Isoniazid Mediates the CYP2B6*6 Genotype-Dependent Interaction between Efavirenz and Antituberculosis Drug Therapy through Mechanism-Based Inactivation of CYP2A6

Efavirenz is commonly used to treat patients coinfected with human immunodeficiency virus and tuberculosis. Previous clinical studies have observed paradoxically elevated efavirenz plasma concentrations in patients with the CYP2B6*6/*6 genotype (but not the CYP2B6*1/*1 genotype) during coadministration with the commonly used four-drug antituberculosis therapy. This study sought to elucidate the mechanism underlying this genotype-dependent drug-drug interaction. In vitro studies were conducted to determine whether one or more of the antituberculosis drugs (rifampin, isoniazid, pyrazinamide, or ethambutol) potently inhibit efavirenz 8-hydroxylation by CYP2B6 or efavirenz 7-hydroxylation by CYP2A6, the main mechanisms of efavirenz clearance. Time- and concentration-dependent kinetics of inhibition by the antituberculosis drugs were determined using genotyped human liver microsomes (HLMs) and recombinant CYP2A6, CYP2B6.1, and CYP2B6.6 enzymes. Although none of the antituberculosis drugs evaluated at up to 10 times clinical plasma concentrations were found to inhibit efavirenz 8-hydroxylation by HLMs, both rifampin (apparent inhibition constant [K_i] = 368 μM) and pyrazinamide (K_i = 637 μM) showed relatively weak inhibition of efavirenz 7-hydroxylation. Importantly, isoniazid demonstrated potent time-dependent inhibition of efavirenz 7-hydroxylation in both HLMs (inhibitor concentration required for half-maximal inactivation [K_I] = 30 μM; maximal rate constant of inactivation [k_inact] = 0.023 min⁻¹) and recombinant CYP2A6 (K_I = 15 μM; k_inact = 0.024 min⁻¹) and also formed a metabolite intermediate complex consistent with mechanism-based inhibition. Selective inhibition of the CYP2B6.6 allozyme could not be demonstrated for any of the antituberculosis drugs using either recombinant enzymes or CYP2B6*6 genotype HLMs. In conclusion, the results of this study identify isoniazid as the most likely perpetrator of this clinically important drug-drug interaction through mechanism-based inactivation of CYP2A6.     

Das Modellprojekt ReWiKs

Several studies point to various barriers in achieving sexual self-determination for people with disabilities as well as a high degree of thematic uncertainty among staff in residential homes. In addition, women with disabilities and people in institutions are especially at risk in a particular way, to be victims of sexual violence. The ReWiKs project develops, based on evaluated guidelines for sexual self-determination, materials in order to reflect the institutional handling of the subject. Training modules and recommendations are also developed. In addition, extracts of materials are created in simple language. All materials are evaluated before their publication in an intensive theory-practice dialogue.     

Rolle der Diabetesberatung im digitalen Zeitalter

Digitization has long since taken hold in the diabetes sector. Digital support including pumps, rtCGM (CGM: continuous glucose monitoring, rtCGM: real time CGM), iscCGM (intermittent scanning CGM), apps as well as measuring devices with pattern recognition and a reminder function has become commonplace in many areas. Training to become a diabetes advisor provides diabetes professionals with appropriate basic knowledge to advise the patient in self-management with technical support. Continuous medical training to empower and support patients in health literacy, data protection and the use of telemedicine is imperative.     

Impact of intratumoral heterogeneity of breast cancer tissue on quantitative metabolomics using high‐resolution magic angle spinning 1H NMR spectroscopy

High‐resolution magic angle spinning (HR MAS) nuclear magnetic resonance (NMR) spectroscopy is increasingly being used to study metabolite levels in human breast cancer tissue, assessing, for instance, correlations with prognostic factors, survival outcome or therapeutic response. However, the impact of intratumoral heterogeneity on metabolite levels in breast tumor tissue has not been studied comprehensively. More specifically, when biopsy material is analyzed, it remains questionable whether one biopsy is representative of the entire tumor. Therefore, multi‐core sampling (n = 6) of tumor tissue from three patients with breast cancer, followed by lipid (0.9‐ and 1.3‐ppm signals) and metabolite quantification using HR MAS ¹H NMR, was performed, resulting in the quantification of 32 metabolites. The mean relative standard deviation across all metabolites for the six tumor cores sampled from each of the three tumors ranged from 0.48 to 0.74. This was considerably higher when compared with a morphologically more homogeneous tissue type, here represented by murine liver (0.16–0.20). Despite the seemingly high variability observed within the tumor tissue, a random forest classifier trained on the original sample set (training set) was, with one exception, able to correctly predict the tumor identity of an independent series of cores (test set) that were additionally sampled from the same three tumors and analyzed blindly. Moreover, significant differences between the tumors were identified using one‐way analysis of variance (ANOVA), indicating that the intertumoral differences for many metabolites were larger than the intratumoral differences for these three tumors. That intertumoral differences, on average, were larger than intratumoral differences was further supported by the analysis of duplicate tissue cores from 15 additional breast tumors. In summary, despite the observed intratumoral variability, the results of the present study suggest that the analysis of one, or a few, replicates per tumor may be acceptable, and supports the feasibility of performing reliable analyses of patient tissue.     

Undergraduate students’ perspectives of healthcare professionals’ use of shared decision-making skills

Essential for future healthcare professionals (HCPs) to delivering ethical and empathetic patient-centred care (PCC) as a team is the understanding of appropriate shared decision-making (SDM) responses when facilitating discussions with patients and family members. The purpose of this study was to evaluate undergraduate students’ perspectives about HCPs’ use of SDM as described in a case-study reflection assignment. An exploratory qualitative approach was used to analyse student-reflection assignments. The sample included 42 undergraduate students enrolled in an interprofessional education (IPE) course at a Midwest university based in the United States. Data consisted of student responses in a course reflection assignment that captured their perspectives about recommended SDM responses by HCPs. Student assignments were randomly selected using stratified sampling to provide representation of eight HCP roles. Analysis revealed two themes related to students’ use of SDM responses. Results provide evidence supporting the tenet that through IPE, healthcare students can develop an understanding of SDM and ethical principles related to PCC.