Search

Although the mossy fiber (MF) synapses of the hippocampal CA3 region display quite distinct properties in terms of the molecular mechanisms that underlie synaptic plasticity, they nonetheless exhibit persistent (>24h) synaptic plasticity that is akin to that observed at the Schaffer collateral (SCH)-CA1 and perforant path (PP)-dentate gyrus (DG) synapses of freely behaving rats. In addition, they also respond to novel spatial learning with very enduring forms of long-term potentiation (LTP) and long-term depression (LTD). These latter forms of synaptic plasticity are directly related to the learning behavior: novel exploration of generalized changes in space facilitates the expression of LTP at MF-CA3 synapses, whereas exploration of novel configurations of large environmental features facilitates the expression of LTD. In the absence of spatial novelty, synaptic plasticity is not expressed. Motivation is a potent determinant of whether learning about spatial experience effectively occurs and the neuromodulator dopamine plays a key role in motivation-based learning. Prior research on the regulation by dopamine receptors of long-term synaptic plasticity in CA1 and dentate gyrus synapses in vivo suggests that whereas D2/D3 receptors may modulate a general predisposition toward expressing plasticity, D1/D5 receptors may directly regulate the direction of change in synaptic strength that occurs during learning. Although the CA3 region is believed to play a pivotal role in many forms of learning, the role of these receptors in persistent (>24h) forms of synaptic plasticity at MF-CA3 synapses is unknown. Here, we report that whereas pharmacological antagonism of D2/D3 receptors had no impact on LTP or LTD, antagonism of D1/D5 receptors significantly impaired LTP and LTD that were induced by solely by means of patterned afferent stimulation, or LTP/LTD that are typically enhanced by the conjunction of afferent stimulation and novel spatial learning. These data indicate an important role for dopamine acting on D1/D5 receptors in the support of long-lasting and learning-related forms of synaptic plasticity at MF-CA3 synapses and provide further evidence for an important neuromodulatory role for this receptor in experience-dependent synaptic encoding in the hippocampal subfields.

The aim of this investigation was to develop a mechanism-based pharmacokinetic-pharmacodynamic (PK-PD) model for the biological system prolactin response following a dopamine inhibition challenge using remoxipride as a paradigm compound. After assessment of baseline variation in prolactin concentrations, the prolactin response of remoxipride was measured following (1) single intravenous doses of 4, 8 and 16 mg/kg and (2) following double dosing of 3.8 mg/kg with different time intervals. The mechanistic PK-PD model consisted of: (i) a PK model for remoxipride concentrations in brain extracellular fluid; (ii) a pool model incorporating prolactin synthesis, storage in lactotrophs, release into- and elimination from plasma; (iii) a positive feedback component interconnecting prolactin plasma concentrations and prolactin synthesis; and (iv) a dopamine antagonism component interconnecting remoxipride brain extracellular fluid concentrations and stimulation of prolactin release. The most important findings were that the free brain concentration drives the prolactin release into plasma and that the positive feedback on prolactin synthesis in the lactotrophs, in contrast to the negative feedback in the previous models on the PK-PD correlation of remoxipride. An external validation was performed using a dataset obtained in rats following intranasal administration of 4, 8, or 16 mg/kg remoxipride. Following simulation of human remoxipride brain extracellular fluid concentrations, pharmacodynamic extrapolation from rat to humans was performed, using allometric scaling in combination with independent information on the values of biological system specific parameters as prior knowledge. The PK-PD model successfully predicted the system prolactin response in humans, indicating that positive feedback on prolactin synthesis and allometric scaling thereof could be a new feature in describing complex homeostatic mechanisms. [ABSTRACT FROM AUTHOR]

The article presents a study that compares the efficiency of the agonist-antagonist interaction (AAI) model and prolactin pool model for assessment of the effect of remoxipride on prolactin. The study assesses the two models in eight male subjects, who were infused with remoxipride with criteria such as goodness-of-fit (GOF) and objective function values (OFV). Result shows that pool model is better to use for circadian rhythm function, while AAI describes better circadian rhythm of prolactin.

Abstract: Remoxipride is a selective dopamine D2 receptor antagonist, and useful as a model compound in mechanism-based pharmacological investigations. To that end, studies in small animals with serial sampling over time are needed. For these small volume samples currently no suitable analytical methods are available. We propose analytical methods for the detection of low concentrations remoxipride in small sample volumes of plasma, brain homogenate, and brain microdialysate, using online solid phase extraction with liquid chromatography–tandem mass spectrometry. Method development, optimization and validation are described in terms of calibration curves, extraction yield, lower limit of quantification (LLOQ), precision, accuracy, inter-day- and intra-day variability. The 20μl plasma samples showed an extraction yield of 76%, with a LLOQ of 0.5ng/ml. For 0.6ml brain homogenate samples the extraction yield was 45%, with a LLOQ of 1.8ng/ml. The 20μl brain microdialysate samples, without pre-treatment, had a LLOQ of 0.25ng/ml. The precision and accuracy were well within the acceptable 15% range. Considering the small sample volumes, the high sensitivity and good reproducibility, the analytical methods are suitable for analyzing small sample volumes with low remoxipride concentrations. [Copyright &y& Elsevier]

