Segmental Analysis of Chlorprothixene and Desmethylchlorprothixene in Postmortem Hair.

Analysis of drugs in hair differs from their analysis in other tissues due to the extended detection window, as well as the opportunity that segmental hair analysis offers for the detection of changes in drug intake over time. The antipsychotic drug chlorprothixene is widely used, but few reports exist on chlorprothixene concentrations in hair. In this study, we analyzed hair segments from 20 deceased psychiatric patients who had undergone chronic chlorprothixene treatment, and we report hair concentrations of chlorprothixene and its metabolite desmethylchlorprothixene. Three to six 1-cm long segments were analyzed per individual, corresponding to ~3-6 months of hair growth before death, depending on the length of the hair. We used a previously published and fully validated liquid chromatography-tandem mass spectrometry method for the hair analysis. The 10th-90th percentiles of chlorprothixene and desmethylchlorprothixene concentrations in all hair segments were 0.05-0.84 ng/mg and 0.06-0.89 ng/mg, respectively, with medians of 0.21 and 0.24 ng/mg, and means of 0.38 and 0.43 ng/mg. The estimated daily dosages ranged from 28 mg/day to 417 mg/day. We found a significant positive correlation between the concentration in hair and the estimated daily doses for both chlorprothixene (P = 0.0016, slope = 0.0044 [ng/mg hair]/[mg/day]) and the metabolite desmethylchlorprothixene (P = 0.0074). Concentrations generally decreased throughout the hair shaft from proximal to distal segments, with an average reduction in concentration from segment 1 to segment 3 of 24% for all cases, indicating that most of the individuals had been compliant with their treatment. We have provided some guidance regarding reference levels for chlorprothixene and desmethylchlorprothixene concentrations in hair from patients undergoing long-term chlorprothixene treatment.

Chlorprothixene in bodies after exhumation.

Toxicological analyses on body tissues and interpretation of results after exhumation are a challenging task. We report five cases in which toxicological analyses had to be performed due to suspicion of homicide by chlorprothixene intoxication. Exhumations had to be carried out following post mortem intervals in earth graves between two and five and a half years. Chlorprothixene and in some cases also its metabolites could be detected in liver and brain. For the interpretation of the results, chlorprothixene concentrations determined in brain should be used because of a relative isolation of the brain within the skull. However, a loss of organ weights due to post mortem degradation, which may lead to an increase of drug levels, should be taken into account.

Unassisted smothering in a pillow.

We report the case of a 33-year-old man admitted to a psychiatric hospital because of paranoid schizophrenia. The man was found dead lying in his bed with the face pressed against a pillow and with elevated buttocks. The autopsy did not reveal a cause of death. The histological findings displayed the signs of the haemorrhagic-dysoric syndrome with acute emphysema; these findings are pathognomonic of obstructive asphyxia. The adverse effects of the neuroleptics demonstrated by the toxicological findings may have accelerated the loss of consciousness and facilitated the unusual position of the body. On the basis of the clinical history, the autopsy findings, the histological features and the toxicological results, asphyxia due to smothering was diagnosed as the cause of death.

Sensitive determination of phenylephrine and chlorprothixene at poly(4-aminobenzene sulfonic acid) modified glassy carbon electrode.

Phenylephrine (i.e. PHE) and chlorprothixene (i.e. CPT), two effective and important antipsychotic drugs with low redox activity, were found generating an irreversible anodic peak at about +0.89 V (vs. SCE) and +1.04 V in 0.05 M HAc-NaAc (pH 5.0) or NH(2)CH(2)COOH-HCl (pH 2.4) buffer solution at poly(4-aminobenzene sulfonic acid) modified glassy carbon electrode (i.e. poly(4-ABSA)/GC), respectively. Sensitive and quantitative measurement for them based on the anodic peaks was established under the optimum conditions. The anodic peak current was linear to PHE and CPT concentrations from 1 x 10(-7) to 1.5 x 10(-5)M and 2 x 10(-6) to 4.5 x 10(-5)M, the detection limits obtained were 1 x 10(-8) and 1 x 10(-7)M, separately. The modified electrode exhibited some excellent characteristics including easy regeneration, high stability, good reproducibility and selectivity. The method proposed was successfully applied to the determination of PHE and CPT in drug injections or tablets and proved to be reliable compared with ultraviolet spectrophotometry. The modified electrode was characterized by electrochemical methods.

Sensitive spectrophotometric methods for quantitative determination of chlorprothixene in pharmaceutical dosage form.

Simple and sensitive UV-VIS spectrophotometric methods for the determination of chlorprothixene hydrochloride have been developed. One of them is based on the oxidation of chlorprothixene (CPT) by ammonium metavanadate with the formation of colourless product. The second method involves the formation of ion-pair between the drug under investigation and inorganic complexes of titanium (IV) thiocyanate followed by its extraction with mixture of butanol-chloroform (1:9, v/v). The optimum conditions for the oxidation of CPT or ion-pair formation are established. The studies are examined by UV-VIS, IR or NMR spectroscopy. The methods permit the determination of CPT over the concentration range of 2.5-25 mug/ml and 4-35 mug/ml using ammonium metavanadate or the titanium (IV) thiocyanate complex, respectively. The methods are rapid, highly reproducible and accurate with +/- 0.8%. The methods are applicable to the assay of the drug under investigation in different dosage forms and the results are in good agreement with those obtained by the official methods. Common excipients used as additives to active ingredient in pharmaceutical preparations do not interfere in the proposed methods. The extractive spectrophotometric method can be applied to the determination of chlorprothixene hydrochloride in tablets after solid phase extraction (SPE).

