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Majinger Nilsson - One of the best experts on this subject based on the ideXlab platform.
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pharmacokinetics and effects on prolactin of Remoxipride in patients with tardive dyskinesia
Psychopharmacology, 1991Co-Authors: Erik Widerlov, Ulf Andersson, Christer Von Bahr, Majinger NilssonAbstract:The pharmacokinetics of Remoxipride, a new selective dopamine-D2 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.
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Pharmacokinetics and effects on prolactin of Remoxipride in patients with tardive dyskinesia.
Psychopharmacology, 1991Co-Authors: Erik Widerlov, Ulf Andersson, Christer Von Bahr, Majinger NilssonAbstract:The pharmacokinetics of Remoxipride, a new selective dopamine-D2 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
Ian C Kilpatrick - One of the best experts on this subject based on the ideXlab platform.
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investigation into the antinociceptive potential of Remoxipride administered intrathecally in sheep
Naunyn-schmiedebergs Archives of Pharmacology, 1997Co-Authors: David C J Main, A E Waterman, Ian C KilpatrickAbstract:Systemic administration of Remoxipride, a dopamine (D2) antagonist, to sheep has previously been shown to generate an antinociceptive action without producing a significant motor impairment. The present study examined whether a spinal locus of action was responsible for this action of Remoxipride. Remoxipride (17.7 mg) administered intrathecally via chronically indwelling catheters produced a greatly variable but significant (p<0.05) increase in nociceptive thresholds as judged by a focused mechanical stimulus (blunt pin) applied to the forelimb of four sheep. However, this dose of Remoxipride induced a marked forelimb motor impairment as judged by a subjective visual analogue scoring system. Conversely, intrathecal xylazine (100 and 200 μg), an α-adrenergic agonist with antinociceptive properties, did not produce forelimb weakness although the higher dose (200 μg) produced significant sedation. In vitro autoradiography was performed on cervical spinal cord sections taken from sheep. Remoxipride displaced [3H] YM-09151-2, a selective D2 antagonist, from densely-labelled areas in the superficial layer of the dorsal horn, lamina X and ventral horn. 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.
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Investigation into the antinociceptive potential of Remoxipride administered intrathecally in sheep
Naunyn-Schmiedeberg's archives of pharmacology, 1997Co-Authors: David C J Main, Avril Waterman, Ian C KilpatrickAbstract:Systemic administration of Remoxipride, a dopamine (D2) antagonist, to sheep has previously been shown to generate an antinociceptive action without producing a significant motor impairment. The present study examined whether a spinal locus of action was responsible for this action of Remoxipride. Remoxipride (17.7 mg) administered intrathecally via chronically indwelling catheters produced a greatly variable but significant (p
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Behavioural analysis of changes in nociceptive thresholds produced by Remoxipride in sheep and rats.
European journal of pharmacology, 1995Co-Authors: David C J Main, Avril Waterman, Ian C KilpatrickAbstract: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 μg/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.
M Hammarlund-udenaes - One of the best experts on this subject based on the ideXlab platform.
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Influence of the dosing interval on prolactin release after Remoxipride.
British journal of clinical pharmacology, 1995Co-Authors: G Movin-osswald, C. Von Bahr, M Hammarlund-udenaes, P. Eneroth, K Walton‐bowenAbstract:1. The prolactin response following administration of the D2-dopamine receptor antagonist Remoxipride was studied in eight healthy male volunteers. The purpose of the study was to investigate the duration of a refractory period of prolactin release following two doses of Remoxipride. A further aim was to compare the prolactin response following Remoxipride and thyrotropin release hormone (TRH) during the refractory period. The subjects received two 30 min intravenous (i.v.) infusions of Remoxipride 50 mg with different time intervals between the two doses, in a randomized six period crossover design. The time intervals between the two Remoxipride doses were 2, 8, 12, 24 and 48 h. On one occasion the Remoxipride dose was followed by an i.v. injection of TRH after 2 h. 2. The plasma peak prolactin concentrations obtained after the first Remoxipride dose correspond to a maximal release of prolactin according to earlier studies. A small second peak of prolactin was observed after 2 h. The release was gradually increased with longer time intervals between the consecutive doses. The refractory period for a second prolactin release similar to the first one after Remoxipride was found to be 24 h for most of the subjects. 3. TRH resulted in a faster and higher increase in prolactin response of a shorter duration than after Remoxipride administered 2 h after the first dose.
