Effects Of Remoxipride Research Articles

Acute Toluene Induces Biphasic Changes in Rat Spontaneous Locomotor Activity Which Are Blocked by Remoxipride

The behavioral hyperactivity elicited by most drugs of abuse has been linked to changes in mesolimbic dopamine neurotransmission. However, the locomotor stimulant effects of toluene, a constituent in many abused inhalants, has not been clearly associated with this site of action. The present study was designed to examine the hypothesis that toluene-induced hyperactivity is also dependent upon intact dopamine neurotransmission. Using photocell-equipped cages, 600–1200 mg/kg toluene produced an inverted U-shaped dose response. However, in the presence of 5 mg/kg remoxipride, a selective D 2-dopamine antagonist toluene-induced hyperactivity was reduced by 57%. The effects of remoxipride appear to be selective as a pretreatment, as it did not reduce either spontaneous locomotor activity or the stimulatory effects of the muscarinic antagonist scopolamine. These results clearly show that toluene induces locomotor hyperactivity through a dopamine-dependent mechanism. Because the mesolimbic dopamine system has been shown to play a role in the rewarding properties of drugs of abuse, its activation by toluene may also underlie the abuse potential of this and other inhalants.

Effects of remoxipride, an atypical antipsychotic, on cocaine self-administration in the rat using fixed- and progressive-ratio schedules of reinforcement

Remoxipride, a selective D2-dopamine receptor antagonist with preferential activity for mesolimbic-mediated behaviors, was assessed for its potential to block cocaine self-administration. The effects of remoxipride (RMX) were evaluated using fixed-ratio-1 (FR-1) and progressive-ratio (PR) schedules of reinforcement. On FR-1, RMX pretreatment increased the rate of cocaine injections, while on a PR, breaking points were reduced. Daily RMX treatment also resulted in breaking point reductions, but the decreases in cocaine's reinforcing potency did not result in extinction of cocaine intake and were not sustained upon cessation of RMX. Thus, RMX can reduce the rewarding effects of cocaine, and if safely tolerated over sustained periods of treatment it, or drugs with a similar pharmacological profile, could provide a therapeutic adjunct in the treatment of cocaine addiction.

The effects of remoxipride and chlorpromazine on eye movements and psychomotor performance in healthy volunteers

Fifteen healthy male volunteers received single doses of 100 mg immediate release remoxipride (IR), 150 mg controlled release remoxipride (CR), 50 mg chlorpromazine (CPZ), 2 mg lorazepam (LZ), and placebo in a randomised, five-period cross-over study. Both saccadic (SEM) and smooth pursuit eye movements (SPEM) as well as a battery of psychomotor performance tests were assessed at 1.5-h intervals over 9 h following drug administration. The areas under the response-time curves and the maximum effect during the study period were analysed by analysis of variance. The most consistent impairments were produced by LZ. The neuroleptics caused impairments to SEM, and tended to impair critical flicker fusion, continuous attention and both paced and unpaced versions of the digit-symbol substitution test as well as subjective measures of sedation. Only LZ impaired SPEM. Neither paced nor unpaced psychomotor tests distinguished between neuroleptics and benzodiazepines. The low therapeutic doses of IR and CR produced similar impairments to a sub-therapeutic dose of CPZ. Selectivity of pharmacological action does not appear to predict selectivity of effect on psychomotor function.

Effects of remoxipride and raclopride on prolactin release from clonal pituitary tumour cells.

The dopamine D2 receptor antagonist remoxipride (30 microM) stimulated prolactin release from the prolactin-producing rat pituitary tumour cell strains GH3 and GH4C1 as well as from transfected GH4C1 cells expressing the short isoform of the rat D2 receptor (GH4ZR7). The effect of remoxipride on prolactin release is probably not due to an interaction with D2 receptors since GH4C1 cells, in contrast to GH3 and GH4ZR7 cells, are completely devoid of D2 receptors; in contrast, we have previously shown that the D2 antagonist haloperidol causes prolactin release from D2 receptor-expressing cells, only. Exposure of GH3 cells to the inhibitor of intracellular Ca2+ mobilization, 8-(diethylamino)-octyl 3,4,5-trimethoxybenzoate hydrochloride (TMB-8) prevented the prolactin-releasing effect of remoxipride whereas pretreatment with the membrane Ca2+ channel antagonist nimodipine did not influence the response. The D2 receptor antagonist raclopride counteracted the reduction of VIP-stimulated prolactin release induced by the D2 agonist quinpirole but caused no prolactin release per se.