Determination of chlorprothixene and amitryptyline hydrochlorides by UV-derivative spectrophotometry and UV-solid-phase spectrophotometry.

Two methods for spectrophotometric determination of chlorprothixene and amitryptyline hydrochlorides were proposed. One of them is based on spectral analysis of their derivative spectra. The measurement of the value at 316.0 nm of first derivative was used for construction of calibration graph for chlorprothixene. The Beer law was obeyed in the concentration range 0.5-50.0 microg ml(-1). The amplitude of the second derivative at 261.4 nm was used for determination of amitryptyline in the range 0.5-75.0 microg ml(-1). The second proposed method is utilized the use of solid sorbent for simultaneous preconcentration and assay of studied compounds. For this purpose the filtration gel Sephadex G100 was applied. The elaborated solid-phase spectrophotometric method was used for determination of chlorprothixene at 268.0 nm in the range 2.5-75.0 microg ml(-1) and amitryptyline at 238.0 nm in the concentration range 10.0-75.0 microg ml(-1).

Simultaneous LC determination of some antidepressants combined with neuroleptics.

A reversed-phase HPLC method with UV detection at 252 nm is presented for the simultaneous determination of some tricyclic antidepressants (amitriptyline, imipramine) and neuroleptics (chlorprothixene, thioridazine) in their quaternary mixtures. Sample analysis was performed on a bonded reversed phase C-18, 5 microm, 250 x 4.6 mm ID (Lichrospher 100RP-18) column using acetonitrile and 0.01 M aqueous solution of triethylamine (1:1) as the mobile phase at 0.9 ml/min. The pH was adjusted to 2.7 with concentrated phosphoric acid. The retention time was for imipramine, amitriptyline, chlorprothixene, and thioridazine 5.8, 6.5, 8.3, 10.8 min, respectively. The linearity was obeyed up to 15 ppm for imipramine and amitriptyline, 12 ppm for chlorprothixene and 10 ppm for thioridazine. The presented method also allows the determination of the mentioned drugs individually in their pharmaceutical preparations.

Adsorptive preconcentration for voltammetric measurements of trace levels of chlorprothixene.

The psychotherapeutic drug chlorprothixene is shown to adsorb strongly onto a glassy carbon surface in an open circuit. By using this phenomenon to preconcentrate the drug at a glassy carbon electrode prior to differential-pulse voltammetric measurements, sensitivity at the ppb level is readily achieved. The adsorptive stripping response was evaluated with respect to electrolyte, solution pH, accumulation time, concentration dependence and other variables. A linear peak current-concentration relationship was observed up to 1 microgram ml-1 of chlorprothixene; the relative standard deviation (at the 0.6 microgram ml-1 level) is 3.2%. For a preconcentration time of 10 min, the detection limit was found to be 2 ng ml-1. The open circuit preconcentration/medium exchange/voltammetric scheme was used to eliminate interference from sample solutions. The application of the method to human urine samples is described.

[Adsorptive stripping voltammetry of chlorprothixene at glassy carbon electrode].

A new electrochemical stripping method for measuring the antipsychotic drug chlorprothixene was reported. The drug, which was adsorbed on the surface of glassy carbon electrode, showed a sharp oxidative stripping peak at about +0.7 V (vs. Ag-AgCl) in voltammetry. The response was linear over the 0.01-1 microgram/ml concentration range. The detection limit was 2 ng/ml, about 400 times higher than UV method. The electrode surface was polished with alumina between the measurements to activate the electrode and provide good reproducibility. The open circuit accumulation/medium exchange/stripping voltammetry scheme has been proposed to avoid interference. The method has been used for direct determination of chlorprothixene in tablets and urine samples.

A nuclear magnetic resonance (NMR) method for the determination of the cis/trans isomeric content of chlorprothixene.

Proton NMR spectroscopy was applied to the assignment of the isomeric identity of commercially available chlorprothixene. Nuclear Overhauser effect studies confirmed that the clinically useful isomer is the cis (Z) configuration. An NMR method for determining the isomeric content of chlorprothixene was developed based on integration of the ratio of areas of signal strength of the cis-N-methyl in comparison to the trans-N-methyl resonances.

Colorimetric determination of thioxanthenes with tetracyanoethylene.

A simple and rapid colorimetric method for the quantitative determination of the thioxanthene derivatives, chlorprothixene, tiotixene and metixene has been performed either in their pure form or in tablets. The procedure is based upon the formation of charge transfer complexes with the pi-acceptor tetracyanoethylene. The spectra of the complex show maxima at 415, 410 and 390 nm with a high apparent molar absorptivity which facilitates the determination of 5-100 micrograms X ml-1 of the studied compounds. The mean recoveries are 100.1 +/- 1.4%, 99.8 +/- 0.8% and 100.2 +/- 1.1% for chlorprothixene, tiotixene and metixene, respectively. This procedure is applied to determine these drugs in certain formulations and the results compare favourably to compendial methods.

Chlorprothixene and chlorprothixene-sulfoxide in body fluids from a case of drug overdose.

A case of fatal drug overdose involving chlorprothixene is presented. Chlorprothixene and chlorprothixene sulfoxide (CPT-SO) metabolite concentrations (mg/L) in body fluids as determined by spectrophotofluorometry were: blood, 0.10 and 0.60; bile, 3.9 and 7.0; urine, 0.4 and 3.4; and stomach contents, 340 mg and 25 mg total, respectively. Qualitative identification of chlorprothixene and CPT-SO was by thin layer and gas liquid chromatography and spectrophotofluorometry following alkaline permanganate oxidation.