Clozapine metabolism and cardiotoxicity: A prospective longitudinal study.

BACKGROUND: Clozapine-induced myocarditis and cardiomyopathy are difficult to detect clinically and may be fatal if not detected early. The current/routine biomarkers for clozapine-induced myocarditis are non-specific indicators of inflammation (C-reactive protein) or cardiomyocyte damage (troponins I and T) that lack sensitivity, and for which changes often arise too late to be clinically useful. METHODS: The Clozapine Safety Study was a prospective, longitudinal, observational study to determine what, if any, the plasma concentrations of clozapine, N-desmethylclozapine, and clozapine-N-oxide in patients contribute to cardiotoxicity. Samples were collected and analysed using liquid chromatography mass spectrometry over a 41-month period from patients in the Auckland District Health Board. RESULTS: Sixty-seven patients were included. Six patients were diagnosed with myocarditis; none were diagnosed with cardiomyopathy in the study period. In patients not undergoing dose titration, clozapine biotransformation may shift to the N-oxide pathway rather than the N-desmethyl pathway with increasing dose. During dose titration, the timeframe in which myocarditis occurs, the rate of increase in the plasma concentration of clozapine-N-oxide, as well as the ratio of N-oxidation relative to N-desmethylation, were significantly higher in patients diagnosed with myocarditis. CONCLUSIONS: The assessment of clozapine-N-oxide formation, and N-oxidation relative to N-desmethylation ratios during treatment, may help identify a biomarker to aid the early detection of patients at risk of developing clozapine-induced cardiotoxicity.

Ethnic disparity in clozapine dosing and cardiotoxicity in New Zealand.

AIMS: To investigate ethnic disparities in the treatment and incidence of cardiotoxicity for patients prescribed clozapine in New Zealand. METHODS: A post hoc analysis was undertaken using data from four studies investigating clozapine cardiotoxicities in New Zealand: two population studies (one prospective, one retrospective) conducted in the Auckland District Health Board (2011-2017), and two studies of coronial autopsy records (2001-2016). The relationship between ethnicity and cases (N=26) of myocarditis and/or cardiomyopathy was examined in comparison to non-cases in the rest of the study population (N=161). Patient demographics, comorbidities, and risk factors were investigated for any associations with ethnicity, where data was available. RESULTS: Maori and Pacific patients were over-represented in the population studies. Moreover, across the cohorts investigated 46% of myocarditis and cardiomyopathy cases were Maori. In contrast, only one case (4%) of cardiomyopathy was identified in a patient of Pacific descent. Where clozapine titration data was available, the rate of dose escalation was higher in Maori and Pacific peoples, as was the cumulative dose received before the first case of cardiotoxicity (day 13 of dose titration). Maori patients were more likely to be co-medicated with sodium valproate than others during clozapine titration, and sodium valproate was also significantly associated with myocarditis in these patients. CONCLUSIONS: The factors underpinning the more rapid titration of Maori and Pacific patients onto clozapine and the increased use of concomitant sodium valproate in Maori are unclear. While the latter may explain the heightened risk of clozapine-induced myocarditis in Maori, further work is required to mitigate the effects of this inequity on the safe use of clozapine in New Zealand.

Incidence and investigation of potential risk-factors for clozapine-associated myocarditis and cardiomyopathy in a New Zealand cohort.

Clozapine is a uniquely effective antipsychotic indicated for treatment-resistant schizophrenia. However, its use is underutilised and often delayed for years due to potential adverse reactions including myocarditis and cardiomyopathy. The purpose of this study was to conduct a retrospective review of the clinical records of patients initiating clozapine in the Auckland District Health Board (ADHB) region to determine the incidence of clozapine-associated myocarditis and cardiomyopathy and to identify potential risk factors associated with these cardiotoxicities. The incidence of clozapine-associated myocarditis and cardiomyopathy over a two-year period in the ADHB region was 3.8% and 1.3% respectively.

Atypical Endovascular Cells in SARS-CoV-2 Pneumonia.

The autopsy findings for 3 cases of SARS-(CoV-2) pneumonia-related deaths are reported with pulmonary histology and immunohistochemistry findings. In 2 cases (cases 1 and 2), the time interval from presentation to death was approximately 1 week, whereas for case 3, the time interval from presentation to death was hours. Case 1 and case 2 presented with shortness of breath, cough, and flu-like symptoms. The decedent from case 3 died shortly after presenting to a local emergency room with high fever, chest and abdominal pain, and shortness of breath. All 3 cases had 1 or more comorbidities. The postmortem interval for cases 1 and 2 was 2 weeks as they died at sea and were stored on board within the respective cruise ships' refrigeration units, whereas case 3 was examined within 24 hours of death. The autopsies were conducted at the Miami-Dade County Medical Examiners Department under routine infectious precautions. Salient clinical history and autopsy findings are summarized. Microscopic examination revealed pneumonia with associated atypical endovascular cells.

To Test or Not To Test?: The Value of Toxicology in a Delayed Overdose Death.

A case demonstrating the necessity of thorough death investigation processes where toxicology plays an active role is presented. A 33-year-old white man presented to the emergency room in respiratory distress after an overdose episode where he was revived on the scene by fire rescue. His condition continued to deteriorate and he expired 6 days after the initial incident. No admission specimens were available for testing; however, there were specimens drawn 4 and 5 days after the incident. Drug paraphernalia from the scene was obtained by the laboratory through collaboration with local law enforcement. Drug paraphernalia was initially tested in the laboratory and after obtaining the results, the antemortem and postmortem specimens were tested identifying mitragynine and U-47700, among other drugs. These results indicate the value in obtaining and testing drug paraphernalia, and the value of testing antemortem specimens even in the event of a delay.

Fatal Complications of Aesthetic Techniques: The Gluteal Region.

Cosmetic procedures are common and utilize many techniques to obtain aesthetically good outcomes for patient satisfaction with acceptable safety standards. Cosmetic procedures that involve the gluteal region are becoming increasingly popular as various procedures can target the gluteal region such as liposuction, tumescent liposuction, cosmetic filler injections, autologous fat transfer, depot drug delivery, and implants. Complications of cosmetic gluteal procedures can be localized or systemic with systemic complications being responsible for most deaths. These reported systemic complications include sepsis, thromboembolism, fat embolism with or without fat embolism syndrome, macroscopic fat embolism, anesthesia-related and blood volume abnormalities. We herein report 10 deaths due to elective gluteal cosmetic procedures. Autologous fat transfer (fat grafting, lipoinjection) following liposuction resulted in 8 of 10 fatal outcomes of the gluteal aesthetic procedures. A comprehensive discussion of gluteal anatomy, gluteal contouring procedures, and the approach to such cases is presented along with the autopsy findings of the reported cases.

Use of Coronial Post-mortem Tissue for Research in New Zealand.

Forensic pathology is remarkably under-represented in research: considering the obstacles a researcher must overcome to obtain post-mortem tissue for research, it is perhaps not surprising. We are investigating whether there is any role for altered drug metabolism in potentially fatal clozapine-associated myocarditis and/or cardiomyopathy. As part of this research, the use of post-mortem tissue taken during a coronial autopsy from individuals who have died from, or with, these clozapine-associated cardiotoxicities was considered fundamental. Currently, there is no clear pathway for using coronial post-mortem tissue for research in New Zealand. We have worked through the Coroners Act 2006 NZ, the Human Tissue Act 2008 NZ and the medico-legal death investigation process in New Zealand to use coronial post-mortem tissue for research. The process to obtaining tissue(s) in New Zealand is probably representative of pathways in other coronial systems.