Effect of a drug holiday on plasma chlorpromazine levels in chronic schizophrenic patients

Low chloropromazine (CPZ) levels have been measured in chronically treated schizophrenics. We tested six such patients to determine whether a 2-week CPZ-free period (drug holiday) would improve plasma CPZ levels. We also monitored psychiatric symptoms, autonomic function, and extrapyramidal signs. We found these patients to have low predose CPZ levels that did not change appreciably after the drug holiday. Peak levels following the holiday averaged 28 ±7 ng/ml higher than those measured prior to the holiday. Drug holidays are safe and should be examined more thoroughly as a means of improving plasma neuroleptic levels in chronically treated schizophrenics.Apreliminary report of this work was presented at the 81st Meeting of the American Society for Clinical Pharmacology and Therapeutics, March 21, 1980, San Francisco, California, USA     

Heterocycles 27. Microwave assisted synthesis and antitumour activity of novel phenothiazinyl-thiazolyl-hydrazine derivatives

A series of new phenothiazinyl-thiazolyl-hydrazine derivatives were synthesized by Hantzsch cyclization of 1-(10-ethyl-10H-phenothiazin-3-yl)-methylidene-thiosemicarbazide with α-halocarbonyl derivatives. Comparison between classical and microwave assisted synthesis emphasizes the great advantages induced by microwaves irradiation which afforded high reaction yields in much shorter reaction time. Structural assignments were based on spectroscopic methods (high resolution NMR, FTIR, MS). The new compounds were tested in vitro for their antiproliferative activity against tumor cell lines using spectrometric methods. Most of the compounds exhibit cytotoxicity against hepatic and colon tumor cells in a dose-dependent mode and a relationship between the structure and their biological activity was observed.     

Chronoamperometric and morphological investigation of nucleation and growth mechanism of poly(azure A) thin films

Nucleation and growth analysis of formation of poly(azure A) thin films was carried out in this study. Electropolymerization of AA was achieved by using potentiodynamic (cyclic voltammetry) and potentiostatic (constant potential) techniques. Nucleation and growth mechanism of poly(AA) was determined by fitting the potentiostatic current density–time (j–t) transients to theoretical nucleation model. Scanning tunneling microscopy (STM) and atomic force microscopy (AFM) were performed to confirm the j–t transient results. Optical characterization was carried out by using UV–vis. absorption spectroscopy. Cyclic voltammetry experiments show that oxide formation of gold working electrode takes place at higher potentials than 900 mV besides electropolymerization of AA. Potentiostatic j–t transient and morphology studies reveal that nucleation and growth mechanism of poly(AA) film follows consecutive two instantaneous 3-D mechanisms besides random adsorption resulting in two different structures. UV–vis. absorption studies indicate that AA monomer exhibit a main band which broadens and shifts to shorter wavelength values and an additional band arises at 335 nm after the electropolymerization process.     

Acute Acepromazine Overdose: Clinical Effects and Toxicokinetic Evaluation

Introduction

Acepromazine is a phenothiazine that is used exclusively in veterinary medicine for multiple purposes. Human overdoses are rarely reported and toxicokinetic data has never been reported. We present a case of intentional acepromazine overdose resulting in central nervous system and cardiovascular toxicity with confirmatory toxicokinetic data.

Case Report

A 54-year-old woman intentionally ingested 950 mg of her dog’s acepromazine. Within 3 h of ingestion, she developed central nervous system and respiratory depression along with hypotension requiring non-invasive ventilation and vasopressors. Clinical toxicity resolved over the following 8 h. Serial plasma acepromazine levels were determined using gas chromatography/mass spectrometry. The initial acepromazine level (1-h post-ingestion) was 63 ng/ml. Follow-up levels at 8-, 10.5-, and 13.5-h post-ingestion were 8.9 ng/ml, 7.6 ng/ml, and 6.3 ng/ml, respectively.

Discussion

Human acepromazine toxicity is rarely reported but results in clinical toxicity (central nervous system depression, respiratory depression, hypotension) are similar to other phenothiazines. Compared to other phenothiazines, it appears to have a short elimination half-life that may account for the brief duration of clinical toxicity with relatively rapid improvement. No significant human cardiac toxicity has been reported. Treatment is supportive.

Conclusion

This case highlights the unique toxicity of acepromazine in demonstrating rapid improvement of severe toxicity within 8 h consistent with a short elimination half-life.     

Binding of tricyclic antidepressants and perazine to human plasma

Summary The binding of amitriptyline (AT), nortriptyline (NT), imipramine (IP), desmethylimipramine (DMI) and perazine (PER) to plasma from healthy volunteers was measured by equilibrium dialysis at 37°C. Tritium-labeled drugs of high specific activity were prepared by methylation of the corresponding secondary and primary amines. The concentrations used in binding experiments were in the low range of those achieved in therapy. Under conditions of rigorous pH control unbound fractions were 7.8±1.0% for AT, 11.0±1.2% for NT, 11.5±1.4% for IP, 15.3±1.6% for DMI and 4.6±0.8% for PER in 43 subjects aged 16–58 years. Binding values did not depend on sex or age, and in females no difference was detected between users and non-users of sexual hormones. A significant negative correlation was established between plasma total cholesterol and the free fractions of AT, NT, DMI and PER. Corresponding alterations were observed intraindividually when the cholesterol levels fluctuated within several weeks or months. The phospholipid concentration in plasma did not correlate with drug binding. The concentration dependence of AT and NT binding pointed to the contribution of plasma constituents present in low concentrations and exhibiting high affinity towards the drugs. Part of these constituents may be lipoproteins.     

