Remoxipride

Abstract

Remoxipride is a substituted benzamide of the same class as sulpiride, and has a pharmacodynamic profile consistent with central antidopaminergic activity. It is a weak, but relatively selective, central dopamine D₂-receptor antagonist and appears to have preferential affinity for extrastriatal dopamine D₂-receptors. It also has marked affibrillationnity for central sigma receptors. Clinical data from noncomparative and comparative studies show that remoxipride has antipsychotic activity in patients with chronic schizophrenia, and acute exacerbation of chronic schizophrenia, with activity on both positive and negative symptoms. Its overall efficacy in these studies was similar to that of haloperidol. Importantly, however, remoxipride produced a substantially lower incidence of extrapyramidal effects than haloperidol. Further long term comparative studies are required to ascertain the relative suitability of remoxipride for preventing relapse in psychotic patients, and to determine whether tardive dyskinesia occurs in remoxipride recipients — the latter has not been reported with remoxipride to date Thus, while further experience (particularly of a long term comparative nature) is needed, at present remoxipride appears to offer an important tolerability advantage over haloperidol Compared with the standard antipsychotics, remoxipride is a weak, but relatively specific central dopamine D₂-receptor antagonist, with minimal effect on central cholinergic, serotonergic, histamine, muscarinic or α₁-adrenergic receptors. Remoxipride appears to have little affibrillationnity for dopamine D₁-receptors, as demonstrated by in vivo receptor binding studies and a lack of effect on dopamine-stimulated adenylate cyclase activity. However, remoxipride also has marked affinity for sigma receptors While there is a need for caution with regard to extrapolation from in vitro studies to humans, observations that remoxipride induces differential increases in dopamine turnover in specific areas of rat brain indicate a preferential affinity for extrastriatal dopaminergic systems. This specificity for particular central dopaminergic systems is also demonstrated by the wide separation of doses of remoxipride effective in animal behavioural models for induction of catalepsy, which is believed to be mediated by striatal dopaminergic systems, and the antagonism of dopamine agonist-induced hyperactivity, thought to be mediated through the mesolimbic system. Remoxipride transiently increases plasma prolactin levels in humans; however, fewer remoxipride than haloperidol recipients had trough plasma prolactin levels outside normal limits during short term studies Remoxipride is almost completely absorbed following oral administration in healthy subjects: absorption rate is limited only by the dissolution rate of the preparation. Bio-availability is greater than 90%, and distribution is rapid, with peak plasma levels reached within 1 to 2 hours of oral administration. Approximately 80% of the absorbed dose is bound to plasma protein. There is a dose-proportional relationship for maximum and steady-state plasma concentrations of remoxipride. The half-life of remoxipride is between 4 and 7 hours. Most of an oral dose is excreted in the urine; 10 to 40% is excreted unchanged and the remainder as metabolites Elimination may be impaired in elderly patients, patients with severe renal dysfunction or severe liver disorders, and in patients who are slow debrisoquine metabolisers. Decreases in urinary pH increase both the elimination rate and the percentage of remoxipride excreted unchanged in urine Short term noncomparative studies in patients with mainly chronic schizophrenia have shown that individualised doses of remoxipride provide an effective replacement for previous antipsychotic treatment. Over 75% of patients display moderate or marked symptomatic improvement at doses up to 600 mg/day. Both positive and negative symptoms appear to respond well to remoxipride. Improvements have been reported for the positive symptoms of thought disturbance, hostility/suspiciousness and hallucinations, and the negative symptoms of emotional withdrawal and motor retardation Most studies reported to date have compared the efficacy of remoxipride with haloperidol. In terms of overall therapeutic efficacy, remoxipride appears to be similar to both thioridazine and haloperidol but, importantly, it appears to produce a lower incidence of extrapyramidal symptoms. Data from a 6-month placebo-controlled trial show that doses of 150 to 300 mg/day were significantly superior to placebo in preventing relapse. However, the high withdrawal rate in the placebo group complicates interpretation of this study. In addition, data from 1 study comparing remoxipride with chlorpromazine and placebo suggest that remoxipride has a greater efficacy than placebo in patients responsive to treatment with other antipsychotics. Further studies with other antipsychotics are needed to extend these initial findings and confirm the place of remoxipride in the therapy of schizophrenia Extrapyramidal symptoms are frequently associated with antipsychotic drug treatment and were present in the majority of patients before treatment with remoxipride. During treatment with remoxipride many of these patients showed a decrease in severity of such symptoms. There are relatively few reports of extrapyramidal effects attributable to remoxipride treatment. Few data are available on the effect of remoxipride on pre-existing tardive dyskinesia: preliminary results indicate either improvement or no effect on existing symptoms. The incidence of tardive dyskinesia with remoxipride, if any, has yet to be determined in longer term studies Occasional cardiovascular effects, including postural hypotension, have been reported during remoxipride administration, but in most patients these would not be clinically important. Other miscellaneous reported adverse reactions occurred with a similar incidence in placebo and remoxipride recipients. Only a small number of patients were withdrawn from therapy due to adverse effects Oral administration of remoxipride should start with a dose of 300mg daily, in 2 divided doses, and the dosage should be adjusted to achieve maximum control of symptoms. The initial dosage should be halved for elderly patients. The majority of patients initially respond to doses of 300 to 450 mg/day although some require up to 600 mg/ day. For long term treatment, the lowest effective maintenance dose (usually 150 to 300 mg/day) should be administered