Prodrugs to Improve the Oral Bioavailability of a Diacidic Nonpeptide Angiotensin II Antagonist

DMP 811 is a diacidic angiotensin II antagonist. It has relatively low oral bioavailability in rats. A prodrug approach to improving oral bioavailability was tested. Five esters were synthesized and their stability in rat plasma in vitro was determined. The hydrolysis rates of these five esters ranged from almost immediate to negligible. A simple n-propyl ester was hydrolyzed very slowly (< 10% in 24 hr) in rat plasma in vitro, and after oral dosing in rats plasma prodrug concentrations were much greater than DMP 811 concentrations. A pivaloyloxymethyl ester (1) was hydrolyzed relatively rapidly in rat plasma in vitro. Prodrug 1 was rapidly hydrolyzed by the intestine in vitro, and the intestinal permeation of DMP 811 was increased. DMP 811 oral bioavailability was 47% in rats dosed with 10 mg/kg 1, compared to 11% for rats dosed with 10 mg/kg DMP 811. However, DMP 811 bioavailability was only 27% after a 2 mg/kg dose of 1. In vitro plasma hydrolysis of 1 was highly species-dependent, with a half-life of 13 hr in human plasma but only 1 min in rat plasma. The prodrug approach has potential for improving the oral bioavailability of DMP 811, but selection of the optimal prodrug must be done in humans or in a species, such as dogs, with hydrolysis characteristics closer to humans.     

Cyclophilin inhibitors in hepatitis C viral infection

Cyclophilins (Cyps) are proteins that are ubiquitously present with peptidyl-prolyl cis-trans isomerase activity and play an important role in de novo protein folding and in isomerization of native proteins in several cellular systems. There is growing evidence that indicates CypB is a positive modulator of the HCV RNA-dependent RNA polymerase in the replication complex. Early in vitro and animal data with selective Cyp inhibitors show a potent anti-HCV effect. This anti-HCV effect was confirmed in the first patient study with the selective Cyp inhibitor Debio-025. Preclinical data suggest that Cyp inhibitors may present a higher barrier to the selection of resistance than protease and polymerase inhibitors and that a combination of Cyp inhibitors with either of these drugs or interferon results in additive or synergistic anti-HCV activity. By interfering at the level of host–viral interaction, Cyp inhibition may open the way for a novel approach to anti-HCV treatment that could be complementary, not only to interferon-based treatment, but also to future treatments that directly target HCV replication enzymes such as protease and polymerase inhibitors.     

Heterogeneous Expression of Programmed Death Receptor-ligand 1 on Circulating Tumor Cells in Patients With Lung Cancer

BackgroundBlockade of the programmed death receptor-1 (PD-1) pathway is effective against solid tumors including lung cancer. PD-ligand 1 (PD-L1) expression on tumor tissue serves as a predictive biomarker for the efficacy of PD-1 pathway blockade. Here, we evaluated the expression of PD-L1 on circulating tumor cells (CTCs) in patients with lung cancer.Materials and MethodsPeripheral whole blood (3 mL) was collected from patients, and CTCs and PD-L1 expression were detected using a microcavity array (MCA) system. Immunohistochemistry for PD-L1 detection was also performed using matched tumor tissues.ResultsSixty-seven patients with lung cancer were enrolled in the study between July 2015 and April 2016 at Wakayama Medical University Hospital. The characteristics of the patients were as follows: median age, 71 years (range, 39-86 years); male, 72%; stage II to III/IV, 14%/85%; non–small-cell lung cancer/small-cell lung cancer/other, 73%/21%/6%. CTCs were detected in 66 of 67 patients (median, 19; range, 0-115), and more than 5 CTCs were detected in 78% of patients. PD-L1-expressing CTCs were detected in 73% of patients, and the proportion score of PD-L1-expressing CTCs ranged from 3% to 100%, suggesting intra-patient heterogeneity of PD-L1 expression on CTCs. Tumor tissues were available from 27 patients and were immunostained for PD-L1, and no correlation was observed between tumor tissues and CTCs based on the proportion score (R² = 0.0103).ConclusionPD-L1 expression was detectable on CTCs in patients with lung cancer, and intra-patient heterogeneity was observed. No correlation was observed between PD-L1 expression in tumor tissues and CTCs.     

Pharmacologically induced changes in wall thickening dynamics and mid-ventricular volumes in dogs assessed by prospectively gated computed tomography

Assessment of regional wall thickening dynamics is important for monitoring the response of normal and ischemic myocardium to pharmacologic interventions. Because regional wall thickness can be measured on computed tomographic (CT) scans of the heart, the ability of electrocardiogram-gated computed tomography to determine the effects of pharmacologic agents on global and segmental left ventricular (LV) function was assessed. Eight conditioned dogs were studied at a control state and during drug-induced changes in contractility and loading conditions brought about by the use of isoproterenol (0.15 μg/kg/min), phenylephrine (0.3 μg/kg/min), and verapamil (0.2 mg/kg infused over 10 minutes). Ten contrast-enhanced CT slices (1 cm thick) at the same mid-LV level were reconstructed for each 10% of the R-R interval throughout an average cardiac cycle using prospectively gated CT scans. End-diastolic and end-systolic frames were selected and analyzed for the following: septal, apical, and lateral wall thickness, percent wall thickening, end-diastolic and end-systolic mid-LV volume, and percent change in mid-LV volume.

During control, end-diastolic and end-systolic LV wall thicknesses (in millimeters) were 12 ± 2 and 15 ± 2 for the septal wall, 8 ± 1 and 11 ± 2 for the apical wall, and 10 ± 1 and 12 ± 1 for the lateral wall, respectively. The percent thickening in these respective segments was 24 ± 8, 36 ± 10, and 28 ± 13. The control end-diastolic and end-systolic mid-LV volumes were 16 ± 3 and 12 ± 3 ml, resulting in a percent change of 27 ± 7%. Phenylephrine induced significant thinning of the walls and impairment of systolic thickening, whereas isoproterenol induced opposite effects. Verapamil produced a significant decrease in mean blood pressure (123 ± 9 versus 99 ± 23 mm Hg, p < 0.025), but end-diastolic wall thicknesses were mildly thicker or showed no change and end-systolic wall thicknesses showed no change compared with those in the control state. Similarly, mid-LV volumes and percent change in mid-LV volumes were not different from those during control. Thus, electrocardiogram-gated computed tomography can be used to assess the effects of pharmacologic interventions on global and segmental LV function.