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At least 19 recordsLinked to original sources

PubMed1982

Avoiding psychic adverse effects during induction of neurolept anaesthesia with levomepromazine. A double-blind study of levomepromazine and droperidol.

Levomepromazine 0.1 mg/kg or droperidol 0.15 mg/kg for induction of neurolept anaesthesia were compared in a double-blind prospective study of 60 patients undergoing upper abdominal surgery. On the morning after surgery, eight of 30 patients (26.7%) who received droperidol remembered having had unpleasant anxiety, or nightmarish or panicky experiences during induction of anaesthesia, whereas only one of 30 patients (3.3%) receiving levomepromazine experienced such unpleasant adverse effects (P less than 0.01). During anaesthesia, the patients induced with levomepromazine needed somewhat less fentanyl, had somewhat less pain intensity, during the first 3 h after surgery, and they required the first postoperative dose of morphine 1.5 h later than the patients receiving droperidol (P less than 0.02). There was no difference in the number of patients receiving naloxone at the end of anaesthesia in the two groups. However, 21 of 30 patients (70%) in the levomepromazine group and only seven of 30 patients (23.3%) in the droperidol group were given physostigmine for arousal at the end of anaesthesia (P less than 0.01). There was no difference between the two groups in the occurrence of postoperative nausea, restlessness, hallucinations, or sedation in the recovery ward. This study shows that levomepromazine is superior to droperidol for induction of neurolept anaesthesia because it gives less psychic adverse effects, more analgesia, and a deeper sedation, which is easily reversed with physostigmine at the end of anaesthesia.

Abdomen↗

PubMed1993

The protective effect of inhaled levomepromazine (Nozinan) on histamine-induced bronchial constriction.

The effect of inhaled levomepromazine (Nozinan, Veractil) on bronchial responsiveness to inhaled histamine was investigated in asthmatics. In a double blind, randomized controlled study, 12 asthmatics (FEV1% pred 52-96%, and PC20 histamine 1.01 mg/ml (geometric mean)) were challenged before and after inhalation of levomepromazine in three different doses. Before and after each inhalation of levomepromazine, PC20, FEV1, the continuous reaction time (CRT) and the subjective sedation score (VAS) were determined. A dose-dependent increase in PC20 was observed after inhalation of levomepromazine. PC20 was increased by up to 4.02 two-fold concentration differences (doubling), i.e. up to a 38-fold increase from the basic values. Inhalation of the two higher doses of levomepromazine had a small sedative effect evaluated from an increase in CRT and the VAS-score and corresponding to the plasma concentrations. We conclude that inhaled levomepromazine has a dose-dependent protective effect on histamine-induced bronchial hyperresponsiveness in asthmatics and that inhalation of levomepromazine was well tolerated. The mechanism by which levomepromazine acts on histamine-induced bronchial hyperresponsiveness is not known but it could be partly explained by the antihistaminic effect. In this respect levomepromazine bears comparison with the most potent second generation antihistamines. The plasma concentrations of levomepromazine measured corresponded to those seen after oral intake of 5-10 mg levomepromazine.

Administration, Inhalation↗

PubMed1981

Binding affinity of levomepromazine and two of its major metabolites of central dopamine and alpha-adrenergic receptors in the rat.

N-Monodesmethyl levomepromazine and levomepromazine sulfoxide have previously been found in higher plasma concentrations than the parent drug in patients who received oral doses of levomepromazine. In the present study levomepromazine, N-monodesmethyl levomepromazine and levomepromazine sulfoxide have been assayed for their binding affinity to rat striatal dopamine receptors and to alpha-adrenergic receptors in rat cortex, and compared with the potency of chlorpromazine and some of its metabolites in the same systems. Levomepromazine sulfoxide was relatively inactive in the dopamine receptor binding test but much more active in the alpha-adrenergic receptor binding test, where it had a binding affinity similar to 7-hydroxy chlorpromazine. Levomepromazine and N-monodesmethyl levomepromazine were active in both systems, having a slightly higher potency than chlorpromazine in the alpha-adrenergic binding test, and a somewhat lower potency than chlorpromazine in the dopamine receptor binding test. The results indicate that N-monodesmethyl levomepromazine may significantly contribute to the antipsychotic effects of levomepromazine while the sulfoxide metabolite lacks neuroleptic potency, and that both metabolites may contribute to the autonomic side-effects of the drug.

Adrenergic alpha-Antagonists↗

PubMed1984

Resin haemoperfusion in levomepromazine poisoning: evaluation of effect on plasma drug and metabolite levels.

