% of those taking 0.125, 0.5, 0.75 and 1.0 mg cabergoline twice weekly (Armitage's test, P > 0.05). Over 95% of reported symptoms were relatively trivial, most frequently transient nausea, headache, dizziness, fatigue and constipation. More severe adverse events, interfering significantly with the patients' lifestyle, occurred in 13 (7.7%) patients taking cabergoline; treatment withdrawal was necessary in only one case. No adverse effects were detected on blood pressure or haematological or biochemical parameters. CONCLUSIONS: We have shown a linear dose-response relationship for cabergoline in the treatment of hyperprolactinaemia in the range 0.125-1.0 mg twice weekly, with normalization of PRL in up to 95% of cases and acceptable tolerability throughout the dose range.

Adolescent↗
PubMed1991

Single dose cabergoline versus bromocriptine in inhibition of puerperal lactation: randomised, double blind, multicentre study. European Multicentre Study Group for Cabergoline in Lactation Inhibition.

OBJECTIVE: To compare the efficacy and safety of a single dose of 1 mg of cabergoline with that of bromocriptine 2.5 mg twice daily for 14 days in the inhibition of puerperal lactation. DESIGN: Prospective, randomised, double blind, parallel group, multicentre study. SETTING: University of hospital departments of obstetrics and gynaecology in different European countries. SUBJECTS: 272 puerperal women not wishing to lactate (136 randomised to each drug). INTERVENTIONS: Women randomised to cabergoline received two 0.5 mg tablets of cabergoline and one placebo tablet within 27 hours after delivery and then placebo twice daily for 14 days. Those randomised to bromocriptine received 2.5 mg of bromocriptine and two placebo tablets within 27 hours and then 2.5 mg of bromocriptine twice daily for 14 days. MAIN OUTCOME MEASURES: Success of treatment (complete or partial) according to milk secretion, breast engorgement, and breast pain; rebound symptomatology; serum prolactin concentrations; and number of adverse events. RESULTS: Complete success was achieved in 106 of 136 women randomised to cabergoline and in 94 of 136 randomised to bromocriptine and partial success in 21 and 33 women respectively. Rebound breast symptomatology occurred respectively in five and 23 women with complete success up to day 15 (p less than 0.0001). Serum prolactin concentrations dropped considerably with both drugs from day 2 to day 15; a prolactin secretion rebound effect was observed in women treated with bromocriptine. cabergoline and 36 receiving bromocriptine (p = 0.054), occurring most during the first treatment day. CONCLUSION: A single 1 mg dose of cabergoline is at least as effective as bromocriptine 2.5 mg twice daily for 14 days in preventing puerperal lactation. Because of the considerably lower rate of rebound breast activity and adverse events and the simpler administration schedule cabergoline should be the drug of choice for lactation inhibition.

Adult↗
PubMed1993

The efficacy and tolerability of long-term cabergoline therapy in hyperprolactinaemic disorders: an open, uncontrolled, multicentre study. European Multicentre Cabergoline Study Group.

