Pharmacokinetics and antipsychotic effect of remoxipride in chronic schizophrenic patients

Abstract

Single dose pharmacokinetics and the antipsychotic effect of 4 weeks treatment with three fixed dose levels of remoxipride (a selective D(2) receptor antagonist) were studied in chronic, stable schizophrenic inpatients. After a placebo washout of 1 month, 15 patients entered the study. Of these, 11 patients received a single 50 mg oral dose of remoxipride for pharmacokinetic evaluations. All 15 patients were randomly assigned to treatment with oral remoxipride either 25 mg t.i.d., 50 mg t.i.d. or 100 mg t.i.d. for 4 weeks. Blood samples for remoxipride and prolactin assays were taken at 0, 0.33, 0.5, 0.66, 1.0, 1.5, 2, 3, 4, 8, 12, 24, 28, 32 and 48 h after drug intake. The pharmacokinetic characteristics were similar to those previously found in normal healthy volunteers: the mean peak plasma concentration of remoxipride after 50 mg was 3.3 μmol/l, the mean time to reach this was 2.1 h; the mean area under the plasma concentration/time curve was 27.8 μmol/1.h.1( -1) and the mean elimination half-life of remoxipride was 5.5 h. A significant increase in prolactin levels was detected 2 h after administration of remoxipride but they had reverted to normal 8 h after drug intake in all but one patient. Antipsychotic effects were estimated using the brief psychiatric rating scale (BPRS) and the Krawiecka rating scale (KRS) at admission, baseline (end of the 4 week placebo washout period) and after 7, 14 and 28 days treatment. Following an increase in mean psychosis ratings for both positive and negative symptoms during the placebo washout period, these decreased during active treatment and at the end of the study were similar to the scores on admission. Thus the possible efficacy of remoxipride in chronic patients with negative symptoms should be further explored in placebo controlled studies. Remoxipride was well tolerated. Sleep disorders occurred in three patients, extrapyramidal symptoms were not aggravated and no clinically significant effects were observed on the cardiovascular system, in clinical chemistry or haematology.

Prolactin response to nemonapride, a new antipsychotic drug, in schizophrenic patients

“…Therefore, the present study suggests a strong D2 receptor blockade property of nemonapride in schizophrenic patients, supporting the results of receptor binding assays (Terai et al, 1983). In line with this, remoxipride, another substituted benzamide, has been reported to markedly increase prolactin concentrations (the mean maximum concentrations 85 ng/ml in females and 36 ng/ml in males) after a single oral 50 mg dose in schizophrenic patients (King et al, 1990).…”

“…The mean Dprolactin was signi®cantly greater in females than males. This result is similar to those for chlorpromazine (Meltzer et al, 1983b;Harnryd et al, 1984), sulpiride (Harnryd et al, 1984), haloperidol (Linkowski et al, 1984) and remoxipride (King et al, 1990). Although plasma concentrations of nemonapride and desmethylnemonapride were below the lowest limit of detection in a considerable number of patients, there appeared to be no signi®cant gender dierence in these concentrations.…”

Ziprasidone and the pharmacokinetics of a combined oral contraceptive

“…The effect of ziprasidone on plasma prolactin concentration in women observed in this study may differ slightly from the effect observed in men, in whom ziprasidone has been associated with only marginal, transient elevations that return to baseline within the dosing interval [15]. This is to be expected, as elevations in plasma prolactin concentrations in women receiving conventional antipsychotic drugs are greater than in men [16–18]. This effect may be attributable to hormonal influences such as oestrogen‐mediated enhancement of prolactin releasing stimuli and the number of lactotrophic cells of the anterior pituitary [18].…”

Deciphering Spinal Endogenous Dopaminergic Mechanisms That Modulate Micturition Reflexes in Rats with Spinal Cord Injury

“…All drugs were prepared in three concentrations to examine the effects of low, middle and high doses administered sequentially at an interval of at least 30 min ( Table 1 ). The half-life information of each drug except SKF 38393 ( Setler et al, 1978 ) was available in the literature: 1.5 h for L-DOPA ( Calabrese et al, 2007 ; Contin and Martinelli, 2010 ), 1.8 h for carbidopa ( Brooks, 2008 ), 33 min for APO ( Gancher, 1995 ), 4.8 h for remoxipride ( King et al, 1990 ; Movin-Osswald and Hammarlund-Udenaes, 1991 ), 9.5 h for quinpirole ( Ballester González et al, 2015 ; Pértile et al, 2017 ), and 30 min for SCH 23390 ( Hietala et al, 1992 ; Giorgi et al, 1993 ). When L-DOPA was tested, rats also received carbidopa (in a 1:10 ratio to the dose of L-DOPA) in the solution to inhibit peripheral effects of L-DOPA, as described below.…”