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Aims: The tolerance to the prolactin response following administration of antipsychotic drugs has been modelled as a depletion of a prolactin pool (pool model) and a model where the tolerance is explained by a feedback loop including the dopamine interaction of prolactin release (agonist-antagonist interaction model, (AAI model)). The AAI model was superior to the pool model when analyzing data from clinical trials of risperidone and paliperidone. Here we evaluated the two models using the remoxipride data, designed to challenge the short-term prolactin response, from which the original pool model was built., Methods: The remoxipride data were collected from a study where eight healthy male subjects received two remoxipride infusions on five occasions. The intervals between the first and second dose on each occasion were 2, 8, 12, 24 and 48 h, respectively. The pool and AAI models were fitted using NONMEM., Results: According to the objective function values the pool model with a circadian rhythm function fitted the data slightly better, while the AAI model was better in describing the circadian rhythm of prolactin. Visual predictive checks revealed that the models predicted the prolactin profiles equally well., Conclusions: According to the analysis performed here, a previous analysis of several clinical studies and literature reports on prolactin concentrations, it appears that the dopamine feedback mechanism included in the AAI model is better than the storage depletion mechanism in the pool model to estimate the bio-rhythm of prolactin time-course and the tolerance development across different populations, drugs, treatment schedules and time., (© 2010 The Authors. British Journal of Clinical Pharmacology © 2010 The British Pharmacological Society.)

Phenothiazines are widely used in older patients, but little experimental work has been carried out in this age group. Two groups of healthy volunteers, a younger group (Y: six males and six females, aged 20-42 years) and an older group (O: six males and eight females, aged 65-77 years) took part in a randomized double-blind three-period crossover study in which they received by mouth single doses of thioridazine (Y: 50 mg; O: 25 mg) remoxipride (Y: 100 mg; O: 50 mg) or placebo. Measures of central nervous system (CNS) and haemodynamic function were carried out before drug administration and at 1.5-h intervals up to 9 h post-dose, and blood samples were collected over a 24-h period. No significant differences in dose-corrected pharmacokinetic variables were found between the two groups. There was evidence of marked CNS depressant effects of thioridazine from both objective and subjective measures. The effects for remoxipride were similar, though generally less marked. After allowance was made for dose, there was little indication of any difference in degree of CNS depression between the two age groups. Haemodynamic measures showed orthostatic reductions in blood pressure with thioridazine which were particularly marked in the older group, who also showed lower compensatory increases in pulse rate. These results indicate potential problems with orthostatic hypotension with thioridazine in older patients. CNS depression may also be a problem, especially in patients with compromised cholinergic function.

The in vivo effects of remoxipride, in relation to some of its identified metabolites, were investigated in adult male Sprague-Dawley rats. The methods used included: (1) estimation of the in vivo rate of brain monoamine synthesis by measuring the accumulation of dihydroxyphenylalanine and 5-hydroxytryptophan after decarboxylase inhibition; (2) observations of spontaneous locomotor activity in a photocell-equipped open-field arena ( approximately 0. 5 m2); (3) treadmill locomotion ( approximately 4 m min-1); (4) inclined grid (60 degrees ) catalepsy test; (5) d-amphetamine-induced (1.0 mg kg-1) hyperlocomotion;(6) quinpirole-induced (0.4 mg kg-1) hypothermia. By use of one or more of these tests, the findings with remoxipride were as follows: First, remoxipride had a late onset of action (up to 3 h). Second, potency and efficacy depended on exposure to hepatic metabolism. Thus, intraperitoneal administration was more effective than the subcutaneous route, whereas virtually all biological effects were lost on intracerebroventricular administration. The ED50 values (micromol kg-1, neostriatal dihydroxyphenylalanine accumulation) for remoxipride and a range of its phenolic aromatic ring metabolites were: remoxipride (approximately 20), NCQ-344 (approximately 0.01), FLA-797 (approximately 0.1), FLA-908 (approximately 2.2), NCQ-436 (approximately 25) and NCQ-469 (approximately 30). Considering remoxipride as a nonclozapine atypical antipsychotic drug, together with the fact that remoxipride behaves as a prodrug in the laboratory studies above, further characterization of the pharmacodynamic profile of its metabolites remains a challenge.