OBJECTIVE: We assessed the efficacy and safety of the new, long-acting dopamine agonist drug cabergoline during long-term therapy of hyperprolactinaemia. DESIGN: Open, prospective, multicentre study. PATIENTS: One hundred and sixty-two females with either a microprolactinoma (n = 100), idiopathic hyperprolactinaemia (n = 54), empty sella syndrome (n = 7) or residual hyperprolactinaemia after surgery for a macroprolactinoma (n = 1). All had previously been treated with cabergoline or placebo for 4 weeks as part of a dose-finding study. MEASUREMENTS: Menstrual pattern, adverse symptoms, blood pressure and pulse, serum PRL, blood count, liver and renal function were assessed after one month and subsequently at two-monthly intervals. RESULTS: Treatment was started at doses of 0.25 mg (n = 3), 0.5 mg (n = 8), 1 mg (n = 150) or 2 mg (n = 1) per week, given either as a single weekly dose (n = 8) or divided into twice-weekly doses (n = 154), and was continued for at least 49 weeks in 123 patients. Final treatment doses ranged from 0.25 mg fortnightly to 2 mg twice weekly: most patients finished the study taking 0.5 mg once (n = 31) or twice (n = 77) weekly. Stable normalization of PRL levels was achieved in 138 subjects (85%), in 129 of whom the effective dose was < 1 mg per week. In the subset of 114 patients completing 49 weeks of therapy and having dose adjustments according to the protocol, the biochemical success rate was 92%. Fifty-nine of the 65 previously amenorrhoeic women (91%) and 44 of the 49 (90%) who were previously oligomenorrhoeic resumed regular menses and/or became pregnant during the study. Adverse events were reported in 64 patients (39.5%). In 84% of cases with adverse events, the symptoms were of mild or moderate severity and most occurred during the first few weeks of therapy; five patients (3%) discontinued treatment because of poor tolerance. The most frequent symptoms were dizziness (13% of patients), headache (13%), nausea (10%) and weakness and/or fatigue (10%). Of 27 patients who had previously been poorly tolerant of other dopamine agonists, 17 (63%) did not experience any side-effects and only one was intolerant of cabergoline. No adverse haematological or biochemical effects were detected except for a slight downward trend in haemoglobin which may have been related to the resumption of regular menses in previously amenorrhoeic or oligomenorrhoeic women. A mild hypotensive effect was observed, mean systolic and diastolic blood pressures falling by 5 and 4 mmHg respectively during treatment. CONCLUSIONS: The results provide evidence for the long-term effectiveness and safety of cabergoline in the treatment of hyperprolactinaemia. Its ability to normalize PRL and restore gonadal function compares favourably with reported data on reference compounds while its tolerability profile and simple administration schedule offer potential advantages in terms of patient acceptability.

Adult↗
PubMed1998

Treatment of lactating sows with the dopamine agonist Cabergoline: effects on LH and prolactin secretion and responses to challenges with naloxone and morphine.

This study was conducted to examine the effects of chronic administration of a long-acting dopamine agonist, Cabergoline, on LH and prolactin secretion during lactation in the sow. The effect of the administration of the opioid antagonist naloxone and the agonist morphine in Cabergoline treated animals was also evaluated. In Part I of the experiment, 16 sows were treated as either CONT sows (n = 4; control, no treatment); CAB sows (n = 4; treated with Cabergoline from days 10 to 26 of lactation); CAB + NAL sows (n = 4; received Cabergoline treatment and naloxone challenges); CAB + MORP sows (n = 4; treated with Cabergoline and morphine challenges). Plasma LH and prolactin concentrations were measured in blood samples taken from all sows during 6-h periods at days 12, 19 and 26 of lactation. To extend the results at the most critical response period at day 26, another 11 sows were allocated in Part II to either Control (n = 3), Cabergoline (n = 4) or Cabergoline and morphine (n = 4) treatments as for Part I, but the effect of treatments were only confirmed in a single period of sampling at day 26 of lactation. Cabergoline treatment alone increased (P < 0.001) mean plasma LH concentrations at day 26 but not at days 12 and 16 of lactation. In contrast, naloxone challenges given in the presence of Cabergoline treatment increased (P < 0.05) mean LH at days 12 and 19 of lactation but not at day 26. Morphine challenges in the presence of Cabergoline treatment decreased (P < 0.05) mean LH concentrations only at day 26 of lactation, but did not completely reverse the effect of Cabergoline. No treatment differences in plasma oestradiol-17 beta were detected at any time. Plasma prolactin decreased (P < 0.001) in response to treatment with Cabergoline but there were no additional effects of naloxone or morphine. These data provide evidence for the existence of dopaminergic and opioidergic regulation of LH secretion in lactation in the sow and the relative influence of these systems changes as lactation progresses. Furthermore, the data suggest that the stimulatory effect of Cabergoline treatment on LH secretion in late lactation may be mediated by its effects on an inhibitory opioidergic mechanism. Finally, the data provide conclusive proof that prolactin does not directly influence LH secretion or estrogenic activity of the ovary during lactation in the sow.

Analysis of Variance↗
PubMed1995

Cabergoline. A review of its pharmacological properties and therapeutic potential in the treatment of hyperprolactinaemia and inhibition of lactation.