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Prolactin release after Remoxipride by an integrated pharmacokinetic-pharmacodynamic model with intra- and interindividual aspects.
The Journal of pharmacology and experimental therapeutics, 1995Co-Authors: G Movin-osswald, M Hammarlund-udenaesAbstract:An integrated pharmacokinetic-pharmacodynamic model is suggested for Remoxipride and its effect on prolactin (PRL) release acting by preventing the inhibitory effect of dopamine D2 receptors in the anterior pituitary. The model was implemented to describe the time course of PRL plasma levels after administration of two consecutive doses of Remoxipride at 5 different time intervals, 2, 8, 12, 24 and 48 hr. The model used is an indirect response model. It consists of three parts: 1) the pharmacokinetics of Remoxipride; 2) a physiological substance model for PRL, incorporating the synthesis of PRL and its release into and elimination from plasma; and 3) a pharmacodynamic model describing the influence of Remoxipride on the PRL release from the pool. A linear pharmacodynamic model gave the best description of the time course of PRL. The limitation in the PRL release is the amount available in the pool, which takes 24 to 48 hr to fully restore, rather than a maximal effect of Remoxipride. The intra- and interindividual variability of Remoxipride as well as of the PRL response was low.
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The pharmacokinetics of Remoxipride and metabolites in patients with various degrees of renal function.
British journal of clinical pharmacology, 1993Co-Authors: G Movin-osswald, M Hammarlund-udenaes, J Boelaert, L. B. NilssonAbstract:1. The pharmacokinetics of Remoxipride, a new neuroleptic, were investigated in an open study with three parallel groups. Twenty-one patients with severely impaired (ClCr 65 ml min-1) renal function were evaluated. A single oral dose of Remoxipride hydrochloride 100 mg was administered, and blood and urine were collected over 48 h. Concentrations of Remoxipride and metabolites were measured by h.p.l.c. 2. In patients with severely decreased renal function, the AUC and Cmax of Remoxipride were increased significantly, and t1/2 was prolonged, as compared with the control patients. The renal clearance and urinary recovery of the unchanged drug were significantly diminished. 3. The unbound fraction of Remoxipride in plasma was decreased in patients with renal failure, in association with a disease-related increase in alpha 1-acid glycoprotein. In spite of a 25% recovery of unchanged drug in the urine in patients with normal renal function, the AUC of unbound drug was twice as high in patients with severely impaired renal function. 4. A strong correlation between creatinine clearance and renal drug clearance was observed indicating a direct relationship between kidney function and the renal clearance of Remoxipride. 5. Remoxipride was the predominant compound in plasma as well as in urine in patients with severely decreased as well as normal renal function. In patients with severely decrease renal function, Remoxipride and all five pharmacologically inactive metabolites showed increased peak plasma concentrations, delayed tmax, increased AUC, prolonged half-lives and decreased renal clearance.
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Remoxipride: pharmacokinetics and effect on plasma prolactin.
British journal of clinical pharmacology, 1991Co-Authors: G Movin-osswald, M Hammarlund-udenaesAbstract:1. The pharmacokinetics of Remoxipride, a new neuroleptic, were investigated in 15 healthy subjects after an intravenous infusion of 50 mg, an intramuscular injection of 100 mg and after administration of two immediate release capsules (A and B), each of 100 mg, in a cross-over study. The effect of the different Remoxipride formulations on plasma prolactin concentrations was also studied. 2. The volume of distribution of Remoxipride was 0.65 +/- 0.11 kg-1 (mean +/- s.d.). Total plasma clearance was 119 +/- 39 ml min-1, of which 31 +/- 13 ml min-1 was due to renal clearance. The absolute bioavailability after the i.m. and oral formulations was greater than 90%, indicating a small extent of first-pass metabolism. The mean elimination half-life was 4.8 +/- 1.4 h. The unbound fraction of Remoxipride and the blood/plasma ratio were 0.19 +/- 0.03 and 0.64 +/- 0.06, respectively. 3. The transient increase in plasma prolactin was similar after all four Remoxipride administrations and independent of the given dose.