Remoxipride in Adolescents with Tourette's Syndrome: An Open Pilot Study

ABSTRACT Remoxipride is a dopamine antagonist with more selective affinity for the mesolimbic dopaminergic system than conventional neuroleptic agents. The possible therapeutic and adverse effects of remoxipride were investigated in 7 adolescents with Tourette's syndrome in an open-label pilot study. The design included a 3-week baseline placebo washin period, an 8-week active treatment period, and a 3-week placebo washout period. Active treatment with remoxipride was administered in the dose range of 50–250 mg daily. Remoxipride treatment improved severity of illness ratings in 6 patients and diminished tic ratings in all 7 patients. During the placebo washout period, all patients deteriorated both on the severity of illness and on the tic ratings. In a sustained attention task, a slight reduction of workpace was observed, but accuracy and stability of performance were not affected. Verbal and visual memory functioning also remained intact. Adverse effects were few and mild in severity. Treatment-emergen...

Remoxipride shows low propensity to block functional striatal dopamine D 2 receptors in vitro

The effect of remoxipride ((S)(−)-3-bromo- N-[(1-ethyl-2-pyrrolidinyl)methyl]-2,6-dimethoxybenzamide) on dopamine D 2 receptor-mediated inhibition of cAMP formation in rat striatal tissue pieces was established together with that of a number of other dopamine D 2 receptor antagonists. The action of remoxipride, three other substituted benzamides, (−)-sulpiride, raclopride and NCQ 298 ((S)-3-iodo- N-[(1-ethyl-2-pyrrolidinyl)methyl]-5,6-dimethoxysalicylamide mesylate) and haloperidol, a butyrophenone, was studied in the presence of (I) (+-) SKF 38393 (7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine) hydrochloride (100 μM) plus pergolide (1 μM) or (II) forskolin (1 μM) plus dopamine (100 μM). In addition, four of the metabolites of remoxipride: FLA 797 ((S)-3-bromo-N[1-ethyl-2-pyrrolidinyl)methyl]-2-hydroxy-6-methoxybenzamide), NCR 181 ((S)(−)-5-bromo- N-[(1-ethyl-2-pyrrolidinyl)methyl]-2-hydroxy-6-methoxybenzamide tartrate), NCQ 436 ((S)(−)- 3-bromo- N-[(1-ethyl-2-pyrrolidinyl)methyl]-5,6-dihydroxy-2-methoxybenzamide semioxalate) and NCQ 469 ((S)(−)-3-bromo- N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-hydroxy-2,6-dimethoxybenzamide hydrochloride), mainly found in rodents, were studied using test system I. The results demonstrate that remoxipride is significantly weaker in blocking functional striatal dopamine D 2 receptors than either of the reference compounds studied and three of the four metabolites. The studies also demonstrate that dopamine D 1 and D 2 receptor interactions at the level of cAMP formation in the striatum are independent of action potentials or Ca 2+.

Effects of remoxipride's metabolites on dopamine D2 receptors and receptor functions in the rat.

The main metabolites of remoxipride formed in rat and man were examined for their affinities for the [3H] SCH 23390-labelled DA D1 and [3H]-raclopride-labelled D2 receptors in rat striatal homogenates. In addition, their effectiveness in blocking postsynaptic DA receptor activity in vivo was measured by the use of several different test models in the male rat. Phenolic metabolites formed mainly in the rat retained (similar to remoxipride) their selectivity for the D2 receptor with very low affinities for the D1 receptor. The pyrrolidone metabolites formed mainly in man showed very low affinities for both the D1 and D2 receptors. The ability of the metabolites to block postsynaptic DA receptor activity in vivo correlated with their affinities for the D2 receptor. Among the metabolites tested, the phenolic compounds FLA 797 (-) and FLA 908 (-) were much more effective than remoxipride in inducing catalepsy, which is consistent with a higher affinity for [3H] raclopride labelled striatal D2 receptors. However, analysis of the effectiveness of the DA receptor blockade (blockade of d-amphetamine locomotion or DA agonist hypothermia) after intraperitoneal or subcutaneous administration suggested that FLA 797 (-)/FLA 908 (-) may only contribute marginally to the D2 receptor-blocking activity of remoxipride in the rat. This conclusion was further supported by the observation that the atypical antipsychotic profile of remoxipride was not mimicked by the active metabolites. The weak DA D2 blocking effect of the pyrrolidone metabolites indicated that remoxipride is responsible for the clinical action.