Cabergoline is a synthetic ergoline which shows high specificity and affinity for the dopamine D2 receptor. It is a potent and very long-acting inhibitor of prolactin secretion. Prolactin-lowering effects occur rapidly and, after a single dose, were evident at the end of follow up (21 days) in puerperal women, and up to 14 days in patients with hyperprolactinaemia. In the only comparative study to date, cabergoline 0.5 to 1.0 mg twice weekly was more effective than bromocriptine 2.5 to 5.0 mg twice daily in the treatment of hyperprolactinaemic amenorrhoea, restoring ovulatory cycles in 72% of women and normalising plasma prolactin levels in 83%, compared with 52 and 58%, respectively, for bromocriptine. In the prevention of puerperal lactation, a single dose of cabergoline 1.0mg was as effective as bromocriptine 2.5mg twice daily for 14 days. A significantly lower incidence of rebound lactation in the third postpartum week was seen with cabergoline. Unpublished data suggest cabergoline 0.25mg twice daily for 2 days is effective in suppressing established puerperal lactation in about 85% of women. Nausea, vomiting, headache and dizziness are characteristic adverse events of the dopaminergic ergot derivatives. Cabergoline appears to be better tolerated than bromocriptine in both patients with hyperprolactinaemia and postpartum women. Most patients intolerant of other ergot derivatives can tolerate cabergoline. Bromocriptine use in the puerperium has been associated with an increased risk of serious thromboembolic events. However, there are no such reports with cabergoline and whether these events will become associated with other dopaminergic agents is unknown. The teratogenic potential of cabergoline has not been extensively investigated in humans. Ten congenital abnormalities have been reported in 199 cabergoline-associated pregnancies. Although there is no pattern to these abnormalities, the limited experience with cabergoline in pregnancy means the drug cannot be considered as a first-line therapy for the treatment of infertility associated with hyperprolactinaemia. At this stage of its development, cabergoline will prove useful in patients with hyperprolactinaemia who have failed treatment with, or are intolerant of, other dopamine agonists such as bromocriptine. If drug treatment is required for the prevention or suppression of puerperal lactation, cabergoline offers significant advantages over bromocriptine and should become the drug treatment of first choice for this indication.

Administration, Oral↗
PubMed1999

Cabergoline in the treatment of hyperprolactinemia: a study in 455 patients.

Cabergoline is a new long-acting dopamine agonist that is very effective and well tolerated in patients with pathological hyperprolactinemia. The aim of this study was to examine, in a very large number of hyperprolactinemic patients, the ability to normalize PRL levels with cabergoline, to determine the effective dose and tolerance, and to assess the effect on clinical symptoms, tumor shrinkage, and visual field abnormalities. We also evaluated the effects of cabergoline in a large subgroup of patients with bromocriptine intolerance or -resistance. We retrospectively reviewed the files of 455 patients (102 males and 353 females) with pathological hyperprolactinemia treated with cabergoline in 9 Belgian centers. Among these patients, 41% had a microadenoma; 42%, a macroadenoma; 16%, idiopathic hyperprolactinemia; and 1%, an empty sella. The median pretreatment serum PRL level was 124 microg/L (range, 16-26,250 microg/L). A subgroup of 292 patients had previously been treated with bromocriptine, of which 140 showed bromocriptine intolerance and 58 showed bromocriptine resistance. Treatment with cabergoline normalized serum PRL levels in 86% of all patients: in 92% of 244 patients with idiopathic hyperprolactinemia or a microprolactinoma and in 77% of 181 macroadenomas. Pretreatment visual field abnormalities normalized in 70% of patients, and tumor shrinkage was seen in 67% of cases. Side effects were noted in 13% of patients, but only 3.9% discontinued therapy because of side effects. The median dose of cabergoline at the start of therapy was 1.0 mg/week but could be reduced to 0.5 mg/week once control was achieved. Patients with a macroprolactinoma needed a higher median cabergoline dose, compared with those with idiopathic hyperprolactinemia or a microprolactinoma: 1.0 mg/week vs. 0.5 mg/week, although a large overlap existed between these groups. Twenty-seven women treated with cabergoline became pregnant, and 25 delivered a healthy child. One patient had an intended abortion and another a miscarriage. In the patients with bromocriptine intolerance, normalization of PRL was reached in 84% of cases, whereas in the bromocriptine-resistant patients, PRL could be normalized in 70%. We confirmed, in a large-scale retrospective study, the high efficacy and tolerability of cabergoline in the treatment of pathological hyperprolactinemia, leaving few patients with unacceptable side effects or inadequate clinical response. Patients with idiopathic hyperprolactinemia or a microprolactinoma, on average, needed only half the dose of cabergoline as those with macroprolactinomas and have a higher chance of obtaining PRL normalization. Cabergoline also normalized PRL in the majority of patients with known bromocriptine intolerance or -resistance. Once PRL secretion was adequately controlled, the dose of cabergoline could often be significantly decreased, which further reduced costs of therapy.