G Movin-osswald - One of the best experts on this subject based on the ideXlab platform.
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Influence of the dosing interval on prolactin release after Remoxipride.
British journal of clinical pharmacology, 1995Co-Authors: G Movin-osswald, C. Von Bahr, M Hammarlund-udenaes, P. Eneroth, K Walton‐bowenAbstract:1. The prolactin response following administration of the D2-dopamine receptor antagonist Remoxipride was studied in eight healthy male volunteers. The purpose of the study was to investigate the duration of a refractory period of prolactin release following two doses of Remoxipride. A further aim was to compare the prolactin response following Remoxipride and thyrotropin release hormone (TRH) during the refractory period. The subjects received two 30 min intravenous (i.v.) infusions of Remoxipride 50 mg with different time intervals between the two doses, in a randomized six period crossover design. The time intervals between the two Remoxipride doses were 2, 8, 12, 24 and 48 h. On one occasion the Remoxipride dose was followed by an i.v. injection of TRH after 2 h. 2. The plasma peak prolactin concentrations obtained after the first Remoxipride dose correspond to a maximal release of prolactin according to earlier studies. A small second peak of prolactin was observed after 2 h. The release was gradually increased with longer time intervals between the consecutive doses. The refractory period for a second prolactin release similar to the first one after Remoxipride was found to be 24 h for most of the subjects. 3. TRH resulted in a faster and higher increase in prolactin response of a shorter duration than after Remoxipride administered 2 h after the first dose.
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Prolactin release after Remoxipride by an integrated pharmacokinetic-pharmacodynamic model with intra- and interindividual aspects.
The Journal of pharmacology and experimental therapeutics, 1995Co-Authors: G Movin-osswald, M Hammarlund-udenaesAbstract:An integrated pharmacokinetic-pharmacodynamic model is suggested for Remoxipride and its effect on prolactin (PRL) release acting by preventing the inhibitory effect of dopamine D2 receptors in the anterior pituitary. The model was implemented to describe the time course of PRL plasma levels after administration of two consecutive doses of Remoxipride at 5 different time intervals, 2, 8, 12, 24 and 48 hr. The model used is an indirect response model. It consists of three parts: 1) the pharmacokinetics of Remoxipride; 2) a physiological substance model for PRL, incorporating the synthesis of PRL and its release into and elimination from plasma; and 3) a pharmacodynamic model describing the influence of Remoxipride on the PRL release from the pool. A linear pharmacodynamic model gave the best description of the time course of PRL. The limitation in the PRL release is the amount available in the pool, which takes 24 to 48 hr to fully restore, rather than a maximal effect of Remoxipride. The intra- and interindividual variability of Remoxipride as well as of the PRL response was low.
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The pharmacokinetics of Remoxipride and metabolites in patients with various degrees of renal function.
British journal of clinical pharmacology, 1993Co-Authors: G Movin-osswald, M Hammarlund-udenaes, J Boelaert, L. B. NilssonAbstract:1. The pharmacokinetics of Remoxipride, a new neuroleptic, were investigated in an open study with three parallel groups. Twenty-one patients with severely impaired (ClCr 65 ml min-1) renal function were evaluated. A single oral dose of Remoxipride hydrochloride 100 mg was administered, and blood and urine were collected over 48 h. Concentrations of Remoxipride and metabolites were measured by h.p.l.c. 2. In patients with severely decreased renal function, the AUC and Cmax of Remoxipride were increased significantly, and t1/2 was prolonged, as compared with the control patients. The renal clearance and urinary recovery of the unchanged drug were significantly diminished. 3. The unbound fraction of Remoxipride in plasma was decreased in patients with renal failure, in association with a disease-related increase in alpha 1-acid glycoprotein. In spite of a 25% recovery of unchanged drug in the urine in patients with normal renal function, the AUC of unbound drug was twice as high in patients with severely impaired renal function. 4. A strong correlation between creatinine clearance and renal drug clearance was observed indicating a direct relationship between kidney function and the renal clearance of Remoxipride. 5. Remoxipride was the predominant compound in plasma as well as in urine in patients with severely decreased as well as normal renal function. In patients with severely decrease renal function, Remoxipride and all five pharmacologically inactive metabolites showed increased peak plasma concentrations, delayed tmax, increased AUC, prolonged half-lives and decreased renal clearance.
