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Background and Objective: Trough abiraterone concentration (ABI Cmin) of 8.4 ng/mL has been identified as an appropriate efficacy threshold in patients treated for metastatic castration-resistant prostate cancer (mCRPC). The aim of the phase II OPTIMABI study was to evaluate the efficacy of pharmacokinetics (PK)-guided dose escalation of abiraterone acetate (AA) in underexposed patients with mCRPC with early tumour progression. Methods: This multicentre, non-randomised study consisted of two sequential steps. In step 1, all patients started treatment with 1000 mg of AA once daily. Abiraterone Cmin was measured 22–26 h after the last dose intake each month during the first 12 weeks of treatment. In step 2, underexposed patients (Cmin < 8.4 ng/mL) with tumour progression within the first 6 months of treatment were enrolled and received AA 1000 mg twice daily. The primary endpoint was the rate of non-progression at 12 weeks after the dose doubling. During step 1, adherence to ABI treatment was assessed using the Girerd self-reported questionnaire. A post-hoc analysis of pharmacokinetic (PK) data was conducted using Bayesian estimation of Cmin from samples collected outside the sampling guidelines (22–26 h). Results: In the intention-to-treat analysis (ITT), 81 patients were included in step 1. In all, 21 (26%) patients were underexposed in step 1, and 8 of them (38%) experienced tumour progression within the first 6 months. A total of 71 patients (88%) completed the Girerd self-reported questionnaire. Of the patients, 62% had a score of 0, and 38% had a score of 1 or 2 (minimal compliance failure), without a significant difference in mean ABI Cmin in the two groups. Four patients were enrolled in step 2, and all reached the exposure target (Cmin > 8.4 ng/mL) after doubling the dose, but none met the primary endpoint. In the post-hoc analysis of PK data, 32 patients (39%) were underexposed, and ABI Cmin was independently associated with worse progression-free survival [hazard ratio (HR) 2.50, 95% confidence interval (CI) 1.07–5.81; p = 0.03], in contrast to the ITT analysis. Conclusion: The ITT and per-protocol analyses showed no statistical association between ABI underexposure and an increased risk of early tumour progression in patients with mCRPC, while the Bayesian estimator showed an association. However, other strategies than dose escalation at the time of progression need to be evaluated. Treatment adherence appeared to be uniformly good in the present study. Finally, the use of a Bayesian approach to recover samples collected outside the predefined blood collection time window could benefit the conduct of clinical trials based on drug monitoring. OPTIMABI trial is registered as National Clinical Trial number NCT03458247, with the EudraCT number 2017-000560-15) [ABSTRACT FROM AUTHOR]

Purpose: Idiopathic pulmonary fibrosis (IPF) is a progressive disease with poor outcome and limited therapeutic options. Imaging of IPF is limited to high-resolution computed tomography (HRCT) which is often not sufficient for a definite diagnosis and has a limited impact on therapeutic decision and patient management. Hypoxia of the lung is a significant feature of IPF but its role on disease progression remains elusive. Thus, the aim of our study was to evaluate hypoxia imaging with [18F]FMISO as a predictive biomarker of disease progression and therapy efficacy in preclinical models of lung fibrosis in comparison with [18F]FDG. Methods: Eight-week-old C57/BL6 mice received an intratracheal administration of bleomycin (BLM) at day (D) 0 to initiate lung fibrosis. Mice received pirfenidone (300 mg/kg) or nintedanib (60 mg/kg) by daily gavage from D9 to D23. Mice underwent successive PET/CT imaging at several stages of the disease (baseline, D8/D9, D15/D16, D22/D23) with [18F]FDG and [18F]FMISO. Histological determination of the lung expression of HIF-1α and GLUT-1 was performed at D23. Results: We demonstrate that mean lung density on CT as well as [18F]FDG and [18F]FMISO uptakes are upregulated in established lung fibrosis (1.4-, 2.6- and 3.2-fold increase respectively). At early stages, lung areas with [18F]FMISO uptake are still appearing normal on CT scans and correspond to areas which will deteriorate towards fibrotic lesions at later timepoints. Nintedanib and pirfenidone dramatically and rapidly decreased mean lung density on CT as well as [18F]FDG and [18F]FMISO lung uptakes (pirfenidone: 1.2-, 2.9- and 2.6-fold decrease; nintedanib: 1.2-, 2.3- and 2.5-fold decrease respectively). Early [18F]FMISO lung uptake was correlated with aggressive disease progression and better nintedanib efficacy. Conclusion: [18F]FMISO PET imaging is a promising tool to early detect and monitor lung fibrosis progression and therapy efficacy. [ABSTRACT FROM AUTHOR]