Adenoma↗
PubMed1996

Dopamine receptor affinities in vitro and stereotypic activities in vivo of cabergoline in rats.

An ergot alkaloid derivative, cabergoline, and its metabolites were investigated for their affinities for dopamine D1 and D2 receptors in rat striatum in vitro in comparison with those of bromocriptine and pergolide. The affinity for D1 receptors was in the following order: pergolide > des-dimethylaminopropyl cabergoline (FCE21904) > cabergoline > or = bromocriptine > or = des-methyl cabergoline (FCE27395) > or = des-ethylcarbamoyl cabergoline (FCE21590). From the effects of GTP on these affinities for the D1 receptor, cabergoline, some of its metabolites, and pergolide were characterized as agonists in contrast to bromocriptine which was classified as an antagonist. The affinity for D2 receptors was ranked as follows: pergolide > or = cabergoline > or = FCE27395 > or = FCE21904 > bromocriptine > FCE21590 > carboxylic acid-type derivative of cabergoline (FCE21589). The affinity of each compound for the D2 receptor was much higher than that for the D1 receptor. The selectivity of cabergoline for D2 receptor was higher than those of bromocriptine and pergolide. Furthermore, these ergot alkaloids were investigated for eliciting stereotypy after subcutaneous administration to normal rats. Pergolide potently induced stereotypy at doses of 0.5 and 1.0 mg/kg, cabergoline slightly induced it only at a high dose of 2.0 mg/kg, whereas bromocriptine did not induce it at any of the doses tested, 10-40 mg/kg. These results suggest that pharmacological properties of cabergoline for the D1 and D2 receptors differ from those of bromocriptine and pergolide.

Animals↗
PubMed1998

Clinical experience with cabergoline in patients with advanced Parkinson's disease treated with levodopa.

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.

Antiparkinson Agents↗
PubMed1988

Inhibitory effect of cabergoline on the development of estrogen-induced prolactin-secreting adenomas of the pituitary.

Cabergoline 1-[(6-allylergolin-8 beta-yl)carbonyl]-1-[3-(dimethylamino) propyl]-3-ethylurea is a recently developed ergot derivative with a long-lasting dopamine agonist action. We now studied the ability of cabergoline to counteract the development of a prolactin-secreting tumor (prolactinoma) induced in female rats by long-term administration of high doses of estrogens. The effect of cabergoline was compared to that of bromocriptine. Cabergoline (0.6 mg/kg p.o.) had a marked and sustained prolactin-lowering effect in freely moving female rats, its effect still being present 3 days after a single dose. Bromocriptine, at a dose 5-fold higher (3 mg/kg s.c.), induced a strong and short-lasting prolactin inhibitory effect which, however, had completely disappeared 24 h post-injection. Intermittent administration of cabergoline (0.6 mg/kg p.o. every 3 days), starting from the first day of estrogen treatment, completely counteracted the development of the prolactinoma, as judged by the weight of the pituitary and the stimulating effect of estrogens on plasma prolactin and mitotic rate and DNA synthesis of pituitary cells. These effects of cabergoline were shared by a 5-fold higher dose of bromocriptine (3 mg/kg s.c.) given daily. The potent anti-tumorigenic effect of cabergoline, coupled to a sustained prolactin-lowering effect, the most prolonged ever seen with an ergot derivative, makes cabergoline a most suitable drug for the treatment of human macroprolactinomas.

Adenoma↗
PubMed1990

In vivo interaction of cabergoline with rat brain dopamine receptors labelled with [3H]N-n-propylnorapomorphine.