Plasma levels of levomepromazine and two of its major metabolites N-desmethyl-levomepromazine and levomepromazine sulphoxide were studied in two poisoned patients treated with resin haemoperfusion at a constant blood flow of 200 ml/min. The mean haemoperfusion clearance of levomepromazine, N-desmethyl-levomepromazine and levomepromazine sulphoxide was 114, 123 and 151 ml/min, respectively, in patient no. 1, and 153, 148 and 184 ml/min, respectively, in patient no. 2. Patient no. 2 had also ingested amitriptyline, and the mean haemoperfusion clearance of amitriptyline and its metabolite nortriptyline was 183 and 183 ml/min respectively. Haemoperfusion did not seem to alter the elimination profile of levomepromazine or the two metabolites in either patient. We conclude that haemoperfusion is of little value in removing levomepromazine, N-desmethyl-levomepromazine or levomepromazine sulphoxide from the body. This is probably due to the large apparent volume of distribution and the high intrinsic hepatic metabolic clearance of these compounds.

Adult↗

PubMed2005

Region specific distribution of levomepromazine in the human brain.

OBJECTIVE: The aim of this study was to examine concentrations of levomepromazine and its metabolite desmethyl-levomepromazine in different regions of human brain and in relationship to drug-free time. METHODS: Drug concentrations were measured in up to 43 regions of 5 postmortem human brains of patients previously treated with levomepromazine. To enable statistical comparison across brain regions several smaller brain areas were put together to form larger brain areas (cortex cerebri, limbic system, cerebellum, basal ganglia, thalamus). Mean values of drug concentrations in these larger brain areas were used in a repeated measurement ANOVA to analyze for region specific distribution. The elimination half-life in brain tissue was estimated with a NONMEM population kinetic analysis using the mean value of all brain regions of an individual case. RESULTS: Levomepromazine and desmethyl-levomepromazine appear to accumulate in human brain tissue relative to blood. Mean concentrations differed largely between individual brains, in part due to differences in dose of drug, duration of treatment and drug-free time before death. There was an apparent region-specific difference in levomepromazine concentrations with highest values in the basal ganglia (mean 316 ng/g) and lowest values in the cortex cerebri (mean 209 ng/g). The elimination half-life from brain tissue is longer than from blood and was calculated to be about one week. Similar results were obtained with desmethyl-levomepromazine. CONCLUSIONS: Levomepromazine shows a region-specific distribution in the human brain with highest values in the basal ganglia. This might be the consequence of low expression of the metabolic enzyme Cyp2D6 in the basal ganglia. If this finding is true also for other neuroleptic drugs it might increase our understanding of preferential toxicity of neuroleptic drugs against basal ganglia structures and higher volumes of basal ganglia of neuroleptic-treated patients. Furthermore, patients exposed to levomepromazine cannot be considered to be free of residual effects of the drug for a number of weeks after withdrawal.

Aged↗

PubMed1982

Pharmacokinetics and first-pass metabolism of levomepromazine in the rat.

The time course of the blood concentrations of levomepromazine and its two major non-polar metabolites in man were studied in the rat after single oral and intraarterial doses of levomepromazine hydrochloride. The blood levels of N-monodesmethyl levomepromazine were on average 179% of the levomepromazine levels after oral doses, but only 15% of the levomepromazine levels after intraarterial doses. The blood levels of levomepromazine sulfoxide, relative to the levomepromazine levels, were also generally higher after oral doses than after parenteral doses, on average 65% and 25%, respectively. Large interindividual variations were observed in the blood levels of levomepromazine and in the systemic availability of the drug after oral doses. The distribution phase lasted for about 8 hrs, the mean apparent volume of distribution was 16.6 l/kg, and the total body clearance was on average 12.3 ml/min. It is concluded that the rat provides a suitable model for the kinetics of levomepromazine in man, and that the sulfoxide and N-monodesmethyl metabolites of the drug are mainly formed by first-pass metabolism after oral doses in the rat, either in the liver or in the gut.

Animals↗

PubMed1990

High-performance liquid chromatographic determination of levomepromazine (methotrimeprazine) and its main metabolites in serum and urine.