Abstract: Dopaminergic agonists, such as apomorphine and amphetamine, have been shown to drastically reduce prepulse inhibition of the acoustic startle reflex. The effects of the indirect dopamine agonist cocaine on prepulse inhibition have only been described in a few reports and have yielded conflicting results, possibly due to individual differences within and between rat strains. In this study we therefore used apomorphine-susceptible and apomorphine-unsusceptible rats, as an animal model for individual differences, to study the effects of cocaine (20, 30mg/kg i.p.) on prepulse inhibition. In addition we tested whether the cocaine-induced deficit in prepulse inhibition could be reversed by the D2-antagonist remoxipride (5mg/kg i.p.), the alpha-1 adrenoceptor antagonist prazosin (2.5mg/kg i.p.) and the 5-HT2-antagonist ketanserin (2.0mg/kg i.p.). Cocaine strongly reduced prepulse inhibition in apomorphine-susceptible rats, but had no effect at all on apomorphine-unsusceptible rats. Remoxipride had no effect on prepulse inhibition, but prazosin and ketanserin increased prepulse inhibition. Both remoxipride and prazosin reversed the cocaine-induced deficit in prepulse inhibition, whereas ketanserin did not. We conclude that apomorphine-susceptible rats are extremely sensitive to the effects of cocaine on prepulse inhibition, while apomorphine-unsusceptible rats are not. The effects of cocaine on prepulse inhibition in apomorphine-susceptible rats were mediated by D2-receptors, but not by 5-HT2-receptors or alpha-1 adrenoceptors. [Copyright &y& Elsevier]

Schizophrenia is a long-term disabling illness that affects approximately 1% of the population. Its course is generally chronic with acute psychotic exacerbations that may require frequent hospitalisations. The clinical picture includes a range of symptoms such as delusions, hallucinations, agitation, suspiciousness, hostility, conceptual disorganisation, blunted affect, emotional and social withdrawal, lack of spontaneity, poverty of speech and a wide range of neurocognitive deficits. Over the past 50 years, antipsychotic medications have emerged as the cornerstone of management in concert with other important interventions, such as psychosocial and economic support and rehabilitation efforts. However, the unrivalled role of conventional antipsychotic medications has been continuously challenged by the wide range of adverse effects of these medications and their lack of usefulness in the treatment of neurocognitive deficits as well as deficit and negative symptoms. In addition, the lack of subjective tolerability of these agents and their negative impact on quality of life have complicated management for a large number of patients. Over the last 15 years, several new atypical antipsychotic medications have been introduced, including amisulpride, remoxipride, risperidone, sertindole, olanzapine, zotepine, quetiapine, ziprasidone and aripiprazole. In general, the new antipsychotics have shown themselves to be at least comparable in efficacy to conventional antipsychotics but with superior subjective tolerability and a more favourable adverse effect profile. The majority of quality of life studies involving new antipsychotic agents have evaluated the benefits of risperidone, olanzapine and clozapine; only a few studies have examined the effects of other new antipsychotics. While most of these studies have methodological and design limitations, the weight of evidence from them nevertheless points to a trend towards a more positive impact on quality of life with atypical agents. A number of recommendations can be made. First, more independent well designed and controlled studies are urgently needed to evaluate the effects of antipsychotic therapy on quality of life in patients with schizophrenia. New comparative studies should explore not only the differences between new and old antipsychotics but also identify any potential differences between individual new agents. The role of cost-effectiveness studies such as cost utility approaches in schizophrenia needs to be revisited, notwithstanding the fact that these types of studies have been reported to be feasible in schizophrenia. Finally, quality-of-life-based pharmacoeconomic studies of antipsychotic agents should not concentrate solely on cost reduction or containment, as it is likely that in order to maximise the benefits of new antipsychotic medications, greater expenditure on rehabilitation programmes and other support services will be necessary in the short-term at least. [ABSTRACT FROM AUTHOR]

Triadimefon (TDF) is a triazole fungicide that blocks the reuptake of dopamine (DA), much like cocaine. A recent study in our laboratory found that intermittent injections of TDF led to robust locomotor sensitization in response to challenge TDF after a 2-week withdrawal period. The current study sought to determine whether the expression of TDF behavioral sensitization could be prevented by the DA D1-like receptor antagonist SCH 23390 (SCH), the DA D2-like receptor antagonist remoxipride (Rem), the competitive NMDA antagonist CPP, or the AMPA antagonist NBQX. Adult male C57/BL6 mice were injected with vehicle or 75 mg/kg TDF twice a week for 7 weeks, with locomotor activity measured periodically across the 14 doses. After a 2-week withdrawal period, mice were pretreated with SCH (0.015 mg/kg), Rem (0.3 mg/kg), CPP (2.5 mg/kg) or NBQX (10.0 mg/kg) followed 30 min later by vehicle or 75 mg/kg TDF and tested for the expression of TDF sensitization. Intermittent administration of TDF led to the development and robust expression of behavioral sensitization in terms of vertical activity. Pretreatment with SCH, NBQX and CPP successfully blocked the expression of vertical sensitization to TDF, while Rem pretreatment did not. All four antagonists, however, attenuated the neurochemical changes normally associated with TDF sensitization as measured 8 h after the 2-week TDF challenge. This paper reveals that NMDA, AMPA and DA D1-like receptors are necessary for the behavioral expression of sensitization to the fungicide triadimefon. [Copyright &y& Elsevier]