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Remoxipride: pharmacokinetics and effect on plasma prolactin.
British journal of clinical pharmacology, 1991Co-Authors: G Movin-osswald, M Hammarlund-udenaesAbstract:1. The pharmacokinetics of Remoxipride, a new neuroleptic, were investigated in 15 healthy subjects after an intravenous infusion of 50 mg, an intramuscular injection of 100 mg and after administration of two immediate release capsules (A and B), each of 100 mg, in a cross-over study. The effect of the different Remoxipride formulations on plasma prolactin concentrations was also studied. 2. The volume of distribution of Remoxipride was 0.65 +/- 0.11 kg-1 (mean +/- s.d.). Total plasma clearance was 119 +/- 39 ml min-1, of which 31 +/- 13 ml min-1 was due to renal clearance. The absolute bioavailability after the i.m. and oral formulations was greater than 90%, indicating a small extent of first-pass metabolism. The mean elimination half-life was 4.8 +/- 1.4 h. The unbound fraction of Remoxipride and the blood/plasma ratio were 0.19 +/- 0.03 and 0.64 +/- 0.06, respectively. 3. The transient increase in plasma prolactin was similar after all four Remoxipride administrations and independent of the given dose.
S.p. Collins - One of the best experts on this subject based on the ideXlab platform.
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the effects of the atypical antipsychotics clozapine Remoxipride and risperidone on the contractile characteristics of rat skeletal muscle in vitro
Pharmacological Research, 1997Co-Authors: L.s. Mendes, S.p. CollinsAbstract:The therapeutic use of the atypical antipsychotics clozapine, Remoxipride and risperidone has been reported to be associated with a reduced occurrence of the extrapyramidal side-effects seen during therapy with classical (or typical) antipsychotics such as trifluoperazine and haloperidol. The aim of this study was to determine the effects of the atypical antipsychotics clozapine, Remoxipride and risperidone on rat skeletal muscle in vitro. Remoxipride and risperidone did not produce contracture in muscle. Clozapine induced a small muscle contracture at high concentrations. Pre-treatment of muscle with trifluoperazine or haloperidol in vitro caused the muscle to display contracture responses to halothane, and haloperidol also potentiated a contracture response to caffeine. Pre-treatment of muscle with Remoxipride and risperidone did not induce contracture in response to halothane and did not potentiate caffeine contracture. Clozapine pre-treatment caused muscle fibre bundles to display a small halothane-induced contracture and caused significant potentiation of caffeine-induced contracture.
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THE EFFECTS OF THE ATYPICAL ANTIPSYCHOTICS CLOZAPINE, Remoxipride AND RISPERIDONE ON THE CONTRACTILE CHARACTERISTICS OF RAT SKELETAL MUSCLEIN VITRO
Pharmacological research, 1997Co-Authors: L.s. Mendes, S.p. CollinsAbstract:Abstract The therapeutic use of the atypical antipsychotics clozapine, Remoxipride and risperidone has been reported to be associated with a reduced occurrence of the extrapyramidal side-effects seen during therapy with classical (or typical) antipsychotics such as trifluoperazine and haloperidol. The aim of this study was to determine the effects of the atypical antipsychotics clozapine, Remoxipride and risperidone on rat skeletal muscle in vitro . Remoxipride and risperidone did not produce contracture in muscle. Clozapine induced a small muscle contracture at high concentrations. Pre-treatment of muscle with trifluoperazine or haloperidol in vitro caused the muscle to display contracture responses to halothane, and haloperidol also potentiated a contracture response to caffeine. Pre-treatment of muscle with Remoxipride and risperidone did not induce contracture in response to halothane and did not potentiate caffeine contracture. Clozapine pre-treatment caused muscle fibre bundles to display a small halothane-induced contracture and caused significant potentiation of caffeine-induced contracture.