A new analytical method has been developed for simultaneous quantitation of levomepromazine and its five main metabolites in serum and urine. The method uses C-2 bonded phase extraction and reversed-phase high-performance liquid chromatography, based on ion-pair formation with dodecyl sulfate. The detection limits were 15 nM for levomepromazine and N-desmethyl levomepromazine, 28 nM for levomepromazine sulfoxide, and 56 nM for 3-hydroxylevomepromazine. 7-hydroxylevomepromazine, and O-desmethyllevomepromazine in serum, and lower in urine. The method was applied to measure steady-state serum and urine concentrations of levomepromazine and metabolites in five psychiatric patients. The concentrations of levomepromazine sulfoxide and N-desmethyllevomepromazine were generally higher than the concentrations of levomepromazine. The hydroxylated and O-demethylated metabolites were also found in higher concentrations than levomepromazine, but mainly as conjugates.

Blood Specimen Collection↗

PubMed2004

Effects of levomepromazine and different desflurane concentrations upon electrocardiographic variables in dogs.

OBJECTIVES: To investigate the effects of levomepromazine and different desflurane concentrations upon electrocardiographic variables. ANIMALS: Twenty adult mongrel dogs of both sexes weighing 6-28 kg. METHODS: Dogs were divided into two groups of 10 animals. Group 1 received 1 mg kg(-1) i.v. of levomepromazine and 15 minutes later anesthesia was induced with propofol (3 mg kg(-1) i.v.). Desflurane end-tidal concentration was set at 1.6 MAC. After 30 minutes at this concentration, measurements were taken and the end-tidal concentration was reduced to 1.4 MAC. Thereafter, it was reduced to 1.2 and then 1.0 MAC at 15-minute intervals. The same procedure was followed for group 2, except that levomepromazine was replaced with 0.2 mL kg(-1) of 0.9% saline solution and more propofol was needed for induction (7 mg kg(-1)). The animals' body temperature was maintained between 38.3 and 39 degrees C using a heating pad. The electrocardiographic tracing was obtained from lead II throughout the experimental period. The measurements were taken immediately before the administration of levomepromazine or placebo (T1), 15 minutes after pre-medication (T2) and 30 minutes after the establishment of 1.6 MAC (T3). The other measurements were made at the concentrations of 1.4, 1.2, and 1.0 MAC, respectively (T(4-6)). The numerical data were submitted to analysis of variance plus F-test (p<0.05). RESULTS: The dogs that received levomepromazine had a decrease in heart rate. However, in both groups it increased with desflurane administration. Levomepromazine, in association with desflurane, did not induce significant electrocardiographic changes, and all mean values (except P-wave duration) were within the reference range for this species. CONCLUSIONS AND CLINICAL RELEVANCE: This study documented that levomepromazine, in association with desflurane, does not induce significant changes in electrocardiographic variables, suggesting that this drug combination has minimal effect on myocardial conduction.

Analgesics, Non-Narcotic↗

PubMed2005

Little effects of low dosage of levomepromazine on plasma risperidone levels.

In the present study, we investigated the effects of levomepromazine on plasma risperidone concentrations in a steady state. Twenty patients taking risperidone at a stable dose for more than 2 weeks who were considered to require levomepromazine coadministration were selected. The scores of excitement in BPRS significantly decreased 2 weeks after the coadministration of levomepromazine. Plasma risperidone concentrations and the ratio of risperidone and 9-hydroxyrisperidone (risperidone/9-hydroxyrisperidone) did not change between before and 2 weeks after the coadministration of levomepromazine. The extrapyramidal symptoms were not worsened by the coadministration of levomepromazine. These results suggest that a low dosage of levomepromazine, use as a sedative adjuvant to risperidone treatment, have no statistically significant effect on the trough plasma concentrations of risperidone.

Adolescent↗

PubMed1989

Levomepromazine (Nozinan) reduces nonspecific bronchial hyperreactivity in asthmatics.

Ten patients with bronchial asthma were challenged with histamine before and after receiving saline and active drug (levomepromazine or antazoline) (a total of six challenges). The antihistaminic effect of levomepromazine (25 mg) was found to be comparable to that of antazoline (100 mg), evaluated from skin prick tests. Prechallenge forced expiratory volume in one second (FEV1) was found to be larger after levomepromazine than after antazoline (p less than 0.05), indicating a direct bronchodilating effect. This increased threshold airway calibre may have influenced the results of challenge, but change in provocative concentration producing 20% fall (PC20) was not statistically significantly correlated to change in FEV1. Levomepromazine increased PC20 2-doubling concentration compared to antazoline (p less than 0.05). Variation was observed in two minutes' ventilation during tidal volume breathing challenge. However, there was no statistically significant variation in two minutes' ventilation during challenge after receiving levomepromazine or antazoline. It was concluded that levomepromazine possesses a bronchodilating capacity and reduces bronchial hyperreactivity.