Concentrations of remoxipride and its phenolic metabolites in rat brain and plasma. Relationship to extrapyramidal side effects and atypical antipsychotic profile.

The cataleptic effect of remoxipride was examined in the horizontal bar test after i.v.,i.p. and s.c. administration to male rats. Remoxipride induced immediate catalepsy after high i.v. doses (ED50 = 49 mumol/kg) while peak effects were seen 60-90 min after i.p. administration (ED50 = 38 mumol/kg). Following s.c. administration remoxipride failed to produce a statistically significant catalepsy in the 20-100 mumol/kg dose range (ED50 > 100 mumol/kg). In contrast, haloperidol was found to be more effective in inducing catalepsy after i.v. (ED50 = 0.4 mumol/kg) than after i.p. or s.c. administration (ED50 = 0.9 mumol/kg). The atypical antipsychotic profile of remoxipride was more pronounced when the compound was given i.v. or s.c. as compared with the i.p. route. Plasma and brain (striatum and nucleus accumbens) concentrations of remoxipride and its active phenolic metabolites FLA 797(-) and FLA 908(-) were measured by high performance liquid chromatography. The 40 mumol/kg dose of remoxipride resulted in plasma and brain concentrations of remoxipride which were 300-1000-fold higher (depending on the route of administration) than the most potent of the phenolic metabolites, e.g., FLA 797(-). The plasma and brain concentrations of remoxipride and its phenolic metabolites were related to DA D2 receptor blocking potency and to the temporal course and effectiveness to induce catalepsy. This analysis suggested that the unbound concentrations of the phenolic metabolites were too low to play a major role in the DA blocking action of remoxipride. However, FLA 797(-) may contribute marginally to the cataleptic effects following high (i.p.) doses of remoxipride.

Dopamine depletion preferentially impairs D1- over D2-receptor regulation of striatal in vivo acetylcholine release.

The roles of D2 and D1 dopaminergic receptors on the regulation of striatal acetylcholine (ACh) release in vivo were examined for a period of 120 min after acute (2 h) or prolonged (16 h) depletion of brain dopamine (DA) by alpha-methyl-p-tyrosine. The reduction of DA transmission did not affect basal ACh output after 2 h but markedly lowered ACh release by 16 h (50%). Acute alpha-methyl-p-tyrosine pretreatment prevented the reduction of ACh release by the D1 antagonist SCH 23390 and its increase by the D2 antagonist, remoxipride, consistent with a drastic reduction of DA transmission at both DA receptors. However, 16 h after alpha-methyl-p-tyrosine, the effect of remoxipride on ACh release was restored, but SCH 23390 still had no effect, suggesting that the D2 inhibitory tone on ACh release had recovered, whereas the reduction of the D1 facilitatory influence persisted. The D1 facilitatory control of ACh neurotransmission thus appears to be more sensitive than the D2 inhibitory control to a reduction in DA transmission. The new model of DA-ACh interaction resulting from these data casts fresh light on the relationship between changes in DA transmission and extrapyramidal motor function.

Effects of remoxipride, a dopamine D-2 antagonist antipsychotic, on sleep-waking patterns and EEG activity in rats and rabbits.

The antipsychotic remoxipride, a selective dopamine D-2 receptor antagonist, was studied for its effects on sleep-waking patterns in the rat and electroencephalographic (EEG) activity in the rabbit. Haloperidol, which has lesser selectivity for D-2 receptors, was used for comparison. In the rat, remoxipride (1-10 mg/kg SC) did not affect either total sleep or non-rapid eye movement (non-REM) sleep. Only REM was slightly reduced by the high dose of 10 mg/kg. Haloperidol (0.1-1 mg/kg PO) enhanced duration of both total sleep and non-REM sleep. In the rabbit, remoxipride (3 and 10 mg/kg IV) induced no significant changes of the EEG power spectrum over 0.1-38.5 Hz or individual frequency bands. In both cortex and hippocampus the drug did not alter the arousal response to acoustic sensory stimuli. Plasma concentration of remoxipride 10 mg/kg IV in rabbits declined biexponentially and was 4 and 2 mumol/l at 30 min and 1 h, respectively. Haloperidol (0.3 and 1 mg/kg) slowed down the EEG activity, enhanced the power spectrum of the cortical and hippocampal activity, and significantly reduced the duration of arousal induced by sensory stimuli. The results indicate that, unlike haloperidol, remoxipride has weak or no sedative effects. The data also provide support to the notion that D-2 receptors are not involved in the regulation of states of sleep and sedation.