Cabergoline is a potent dopaminergic agent that interacts with agonists and antagonists of dopamine receptors in vitro. We studied the binding of [3H]N-n-propylnorapomorphine ([3H]NPA) to dopamine receptors after i.v. and oral administration of cabergoline to determine whether cabergoline crosses the blood-brain barrier; bromocriptine was used as a reference drug. Cabergoline and/or its active metabolite(s) did cross the blood-brain barrier and reach dopamine receptors. Comparative time-course analysis of the regional inhibition of [3H]NPA binding showed that cabergoline was more potent than bromocriptine in inhibiting [3H]NPA binding and that it occupied the receptor for longer. These effects were observed in all areas of the rat brain studied (striatum, olfactory tubercles, adeno- and neurohypophysis, thalamus and hypothalamus). Further studies in the striatum and adenohypophysis showed that cabergoline receptor occupancy was dose-dependent and still detectable 72 h after i.v. administration of the drug. While cabergoline was more potent in the striatum than in the adenohypophysis when administered i.v., the reverse was observed after its oral administration. Cabergoline was equally potent in the adenohypophysis after oral and i.v. administration, as determined 1 and 8 h later.

Administration, Oral↗
PubMed1997

Clinical and pharmacokinetic evaluation of L-dopa and cabergoline cotreatment in Parkinson's 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.

Aged↗
PubMed1998

Cabergoline in the treatment of acromegaly: a study in 64 patients.

Cabergoline is a new, long acting, dopamine agonist that is more effective and better tolerated than bromocriptine in patients with hyperprolactinemia. Because dopamine agonists still have a place in the medical management of acromegaly, cabergoline might be a useful treatment. We, therefore, evaluated the effect of long term administration of cabergoline in a large group of unselected acromegalic patients. Sixty-four patients were included in a multicenter, prospective, open labeled study. A subgroup of 16 patients had GH-/PRL-cosecreting pituitary adenomas. Cabergoline was started at a dose of 1.0 mg/week and was gradually increased until normalization of plasma insulin-like growth factor I (IGF-I) levels, occurrence of unacceptable side-effects, or a maximal weekly dose of 3.5 mg (7.0 mg in 1 case) was reached. Treatment with cabergoline suppressed plasma IGF-I below 300 micrograms/L in 39% of cases and between 300-450 micrograms/L in another 28%. With pretreatment plasma IGF-I concentrations less than 750 micrograms/L, a suppression of IGF-I below 300 micrograms/L was obtained in 53% of cases, and a suppression between 300-450 micrograms/L was obtained in another 32%. By contrast, with pretreatment plasma IGF-I concentrations above 750 micrograms/L, only 17% of cases showed a suppression of IGF-I below 300 micrograms/L, and there was IGF-I suppression between 300-450 micrograms/L in another 21%. In GH-/PRL-cosecreting adenomas, 50% of cases suppressed plasma IGF-I levels below 300 micrograms/L, and another 31% did so between 300-450 micrograms/L, in contrast to only 35% and 27%, respectively in GH-secreting adenomas. Similar results were obtained concerning the secretion of GH. Tumor shrinkage was demonstrated in 13 of 21 patients, with a mass reduction by more than half in 5 GH-/PRL-cosecreting adenomas. Except for slight gastrointestinal discomfort and orthostatic hypotension in a few patients at the beginning of therapy, cabergoline treatment was well tolerated. Only 2 patients stopped medication because of nausea. The weekly dose of cabergoline ranged between 1.0-1.75 mg. A further increase in the dose was only effective in 1 GH-/PRL-cosecreting adenoma. The results of this study suggest that cabergoline is an effective, well tolerated therapy that should be considered in the management of acromegaly, especially if the pituitary adenoma cosecretes GH and PRL or if pretreatment plasma IGF-I levels are below 750 micrograms/L.

Acromegaly↗
PubMed1998

Early treatment of Parkinson's disease with cabergoline delays the onset of motor complications. Results of a double-blind levodopa controlled trial. The PKDS009 Study Group.

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.

Activities of Daily Living↗
PubMed1994

Fluctuating Parkinson's disease. Treatment with the long-acting dopamine agonist cabergoline.