Triadimefon (TDF) is a triazole fungicide that blocks the reuptake of dopamine (DA) and leads to increased locomotor activity levels in mice and rats, effects similar to those of indirect DA agonists such as cocaine. We recently found in mice that intermittent TDF administration led to robust locomotor sensitization, a phenomenon reflecting neuronal plasticity, following challenge with the same TDF dose after a 2-week withdrawal period. The current study sought to determine whether antagonists to DA D1-like receptors (SCH 23390; SCH), DA D2-like receptors (remoxipride; Rem), ionotropic glutamate n-methyl-d-aspartate (NMDA) receptors (CPP), or ionotropic glutamate alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors (NBQX) could prevent the development of TDF behavioral sensitization, therefore indicating their mechanistic involvement in TDF sensitization. Mice were treated with either vehicle, SCH (0.015 mg/kg), remoxipride (Rem, 0.3 mg/kg), CPP (2.5 mg/kg) or NBQX (10.0 mg/kg), followed 30 min later by vehicle or 75 mg/kg TDF (TDF), twice a week for 7 weeks, with locomotor activity measured post-dosing once a week. After a 2-week withdrawal period, mice were challenged with 75 mg/kg TDF or vehicle, to test for the presence of behavioral sensitization. Pretreatment with SCH, CPP, or NBQX, but not Rem, blocked the development of behavioral sensitization to TDF specifically for vertical activity. Antagonists that blocked TDF vertical sensitization also attenuated the increase in extracellular DA turnover (homovanillic acid [HVA]/DA) normally associated with this behavioral response. Therefore, DA D1, NMDA and AMPA receptors appear to be necessary for the development of behavioral sensitization to TDF. As such, TDF may be considered an environmental risk factor for behavioral dysfunctions linked to glutamatergic and dopaminergic systems. [ABSTRACT FROM AUTHOR]

Intracerebroventricular (IVT) administration of adrenomedullin (AM) to conscious male hydrated rats increases urinary volume and sodium excretion. The possible involvement of brain dopamine (DA) system on the renal action of IVT-AM was investigated. AM-induced diuretic and natriuretic action was prevented following selective central dopaminergic denervation with 6-hydroxydopamine (6OHDA) in combination with desmethylimipramine (DMI). Selective D2 DA receptor antagonism with haloperidol, sulpiride, and remoxipride; or with the D1 DA receptor antagonist, SCH 23390, blunted the increase in urinary volume and sodium excretion induced by IVT-AM. The present results suggest that AM acts centrally, at least in part, via an interaction with endogenous DA through the activation of both DA D1/D2 receptor subtype. [Copyright &y& Elsevier]

Remoxipride, a dopamine D2 antagonist, decreases responding that results in the presentation of small amounts (~0.1 ml) of ethanol in limited-access paradigms. This type of operant response is a combined appetitive/consummatory response that is differentially affected by changing stimulus properties of consumed ethanol (i.e., taste, pharmacology) over the course of the session. In the present experimental design, ethanol-directed appetitive and consummatory responses were procedurally separated to investigate the specific effects of remoxipride on these distinct behaviors. Male Long–Evans rats were trained to make a series of lever-press responses once each day that resulted in access to a sipper tube spout containing 10% ethanol for 20 min. Three doses of remoxipride were tested: 5.0, 10.0, and 15.0 mg/kg (–30 min, i.p.). In Experiment 1, a response requirement of 20 was used, and both reinforced and nonreinforced sessions were examined. In nonreinforced sessions, subjects were permitted to lever press for 20 min, after which the session ended without sipper tube presentation. These sessions were conducted to remove the possibility that limiting responding might obscure a drug effect on the seeking response. In Experiment 2, a low response requirement (4) was used to investigate the effects of remoxipride on ethanol intake. Average baseline ethanol intake (Experiment 1) was 0.69 g/kg, with blood ethanol concentrations at the end of the session at 64 mg%. At all doses tested, remoxipride had no effect on the measures of ethanol consumption (e.g., total intake, lick latency, lick rate) in either experiment. However, remoxipride dose dependently decreased the number of appetitive responses made, while having no effect on response latency or rate, during both reinforced and nonreinforced sessions in Experiment 1. In these experiments, the systemic antagonism of the dopamine D2 receptor decreased ethanol seeking without causing a general impairment of motor function. The procedural separation of seeking and intake responses revealed that appetitive responding was more sensitive than consummatory responding to remoxipride treatment. [Copyright &y& Elsevier]

ABSTRACT Remoxipride is a substituted benzamide that acts as a weak but very selective antagonist of dopamine D2 receptors. It was introduced by Astra (Roxiam) at the end of the eighties and was prescribed as an atypical antipsychotic. This article reviews its putative selective effects on mesolimbic versus nigrostriatal dopaminergic systems. In animals, remoxipride has minimal cataleptic effects at doses that block dopamine agonist-induced hyperactivity. These findings are predictive of antipsychotic activity with a low likelihood of extrapyramidal symptoms. Remoxipride also appears to be effective in more recent animal models of schizophrenia, such as latent inhibition or prepulse inhibition. In clinical studies, remoxipride shows a relatively low incidence of extrapyramidal side effects and its effects on prolactin release are short-lasting and generally mild. The clinical efficacy of remoxipride is similar to that of haloperidol or chlorpromazine. Although its clinical use was severely restricted in 1993, due to reports of aplastic anemia in some patients receiving remoxipride, this drug has been found to exhibit relatively high selectivity for dopamine D2 receptors making remoxipride an interesting tool for neurochemical and behavioral studies. [ABSTRACT FROM AUTHOR]

Analysable EEGs were recorded from 13 schizophrenic patients (three taking high-dose remoxipride; five haloperidol; five low-dose remoxipride). EEG data did not differ between high-dose remoxipride and haloperidol patients, so they were combined into a single adequate dosage group. There were four clinical responders (two high-dose remoxipride; two haloperidol) and four non-responders (one high-dose remoxipride; three haloperidol) on adequate dosage. All low-dose remoxipride patients were non-responders. Of those on adequate dosage, responders had the same pretreatment EEG alpha activity as non-responders, but their posttreatment eyes-closed alpha at 8·5 Hz in the right posterior temporal area was higher (p < 0·05). The same was true when they were compared with non-responders on inadequate dosage. Alpha activity of all responders pretreatment did not differ from all non-responders, but posttreatment it was higher (p < 0·05) at the left frontal, left middle temporal and right posterior temporal sites. In contrast, after treatment the inadequate dose non-responders had lower voltage (p < 0·05) in almost all alpha frequencies in the left frontal, right posterior temporal and occipital areas. These results replicate previous studies of schizophrenia which show that increased alpha activity is the most reliable indicator of clinical response to haloperidol, and suggest that the same is true of remoxipride. © 1997 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