Effects of remoxipride on measures of psychological performance in healthy volunteers

The acute psychomotor effects after oral doses of 30, 60 and 120 mg remoxipride, a new selective D2 receptor blocker, and placebo were investigated in a double-blind crossover study in 11 healthy male volunteers. Two out of the first three subjects given 120 mg remoxipride experienced marked akathisia, and therefore no subsequent subjects were given this dose. There were no other clearly drug-related adverse effects reported below 120 mg, although restlessness was reported at 60 mg. Remoxipride was associated with increases in error scores on a continuous attention task and on auditory vigilance, and with a reduction in critical flicker frequency, suggesting a decrease in arousal level. There were no significant changes in psychomotor measures such as choice reaction time, decision making time, or body sway. Subjective assessments using visual analogue scales showed a slight dose-related increase in drowsiness, while the calm-excited scale showed a small change in the excited direction with 30 mg only. The peak effects were at 4-6 h after drug intake, which was later than expected from previous pharmacokinetic data. These results indicate that remoxipride may have a slight depressant effect in the dose-range used. The pattern of changes is consistent with current theories on the role of dopamine in attention and arousal, and with the effects of other neuroleptics. It differs, however, from tranquilisers such as the benzodiazepines, which show a more global pattern of effects.

Lack of Effect of Remoxipride on Antidiuretic Hormone Secretion in Healthy Volunteers

Remoxipride is a recently developed benzamide derivative with well established antipsychotic efficacy. Several other antipsychotic compounds have been shown to induce alterations in water and electrolyte balance due to an effect on the secretion of antidiuretic hormone (ADH). 11 healthy male volunteers (mean age 33 years) participated in a double blind, placebo controlled, crossover study to investigate whether remoxipride interacts with the secretion of ADH following fluid restriction.

Effects of remoxipride on psychomotor performance, alone and in combination with ethanol and diazepam*

The effects of remoxipride, alone and in combination with ethanol and diazepam, on sensory, cognitive, and neuromotor performance were studied in 12 healthy volunteers (7 men, 5 women). The study was of double-blind randomized, crossover design with each subject receiving six different single-dose experimental treatments at six sessions. Tests of sensory, cognitive, and neuromotor functions were carried out, together with subjective assessments. Remoxipride alone seemed to have no effect on the sensory functions measured, but it affected cognitive and neuromotor functions to a limited extent. In general the effects of ethanol and diazepam alone were more pronounced than those of remoxipride. When remoxipride was combined with either ethanol or diazepam, there was a tendency for the effect to be additive.

Drug interaction studies with remoxipride

The interaction potential of remoxipride was investigated with biperiden, warfarin, diazepam, and ethanol. The studies were conducted in 12 healthy volunteers each of whom received single doses of remoxipride, the interacting drug, and the combination in a randomized crossover design. Remoxipride and biperidene had no influence on each other's pharmacokinetics. The pharmacokinetics of warfarin enantiomers were uninfluenced by remoxipride. Ethanol and diazepam had no effect on the pharmacokinetics of remoxipride. The effect of remoxipride on the elevation of plasma prolactin levels was not modified by biperiden and the effect of warfarin on the prolongation of prothrombin time was uninfluened by remoxipride. Remoxipride showed no pharmacokinetic interaction with any of the drugs studied, nor was any pharmacodynamic interaction observed in the remoxipride versus biperiden and remoxipride versus warfarin studies.

Effects of remoxipride and some related new substituted salicylamides on rat brain receptors.

A number of potential neuroleptic drugs of the substituted benzamide type have been compared with some reference neuroleptic drugs regarding their affinities for rat brain receptors using in vitro receptor binding techniques. The effects on dopamine-stimulated adenylate cyclase were also investigated. All 6-methoxysalicylamides were very potent inhibitors of the dopamine-D2 receptor and possessed much less affinity for other receptors as well as for the dopamine-stimulated adenylate cyclase. In contrast, the classical neuroleptic drugs were not selective dopamine-D2 receptor blockers. Several of these neuroleptics were thus potent inhibitors of alpha 1-receptors, 5-HT2 receptors, muscarinic receptors and histamine-H1 receptors. Sulpiride was the most selective dopamine-D2 receptor blocker of the reference compounds with a selectivity ratio of 65. The 6-methoxysalicylamides had selectivity ratios ranging from 18 to 167.