OBJECTIVE: Assessment of the very long-acting dopamine agonist medication cabergoline in the control of motor fluctuations in Parkinson's disease. DESIGN: Open-label trial (13 weeks). SETTING: Referral centers (Mayo Clinic, Rochester, Minn, and Scottsdale, Ariz). PATIENTS: Volunteer sample of 41 patients with idiopathic Parkinson's disease who were experiencing motor fluctuations while receiving stable doses of carbidopa and levodopa. INTERVENTION: Adjunctive oral cabergoline was incrementally administered once daily with the maintenance dose determined by the clinical response (maximum dose, 5 mg/d). MAIN OUTCOME MEASURES: 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. RESULTS: 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. CONCLUSIONS: 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).

Adult↗
PubMed1994

Pharmacodynamics and relative bioavailability of cabergoline tablets vs solution in healthy volunteers.

The effect of formulation on the urinary pharmacokinetics, pharmacodynamics, and relative bioavailability of cabergoline was investigated. Twelve healthy female volunteers, aged 23-35 years, were treated, according to an open, randomized, crossover design, with cabergoline (1-mg single oral dose) both as tablets and as a solution. The two administrations were separated by a 4-week wash-out period. Cabergoline and prolactin were measured in urine and plasma, respectively, by specific radioimmunoassays. Blood samples were collected before and up to 30 days after dosing. Urine was collected before and up to 8 days after dosing. Cabergoline elimination half-lives calculated from urinary data were 68 and 63 h after administration of the tablets and the solution, respectively. Urinary excretion of unchanged cabergoline accounted, on average, for 1.92% (range, 0.14-3.26) and 1.80% (range, 0.67-3.09) of the dose after administration of the tablets and the aqueous solution, respectively. Relative bioavailability of tablets vs solution was 99% (geometric mean with the 90% confidence intervals of 68-144%). Prolactin levels in 10 out of 12 subjects fell below the detection limit of the assay (1.5 micrograms/L) after both treatments. The mean maximum prolactin decrease (ca. 70%) was achieved by 2 or 3 h after dosing; the effect persisted up to 9 days, being completely exhausted 23-28 days after dosing. The analysis of variance performed on the pharmacodynamic effects of the two cabergoline formulations indicated that the percent decreases of plasma prolactin levels were not significantly different for tablets and solution. These results indicate that the pharmacodynamics and relative bioavailability of cabergoline are not influenced by formulation, as tablets or solution.

Adult↗
PubMed1994

A cross-over study with the two novel dopaminergic drugs cabergoline and quinagolide in hyperprolactinemic patients.

Cabergoline and quinagolide, two new dopamine agonist drugs with long-lasting activity, are currently under investigation for the treatment of hyperprolactinemia. At present, studies comparing these drugs for tolerability and efficacy in the same patients are lacking. It was our aim to make such a comparison in an open randomized cross-over trial. Cabergoline (0.5 mg twice weekly) and quinagolide (75 micrograms once daily) were given orally. Each drug was administered for 12 weeks. Treatment with the second drug was started after the recurrence of hyperprolactinemia. Twelve women with hyperprolactinemia due to idiopathic disease (n = 6), microprolactinoma (n = 5) or postsurgical empty sella (n = 1) were evaluated. Six women were amenorrheic and 6 were oligomenorrheic. Ten had spontaneous or provoked galactorrhea. Baseline characteristics (age, clinical signs and PRL levels) of patients initially allocated to the two treatment groups were similar. Nine patients completed both treatment cycles and PRL levels were lower under cabergoline (10.7 +/- 3.7 micrograms/L) than under quinagolide (25.0 +/- 7.7 micrograms/L; p < 0.05). One patient discontinued cabergoline because of dryness of the eyes after having completed the quinagolide cycle and 2 patients initially treated with cabergoline discontinued quinagolide because of gastrointestinal symptoms. After completion of the first treatment cycle, the time of recurrence of hyperprolactinemia was significantly longer after cabergoline (14 +/- 7 weeks) than after quinagolide (5 +/- 1 weeks; p < 0.05). At week 12, normal PRL levels (< 20 micrograms/L) were observed in 10 and 6 women during cabergoline and quinagolide, respectively. Only one case was resistant to both drugs. The clinical effects of the two treatments were similar.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