A double-blind, randomized, multicentre study comparing the efficacy and safety of intramuscular (i.m.) remoxipride to that of i.m. haloperidol was undertaken in 119 psychotic patients (mean age: 37 ± 13.4 years). The study period was I week i.m., followed by 3 weeks of oral treatment. Dosage was 200-600 mg/day for remoxipride and 10-30 mg/day for haloperidol during i m. and 150-600 mg/day for remoxipride and 10-40 mg/day for haloperidol during oral treatment. Both drugs produced marked clinical improvements during i.m. and oral treatment. During the i.m. week, the median Brief Psychiatric Rating Scale (BPRS) total score decreased from SI to 34 in the remoxipride group and from 53 to 38 in the haloperidol group. Over the 4-week treatment period, there was a significantly greater reduction in some factors' for remoxipride-treated patients when compared to haloperidol-treated patients. Somnolence was reported by 14% of haloperidol-treated patients during i.m. treatment. Akathisia and tremor occurred significantly less in remoxipride-treated patients as compared to haloperidol-treated patients. Intramuscularly administered remoxipride is as effective as haloperidol in reducing acute phase psychotic symptoms, and is associated with fewer extrapyramidal symptoms. [ABSTRACT FROM AUTHOR]

In this placebo and verum (lorazepam 2 mg) controlled double-blind crossover study the acute effects of Remoxipride 50 mg and 100 mg; Haloperidol 2.5 mg and Thioridazine 50 mg were examined in 18 healthy volunteers. CNS function was assessed using a battery of psychometric measures, viz: Critical Flicker Fusion Threshold (CFFT); Choice Reaction Time (CRT); Tracking Accuracy (RMS) and Peripheral Reaction Time (PRT); Sternberg Memory Scanning (SMS); Word Memory (WM) as well as Line Analogue Ratings of subjective sedation (LARS) and the Leeds Sleep Evaluation Questionnaire (LSEQ). Both doses of remoxipride were associated with a reduction of CFFT: 0.9 Hz for 50 mg and 1.3 Hz for 100 mg. The 100 mg dose caused an increase (impairment) in CRT total time of 38 msec. Haloperidol reduced CFFT, while thioridazine and lorazepam impaired performance on the majority of objective measures, as expected for known sedative drugs. Thioridazine led to hypotension in three subjects, and to subjective sedation (LARS), but no treatment affected responses on the LSEQ administered the morning of the day following treatment. These results show that remoxipride has some depressant effects on CNS function, but that these are less prominent than those of sedative neuroleptics such as thioridazine. [ABSTRACT FROM AUTHOR]

A multicentre parallel group study was carried out to compare the efficacy and safety of remoxipride, a new antipsychotic drug, with haloperidol in the treatment of acute schizophrenia. Patients were randomly assigned to the two groups and assessments were made under double-blind conditions. Treatment was preceded by a washout period and lasted 6 weeks. Eighty-nine consecutively admitted men and women meeting the Research Diagnostic Criteria for schizophrenia in an acute phase of the illness were treated with remoxipride 75-300mgb.d. or haloperidol 5 -20 mg b.d. The main assessments were changes in scores on the Brief Psychiatric Rating Scale, Krawieeka Rating Scale and Clinical Global Impression. Both neuroleptics produced clinical improvement but there were no significant differences in overall efficacy measurements between the two drugs. There were relatively few unwanted side-effects. There were significantly less extra-pyramidal symptoms and blurred vision with remoxipride, and less constipation with haloperidol. The results indicate that remoxipride is an effective antipsychotic drug with a low incidence of extrapyramidal side-effects. [ABSTRACT FROM AUTHOR]

The influence of urinary pH on the plasma and urinary kinetics of remoxipride in man has been studied in an open crossover trial in ten healthy male volunteers. Ammonium chloride (urinary pH 5.2) and sodium hydrogen carbonate (urinary pH 7.8) were used as pretreatments on two occasions in randomized order. On each occasion remoxipride 50 mg solution was administered orally and plasma and urinary concentrations of the drug were determined by HPLC and plasma prolactin concentrations by RIA. Remoxipride was rapidly distributed in the body according to a one-compartment model. The mean plasma elimination half-life (t) was 3.6 h in the ammonium chloride experiment and 6.2 h in the sodium hydrogen carbonate experiment. The mean plasma clearance of remoxipride was 141 and 89.9 ml·min in the acidic and alkaline conditions, respectively, and the corresponding mean renal clearances were 58.5 ml·min and 11.7 ml·min. The urinary excretion of remoxipride up to 72 h after drug administration was 43.1% and 12.3% following acidification and alkalinization, respectively. Remoxipride induced a similar rapid, transient elevation of plasma prolactin under both conditions. Thus, the urinary pH has a marked effect on the elimination kinetics of remoxipride. After an overdose, treatment with ammonium chloride might be valuable in hastening elimination of remoxipride from the body. [ABSTRACT FROM AUTHOR]