Phenothiazine melanosis in schizophrenic patients

The effect of prolonged treatment with phenothiazine compounds on the skin melanin concentration of schizophrenics was measured by reflectance spectrophotometry. Caucasian and Bantu-speaking South African Negroes of both sexes were tested in this study, which comprised 182 phenothiazine-treated chronic schizophrenics, 182 matched drug-treated chronic control patients, and 163 normal subjects. The schizophrenics had significantly higher skin melanin concentrations than the normal subjects, but they did not differ in melanin content from the drugtreated controls. Thus, melanosis represented a non-specific response to the phenothiazines and was not peculiar to schizophrenics. Possible interrelationships between phenothiazines, melanosis and neuropsychiatric illness were discussed.Some of this material will appear as part of an abstract in the British Journal of Psychiatry (1972).Based on part of an M.D. Thesis accepted by the University of the Witwatersrand.     

Effects of conjugated estrogens on plasma butaperazine levels

A randomly assigned control-experimental grouping with a crossover design, using subjects as their own controls, was utilized to study the effects of conjugated estrogens on plasma butaperazine (Repoise) levels in post-menopausal female subjects. Significantly higher plasma butaperazine levels were measured following both a single loading dose and with maintenance doses of oral butaperazine in subjects when they were taking conjugated estrogens as compared to when they were not taking conjugated estrogens. The underlying mechanisms for these findings and their clinical implications are discussed briefly.This research was supported in part by grant GM 15431 from the National Institutes of Health, grant MH 11468 from the National Institute of Mental Health, and by research support from the State of Tennessee Department of Mental Health.     

Legal-medical and toxicological evaluation of 18 lethal cases of poisoning by phenothiazine derivatives

Summary 18 lethal cases caused by phenothiazine drugs were presented on the base of autopsic, histopathological and analytical examinations of autopsy material.In toxicological-analytical examinations chromatographic and spectrophotometric methods were used. In 6 cases the combined poisoning with several drugs was found. 16 cases of poisoning were of suicidal character.The concentrations of drugs and doses of the drugs and the found changes in the liver may show the relatively great toxicity of the neuroleptics of this group.The authors are of the opinion that the phenothiazine drugs should be under strict control and should be examined on toxicity and metabolism. It would be desirable to introduce diagnostic and organizing instructions for the proper life-saving action in cases of intoxication.

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Zusammenfassung Es wurde über die Sektionsbefunde und die Ergebnisse der histopathologischen Untersuchungen berichtet. In allen Fällen wurde auch eine qualitative und quantitative chemische Analyse von Organen und Körperflüssigkeiten mit Anwendung der Ionen-Austauschpapier-Dünnschichtchromatographie und der Spektrophotometrie vorgenommen.In 2 Fällen handelte es sich um eine unbewußte Überdosierung, in 16 anderen um Suicide. Form der Arzneimittel: Promazin 4 Fälle, Chloropromazin 3 Fälle, Levopromazin 3 Fälle, einzelne Vergiftungsfälle erfolgten mit Promethazin und Pernazin, andere mit gemischten psychotropen Substanzen.Die ermittelten Konzentrationen der Phenothiazinderivate in Organen wurden in einer Tabelle zusammengestellt.Die Ergebnisse, insbesondere die histopathologisch festgestellten degenerativen Prozesse in der Leber und Ecchymosen im Zentralnervensystem wie auch die nicht hohen Dosen der Phenothiazine weisen auf Toxicität dieser Arzneimittel hin. Der Einfluß auf den Organismus und die Toxicität dieser Drogen erfordern weitere Forschungsuntersuchungen. Phenothiazinderivate sollten unter genaue ärztliche Kontrolle gestellt werden.

     

Effect of phenothiazine neuroleptic drugs and tricyclic antidepressants on phosphodiesterase activity in rat cerebral cortex

The activity of phosphodiesterase (PDE) of rat cerebral cortex following the administration in vitro and in vivo of various concentrations of neuroleptic phenothiazine drugs and tricyclic antidepressive drugs has been investigated. It has been shown that PDE activity is inhibited by phenothiazine neuroleptic drugs (fluphenazine > trifluperazine > thioproperazine > chlorpromazine = thioridazine). Tricyclic antidepressants nortriptyline, chlorimipramine, protiptyline, imipramine and desipramine at a concentration of 10^–3 M caused 60–80% inhibition of PDE activity. It has also been found that the investigated phenothiazine compounds inhibit the high affinity PDE activity more than the PDE activity of low affinity to the substrate.The results obtained suggest that the mechanism of the neuroleptic action of phenothiazine drugs is partially connected with their influence on cyclic 3,5-AMP metabolism.Supported by Polish Academy of Sciences, 09.4.1.5.