Morphological and Functional Alterations of the Cardiovascular System during Acute Clozapine Poisoning (Experimental Study)

A S Babkina,S N Kalabushev,Yu V Zarzhetsky,A R Asanov,Z I Tsokolaeva,I A Ryzhkov,V V Antonova

doi:10.15360/1813-9779-2019-4-67-75

Abstract

Purpose of the study. To evaluate the influence of sublethal dose of Clozapine on the functional and morphological parameters of the cardiovascular system in rats 4 hrs. after the drug administration.Materials and methods. The experiments were carried out on male Wistar rats weighing 200–250g (n=14). Group I received 0.9% NaCl solution administered via enteral feeding tubing under general anesthesia using Sevoflurane; group II — Clozapine dosed at 150 mg/kg in 0.9% NaCl solution; group III — Clozapine dosed at 150 mg/kg in 40% ethyl alcohol solution. 4 hrs. after drug administration, arterial blood pressure (ABP), heart rate (HR), microcirculation in the skin using laser Doppler flowmetry (LSF), fluorescence intensity of coenzymes NADH and FAD were evaluated. After euthanasia, autopsy including withdrawal of the internal organs of rats for morphological analysis was performed. Thereafter, paraffin sections of hearts were made and subsequently stained with hematoxylin and eosin, which were later examined with the help of light microscope Nikon Eclipse Ni-U.Results. In both Clozapine groups, ABP and blood flow in the skin were lower than in the control group: ABP — by 12% in group I and by 15% in group II; blood flow — by 48% and 37%, respectively. No significant difference between the groups was observed in respect of the microcirculation indices studied. Increased fluorescence intensity of coenzyme NADH in the skin was found in the Clozapine groups compared to the control group (2.3-fold in group I and 1.9-fold in group II). Histological analysis of the hearts of animals that received Clozapine established uneven blood filling, erythrocyte sludges, fine-focal hemorrhaging, endotheliocyte nuclei oriented perpendicular to the basal membrane, uneven staining of myocardium with hypereosinophilic segments, fragmentation and undulating deformity of muscle fibers.Conclusion. During acute Clozapine poisoning, morphological signs of disturbed circulation and myocardium damage are found in the heart, which are accompanied with development of myocardium dysfunction with arterial hypotension and decreased peripheral blood flow, also disturbed oxidative metabolism in peripheral tissues.

Highlights

Клозапин — производное дибензодиазепина, атипичный нейролептический препарат, используемый в психиатрической практике преимущественно для лечения резистентных к большинству нейролептиков заболеваний [1, 2]
Group I received 0.9% NaCl solution administered via enteral feeding tubing under general anesthesia using Sevoflurane; group II — Clozapine dosed at 150 mg/kg in 0.9% NaCl solution; group III — Clozapine dosed at 150 mg/kg in 40% ethyl alcohol solution. 4 hrs. after drug administration, arterial blood pressure (ABP), heart
No significant difference between the groups was observed in respect of the microcirculation indices studied

Summary

Introduction

Клозапин — производное дибензодиазепина, атипичный нейролептический препарат, используемый в психиатрической практике преимущественно для лечения резистентных к большинству нейролептиков заболеваний [1, 2]. Выраженное угнетение центральной нервной системы и высокий риск летального исхода при передозировке клозапина обусловливают случаи его использования в криминальных, суицидальных целях [3, 4]. Танатогенез при остром отравлении клозапином до конца не выяснен. Что при приеме высоких доз клозапина причиной летального исхода является острая сердечная недостаточность или паралич дыхательного центра [6]. Возникновение жизнеугрожающих побочных эффектов отмечено также и при приеме терапевтических доз препарата. В экспериментальном исследовании было выявлено повышение уровней норадреналина, адреналина, тропонинов, МВ фракции креатинфосфокиназы, интерлейкинов, фактора некроза опухоли альфа, цитокинов в крови мышей, получавших клозапин [12, 13] Al-Wahab и соавт. в экспериментальном исследовании было выявлено повышение уровней норадреналина, адреналина, тропонинов, МВ фракции креатинфосфокиназы, интерлейкинов, фактора некроза опухоли альфа, цитокинов в крови мышей, получавших клозапин [12, 13]

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