The present study is a retrospective study of remoxipride therapy. A total of 103 patients, 65 years or older, with a DSM-III-R diagnosis of dementia or delirium, were included. They had all been treated with remoxipride because of psychotic symptoms or behavioural disturbances. The dose range of remoxipride was 50-300 mg, the median dose being 75 mg. The clinical effect was rated as good in two thirds of the patients, and side-effects were noted in one fourth. When psychomotor hyperactivity was the dominating problem, a good effect was rated in 81% of the patients. Side-effects were few and mild, the most common being tiredness; only 5 patients showed extrapyramidal symptoms.

The disposition of remoxipride was evaluated in 13 male chronic schizophrenic patients. A single 150 mg dose of remoxipride was administered and blood sampling performed over the following 48 hours. The mean (SD) oral clearance and half-life of remoxipride were 74.46 (25.9) ml/min and 5.46 (0.87) hours, respectively. The mean (SD) AUC for remoxipride was 25,320 (9,820) ng.h/ml. A wide interpatient variability was observed. Compared to Caucasian studies there were no significant differences in the disposition of remoxipride.

The antinociceptive potential of remoxipride was investigated in sheep and rats with concurrent motor function assessments. Previous studies of sheep given intravenous remoxipride have revealed increases in mechanical nociceptive thresholds. Here, further investigation in sheep demonstrated elevated thermal nociceptive thresholds with no effect on subjectively assessed sedation or motor impairment scores. However, in rats, the dose of remoxipride (100 mg/kg i.p.) required to produce nociceptive thresholds similar to those elicited by morphine (30 mg/kg i.p.), itself reduced rotarod performance. Medetomidine (200 micrograms/kg i.p.) evoked sedation without influencing rotarod performance or antinociception. The antinociceptive, motor deficit and cataleptogenic actions of remoxipride were similar to those induced by two other dopamine antagonists, haloperidol (5 mg/kg) and raclopride (16 mg/kg i.p). 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. This study emphasizes the importance of motor function assessment during acute antinociceptive testing.

Despite the enormous benefits provided by antipsychotic medication in the management of schizophrenia, available compounds have serious limitations. Firstly, they are not always effective. Secondly, positive psychopathological symptoms may benefit more than negative or deficit symptoms. Thirdly, antipsychotics are generally associated with a variety of neurological adverse effects. Three drugs have recently been or are close to being introduced into widespread clinical use: clozapine, risperidone and remoxipride. Each of these compounds appears to have some advantages over traditional antipsychotic agents, particularly in terms of reduced propensity to induce adverse neurological effects. All three drugs have been shown to be clinically effective in large scale trials. Future clinical trials are required to establish their relative merits in comparison with one another.

Previous experiments have shown that blockade of dopamine D1 or D2 receptors by SCH 23390 or pimozide increases aromatic L-amino acid decarboxylase (AADC) activity in the rat striatum and the mesolimbic system. This study examined whether other dopamine receptor antagonists affect AADC activity and if there is an interaction between dopamine D1 and D2 receptor blockade on AADC activity. The possible effect of dopamine receptor agonists on AADC activity has been investigated as well. Administration of cis-flupenthixol (0.5 and 1 mg/kg) increased striatal AADC activity (by 25 and 26% above controls) and similar effects were observed with remoxipride (0.5-4 mg/kg) (by 18-27% above controls). Pretreatment with cycloheximide (10 mg/kg) did not change the increases produced by cis-flupenthixol (0.5 mg/kg). The administration of non-neuroleptic trans-flupenthixol did not change AADC activity. Combined treatment with SCH 23390 (0.1 mg/kg) and remoxipride (0.5 mg/kg), but not combination of SCH 23390 (0.1 mg/kg) and pimozide (0.3 mg/kg), showed higher increases of AADC activity than by the individual treatments, suggesting an interaction between the effects of the two drugs. Bromocriptine, but not (-)-quinpirole and d-amphetamine, significantly reduced the striatal AADC activity by 23% at the dose of 10 mg/kg. The results further demonstrate that AADC is a regulated enzyme in the rat brain.