Adult↗

PubMed1995

Bioequivalence and absolute bioavailability of oblong and coated levomepromazine tablets in CYP2D6 phenotyped subjects.

The bioequivalence and absolute bioavailability of oblong and coated levomepromazine tablets were studied in 12 healthy volunteers. A 1-hour intravenous infusion served as the reference. Serum concentrations of levomepromazine were quantified with a specific high-performance liquid chromatographic method and electrochemical detection. The 2 oral formulations were bioequivalent. After oral administration of oblong and coated levomepromazine tablets the mean serum concentration versus time profiles were similar and the pharmacokinetic parameters showed wide interindividual variations. There was a 21% absolute bioavailability of levomepromazine, indicating a pronounced presystemic metabolism. The total serum clearance and the apparent volume of distribution at steady state were 48 +/- 14 l/min and 980 +/- 213 l, respectively. These pharmacokinetic parameters were also investigated with respect to the CYP2D6 polymorphism, i.e. via dextromethorphan phenotyping of 9 subjects, 3 subjects were poor metabolizers, and 6 extensive metabolizers. The Spearman's rank-ordered correlation analysis did not reveal a significant correlation between the pharmacokinetic parameters AUC, Cmax and t1/2 after oral administration of oblong and coated levomepromazine tablets and the metabolic ratios of dextromethorphan, suggesting that levomepromazine is not metabolized to any major extent by the isoenzyme CYP2D6.

Administration, Oral↗

PubMed1976

Effects of levomepromazine, chlorpromazine and their sulfoxides on isolated rat atria.

The effects of levomepromazine, chlorpromazine and their sulfoxides were studied on spontaneously beating and on electrically driven rat atria in vitro. Levomepromazine, chlorpromazine and levomepromazine sulfoxide produced a dose-dependent decrease in the work index of spontaneously beating atria and in the contractile force of electrically driven atria, while chlorpromazine sulfoxide was relatively inactive in these respects. At higher concentrations, levomepromazine sulfoxide caused a pronounced increase in the threshold for electrical stimulation and the effective refractory period. Compared to chlorpromazine, levomepromazine looses less of its cardio-depressive effect through sulfoxidation.

Animals↗

PubMed1976

Anticholinergic and cardiodepressive effects of levomepromazine and two of its metabolites on isolated rat atria.

The effects of monodesmethyl levomepromazine on effective refractory period (ERP) threshold for electrical stimulation and contractile force on isolated rat atria were compared to the effects of levomepromazine and levomepromazine sulfoxide. All agents caused an apparently dose-dependent increase in ERP, and antagonized acetylcholine-induced reductions in ERP. Levomepromazine and monodesmethyl levomepromazine decreased excitability and contractile force to a similar extent.

Acetylcholine↗

PubMed2006

Simultaneous determination of the antipsychotic drugs levomepromazine and clozapine and their main metabolites in human plasma by a HPLC-UV method with solid-phase extraction.

A HPLC method with UV detection has been developed for the simultaneous determination of levomepromazine, clozapine and their main metabolites: N-desmethyl-levomepromazine, levomepromazine sulphoxide, O-desmethyl-levomepromazine, N-desmethylclozapine and clozapine N-oxide. The analytes were separated on a C8 reversed-phase column using a mobile phase composed of acetonitrile and a pH 2.0, 34 mM phosphate buffer containing 0.3% triethylamine (29:71, v/v). Loxapine was used as the internal standard. A reliable biological sample pre-treatment procedure by means of solid-phase extraction on C1 cartridges was implemented, which allows to obtain good extraction yields (>91%) for all analytes and appropriate sample purification from endogenous interference. The method was validated in terms of extraction yield, precision and accuracy. These assays gave RSD% values for precision always lower than 4.9% and mean accuracy values higher than 92%. The method is suitable for the therapeutic drug monitoring (TDM) of patients undergoing polypharmacy with levomepromazine and clozapine.

Antipsychotic Agents↗

PubMed2003

Simultaneous determination of levomepromazine, midazolam and their major metabolites in human plasma by reversed-phase liquid chromatography.

