Disease relevance of Remoxipride

• Remoxipride caused less parkinsonism than the prior neuroleptic therapy and appeared to have little masking effect on tardive dyskinesia [1].
• Several cases of aplastic anemia led to the withdrawal of remoxipride from the market in December 1993 [2].
• 5. The dopamine D(2) antagonist remoxipride (10 mg kg(-1)) did not alter MDMA-induced hyperthermia, but the D(1) antagonist SCH 23390 (0.3 - 2.0 mg kg(-1)) dose-dependently antagonized it [3].
• Tocainide (100 mg/kg i.p.) induced thermal antinociception with normal rotarod performance and no catalepsy suggesting that Na+ channel blockade by remoxipride is not responsible for the changes in nociceptive thresholds [4].
• Symptomatic relief from treatment-induced psychosis in Parkinson's disease: an open-label pilot study with remoxipride [5].

Psychiatry related information on Remoxipride

• Two out of the first three subjects given 120 mg remoxipride experienced marked akathisia, and therefore no subsequent subjects were given this dose [6].
• Initial Brief Psychiatric Rating Scale scores decreased by a mean 8.7 points in both remoxipride and thioridazine groups [7].
• A total of 144 patients (remoxipride = 73, thioridazine = 71) with DSM-III-R schizophrenia or schizophreniform disorder commenced the study, and 89 patients (remoxipride = 45, thioridazine = 44) completed the 6 weeks of the trial [7].
• 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 [8].
• Remoxipride reduced the psychotic symptomatology, especially hallucinations and delusions [9].

High impact information on Remoxipride

• A common action of clozapine, haloperidol, and remoxipride on D1- and D2-dopaminergic receptors in the primate cerebral cortex [10].
• The agonist effects on depotentiation were prevented by the D2-like antagonist remoxipride [11].
• The atypical neuroleptics remoxipride, clozapine, perlapine, seroquel, and melperone had low affinity for the dopamine D2 receptor (radioligand-independent dissociation constants of 30 to 90 nM) [12].
• 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 [13].
• Early phase II clinical trial of remoxipride in treatment of schizophrenia with measurements of prolactin and neuroleptic activity [1].

Chemical compound and disease context of Remoxipride

• In healthy subjects, an acute dose of 3 mg haloperidol caused more severe alteration in cognitive functioning, cortical arousal, and psychomotor performance than a clinically equipotent dose of 150 mg remoxipride [14].
• Apomorphine-induced hypotension was competitively antagonized by either SCH 23390 or remoxipride, selective D1- and D2-receptor antagonists, respectively, but only remoxipride antagonized the bradycardia [15].
• Because one patient with moderately severe levodopa-induced dyskinesias experienced a reduction in the abnormal movements without a substantial increase in parkinsonism, we began a trial of remoxipride for disabling peak-dose dyskinesias [16].
• 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 [17].
• It was shown that prenatal metallic mercury, organic tin and the neuroleptic compounds, haloperidol and remoxipride altered various parameters of spontaneous motor activity, retarded maze learning in the radial arm maze and potentiated d-amphetamine-induced activity [18].

Biological context of Remoxipride

• The pharmacokinetics of remoxipride is similar in these TD patients and in non-TD patients in previous studies [19].
• The area under the total plasma concentration versus time curves (AUC) of remoxipride increased proportionally with dose from day 1 to 15 [19].
• Recently, these two remoxipride metabolites were shown to induce apoptosis in human bone marrow progenitor cells [2].
• 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% [20].
• In the rat, remoxipride (1-10 mg/kg SC) did not affect either total sleep or non-rapid eye movement (non-REM) sleep [21].

Anatomical context of Remoxipride

• However, this dose of remoxipride induced a marked forelimb motor impairment as judged by a subjective visual analogue scoring system [22].
• The unbound fraction of remoxipride and the blood/plasma ratio were 0.19 +/- 0.03 and 0.64 +/- 0.06, respectively [23].
• High concentrations of the neuroleptic remoxipride block voltage-activated Na+ channels in central and peripheral nerve membranes [24].
• Even though there are possible anatomical substrates within the spinal cord for both an antinociceptive and motor disturbance action of remoxipride, the behavioural data suggest that the spinal cord is unlikely to be the primary site of antinociceptive action for systemically-administered doses of remoxipride [22].
• Nemonapride, D,L-sulpiride, and remoxipride significantly reduced the number of spontaneously active dopamine neurones in the ventral tegmental area, indicating an antipsychotic potential, while raclopride and zacopride induced but minor effects [25].

Associations of Remoxipride with other chemical compounds

• 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 (D2)-receptor antagonist [26].
• We have used 123I-IBZM single photon emission tomography (SPET) to characterize the patterns of striatal D2 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 [27].
• Pretreatment with dopamine receptor blockers [D1 (SCH 39166, 0.1 mg/kg) or D2 (remoxipride, 3.0 mg/kg and nemonapride, 0.003 mg/kg)] and low-efficacy agonists [D1 (SKF 77434; 3.0 mg/kg) or D2 (SDZ 208-911 and SDZ 208-912; 0.01-0.03 mg/kg)] antagonized the discriminative-stimulus effects of methamphetamine [28].
• This Mg(2+)-free LTP was blocked by dopamine depletion and by the dopamine D-1/D-5 receptor antagonist SCH 23390 but was not blocked by the dopamine D-2 receptor antagonist remoxipride or the GABA(A) antagonist picrotoxin [29].
• The potential antipsychotic agents BMY 14802, remoxipride, tiospirone and gevotriline (WY 47,384) have a relatively high affinity for sigma binding sites in brain tissue [30].

Gene context of Remoxipride

• The newer, atypical antipsychotics such as quetiapine, remoxipride, clozapine, olanzapine, sertindole, ziprasidone, and amisulpride all bind more loosely than dopamine to the dopamine D2 receptor and have dissociation constants higher than that for dopamine [31].
• While 5-HT2A receptors are readily blocked at low dosages of most atypical antipsychotic drugs (with the important exceptions of remoxipride and amisulpride, neither of which is available for use in Canada) the dosages at which this happens are below those needed to alleviate psychosis [31].
• A further aim was to compare the prolactin response following remoxipride and thyrotropin release hormone (TRH) during the refractory period [32].
• 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 [33].
• MDMA (5 mg kg(-1) i.p.) produced a rapid decrease in rectal temperature in rats at Ta 15 degrees C. This response was blocked by pretreatment with the dopamine D2 receptor antagonist remoxipride (10 mg kg(-1) i.p.), but unaltered by pretreatment with the D1 antagonist SCH23390 (1.1 mg kg(-1) i.p) [34].

Analytical, diagnostic and therapeutic context of Remoxipride

• 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) [35].
• In the present 6-week double-blind, randomised, multicentre study, the atypical neuroleptic remoxipride was compared to haloperidol in acute schizophrenic patients (DSM-III) [36].
• 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 [21].
• This overview includes pooled data from all patients who have been treated long term with remoxipride in clinical trials, focusing on patients treated for more than 6 months (n = 283) [37].
• Determination of remoxipride in plasma and urine by reversed-phase column liquid chromatography [38].

References