ISSN:0001-690X    

DOI:10.1111/j.1600-0447.1990.tb05278.x

出版商:Blackwell Publishing Ltd    

年代:1990

数据来源: WILEY

摘要:

AbstractThe hypothesis that central biogenic amines may play a role in the pathophysiology of schizophrenia was originally based upon the fact that hallucinogenic and antipsychotic drugs have profound effects on central transmitter pathways where dopamine, noradrenaline and serotonin are involved. The structural similarities between hallucinogenic drugs such as amphetamine and mescaline, and catecholamines on the one hand and lysergic acid diethylamide (LSD) and indolamines such as serotonin on the other hand have by direct experimentation been shown to explain their important effects on the transmitter systems. The marked effect of several classes of chemically different antipsychotic drugs on central dopamine receptor function formed the basis for the dopamine hypothesis regarding the mechanisms of action of these drugs and also for the hypothesis that dopamine D2 receptor function played a significant role in the pathophysiology of schizophrenia. Direct experimental analysis of aminergic functions in the brain of schizophrenic patients, both during life and post mortem, has been and will for die foreseeable future continue to be a rational approach to the further elucidation of the validity of these hypotheses. Analysis of metabolite levels in the cerebrospinal fluid and plasma of schizophrenic patients has shown great variation in the results with reports of both elevated and reduced release of amines in the brains of schizophrenic patients. Analysis of the aminergic receptor structures in the postmortem human brain has relatively consistently revealed an increased density of D2 receptors in the major basal ganglia of schizophrenic patients. Whether these alterations represent a primary feature of brain structure in schizophrenia or a drug‐induced effect still remains to be shown. Positron emission tomographic (PET) scan studies of D2 receptors in schizophrenia have demonstrated both increased densities and absence of change in the characteristics of D2 receptors in the patients as compared to matched controls. This review gives a critical account of the biochemical studies that examine the possible role of biogenic amine abnormalities in the brains of schizophrenic patient

ISSN:0001-690X    

DOI:10.1111/j.1600-0447.1990.tb05279.x

出版商:Blackwell Publishing Ltd    

年代:1990

数据来源: WILEY

摘要:

AbstractA variety of biological factors may account for the atypical lack of parkinsonism that is a characteristic of the administration of the many ‘atypical’ neuroleptics. Although dopamine D2receptor blockade continues to be a dominant feature of successful neuroleptics, the concomitant blockade of muscarinic or serotonergic S2receptors helps to prevent neuroleptic‐induced parkinsonism for some atypical neuroleptics (clozapine, thioridazine, risperidone). The D2‐selective benzamides, however, do not block other known receptors (with the possible exception of sigma sites). Therefore, the atypical nature of the benzamides may be based on their sensitivity to the level of endogenous dopamine released in the different regions of the brain. Finally, atypical neuroleptic action may possibly stem from direct linkage between different receptors coupled through components of the G protein

ISSN:0001-690X    

DOI:10.1111/j.1600-0447.1990.tb05280.x

出版商:Blackwell Publishing Ltd    

年代:1990

数据来源: WILEY

摘要:

AbstractRemoxipride blocks dopamine agonist‐induced effects in the rat, mediated by dopamine D2 receptors with an in‐vivo potency less than that of haloperidol but greater than that of chlorpromazine, thioridazine, and sulpiride. Unlike haloperidol and sulpiride, remoxipride has weaker antagonistic effects towards presynaptic dopamine activity compared to its effects on postsynaptically mediated activity. Remoxipride causes a preferential inhibition of dopamine agonist‐induced locomotion as compared to stereotyped behaviour, suggesting that it may exert a preferential blockade of mesolimbic dopamine neurotransmission. The low tendency of remoxipride to cause catalepsy in the rat is indicative of a weak effect on striatal dopamine neurotransmission and predicts a low liability to induce extrapyramidal side effects in man. Remoxipride causes a smaller elevation of prolactin than sulpiride at doses producing central dopamine receptor blockade. The results suggest that remoxipride, unlike haloperidol, can discriminate between different types of dopamine mediated functions probably by having a preferential action on subpopulations of functionally coupled dopamine D2 rece

ISSN:0001-690X    

DOI:10.1111/j.1600-0447.1990.tb05281.x

出版商:Blackwell Publishing Ltd    

年代:1990

数据来源: WILEY

摘要:

AbstractIn vitro receptor ligand binding studies in the rat showed that remoxipride displaced different radioligands at the dopamine D2, but not the D1receptor. Remoxipride did not block dopamine‐stimulated adenylate cyclase activity in vitro suggesting that it did not directly interact with the dopamine D1receptor. Like other antipsychotic compounds, it increased dopamine turnover in the dopamine‐rich areas of the brain. It showed no affinity for a wide range of neurotransmitter receptors, with the exception of the opiate sigma receptor. The affinity of remoxipride for the D2receptor was low in vitro, while in vivo, the affinity was relatively high. Remoxipride was far more potent in preventing [3H]raclopride‐binding than [3H]spiperone‐binding to the D2receptor in vivo. When the D2receptor was labelled with [3H]spiperone, remoxipride was shown to exert a preferential blockade of this binding in extrastriatal areas of the brain (for example, olfactory tubercle, septum, substantia nigra) in vivo. After the injection of high doses of remoxipride most if not all drug in the brain was identified as authentic remoxipride.After injection of [3H]remoxipride in smaller and larger doses, radioactivity was detected in all areas of brain examined, including cerebellum and neocortex. Most of the remoxipride‐derived radioactivity was found in the choroid plexus and circumventricular organs, while smaller amounts were recovered in the striatum, olfactory tubercle, and substantia nigra. Taken together, these findings suggest that remoxipride acts at both the central D2and sigma receptors and that its affinity for the D2receptor is relatively low in vitro. A regional preference for D2receptors can be observed in vivo depending upon the radioli