A sensitive and reliable high-performance liquid chromatographic (HPLC) assay is a prerequisite for pharmacokinetic analysis of continuous infusion of levomepromazine adjuvant to midazolam. We developed such a method to determine the levels of levomepromazine, midazolam and their major metabolites (levomepromazinesulfoxide, desmethyl-, didesmethyllevomepromazine, O-desmethyllevomepromazine and alpha-hydroxy-midazolam) simultaneously. Desmethylclomipramine was used as an internal standard (I.S.). The lower limit of quantification of this assay was set for levomepromazine 4.1 microg/l, levomepromazinesulfoxide 4.9 microg/l, O-desmethyllevomepromazine 18.4 microg/l, alpha-hydroxymidazolam 26.6 microg/l, midazolam 23.4 microg/l, didesmethyllevomepromazine 15.8 microg/l, and desmethyllevomepromazine 6.6 microg/l. The between- and within day assay variations were commonly below 5%. The recovery in human plasma for the different analytes varied between 85 and 11%. The accuracy of this assay varied between 95 and 105% for the different concentrations. The linearity of this assay was set between 25 and 800 microg/l (r(2)>0.999 of the regression line). The first results of pharmacokinetic analysis of midazolam indicated that half-life varied between 1.1 and 1.9 h. Pharmacokinetic analysis using a one-compartment model of levomepromazine revealed that the apparent volume of distribution was 4.1+/-2.4 l per kg lean body mass and the metabolic clearance was 309+/-225 l per hour per 70 kg. This assay proved to be robust and reproducible. It can reliably be used for further study of the pharmacokinetics of continuous infusion of levomepromazine.

Analgesics, Non-Narcotic↗

PubMed2000

Low dosage of levomepromazine did not increase plasma concentrations of fluvoxamine.

The cytochrome enzyme P450 2D6 (CYP2D6) is thought to play a role in the human metabolism of fluvoxamine. Levomepromazine is a potent inhibitor of CYP2D6. We coadministered a low dosage of levomepromazine and fluvoxamine in 15 patients and found that the low dosage of levomepromazine was effective in counteracting the fluvoxamine-induced insomnia and did not increase plasma fluvoxamine levels. These results suggest that the inhibition of CYP2D6 by levomepromazine has little effect on fluvoxamine metabolism. Therefore, a low dosage of levomepromazine, used as a hypnotic agent, appears to be effective and safe when coadministered with fluvoxamine. Since this was a pilot study without a placebo control, a double-blind placebo-controlled study is needed to confirm our preliminary findings.

Adult↗

PubMed1979

Analgesic treatment with levomepromazine in acute myocardial infarction. A randomized clinical trial.

The efficacy of a non-narcotic analgesic is evaluated in a double-blind randomized series of patients with acute myocardial infarction (AMI). Levomepromazine or pethidine were given in 328 consecutive cases to 316 patients within 24 hours after the onset of symptoms. Levomepromazine, 12.5 mg, appeared as effective as pethidine, 50 mg, in the alleviation of pain, though the initial dose had to be higher. Nausea and vomiting were half as frequent in the levomepromazine group as in the pethidine group (p less than 0.001). The incidences of arrhythmias, lung oedema, hypotension and thromboembolic complications did not differ between the groups. The mortality rate in the first 4 weeks was 22% in the levomepromazine group and 37% in the pethidine group (p less than 0.005), and after one year 39 and 50% (p less than 0.05), respectively. It is concluded that levomepromazine is better tolerated than pethidine in AMI. This suggests that the present management of pain in AMI should be reconsidered.

Acute Disease↗

PubMed1994

Effect of levomepromazine and metabolites on debrisoquine hydroxylation in the rat.

The influence of the major metabolites of the phenothiazine derivative, levomepromazine (methotrimeprazine), on hydroxylation of debrisoquine was examined in male Sprague-Dawley rats. The metabolic ratio of debrisoquine/4-hydroxy debrisoquine was first determined in rats after oral administration of 10 mg/kg of debrisoquine. Then the same dose of debrisoquine was co-administered with various doses of levomepromazine or one of its metabolites. Levomepromazine and its sulphoxidated, N-demethylated and O-demethylated metabolites caused highly significant and dose-dependent increases in the debrisoquine metabolic ratio. 3-Hydroxy levomepromazine had no significant effect on the metabolism of debrisoquine. This indicates that the non-hydroxylated metabolites of levomepromazine have relatively high affinities for the cytochrome P450 enzyme which converts debrisoquine to 4-hydroxy debrisoquine in the rat. Such metabolites may therefore be responsible for a considerable part of the inhibitory effect of debrisoquine hydroxylation previously reported in patients treated with phenothiazine neuroleptics.

Administration, Oral↗