DA agonists - Ergot derivaties: Cabergoline

Abstract

Cabergoline is an orally administered synthetic tetracyclic ergoline derivative that acts in vitro and in vivo as a selective D2 receptor agonist with no substantial affinity for D1 receptors. As with other ergotamine derivatives, it has also some affinity for nondopamine receptors (noradrenergic and serotonergic). Cabergoline improves the symptoms of the primate model of Parkinson's disease (PD) after MPTP intoxication. Cabergoline lowers prolactin secretion, and like all effective D2-agonists, induces nausea, vomiting and orthostatic hypotension in healthy volunteers. 1 PHARMACOKINETICSOne major characteristic of cabergoline is its long duration of effect with oral administration, probably because its elimination half-life is approximately 65 hours. For example, cabergoline is highly effective in suppressing prolactin levels with a duration of action up to 21 days after a single 1 mg oral dose. Such a pharmacokinetic profile allows a once-daily dosing treatment regimen. The cabergoline Tmax is observed at 2.5 hours, and it is metabolized into several metabolites excreted mainly by the fecal route. 1 REVIEW OF CLINICAL STUDIES PREVENTION OF DISEASE PROGRESSIONNo qualified studies were identified. SYMPTOMATIC CONTROL OF PARKINSONISM MONOTHERAPYTo date, there are no Level-I, placebo-controlled studies that have investigated the efficacy of cabergoline as monotherapy. Two clinical reports were identified, but correspond to the same L-dopacontrolled study that performed two different analyses: one planned interim analysis at 1 year 2 , and a final analysis at 3 to 5 years. 3 In this study, cabergoline was initiated as monotherapy, and L-dopa supplementation was added in patients if required (i.e. based on dose limiting adverse reactions and if they reached maximal dose of cabergoline). 2 : This is the only available study assessing the effects of cabergoline monotherapy (with secondary open Ldopa supplementation if needed) at one-year. It is a randomized, L-dopa-controlled (Level I), double-blind study conducted in 413 de novo patients with PD (mean age approximately 61 years). Cabergoline could be titrated up to 4 mg/d on a once a day regimen, and L-dopa up to 600 mg/d tid. Open label L-dopa supplementation was allowed during the course of the study. PD disability was evaluated using mean UPDRS (Unified Parkinson's Disease Rating Scale) scores and the CGI (Clinical Global Impression) scale. The proportion of patients experiencing a 30% decrease in parkinsonian disability and the proportion requiring the addition of L-dopa were also analysed. Thirty-seven (9%) patients withdrew from the study by 1 year. At this 1-year interim analysis, mean cabergoline daily dose was 2.8 mg/d and that of L-dopa was 468 mg/d. Thirty-eight percent of the patients received L-dopa supplementation in the cabergoline group (mean daily dose 305 mg/d). At baseline, UPDRS was 29.1 in the L-dopa and 27.5 in the cabergoline group. After 1-year of treatment, the decrease in scores was higher in the L-dopa (16.5) than in the cabergoline group (...