Introduction: Thiopental is a thiobarbiturate given in the case of brain injuries to reduce intracranial pressure and to manage cerebral ischemia. A pharmacokinetic model has been described previously in critically ill patients with a different therapeutic strategy. New treatment options prompted us to investigate if drug-drug interactions occur. A new model is proposed describing the influence of concomitant administration of esomeprazole on the distribution of thiopental. Method: The study population comprised 52 critically ill patients (body weight 47.1-114 kg) aged 18-78 years who had been admitted into the critical care unit for treatment of intracranial hypertension. A total mean dose of 282.8 ± 172.7 mg/kg was given in 96 ± 72 h. Pharmacokinetic analysis was performed by using a nonlinear mixed-effect population model. Result: A one-compartment open model with first-order elimination identified two covariates, namely, body weight on clearance and volume of distribution, and the administration of esomeprazole on volume of distribution. The mean values (% relative standard error) for total clearance (CL) and for central volume of distribution (V) in patients with and without concomitant esomeprazole were 5.3 L/h (9.2 %) and 256.1 (6.4 %) and 153.2 l (19.2 %), respectively. Conclusion: Based on these results, we conclude that concomitant administration of esomeprazole increases the volume of distribution and the half-live of thiopental. This drug-drug interaction should be considered when a target concentration has to be reached. [ABSTRACT FROM AUTHOR]

The present study aimed to assess the effects of a COX-2 inhibitor, celecoxib, a HMG-CoA reductase inhibitor, atorvastatin, and the association of both on monocrotaline (MC)-induced pulmonary hypertension in rats. Celecoxib (Cib, 25 mg kg−1 day−1), atorvastatin (AS, 10 mg kg−1 day−1) or vehicle, were given orally, separately or in combination, for 26 days to Wistar male rats injected or not with MC (60 mg/kg intraperitoneally). At 4 weeks, MC-injected rats developed a severe pulmonary hypertension, with an increase in lung to body weight ratio (L/BW), right ventricular pressure (RVP in mmHg, 31 ± 3 and 14 ± 1 for MC and control groups, respectively, P < 0.05) and right ventricle/left ventricle + septum weight ratio (RV/LV+S) associated with a decrease in acetylcholine- and sodium-nitroprusside-induced pulmonary artery vasodilation in vitro. Hypertensive pulmonary arteries exhibited an increase in wall thickness (wall thickness to external diameter ratio, 0.42 ± 0.01 vs 0.24 ± 0.01 for MC and control groups, respectively, P < 0.001). Whole lung eNOS expression was decreased, and an increase in apoptosis, evaluated by cleaved caspase-3 expression, was evidenced by Western blotting. Cib (RVP in mmHg, 19 ± 3 and 31 ± 3 for MC+Cib and MC groups, respectively, P < 0.05), but neither AS nor AS+Cib significantly limited the development of pulmonary hypertension ( P < 0.05), although the three treatments exhibited protective effects against MC-induced lung and right ventricle hypertrophy evaluated by L/BW and RV/(LV+S) ratios, respectively ( P < 0.05). AS, Cib and AS+Cib treatments reduced MC-induced thickening of small intrapulmonary artery wall (0.42 ± 0.01, 0.24 ± 0.01, 0.26 ± 0.01 and 0.28 ± 0.01 for MC, MC+AS, MC+Cib and MC+AS+Cib groups, respectively, P < 0.001). In control rats, Cib reduced acetylcholine-induced pulmonary artery vasorelaxation. Treatment of MC rats by either Cib or AS did not modify acetylcholine-induced pulmonary artery relaxation, whereas combination of both drugs significantly worsened it ( P < 0.05). AS, but neither Cib nor the combination of both, prevented apoptosis (AS, P < 0.05) and partially restored eNOS expression (AS, P < 0.05) in whole lung of MC rats. In conclusion, celecoxib exhibited beneficial effects against the development of monocrotaline-induced pulmonary artery hypertension and right ventricular hypertrophy. These beneficial effects of celecoxib might be, at least partly, explained by its effects on pulmonary artery thickening and pulmonary hypertrophy, even if it did not show any effect on pulmonary artery vasorelaxation and whole lung eNOS expression or apoptosis. The combination of celecoxib and atorvastatin was unable to prevent MC-induced pulmonary hypertension, decreased endothelium-dependent vasorelaxation and showed a trend toward an increased in RVP that deserves further studies. [ABSTRACT FROM AUTHOR]

Hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, so called statins, improve endothelial function and exert antiproliferative effects on vascular smooth muscle cells of systemic vessels. This study aimed at comparing the protective effects of two statins, pravastatin and atorvastatin, against monocrotaline (MC)-induced pulmonary hypertension in rats. Pravastatin or atorvastatin (PS or AS, 10 mg/kg per day) or vehicle were given orally for 28 days to Wistar male rats injected or not with MC (60 mg/kg intraperitoneally). At 4 weeks, MC-injected rats developed severe pulmonary hypertension, with an increase in right ventricular pressure (RVP) and right ventricle/left ventricle + septum weight ratio associated with a decrease in acetylcholine- or sodium-nitroprusside-induced pulmonary artery dilation observed in vitro. Hypertensive pulmonary arteries exhibited an increase in medial thickness and endothelial cell apoptosis and a decrease of endothelial nitric oxide synthase (eNOS) expression. MC-rat lungs showed a significant decrease of eNOS ( P < 0.01) and increase of cleaved caspase-3 ( P < 0.05) expression determined by Western blotting. PS ( P = 0.02) but not AS ( P = 0.30) significantly limited the development of pulmonary hypertension (RVP in mmHg: 30 ± 3, 36 ± 4 vs. 45 ± 4 and 14 ± 1 for MC + PS, MC + AS, MC, and control groups, respectively). Both statins significantly reduced MC-induced right ventricle hypertrophy [RV/left ventricular (LV) + S, in mg/g: 0.46 ± 0.04, 0.39 ± 0.03, 0.62 ± 0.05 and 0.29 ± 0.01 for MC + PS, MC + AS, MC, and control groups, respectively; P < 0.05),and reduced MC-induced thickening (61 ± 6 μm, 82 ± 5 μm, 154 ± 4 μm, and 59 ± 2 μm for MC + PS, MC + AS, MC, and control groups, respectively; P = 0.01) of small intrapulmonary artery medial wall, with MC + AS still being different from the control group. PS but not AS partially restored acetylcholine-induced pulmonary artery vasodilation in MC rats (Emax=65 ± 5%, 49 ± 6%, 46 ± 3%, and 76 ± 4% for MC + PS, MC + AS, MC, and control groups, respectively; P < 0.05 for MC + PS vs. other groups). Both statins prevented apoptosis and restored eNOS expression of pulmonary artery endothelial cells as well as in the whole lung with a more pronounced effect with PS compared with AS. In conclusion, despite its effects on eNOS expression, apoptosis, and medial wall thickening, AS was unable to significantly reduce pulmonary hypertension and to restore endothelium-dependent relaxation, suggesting intermolecular differences between the two HMG-CoA reductase inhibitors in the protection against MC-induced hypertension. [ABSTRACT FROM AUTHOR]

HMG-CoA reductase inhibitors improve endothelial function and exert antiproliferative effects on vascular smooth muscle cells of systemic vessels. This study was aimed to assess the protective effects of pravastatin (an HMG-CoA reductase inhibitor) against monocrotaline-induced pulmonary hypertension in rats. Pravastatin (PS, 10 mg/kg/day) or vehicle were given orally for 28 days to Wistar male rats injected or not with monocrotaline (MC, 60 mg/kg intraperitonealy) and treated or not by Nω-nitro-L-arginine methyl ester (L-NAME) 15 mg/kg/day. At 4 weeks, monocrotaline-injected rats developed severe pulmonary hypertension, with an increase in right ventricular pressure (RVP) and right ventricle/left ventricle+septum weight ratio (RV/LV+S), associated with a decrease in pulmonary artery dilation induced either by acetylcholine or sodium nitroprusside. Hypertensive pulmonary arteries exhibited an increase in medial thickness, medial wall area, endothelial cell apoptosis, and a decrease of endothelial nitric oxide synthase (eNOS) expression. Monocrotaline-rat lungs showed a significant decrease of eNOS expression (4080±27 vs 12189±761 arbitrary density units [ADU] for MC and control groups respectively, P<0.01) and a significant increase of cleaved caspase-3 expression by western blotting (Control=11628±2395 vs MC=2326±2243 ADU, P<0.05). A non-significant trend toward a reduced mortality was observed with pravastatin (relative risk of death = 0.33; 95% confidence interval [0.08-1.30], P=0.12 for MC+PS vs MC groups). Pravastatine induced a protection against the development of the pulmonary hypertension (RVP in mmHg: 30±3 vs 45±4 and RV/LV+S: 0.46±0.04 vs 0.62±0.05 for MC+PS and MC groups respectively, P<0.05) and was associated with a significant reduction of MC-induced thickening (61±6 μm vs 81±3 μm for MC+PS and MC groups respectively, P=0.01) of the medial wall of the small intrapulmonary arteries. Pravastatin partially restored acetylcholine-induced pulmonary artery vasodilation in MC rats (Emax=65±5% and 46±3% for MC+PS and MC group respectively, P<0.05) but had no effect on acetylcholine-induced pulmonary artery vasodilation in MC+L-NAME rats. It also prevented apoptosis and restored eNOS expression of pulmonary artery endothelial cells, as well as in the whole lung. Pravastatin reduces the development of monocrotaline-induced pulmonary hypertension and improves endothelium-dependent pulmonary artery relaxation, probably through a reduced apoptosis and a restored eNOS expression of endothelial cells. [ABSTRACT FROM AUTHOR]