An autopsy case of heatstroke under the influence of psychotropic drugs.

We present here a fatal case of heatstroke, involving olanzapine and levomepromazine medications. A male in his sixties was found dead in his storage room in the middle of August, with a high rectal temperature. Autopsy revealed congestion of the lungs without any specific findings. Quantitative toxicological analysis demonstrated concentrations of olanzapine, levomepromazine, 7-aminonitrazepam, and 7-aminoflunitrazepam in a femoral blood sample of 0.433 µg/mL, 0.177 µg/mL, 0.604 µg/mL, and 0.041 µg/mL, respectively. The concentration of olanzapine exceeded toxic levels; however, levomepromazine level was within the therapeutic range. Due to the blocking mechanism of both olanzapine and levomepromazine against muscarinic receptors, they might depress sweating and impair heat dissipation. Based on autopsy findings, results of toxicological examination, and investigation by the authorities, we concluded that the cause of death was heatstroke under the influence of olanzapine and levomepromazine.

Possible levomepromazine-clozapine interaction: two case reports.

OBJECTIVE: To report and comment upon two cases of suspected pharmacological interaction between the "classical" neuroleptic levomepromazine (LMP) and the "atypical" antipsychotic clozapine (CLZ). CASE SUMMARY: The patients who simultaneously took the two drugs had unusually low plasma levels of CLZ and its metabolites, even though they took high doses of CLZ. The patients were considered "non-responders" to the treatment by the psychiatrist. When LMP was withdrawn from the therapy, plasma concentrations of CLZ returned to therapeutic levels and one of the two patients experienced the anticipated therapeutic response. DISCUSSION: No information can be found in the literature regarding possible interactions between LMP and CLZ. However, the results of the two cases reported herein point out to a possible lack of therapeutic efficacy of CLZ therapy during this kind of polypharmacy. CONCLUSION: While two cases are too few to draw any conclusion, it would be prudent on the part of psychiatrists to consider a possible drug interaction in patients receiving both CLZ and LMP who fail to respond to the therapy.

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.

Influence of the antiparkinsonian drugs on the plasma level of neuroleptics.

The interaction between various neuroleptics and antiparkinsonian drugs was analyzed by measuring the neuroleptic plasma level before and after withdrawal of antiparkinsonian drugs. The population completing the study consisted of 32 chronic schizophrenics treated with chlorpromazine (8), levomepromazine (14), thioridazine (6), or haloperidol (4). Twenty-five were also receiving benztropine; 4, trihexyphenidyl; and 3, procyclidine. During the first 4 weeks patients remained on neuroleptics and antiparkinsonians, the latter being withdrawn during the 5th week, and the neuroleptics alone being administered during 16 following weeks. The plasma level of neuroleptics was assayed by gas liquid chromatography, once weekly in the morning at two different times. The analysis of variance showed a significant difference in neuroleptic plasma level when patients took neuroleptics only versus the period they had received neuroleptics and antiparkinsonians. The multiple comparison based on Studentized range Q0-05 revealed a significant progressive increase of neuroleptic plasma level during 12 weeks after withdrawal of antiparkinsonian drugs after which a plateau was reached. The hypothetical mechanisms of action of antiparkinsonians on neuroleptic plasma level are discussed.

Pharmacokinetics of methotrimeprazine after single and multiple doses.

Concentrations of methotrimeprazine and a metabolite, methotrimeprazine sulfoxide, were measured in plasma after a single intramuscular dose and after single and multiple oral doses of methotrimeprazine. The highest plasma concentrations of methotrimeprazine were found 30 to 90 min after intramuscular injection, and 1 to 3 hr after oral administration. On average 50% of orally administered drug reached the general circulation as unchanged methotrimeprazine. The apparent volume of distribution (Vbeta) was 23 to 42 L/kg body weight, and the biologic half-life, 15 to 30 hr. The sulfoxide could not be traced in plasma after a 25-mg intramuscular dose, but was found in higher plasma concentrations than the unmetabolized drug after single and multiple oral doses. This could be due to oxidation of the drug either in the gastrointestinal lumen or in the intestinal wall, or during its first passage through the liver. The apparent half-life of the sulfoxide was on average 30% shorter than the half-life of methotrimeprazine.

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.

GLC determination of methotrimeprazine and its sulfoxide in plasma.

