clozapine and Kidney-Diseases

Clozapine is widely employed in the treatment of schizophrenia. Compared with that of atypical first-generation antipsychotics, atypical second-generation antipsychotics such as clozapine have less severe side effects and may positively affect obesity and blood glucose level. However, no systematic study of clozapine's adverse metabolic effects-such as changes in kidney and liver function, body weight, glucose and triglyceride levels, and retinopathy-was conducted. This research investigated how clozapine affects weight, the bodily distribution of chromium, liver damage, fatty liver scores, glucose homeostasis, renal impairment, and retinopathy in mice fed a high fat diet (HFD). We discovered that obese mice treated with clozapine gained more weight and had greater kidney, liver, and retroperitoneal and epididymal fat pad masses; higher daily food efficiency; higher serum or hepatic triglyceride, aspartate aminotransferase, alanine aminotransferase, blood urea nitrogen, and creatinine levels; and higher hepatic lipid regulation marker expression than did the HFD-fed control mice. Furthermore, the clozapine group mice exhibited insulin resistance, poorer insulin sensitivity, greater glucose intolerance, and less Akt phosphorylation; their GLUT4 expression was lower, they had renal damage, more reactive oxygen species, and IL-1 expression, and, finally, their levels of antioxidative enzymes (superoxide dismutase, glutathione peroxidase, and catalase) were lower. Moreover, clozapine reduced the thickness of retinal cell layers and increased

Topics: Adipocytes; Animals; Biomarkers; Body Weights and Measures; Chromium; Clozapine; Disease Models, Animal; Fatty Acid-Binding Proteins; Fluorescent Antibody Technique; Gene Expression; Gene Expression Regulation; Glucose Intolerance; Immunohistochemistry; Insulin; Kidney Diseases; Liver; Mice; Mice, Obese; Nitric Oxide Synthase Type II; Non-alcoholic Fatty Liver Disease; Obesity; Proto-Oncogene Proteins c-akt; Reactive Oxygen Species; Retinal Diseases; Sterol Regulatory Element Binding Protein 1

Physiologically based pharmacokinetic (PBPK) modeling permits clinical scientists to reduce practical constraints for clinical trials on patients with special diseases. In this study, simulations were carried out to validate the pharmacokinetic parameters of clozapine and sildenafil using Simcyp. A full PBPK model was built in the simulator for clozapine and sildenafil based on physicochemical properties and observed clinical results. The model used was Advanced, Dissolution, Absorption and Metabolism (ADAM) for both drugs.. The PBPK model adequately predicted the pharmacokinetic parameters of clozapine and sildenafil for the healthy adult population. In the simulation results, the bioavailability of both drugs was remarkably raised in both renal and hepatic impairment in young and elderly populations.. PBPK modeling could be helpful in the investigation and comparison of the pharmacokinetics in populations with specific disease conditions.

Topics: Adult; Clozapine; Humans; Kidney Diseases; Liver Diseases; Male; Middle Aged; Models, Biological; Sildenafil Citrate; Young Adult

17 patients (13 males and 4 females) were examined for side effects due to long-term treatment with 8-chloro-11-(4-methylpiperazin-1-yl)-5H-dibenzo(b,e)(1,4)diazepine (clozapine) with emphasis on alterations in bone marrow, liver, and kidney function. 16 patients were schizophrenic, one patient was diagnosed psychosis e causa dubia. The age range was 25-68 years, with an average of 38.2 years. The daily clozapine dose varied from 225 to 800 mg with a total intake during the trial period of 149.1-891.6 g yielding an average of 479.8 g. The treatment period varied from 20 to 51 months, with an average of 35.9 months. None of the patients had to discontinue the treatment because of side effects. The laboratory data including hematological, and nephrological parameters revealed no significant changes related to clozapine treatment within the treatment period. No changes were observed in ECG. 12 patients experienced side effects, 8 of them receiving concomitant psycholeptic medication. 9 patients complained of temporary fatigue and 5 of these experienced continuous drowsiness. There were 8 cases of nocturnal hypersalivation and two cases of increased appetite. One patient developed light tachycardia and one patient orthostatic hypotension. Clozapine is known to be an effective anti-psychotic drug, but due to reports of agranulocytosis in 16 Finnish patients the drug was withdrawn from the Danish market in 1975 although later its use was merely restricted to special cases. This study does not indicate that clozapine contains greater risk of clinical side effects than commonly used psycholeptic drugs.

Topics: Adult; Aged; Bone Marrow Diseases; Chemical and Drug Induced Liver Injury; Clozapine; Dibenzazepines; Female; Humans; Kidney Diseases; Male; Middle Aged; Psychotic Disorders; Time Factors