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 (ED=49 μmol/kg) while peak effects were seen 60-90 min after i.p. administration (ED=38 μmol/kg). Following s.c. administration remoxipride failed to produce a statistically significant catalepsy in the 20-100 μmol/kg dose range (ED > 100 μmol/kg). In contrast, haloperidol was found to be more effective in inducing catalepsy after i.v. (ED=0.4 μmol/kg) than after i.p. or s.c. administration (ED=0.9 μmol/ 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 μmol/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 D 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. [ABSTRACT FROM AUTHOR]

Remoxipride and its active metabolites, the phenolic compounds FLA 797(−) and FLA 908(−) and the catecholic NCQ 436(−) and haloperidol, were examined for their ability to block hypothermia in the rat induced by dopamine (DA) D receptor stimulation. In addition, plasma levels of remoxipride and its active metabolites were measured using HPLC methods. Remoxipride (1 μmol/kg), given 30 or 15 min prior to, or 5 and 15 min after, the DA agonists, blocked the hypothermia induced by the DA D receptor agonists quinpirole (0.25mg/kg s.c.) and pergolide (0.1 mg/kg s.c). Administration of remoxipride by the i.v. or s.c. routes was more effective than by the i.p. route. FLA 797(−), FLA 908(−), and haloperidol were more effective than remoxipride in preventing the hypothermia caused by quinpirole, while NCQ 436(−) was less effective than remoxipride. The variation in time of remoxipride's action and effectiveness in blocking the induced hypothermia followed the variations in plasma concentrations. The plasma concentrations of the active metabolites were below the limit of determination (<2 nmol/l). Based on estimation of free brain concentrations at effective dose levels together with in vitro affinities for the DA D receptor it was concluded that the metabolites FLA 797(−), FLA 908(−), and NCQ 436(−) do not appear to contribute to the antagonism of DA D mediated neurotransmission following a low remoxipride dose (1 μmol/kg). [ABSTRACT FROM AUTHOR]

Risperidone and remoxipride are recently introduced atypical antipsychotics, with clinical efficacy comparable to that of classical antipsychotics but lower propensity to induce extrapyramidal side effects (EPS). It is unclear whether these properties relate to weak dopamine D receptor blockade in vivo, as has been suggested for the archetypal atypical antipsychotic clozapine. We have usedI-IBZM single photon emission tomography (SPET) to characterize the patterns of striatal D receptor binding in vivo in DSMIII-R-diagnosed schizophrenic and schizo-affective patients treated with either risperidone ( n=6) or remoxipride ( n=4) but predominantly EPS free. These groups were compared to age- and BPRS- matched subjects from a previously reported D receptor binding database of patients treated with clozapine ( n=10) and classical antipsychotics ( n=10). Patients on risperidone and remoxipride had high levels of D receptor blockade, comparable to those of patients on classical antipsychotics, and significantly greater than those obtained with clozapine-treated patients (risperidone versus clozapine, P<0.005; remoxipride versus clozapine, P<0.025). These results suggest high levels of striatal D receptor occupancy in association with remoxipride and risperidone treatment and argue against modest D antagonism as the explanation for the low incidence of EPS associated with these drugs. [ABSTRACT FROM AUTHOR]

The effect of various typical (haloperidol) and atypical (clozapine, raclopride, remoxipride) antipsychotics on phencyclidine (PCP)-induced disruption of sensorimotor gating was tested in rats using an acoustic startle paradigm. Clozapine (4-40 µmol/kg), haloperidol (1-5 µmol/kg) and raclopride (1-12 µmol/kg) failed to reverse PCP-induced disruption of prepulse inhibition (PPI) of the acoustic startle response. In contrast, remoxipride (12-60 µmol/kg) caused a dose-dependent block of this effect. PCP-induced disruption of PPI is a widely accepted animal model of a corresponding behavioural deficit observed in schizophrenia although little evidence has been presented that it is in fact sensitive to antipsychotic agents. The present results indicate that remoxipride behaves in a unique way in this model compared to clozapine, haloperidol and raclopride. [ABSTRACT FROM AUTHOR]

The dose-dependent and time-dependent effects of the novel antipsychotic compound remoxipride, as well as the reference compounds chlorpromazine, clozapine, haloperidol, pimozide and sulpiride upon the retention of two-way active avoidance (conditioned avoidance responses, CARs) were studied in male rats. The dose-dependent effects of remoxipride as well as haloperidol and chlorpromazine on the acquisition of CARs were also studied. The acquisition and retention of CARs were tested in shuttleboxes using a 1.0-mA shock intensity and a 10-stone signal (1000 Hz). All the compounds studied, including remoxipride, caused a dose-dependent impairment of acquisition and retention of CARs. The effect of remoxipride on CAR acquisition correlated with remoxipride's effectiveness to block the hyperactivity induced by the dopamine (DA) agonist apomorphine. Unlike chlorpromazine and haloperidol, the potency of remoxipride and clozapine for antagonising CAR retention was found at dose levels much lower than those producing cataleptic effects or blocking apomorphine-induced stereotypies. Based on the DA receptor blocking profile and the relative effectiveness to block CAR it is concluded that the mechanism(s) by which clozapine and remoxipride affect CAR differ from typical neuroleptic drugs. This difference may reflect an action upon different subtypes of functionally coupled DA D receptors. [ABSTRACT FROM AUTHOR]