A GLC method, based on flame-ionization detection, was developed for the assay of methotrimeprazine and its sulfoxide in plasma. For a 6-ml aliquot, the sensitivity was 2-3 ng/ml for the unchanged drug and 4-5 ng/ml for the sulfoxide. The coefficient of variation, calculated from duplicate analyses of plasma samples, was 8-15% for concentrations between 10 and 100 ng/ml. Patients treated with orally administered methotrimeprazine had higher plasma levels of the sulfoxide than of unmetabolized drug. The method also was applied to the analysis of promazine and chlorpromazine in patient plasma.

Identification of nonpolar methotrimeprazine metabolites in plasma and urine by GLC-mass spectrometry.

Two metabolites of methotrimeprazine, the sulfoxide and the demethylated analog, were identified in extracts from patient plasma by combined GLC-mass spectrometry. Methotrimeprazine and its sulfoxide had similar mass spectra but different GLC retention times. In addition to the metabolites found in plasma, two other metabolites, the didesmethyl analog and the monodesmethyl sulfoxide, were identified in a urine extract.

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.

Analysis of etorphine in postmortem samples by HPLC with UV diode-array detection.

Etorphine is a synthetic narcotic analgesic usually used in veterinary medicine. It possesses an analgesic potency up to 1000 times greater than morphine and is therefore used in low doses, primarily for tranquilising large animals. For veterinary use, etorphine is usually available in its commercial formulation as Immobilon, when in combination with acepromazine or methotrimeprazine. Due to the potency of etorphine, only very low doses are required to produce adverse or fatal effects. This paper describes a method for detecting and quantifying etorphine using HPLC with UV diode array detection (HPLC-DAD) and demonstrates the advantage of the technique for the detection of Immobilon at low doses. In a forensic case involving Immobilon, the etorphine concentrations measured in postmortem femoral vein and heart blood specimens were 14.5 and 23.5 micrograms/l, respectively. No etorphine was detected in the urine. To our knowledge this is the first time postmortem etorphine concentrations have been reported.

[Relations between the levels of neuroleptics and the doses, the therapeutic effects and the side effects]. / Relation des taux des neuroleptiques avec les doses, les actions thérapeutiques et les effets secondaires.

The mass fragmentography and the gas-liquid chromatography are available actually for quantitation of very low levels of neuroleptics. The Radio-immunological assay is full of promise. Their plasma levels are not correlated with their dosage in a man to another, but, for some of them, there is lineary relation for one person. A correlation between their levels and their clinical efficacy is not certainly demonstrated for thioridazine and non transformed chlorpromazine; it could be possible for his sulphoxide metabolite and for butaperazine. The sides-effects are relatively correlated with their levels in the begining of the therepautic. The antiparkinsonian drugs, the antidepressants and the lithium could influenced them.

Simultaneous determination of 25 common pharmaceuticals in whole blood using ultra-performance liquid chromatography-tandem mass spectrometry.

An ultra-performance liquid chromatography-tandem mass spectrometry method was developed and validated for the quantification of 25 common pharmaceuticals in whole blood. The selected pharmaceuticals represent the most frequently detected drugs in our forensic laboratory with basic properties such as analgesics, antidepressants, antihistamines, antihypertensives, antipsychotics and ß-blockers. Whole blood samples were extracted with butyl acetate after adjusting pH with 2M NaOH. The target analytes were separated on a 100 × 2.1 mm ACQUITY BEH 1.7 µm C18 column by a formic acid/acetonitrile gradient elution using a Waters ACQUITY Ultra-Performance Liquid Chromatography system. Quantification was performed on a Waters tandem quadrupole ACQUITY TQD using multiple reaction monitoring in positive mode. The analytes were eluted within 11 min. The limit of quantification (LOQ) ranged from 0.002 to 0.01 mg/kg depending on the analyte. A good linear behavior was achieved for all analytes in the range from LOQ to 1.0 or 2.0 mg/kg blood. The absolute recoveries were between 55-87% for all compounds except norfluoxetine (44%). The method showed acceptable precision and accuracy for almost all analytes. Only unstable compounds like levomepromazine, methylphenidate, mirtazapine, norfluoxetine and zuclopenthixol deviated more. The method was successfully applied to more than 200 authentic blood samples within a year from forensic investigations.

Quantitative determination of phenothiazine derivatives in human plasma using monolithic silica solid-phase extraction tips and gas chromatography-mass spectrometry.