ISSN:0001-690X    

DOI:10.1111/j.1600-0447.1990.tb05282.x

出版商:Blackwell Publishing Ltd    

年代:1990

数据来源: WILEY

摘要:

AbstractVariability in the outcome of treatment with antipsychotic drugs may be due to differences in compliance and to variations in pharmacokinetics and concentration‐response relationships at the receptor level. Among the various chemical classes of neuroleptics, the butyrophenones, the phenothiazines, and the thioxanthenes have similar pharmacokinetics, and show larger inter‐individual variations in plasma drug levels after oral than after intramuscular doses. Compared to the “classical” neuroleptics, the more water‐soluble benzamide derivatives have significantly shorter elimination half‐lives, and show smaller inter‐patient variations in plas

ISSN:0001-690X    

DOI:10.1111/j.1600-0447.1990.tb05283.x

出版商:Blackwell Publishing Ltd    

年代:1990

数据来源: WILEY

摘要:

AbstractThe clinical pharmacokinetics of remoxipride, a pure enantiomer, have been studied in healthy volunteers and patients. After oral administration the drug is rapidly and almost completely absorbed with a bioavailability above 90%. Thus remoxipride is a low clearance drug, with a systemic plasma clearance of about 120 ml/min, and without any first‐pass metabolism. The apparent volume of distribution is 0.7 1/kg, about 80% being bound to plasma proteins (mainly alphai‐acid glycoprotein). Remoxipride has a plasma half‐life in the range of 4–7 h and is eliminated by both hepatic metabolism and renal excretion. Slightly more than 70% of the dose is recovered as urinary metabolites and about 25% is excreted unchanged. Steady‐state plasma levels are reached within 2 days, and they increase linearly with doses up to 600 mg daily. There is no evidence that active metabolites of remoxipride are present in the blood. Decreased renal function is associated with increased levels of remoxipride, whereas moderate cirrhosis of the liver only slightly affects elimination. There are no pharmacokinetic interactions between remoxipride and diazepam, ethanol, biperiden, or

ISSN:0001-690X    

DOI:10.1111/j.1600-0447.1990.tb05284.x

出版商:Blackwell Publishing Ltd    

年代:1990

数据来源: WILEY

摘要:

AbstractTwenty‐four stable, chronic schizophrenic inpatients were entered in a double‐blind, crossover study designed to compare single‐dose and steady‐state pharmacokinetics of remoxipride immediate release (IR) 200 mg twice daily and controlled release (CR) 400 mg once daily. The CR formulation showed a significantly delayed absorption of remoxipride from the gastrointestinal tract. At steady state there was significantly less fluctuation in plasma concentrations. The other pharmacokinetic variables studied showed no difference. The mean relative bioavailability with regard to the amount of remoxipride absorbed after administration in CR form as compared with the IR form was 97%. Both formulations were well tolerated and there was no difference in either the incidence or the severity of adverse events. It was concluded that, from a pharmacokinetic point of view, the CR formulation of remoxipride was suitable for a once daily dosage s

ISSN:0001-690X    

DOI:10.1111/j.1600-0447.1990.tb05285.x

出版商:Blackwell Publishing Ltd    

年代:1990

数据来源: WILEY

摘要:

AbstractThe possible relationship between plasma concentration of remoxipride and antipsychotic effect/adverse symptoms has been evaluated in a 6‐week double‐blind dose‐finding study in schizophrenic patients. The study comprised 3 parallel groups with fixed daily doses of 30–90 mg, 120–240 mg or 300–600 mg, divided in order to be given three times a day. A total of 79 patients from the three groups, who were treated with the maximum dose for 4 weeks or more, were included in the analysis. All patients had reached steady‐state at week 2 and the intra‐individual trough remoxipride plasma levels remained stable over the study period. The mean steady‐state trough concentrations were found to be linearly related to the dose. Responders to remoxipride treatment were observed over the total concentration range of 0.24–13.50 μmol/l. Reductions of dose or discontinuations of treatment due to adverse symptoms were not associated with elevated remoxipride concentrations. In conclusion, no obvious relationship between plasma concentration of remoxipride and its antipsychotic effect or adverse symp

ISSN:0001-690X    

DOI:10.1111/j.1600-0447.1990.tb05286.x

出版商:Blackwell Publishing Ltd    

年代:1990

数据来源: WILEY

摘要:

AbstractA study was undertaken in seven schizophrenic patients to evaluate the tolerability and examine the pharmacokinetics of intramuscularly administered remoxipride after a single 200 mg dose and at steady state following repeated doses of 200 mg twice daily for one week. Comparisons of AUC, t1/2 and tmaxusing the Wilcoxon's signed rank test showed no significant difference between single dose and steady state indicating that the pharmacokinetics of intramuscular remoxipride were linear. The steady‐state Cmaxwas found to be significantly larger than that after single dose and the increase was accounted for by the predicted accumulation factor, assuming linear kinetics. Although the inter‐individual variability in plasma concentrations was large, the intra‐individual variability was low as shown by the reproducibility of the single‐dose and steady‐state plasma curves. Remoxipride, administered intramuscularly, was well

ISSN:0001-690X    

DOI:10.1111/j.1600-0447.1990.tb05287.x

出版商:Blackwell Publishing Ltd    

年代:1990

数据来源: WILEY