Twelve healthy male volunteers took part in a double-blind randomised cross-over study composed of three treatment sessions: remoxipride 100 mg; remoxipride 100 mg plus biperiden 4 mg; and biperiden 4 mg. Plasma and urine concentrations of remoxipride and biperiden, plasma prolactin levels, salivary flow and adverse events were recorded to assess pharmacodynamic interactions. Remoxipride and biperiden had no effect on each other's plasma concentrations. Biperiden did not affect the urinary recovery or renal clearance of remoxipride. Prolactin levels were unaffected by biperiden but increased following remoxipride administration. Differences in prolactin C and t following remoxipride versus concomitant (remoxipride + biperiden) treatment were not statistically significant. However, a slight but statistically significant ( P=0.04) increase in prolactin AUC was observed after concomitant treatment. No significant differences could be observed between the recorded salivary flow in all the treatment sessions. Single doses of remoxipride and biperiden showed no pharmacokinetic or pharmacodynamic interaction. [ABSTRACT FROM AUTHOR]

Sixty-two DSM III chronic schizophrenic inpatients were selected for a double-blind, placebo controlled, multi-centre, relapse prevention study of remoxipride, a selective dopamine (D)-receptor antagonist. After a 1 month placebo washout, 23 patients had relapsed and were withdrawn. Of the remaining patients 19 were randomised to remoxipride (150-300 mg daily) and 20 to placebo. Their median age was 58 years, 26 were male, and the median duration of illness was 33 years. After 24 weeks a further total of 8 remoxipride and 17 placebo patients had been withdrawn. Excluding three patients withdrawn for reasons other than relapse, the comparative relapse rates were 37% and 75%, respectively ( P=0.015). Efficacy analyses using clinical global impression ( P=0.04) and change in BPRS scores ( P=0.016) were in favour of remoxipride. Extrapyramidal symptoms were minimal in both groups. Treatment emergent adverse events were similar in the two groups. Remoxipride is therefore of potential value as a safe drug which is both effective and well tolerated in the long term management of chronic schizophrenic patients. [ABSTRACT FROM AUTHOR]

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 µmol/1 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. [ABSTRACT FROM AUTHOR]

The present study examined the behavioural effects of sigma agonists and PCP-like non-competitive N-methyl- D-aspartate (NMDA) antagonists in guineapigs. Subcutaneous (SC) injection of the putative sigma agonist (+)NANM (1 and 10 mg/kg SC) and (−) NANM (1 and 10 mg/kg SC) produced a behavioural response in guinea-pigs which was characterized by sedation and exophthalmos, with locomotor depression, flattened posture and flaccidity, whereas the sigma ligand pentazocine induced sedation but no flattened posture. Ketamine (20 mg/kg SC) and (+)dizocilpine (0.025, 0.1 and 1 mg/kg SC) produced similar effects to those of (+) and (−)NANM. However, the putative sigma receptor ligand DTG (1 and 10 mg/kg SC) had no observable effect on behaviours in guinea-pigs, similar to results for other species. The behavioural effects produced by (+) and (−)NANM were not reversed by injection 1 h later of naloxone hydrochloride (15 mg/kg SC), haloperidol (10 mg/kg SC) or DTG (10 and 30 mg/kg SC), but the effects of all drugs were reversed by the selective dopamine D-2 agonist quinpirole (3 mg/kg IP). Moreover, injection of naloxone (15 mg/kg SC), DTG (10 and 30 mg/kg SC) or haloperidol (1 and 10 mg/kg SC) 10 min before, did not reverse the behaviour induced by (+)NANM (10 mg/kg SC). These data indicate that sigma and PCP-like drugs have a similar gross behavioural effect in guinea-pigs, possibly mediated by noncompetitive antagonism of the NMDA subtype of glutamate receptors. The results demonstrating behavioural depression were in contrast to the stimulatory effects of these drugs at similar doses in other rodent species. Single dose dependence to (+) and (−)NANM as indicated by withdrawal after sigma or opiate receptor antagonist treatment could not be demonstrated. [ABSTRACT FROM AUTHOR]

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 effecs 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. [ABSTRACT FROM AUTHOR]

Six female and six male healthy volunteers received 100 mg remoxipride, 200 mg sulpiride and placebo as single oral doses in a double blind trial with a randomized crossover design. The main objective was to compare the effect of the two drugs on serum prolactin levels, but effects on other hormones were also investigated. Remoxipride and sulpiride increased the serum levels of prolactin to similar peak levels. This effect was larger in female than in male subjects. Sulpiride increased prolactin levels at much lower plasma concentrations than remoxipride, and sulpiride's effect on prolactin lasted for considerably longer than remoxipride's. No consistent effects on serum levels of LH, FSH, GH, oestradiol, progesterone, testosterone or cortisol could be detected after remoxipride and sulpiride compared to placebo. No drug-related effects on plasma homovanillic acid (HVA) were found. [ABSTRACT FROM AUTHOR]

The pharmacokinetics of remoxipride, a new selective dopamine-D receptor antagonist with antipsychotic action, was evaluated in eight elderly psychiatric patients with tardive dyskinesia (TD). The daily oral doses of remoxipride were gradually increased from 50 mg per day to 200 mg t.i.d. over 2 weeks. The pharmacokinetics following the initial 50 mg dose (day 1) and the last 200 mg dose (day 15) of the drug were compared in serial samples. Plasma prolactin concentrations were assessed at the same time points. The area under the total plasma concentration versus time curves (AUC) of remoxipride increased proportionally with dose from day 1 to 15. The mean 'dose corrected' AUC values for the total concentrations were 96.8 at day 1 (4×24.2, 50 mg single oral dose) and 92.2 µmol·h/l at day 15 (200 mg). The unbound fraction of remoxipride calculated on AUC was slightly higher on day 15 (20%) than on day 1 (15%) ( P<0.05), indicating slightly concentration-dependent protein binding of the drug. The mean elimination half-life of total remoxipride was slightly longer on day 15 than day 1 (7.5 versus 5.3 h, P<0.01) The corresponding half-lives for the unbound concentrations were 6.4 and 3.9 h, respectively ( P<0.01). The pharmacokinetics of remoxipride is similar in these TD patients and in non-TD patients in previous studies. Following repeated administration of remoxipride, tolerance to the prolactin-releasing action of remoxipride is observed. In plots of the relationship between the concentration of remoxipride and the prolactin increase during a dosage interval, the curve on day 15 was positioned markedly to the right of that on day 1. This indicates a decreased sensitivity to the prolactin releasing action of remoxipride following continuous treatment. [ABSTRACT FROM AUTHOR]

