Model-based precision dosing and remedial dosing recommendations for delayed or missed doses of isoniazid in Chinese patients with tuberculosis.

AIMS: Isoniazid (INH) has been used as a first-line drug to treat tuberculosis (TB) for more than 50 years. However, large interindividual variability was found in its pharmacokinetics, and effects of nonadherence to INH treatment and corresponding remedy regime remain unclear. This study aimed to develop a population pharmacokinetic (PPK) model of INH in Chinese patients with TB to provide model-informed precision dosing and explore appropriate remedial dosing regimens for nonadherent patients. METHODS: In total, 1012 INH observations from 736 TB patients were included. A nonlinear mixed-effects modelling was used to analyse the PPK of INH. Using Monte Carlo simulations to determine optimal dosage regimens and design remedial dosing regimens. RESULTS: A 2-compartmental model, including first-order absorption and elimination with allometric scaling, was found to best describe the PK characteristics of INH. A mixture model was used to characterize dual rates of INH elimination. Estimates of apparent clearance in fast and slow eliminators were 28.0 and 11.2 L/h, respectively. The proportion of fast eliminators in the population was estimated to be 40.5%. Monte Carlo simulations determined optimal dosage regimens for slow and fast eliminators with different body weight. For remedial dosing regimens, the missed dose should be taken as soon as possible when the delay does not exceed 12 h, and an additional dose is not needed. delay for an INH dose exceeds 12 h, the patient only needs to take the next single dose normally. CONCLUSION: PPK modelling and simulation provide valid evidence on the precision dosing and remedial dosing regimen of INH.

Smoking alters the evolutionary trajectory of non-small cell lung cancer.

Smoking is the biggest risk factor for lung cancer. Smokers have a much higher chance of developing lung tumors with a worse survival rate; however, non-smokers also develop lung tumors. A number of questions remain including the underlying difference between smoker and non-smoker lung cancer patients and the involvement of genetic and epigenetic processes in tumor development. The present study analyzed the mutation data of 100 non-small cell lung cancer (NSCLC) patients, 12 non-smokers, 48 ex-smokers and 40 smokers, from Tracking Non-Small Cell Lung Cancer Evolution through Therapy Consortium. A total of 68 genes exhibited different mutation patterns across non-smokers, ex-smokers and smokers. A number of these 68 genes encode membrane proteins with biological regulation, metabolic process, and response to stimulus functions. For each group of patients, the top 10 most frequently mutated genes were selected and their oncogenetic tree inferred, which reflected how the genes evolve during tumor genesis. By comparing the oncogenetic trees of non-smokers and smokers, it was identified that in non-smokers, the mutation of epidermal growth factor receptor (EGFR) was an early genetic alteration event and EGFR was the key driver, but in smokers, the mutation of titin (TTN) was more important. Based on network analysis, TTN can interact with spectrin α erythrocytic 1 through calmodulin 2 and troponin C1. These genetic differences during tumorigenesis of non-smoker and smoker lung cancer patients provided novel insights into the effects of smoking on the evolutionary trajectory of non-small cell lung cancer and may prove helpful for targeted therapy of different lung cancer subtypes.

Efficacy of regional arterial embolization before pleuropulmonary resection in 32 patients with tuberculosis-destroyed lung.

BACKGROUND: Treatment of tuberculous-destroyed lung (TDL) with pleuropulmonary resection is challenging. Pulmonary hemorrhage is a frequent complication of this surgical procedure. Continuous efforts have been made to investigate clinical procedures that may reduce intraoperative bleeding effectively. In this study, we evaluated the feasibility and safety of regional arterial embolization before pleuropulmonary resection in patients with TDL. METHODS: The clinical data of 32 patients with TDL were retrospectively reviewed and analyzed. These patients were admitted to the hospital between July 2009 and November 2016. All of the patients had moderate to massive hemoptysis and received regional arterial embolization in affected areas. Then, these patients underwent pleuropulmonary resection within 1 week to 2 months after embolization. RESULTS: The results showed that 25 patients (78.1%) had bronchial artery, and all patients had non-bronchial systemic artery found in affected areas. Mild to moderate chest pain was reported in 6 patients, and fever was reported in 2 patients. Intraoperative blood loss during pleuropulmonary resection in patients who had received preoperative regional arterial embolization was 625.6 ± 352.6 ml. Duration of the operation was 120.3 ± 75.2 min. Bronchopleural fistulae and empyema were found in 3 cases (9.4%). CONCLUSION: Performance of regional arterial embolization before pleuropulmonary resection offers a safe and feasible option that reduces intraoperative blood loss and shortens operative time in patients with TDL.