Clozapine: Mechanisms of Toxicity and Side Effects

Babkina, Anastasiya S.; Голубев, А. М; Сундуков, Д. В.; Баширова, А. Р.; Голубев, М. А.

doi:10.15360/1813-9779-2018-2-35-45

Cited by 7 publications

(2 citation statements)

References 55 publications

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“…Clozapine, a dibenzodiazepine, is atypical antipsychotic drug which has a lipophilic character, it remains the most effective second-generation antipsychotic medication, as it characterized by high affinity to dopamine ‘D4’ receptors. Also, being D2 antagonists with rapid dissociation helps in minimizing the extrapyramidal symptoms, without making any disturbance in normal dopamine neurotransmission (Babkina et al, 2018 ). The CLZ blocking effect of serotonin 5HT2A receptor prevents the Parkinson-like motor side effects of antipsychotics (Seeman, 2014 ).…”

Section: Introductionmentioning

confidence: 99%

Brain targeting efficiency of intranasal clozapine-loaded mixed micelles following radio labeling with Technetium-99m

Sayed

Elsharkawy²,

Amin

et al. 2021

Drug Delivery

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The research objective is to design intranasal (IN) brain targeted CLZ-loaded polymeric nanomicellar systems (PNMS) aiming to improve central systemic CLZ bioavailability. Direct equilibrium method was used to prepare CLZ-PNMS using two hydrophobic poloxamines; Tetronic V R 904 (T904) and Tetronic V R 701 (T701) and one hydrophilic poloxamer; Synperonic V R PE/F127 (F127). Optimization is based on higher percent transmittance, solubilizing efficiency, and in vitro release after 24 h with smaller particle size was achieved using Design-Expert V R software. The optimized formula was further evaluated via TEM, ex vivo nasal permeation in addition to in vivo biodistribution using radiolabeling technique of the optimized formula by Technetium-99m ( 99m Tc). The optimized formula M5 has small size (217 nm) with relative high percentage of transmittance (97.72%) and high solubilization efficacy of 60.15-fold following 92.79% of CLZ released after 24 h. Ex vivo nasal permeation showed higher flux of 36.62 lg/ cm 2 .h compared to 7.324 lg/cm 2 .h for CLZ suspension with no histological irritation. In vivo biodistribution results showed higher values of radioactivity percentage of the labeled optimized formula ( 99m Tc-M5) in brain and brain/blood ratio following IN administration of 99m Tc-M5 complex which were greater than their corresponding values following intravenous route. It is obvious that nasal delivery of CLZ-PNMS could be a promising way to improve central systemic CLZ bioavailability.

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Section: Introductionmentioning

confidence: 99%

Brain targeting efficiency of intranasal clozapine-loaded mixed micelles following radio labeling with Technetium-99m

Sayed

Elsharkawy²,

Amin

et al. 2021

Drug Delivery

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“…The toxic effects of clozapine may occur even at a therapeutic dose and include myocarditis, cardiomyopathies, cardiac rhythm and conduction disorders, orthostatic hypotension, agranulocytosis, thrombosis, bowel obstruction, metabolic disorders, malignant neuroleptic syndrome, cerebral edema, and several other life-threatening conditions [6,7].…”

Section: Introductionmentioning

confidence: 99%

Global DNA Methylation Of Brain Neurons In Acute Poisoning With Clozapine And Its Combination With Alcohol: An Experimental Study

et al. 2021

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Background — Acute poisoning with atypical neuroleptic clozapine is characterized by rapid progression, high risk of death and severe neurological manifestations. Neurotoxic effects of this pharmaceutical drug have also been reported at therapeutic doses. The pathogenesis of brain damage in acute clozapine poisoning is not fully understood. Changes in DNA methylation level may play an important role in the mechanisms of drug neurotoxicity. The available data on the effect of clozapine on brain cell DNA provide a rationale for studying the epigenetic aspects of the pathogenesis of acute poisoning with this neuroleptic agent. The objective of our study was to evaluate the global DNA methylation level in rat brain neurons in acute poisoning with clozapine and its combination with ethanol. Material and methods — Clozapine – 150 mg/kg in 2.0 ml of normal saline solution, or clozapine – 150 mg/kg in 2.0 ml of 40% ethanol were administered via a gastric tube to adult male Wistar rats (n=21) under anesthesia with sevoflurane. In the control group, saline was administered via a gastric tube. Animals were euthanized four hours after drug administration. Autopsy was performed with the collection of brain samples for histochemical examination and determination of the DNA methylation level using the fluorometric method. To detect DNA in sections of paraffin-embedded tissue, we used the Feulgen staining. The TUNEL method was employed to detect DNA fragmentation. Results — An increase in the level of global DNA methylation in brain neurons was found in the clozapine and clozapine+ethanol groups. The average level of methylated DNA in the clozapine+ethanol group was higher than in the control group or clozapine group (2.56±0.31 vs. 1.35±0.1, p=0.007 and 1.70±0.33, p=0.044, respectively). An increase in the mean optical density of the cortical neuron nuclei was observed in the clozapine+ethanol group compared with the control group and clozapine group. DNA fragmentation was not detected in any experimental group. Conclusion — Acute poisoning with clozapine in combination with alcohol caused an increase in the global DNA methylation level in brain neurons, which may have played a significant role in the pathogenesis of acute clozapine poisoning and could be an important factor in the neurotoxicity of this medication.

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Laser-Induced Fluorescence Spectroscopy in the Diagnosis of Tissue Hypoxia (Review)

Babkina

2019

Obŝaâ reanimatologiâ

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The aim of review is to discuss the results of studies on diagnosis of tissue hypoxia by laser-induced spectroscopy, as well as to identify promising trends and prospects of this technique for its further application in experimental and clinical medicine.The review presents the findings of studies of the fluorescence intensity of endogenous fluorophore molecules (reduced nicotinamide adenine dinucleotide, oxidized flavin adenine dinucleotide) as markers of ischemic injury of internal organs (brain, heart, liver, kidneys, etc.). The principles of fluorescence laser-induced spectroscopy in vivo are discussed. The historical aspects of the subject are also covered. The results of the use of the technique in experimental and clinical studies of tissue hypoxia and ischemia are shown. Difficulties in interpreting the intensity values of autofluorescent signal of the studied molecules are revealed. It was noted that the tissue autofluorescence in a long-term anoxia remains unknown, and there are no structured ideas about the impact of exogenous and endogenous factors on autofluorescence intensity.In conclusion, the use of laser-induced fluorescence spectroscopy to diagnose tissue ischemia is a promising area of experimental and clinical medicine, which still has various unresolved issues, despite a large number of studies in this domain.

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Clozapine: Mechanisms of Toxicity and Side Effects

Cited by 7 publications

References 55 publications

Brain targeting efficiency of intranasal clozapine-loaded mixed micelles following radio labeling with Technetium-99m

Brain targeting efficiency of intranasal clozapine-loaded mixed micelles following radio labeling with Technetium-99m

Global DNA Methylation Of Brain Neurons In Acute Poisoning With Clozapine And Its Combination With Alcohol: An Experimental Study

Laser-Induced Fluorescence Spectroscopy in the Diagnosis of Tissue Hypoxia (Review)

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