In the present 6-week double-blind, randomised, multicentre study, the atypical neuroleptic remoxipride was compared to haloperidol in acute schizophrenic patients (DSM-III). Seventy-one patients entered the study, 36 in the remoxipride group and 35 in the haloperidol group. There were ten early withdrawals, four in the remoxipride group and six patients in the haloperidol group. The Present State Examination (PSE) profile revealed a similar reduction in the symptom clusters of psychosis in both treatment groups. Forty-seven per cent of the patients in the remoxipride group and 34% of the patients in the haloperidol group showed clinically relevant improvement (reduction of BPRS total score ≥ 50%). All extrapyramidal symptoms except 'glabella tap' occurred significantly less frequently in the remoxipride group as compared to the haloperidol group. Substantially lower incidences of EPS were found by active questioning in the remoxipride group compared to the haloperidol group. In addition, considerably lower incidences were observed in the remoxipride group with respect to drowsiness/somnolence, tiredness/fatigue and concentrating difficulty. At the end of treatment 66% of the patients in the haloperidol group and 22% in the remoxipride group were using anticholinergics. No consistent changes were found in the mean plasma HVA level in either treatment group. In responders (reduction of BPRS total score ≥ 50%) lower baseline HVA levels were observed in both treatment groups. This study indicates that the newly developed neuroleptic remoxipride is an effective antipsychotic compound, which is clinically safe and well tolerated. In particular, few EPS were induced by remoxipride, as compared to haloperidol. [ABSTRACT FROM AUTHOR]

Twenty-four stable, chronic schizophrenic inpatients were entered in a double-blind crossover study designed to compare single dose and steady state pharmacokinetic profiles of an immediate release formulation (IR) 200 mg BID and a controlled release formulation (CR) of remoxipride 400 mg once daily. The rate of absorption of remoxipride CR was significantly lower than the IR formulation and t was prolonged from 1.3 to 7.9 h after a single dose and from 2.2 to 6.0 h after repeated dosing. Although the single dose of remoxipride CR was twice as large as the single dose of the IR, the C was similar for both formulations after a single dose. However, the C at steady state was slightly lower for CR. There was significantly less fluctuation in plasma concentrations at steady state with the CR formulation, although the average plasma concentration of remoxipride IR and CR was similar. The mean relative bioavailability with regard to the amount of remoxipride absorbed after remoxipride CR 400 mg once daily compared to IR 200 mg BID was 97%. It was concluded that the CR formulation is suitable for a once-daily administration from a pharmacokinetic point of view. [ABSTRACT FROM AUTHOR]

The tolerability and pharmacokinetics of remoxipride were studied in 18 healthy normal male volunteers. Increasing oral doses of 0.5-100 mg were given to eight male volunteers in one study (study I). In addition, an intravenous (IV) infusion of 20 mg remoxipride and a 20 mg oral dose were given in an open crossover study to ten males (study II). Remoxipride was well tolerated with respect to cardiovascular effects, clinical chemistry, body temperature and adverse effects in all subjects. Following IV administration, remoxipride plasma concentrations declined exponentially in five subjects and biexponentially in the remaining five. The mean apparent volume of distribution was 0.5 1/kg (SD=0.10) and the mean half-life 4.1 h (range 2.6-6.6). The recovery of unchanged remoxipride in urine was 10-36%, and the mean renal clearance was 32 ml/min (SD=13). Remoxipride was a low clearance drug with a total plasma clearance of about 120 ml/min (SD=41). The mean oral bioavailability was 96%. There was a linear relationship between the peak plasma concentration as well as the area under the concentration versus time curve and the administered dose. A transient increase in plasma prolactin concentrations occurred but there were no effects on plasma growth hormone levels. [ABSTRACT FROM AUTHOR]

Remoxipride, a new potential antipsychotic drug, was administered over 4 days at two dose levels, 70 and 140 mg t.i.d., to eight healthy male volunteers. Pharmacokinetics, safety, tolerability, and effect on plasma prolactin levels were evaluated. Remoxipride exhibited essentially linear pharmacokinetics. Only minor deviations in biochemical and physiological safety parameters were found. The drug was well tolerated by all subjects at the 70 mg dose level. At 140 mg akathisia appeared in seven subjects. The drug induced a rapid and transient increase in plasma prolactin concentrations at both dose levels after single doses. During steady state, a significant reduction in the prolactin response was observed as compared to after the first dose. [ABSTRACT FROM AUTHOR]

Remoxipride in a dose range of 150-600 mg/day was evaluated in a single-blind placebo controlled study in eight patients with persistent tardive dyskinesia (TD). Dyskinesia score was significantly reduced without an increase in parkinsonism. The maximum mean reduction in dyskinesia rating score was 44%. After withdrawal of remoxipride TD scores returned to baseline levels without rebound deterioration. A negative correlation between remoxipride concentrations and the dyskinesia scores were found. Adverse effects were few and mild and no clinically relevant changes were seen in clinical chemistry, haematology or cardiovascular assessments. It is concluded that remoxipride in the dose range used has anti-dyskinetic effects but does not induce parkinsonism. [ABSTRACT FROM AUTHOR]

