New approach methodologies predicting human cardiotoxicity are of interest to support or even replace in vivo-based drug safety testing. The present study presents an in vitro–in silico approach to predict the effect of inter-individual and inter-ethnic kinetic variations in the cardiotoxicity of R- and S-methadone in the Caucasian and the Chinese population. In vitro cardiotoxicity data, and metabolic data obtained from two approaches, using either individual human liver microsomes or recombinant cytochrome P450 enzymes (rCYPs), were integrated with physiologically based kinetic (PBK) models and Monte Carlo simulations to predict inter-individual and inter-ethnic variations in methadone-induced cardiotoxicity. Chemical specific adjustment factors were defined and used to derive dose–response curves for the sensitive individuals. Our simulations indicated that Chinese are more sensitive towards methadone-induced cardiotoxicity with Margin of Safety values being generally two-fold lower than those for Caucasians for both methadone enantiomers. Individual PBK models using microsomes and PBK models using rCYPs combined with Monte Carlo simulations predicted similar inter-individual and inter-ethnic variations in methadone-induced cardiotoxicity. The present study illustrates how inter-individual and inter-ethnic variations in cardiotoxicity can be predicted by combining in vitro toxicity and metabolic data, PBK modelling and Monte Carlo simulations. The novel methodology can be used to enhance cardiac safety evaluations and risk assessment of chemicals.
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Cannabis is commonly characterized as the most normalized illicit drug. However, it remains a prohibited substance in most parts of the world, including Europe, and users can still be subject to stigmatization. The objective of this study is to assess to what extent and how cannabis users in different countries with different cannabis policies perceive, experience and respond to stigmatization. We conducted a survey in the Dutch coffeeshops among 1225 last year cannabis users from seven European countries, with national cannabis policies ranging from relatively liberal to punitive. Three dimensions of cannabis-related stigma were investigated (discrimination, perceived devaluation and alienation) and a sum score was used to reflect the general level of stigmatization. Perceived devaluation was the highest-scoring dimension of stigma and discrimination the lowest-scoring. The general level of stigmatization was lowest in the Netherlands and highest in Greece. This indicates that punitive cannabis policy is associated with stigma and liberal cannabis policy is associated with de-stigmatization. Besides country, daily cannabis use was also found to be a significant predictor of stigma, but gender, age, household type and employment status were not.
From Narcis.nl :" Patients with substance use disorder (SUD) are frequently suffering from co-occurring somatic disorders, increasing the risk of mortality. Somatic health care utilization (sHCU) often remains unknown to the physician during SUD treatment. This paper analyses sHCU and associated costs among patients in SUD treatment compared to matched, non-substance dependent controls. METHODS: Health care utilization data on 4972 SUD patients were matched to 19,846 controls by gender, birth year and ethnic origin. Subcategories of patients were formed based on SUD and on co-morbid psychiatric disorder. Data on sHCU during the year prior to the last treatment contact (the 'index date') for both patients and their matched controls were extracted from a health insurance database. RESULTS: Patients had a higher sHCU (with increased associated costs) than controls, especially when alcohol dependence was involved. In particular, sHCU for cardiovascular, respiratory, infectious diseases, injuries and accidents was increased among patients. However, the use of preventive medication, such as lipid-lowering drugs, is lower among SUD patients. Co-morbidity of psychiatric disorders led to further increase of sHCU, whereas patients with comorbid non-affective psychotic disorder (NAPD) showed lower sHCU and costs. CONCLUSION: Patients with SUD overall have a high sHCU, associated with high costs. There are indications that SUD patients have less access to preventive medication. Patients with comorbid NAPD are at risk of possible underutilization of somatic health care. Furthermore, we conclude that these larger administrative databases allow for comparisons between various diagnostic categories."
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