Solid-phase extraction (SPE) using micropipette tips is a useful technique to prepare samples prior to mass spectrometry. However, most commercial SPE tips have loading capacities that are insufficient for quantitative determination. In this paper, we describe a rapid method for quantitative microanalysis of five phenothiazine derivatives, chlorpromazine, levomepromazine, promazine, promethazine and trimeprazine, using a recently introduced C(18) monolithic silica SPE tip, the MonoTip C(18), for extraction from human plasma. The drugs could be extracted within 5 min from 0.1-mL plasma samples, eluted with methanol, and the eluate injected directly into a gas chromatograph prior to mass spectrometry analysis. Only 0.7 mL of solvent was required for each step of the extraction process. The recoveries of the five phenothiazines spiked into plasma were 91-95% and the limits of quantification for each drug were between 0.25 and 2.0 ng/0.1 mL. The maximum intra- and inter-day coefficient of variation was 11%. The validated method was successfully used to quantify the plasma concentration of levemepromazine in a human subject after oral administration of the drug. This new method is expected to have wide applications as a pretreatment for the rapid, quantitative determination of drug concentrations in plasma samples.

High performance liquid chromatographic determination of levomepromazine in human breast milk and serum using solid phase extraction.

A high performance liquid chromatographic (HPLC) method has been developed for the determination of levomepromazine in human breast milk and serum. The levomepromazine was extracted by a rapid and simple extraction method using a Sep-Pak C18 cartridge. The extracts were separated by HPLC on a C8 bonded reversed phase column and detected by UV absorbance at 254 nm. There was no interference with endogenous substance in human breast milk and serum. A linear relationship was obtained for the levomepromazine over the concentration range of 10-300 ng/mL. The recoveries of levomepromazine added to human breast milk and serum were 92.5-99.1% and 86.9-103.9%, respectively.

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.

Pharmacokinetics and relative bioavailability of levomepromazine after repeated administration of tablets and syrup.

Plasma levels of levomepromazine and its sulphoxide were measured in 8 psychiatric patients after repeated doses of levomepromazine tablets or syrup. The rate and extent of absorption of the drug were similar for the two dosage forms, although the extent of presystemic metabolism appeared to be slightly greater after administration of syrup than of tablets. The biological half-life of levomepromazine ranged from 16.5 h to 77.8 h, and a 13-fold variation was seen in the ratio of the total clearance to the absorbed fraction of the dose (Cl/Fpo). It is postulated that individual variation in the dose required for therapy was due in part to individual variation in the pharmacokinetics of the drug.

Levomepromazine elimination in patients during active and sham hemodialysis.

The effect of active and sham dialysis on the plasma concentration of levomepromazine was studied in seven schizophrenic patients undergoing hemodialysis treatment in a double-blind crossover study. Samples of blood were collected before, after 2 h and 5 h of treatment, and once a week during the treatment program. The plasma concentrations decreased during both active and sham dialysis. The data indicate that there was no significant difference in the elimination of the drug between active and sham hemodialysis.

Gas chromatographic mass spectrometric identification of O-demethylated and mono-hydroxylated metabolites of levomepromazine in blood from psychiatric patients by selected ion recording with high resolution.

An O-demethylated and two mono-hydroxylated metabolites of levomepromazine have previously been identified as conjugates in the urine from psychiatric patients. The three metabolites were identified in hydrolysed and nonhydrolysed plasma and erythrocytes from three patients by selected ion monitoring of the trimethylsilyl derivatives, with a mass spectrometric resolution of 5000. The three metabolites were mainly found as conjugates in the plasma, and smaller amounts were found unconjugated in the plasma and the erythrocytes.

Solid-phase microextraction for the assay of levomepromazine in human plasma.

Solid-phase microextraction (SPME) was investigated as sample preparation for the assay of the neuroleptic drug levomepromazine in human plasma. A mixture of human plasma, water, chloramitriptyline as internal standard, and aqueous NaOH was extracted with a 100-microm polydimethylsiloxane (PDMS) fiber (Supelco). The desorption of the fiber was performed in the injection port of a gas chromatograph at 260 degrees C [HP 5890; BPX-5 (SGE): 30 m x 0.53 mm ID, 1-microm film capillary; nitrogen-phosphorus selective detection]. As repeatedly found for SPME analysis of drugs in plasma, the recovery was low (i.e., 7% for levomepromazine). However, the analyte and internal standard were well separated and the calibration was linear from 5 to 180 ng/mL. The within-day precision was 2%, 4%, and 19% at concentrations of 160 ng/mL, 80 ng/mL, and 5 ng/mL, respectively. The between-day precision was 3%, 7%, and 19%, respectively. The limit of determination was 5 ng/mL. The comparison with an established liquid-liquid extraction gas-liquid chromatography method revealed good agreement for spiked samples and patient samples. No interfering peaks of drugs coadministered with levomepromazine or of endogenous substances were found. It is concluded that the method can be used in the therapeutic drug monitoring and clinical toxicology of levomepromazine.

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.