The regional brain distribution and binding of the antipsychotic benzamide drug remoxipride was studied in the male rat. After i.v. injections of H-remoxipride (1 μmol · kg) more than 85% of the radioactivity was identified as authentic remoxipride in brain by using reversed-phase liquid chromatography. Autoradiographic and spectroscopic analysis showed that H-remoxipride was distributed relatively even in different brain areas, with exception of the following structures, which showed highest drug concentrations: the choroid plexus, septum, medial part of the caudate nucleus, different areas of the thalamus and hypothalamus situated close to the cerebral ventricles. A closer analysis of the autoradiograms showed a gradient of radioactivity extending from the cerebral ventricles to the deeper parts of the brain at 30 minutes after injections. After 60 minutes radioactivity was detected throughout all forebrain dopamine receptive areas. These findings suggest that remoxipride enters the cerebrospinal fluid (CSF) via the vascular bed of the choroid plexus and that it enters the brain interstitial fluid from the CSF. In the caudate nucleus, nucleus accumbens, olfactory tubercle and olfactory bulb 30-40% of the radioactivity was reduced by pretreatment with the dopamine D-2 selective drug raclopride. In addition, small, but significant, reductions (10-15%) ofH-remoxipride derived radioactivity was found in the neocortex, hippocampus and the cerebellum, suggesting that remoxipride interacts with a D-2 receptor also in these cortical structures. Taken together, these studies show that after i.v. injections,H-remoxipride enters the brain primarily in unmetabolized form when given in doses that affect DA receptor mediated behaviours, that it distributes to most areas throughout the neuraxis and that it binds to D-2 receptors in different parts of the basal ganglia, neocortex, hippocampus and cerebellum. [ABSTRACT FROM AUTHOR]

Remoxipride, a D2-dopamine receptor antagonist, is well tolerated and completely absorbed after oral administration. Because of its extremely bitter taste, an oral palatable suspension was developed by using a taste-masking microencapsulation. The bioavailability of remoxipride was investigated in two studies in healthy volunteers after administration of a 100-mg dose in suspension. The first study used a capsule as reference, and the second study a plain solution. Taste assessment was carried out in the second study. The extent of bioavailability was the same when comparing the oral suspension to a capsule and to a plain solution. However, the rate of absorption is delayed, and Tmax was 3.0 hr after the suspension, 1.0 hr after the oral solution, and 1.6 hr after the capsule. The release rate in vitro from the suspension was determined by applying the USP-paddle method. By using numerical convolution and deconvolution, the release rates in vivo and in vitro were shown to be similar when using water with 0.5% sodium lauryl sulfate as dissolution liquid. The taste-masked oral suspension is suitable for full-scale production, with good control of the encapsulation process and of the preparation of a suspension. [ABSTRACT FROM AUTHOR]

To explore the oral absorption of remoxipride, spheres of remoxipride were labeled with indium-111 colloid before coating with a release-controlling ethylcellulose membrane. Since the labeling remained inside the coating, it was suitable as a marker. Eight healthy volunteers were given a single dose of 100 mg remoxipride in In-marked spheres as a multiple-unit capsule. The radioactivity and the position of the spheres (microcapsules) were followed externally for 30 hr by gamma scintigraphy. Parallel to this, plasma concentrations were drawn for 48 hr to confirm the extended dissolution and absorption of remoxipride. The hard gelatin, multiple-unit capsule released the microcapsules within the stomach. These were then rapidly emptied into the small intestine, within 0.5-1 hr. There was then an immediate distribution in the upper small intestine before collection in the lower portion, within 2-5 hr. After passing into the large intestine, there was again an extended distribution of the microcapsules. A mean C of 2.7 µM remoxipride was achieved 4 hr after drug administration and a mean AUC of 26.1 µmol · L hr was achieved. Judging from the absorption versus time profile, calculated according to the Wagner-Nelson method, and the scintigraphic images, it is concluded that the main absorption occurs from the small intestine. Data from four volunteers, however, indicated a comparatively good absorption also from the large intestine. Due to the good absorption properties, it is reasonable to expect a low variation in the extent of bioavailability of remoxipride after administration in an extended-release, multiple-unit capsule formulation. [ABSTRACT FROM AUTHOR]

The ability of the dopamine receptor antagonists haloperidol, raclopride and remoxipride to prevent the B-HT 920-induced decrease in striatal and limbic L-DOPA accumulation in gamma-butyrolactone (GBL)- and NSD 1015-treated rats (termed 'GBL-reversal') was used to define the effects of these compounds on 'presynaptic' dopamine receptors. The doses of the dopamine antagonists producing antagonism of GBL-reversal were in each case roughly similar to the doses required to increase dopamine turnover in striatal and limbic areas. The potencies of haloperidol, raclopride and remoxipride in the GBL model were compared with their potencies in behavioural models for postsynaptic dopamine receptors. Haloperidol produced antagonism of GBL-reversal over a similar dose range to that required for antagonism of apomorphine-induced hyperactivity and stereotypy syndromes. Raclopride was effective in the order of potency: antagonism of apomorphine-induced hyperactivity > antagonism of GBL-reversal > antagonism of apomorphine-induced stereotypy. For remoxipride, the dose-response curve for antagonism of GBL-reversal was superimposable over that for antagonism of apomorphine-induced stereotypies, with an ED value about 12 times higher than that for antagonism of apomorphine-induced hyperactivity. Thus, the relative potencies of dopamine receptor antagonists at 'pre-' and postsynaptic dopamine receptors vary considerably from compound to compound. [ABSTRACT FROM AUTHOR]