Clozapine: Mechanisms of toxicity and side effects

Clozapine is an atypical antipsychotic agent with a confirmed effectiveness which is widely used in the clinical practice. However, its administration is associated with a high risk of serious adverse events. Life-threatening conditions related to administration of clozapine may be a result of idiosyncrasy, acute poisoning resulting from unintentional overdose of the prescribed dug, suicidal behavior, and criminal actions. The review presents current data on the mechanism of therapeutic and toxic effect of clozapine. It describes the effect of clozapine on cell receptors and ultracellular structures. It dwells on the contribution of major and intermediate metabolites of this medicinal agent to the development of toxic effects. © 2018, V.A. Negovsky Research Institute of General Reanimatology. All rights reserved

Morphological changes in the heart with clozapine poisoning (Experimental study)

Objective: to identify histomorphological changes in the heart for acute poisoning with clozapine and combined poisonings with ethanol and clozapine 3 and 24 hours after poisoning. Materials and methods: the experiments were performed in mongrel male rats weighing 290—350 g. Clozapine was administered at a dose of 150 mg/kg animal weight under anesthesia with chlorolase. After 3 hours and 24 hours the animals were sacrificed by decapitation. Histological sections of the heart of 5 rats that had received clozapine orally at a dose of 150 mg/kg and of 5 rats that had received ethanol and clozapine orally in the above doses 3 hours after the poisoning were examined. There was also a study of histological sections of the heart of rats (n=10) that had received similar preparations in the above doses and were withdrawn from the experiment 24 hours after the administration of the preparations. The comparison was performed by evaluating the histological sections of the heart of rats (n=5) that had not received the above substances. The presence of following morphological signs was evaluated: circulatory disorders (plethora, hemorrhages), eosinophilia, fragmentation of cardiomyocytes, cell reaction, and homogeneity of the cytoplasm. The evaluation was carried out using the Fisher criterion. The presence of a sign was considered reliable when it appeared in 4—5 cases in one group and was completely absent in another. Results: in the control group of animals the histological examination of the heart showed no circulatory disorders, eosinophilia, fragmentation of cardiomyocytes, or homogeneity of the cytoplasm. The earliest change in the heart with the effect of clozapine was blood circulation disorders that appeared already 3 hours after the administration of the medicine and increased by 24 hours. Eosinophilia of the myocardium, which is specific for clozapine poisoning, was observed in all experimental groups. In the clozapine and ethanol group, homogenization of the cytoplasm was observed after 3 hours, indicating cell death. In the group receiving clozapine as a monopreparation, similar changes were not observed. Perhaps, the appearance of such changes is associated with the influence of ethanol. In the group affected by clozapine and ethanol there were circulatory disorders (plethora of veins and venules, small pericapillary hemorrhages) after 3 hours. By 24 hours these disorders intensified. Arterial and venous plethora, periarterial and pericapillary hemorrhages were observed. Conclusion. The changes revealed by histological examination of the heart in animals receiving clozapine and a combination of ethanol and clozapine, together with the results of forensic analysis, can be used to diagnose relevant poisonings and to establish their prescription. © 2017, V.A. Negovsky Research Institute of General Reanimatology. All rights reserved

Morphometry of cortical neurons in acute clozapine and ethanol poisoning

The aim of the study is to summarize the histology and morphometry of cortical neurons in acute clozapine and ethanol poisoning. Material and methods. Histological examination of the parietal cortical brain samples of 26 patients died during the Day 1 of acute clozapine and ethanol poisoning (23 males and 3 females aged 22–63 years) was per-formed. The blood ethanol level was 1.4–4.1‰. The level of clozapine in the blood ranged between 0.24 and 5.8 mg%, in the liver between 0.097 and 6.5 mg%, in kidneys between 0.03 and 3.5 mg%. The cortical samples for morphometric examination were placed in 10% neutral paraformaldehyde, the histological sections were done and stained with hematoxylin and eosin, as well as according to Niessl. The morphological analysis was performed using the video light microscopy. The number of damaged neurons (with separate quantification of reversible, intermediate, and irreversible damage) was assessed. The statistical analysis was done using the non-parametric methods. Results. The signs of brain neuronal damage in acute clozapine and ethanol poisoning, as well as forensic chemical tests, might be used for establishing the direct cause of death. © 2020, V.A. Negovsky Research Institute of General Reanimatology. All rights reserved

Morphological changes in the heart with clozapine poisoning (Experimental study)

Objective: to identify histomorphological changes in the heart for acute poisoning with clozapine and combined poisonings with ethanol and clozapine 3 and 24 hours after poisoning. Materials and methods: the experiments were performed in mongrel male rats weighing 290—350 g. Clozapine was administered at a dose of 150 mg/kg animal weight under anesthesia with chlorolase. After 3 hours and 24 hours the animals were sacrificed by decapitation. Histological sections of the heart of 5 rats that had received clozapine orally at a dose of 150 mg/kg and of 5 rats that had received ethanol and clozapine orally in the above doses 3 hours after the poisoning were examined. There was also a study of histological sections of the heart of rats (n=10) that had received similar preparations in the above doses and were withdrawn from the experiment 24 hours after the administration of the preparations. The comparison was performed by evaluating the histological sections of the heart of rats (n=5) that had not received the above substances. The presence of following morphological signs was evaluated: circulatory disorders (plethora, hemorrhages), eosinophilia, fragmentation of cardiomyocytes, cell reaction, and homogeneity of the cytoplasm. The evaluation was carried out using the Fisher criterion. The presence of a sign was considered reliable when it appeared in 4—5 cases in one group and was completely absent in another. Results: in the control group of animals the histological examination of the heart showed no circulatory disorders, eosinophilia, fragmentation of cardiomyocytes, or homogeneity of the cytoplasm. The earliest change in the heart with the effect of clozapine was blood circulation disorders that appeared already 3 hours after the administration of the medicine and increased by 24 hours. Eosinophilia of the myocardium, which is specific for clozapine poisoning, was observed in all experimental groups. In the clozapine and ethanol group, homogenization of the cytoplasm was observed after 3 hours, indicating cell death. In the group receiving clozapine as a monopreparation, similar changes were not observed. Perhaps, the appearance of such changes is associated with the influence of ethanol. In the group affected by clozapine and ethanol there were circulatory disorders (plethora of veins and venules, small pericapillary hemorrhages) after 3 hours. By 24 hours these disorders intensified. Arterial and venous plethora, periarterial and pericapillary hemorrhages were observed. Conclusion. The changes revealed by histological examination of the heart in animals receiving clozapine and a combination of ethanol and clozapine, together with the results of forensic analysis, can be used to diagnose relevant poisonings and to establish their prescription. © 2017, V.A. Negovsky Research Institute of General Reanimatology. All rights reserved

Clozapine: Mechanisms of toxicity and side effects

Clozapine is an atypical antipsychotic agent with a confirmed effectiveness which is widely used in the clinical practice. However, its administration is associated with a high risk of serious adverse events. Life-threatening conditions related to administration of clozapine may be a result of idiosyncrasy, acute poisoning resulting from unintentional overdose of the prescribed dug, suicidal behavior, and criminal actions. The review presents current data on the mechanism of therapeutic and toxic effect of clozapine. It describes the effect of clozapine on cell receptors and ultracellular structures. It dwells on the contribution of major and intermediate metabolites of this medicinal agent to the development of toxic effects. © 2018, V.A. Negovsky Research Institute of General Reanimatology. All rights reserved