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Allisartan isoproxil (AI) is an angiotensin II type 1 receptor blocker and be converted into the active substance EXP3174 in vivo. We evaluated the drug–drug interactions of AI and an indapamide sustained‐release (Ind SR) preparation, as well as the pharmacokinetic characteristics and safety of AI and Ind SR in healthy subjects. The trial was set up in 6 sequences and 3 cycles, and each cycle contained a 7‐day washout period. Subjects received 3 different trial drugs (A, AI; B, Ind SR; C, AI + Ind SR) during 3 different cycles. Twenty‐four subjects were enrolled in the clinical trial. Of these, 22 completed the study, 2 subjects dropped out due to adverse events (AEs). For subjects given AI alone or combined with Ind SR, the pharmacogenetic parameters Cmaxand the geometric mean ratio of steady state (combined/single) of EXP3174 was 130%. The geometric mean ratio of area under the concentration–time curve over the dosing interval at steady state (combined/single use) was 144.5%. Therefore, the combination of Ind SR had an impact on the pharmacokinetics of AI. Then, the results indicated that the AI combination had no effect on the pharmacokinetics of Ind SR. Serious AEs did not occur. The AEs in this clinical trial were the same as those for AI and Ind SR. Combined administration resulted in 2 cases (2 subjects) of Grade 3 hypotension and 1 case of Grade 3 hypotension with AI alone. Considering that this trial included healthy volunteers, the risk of hypotension was expected to be manageable.

Allisartan isoproxil (AI) is a blocker of the angiotensin II type 1 receptor. We evaluated the safety and pharmacokinetics of single‐ and multiple‐dose AI in healthy Chinese individuals. Participants were assigned to receive AI or placebo. Plasma concentration of EXP3174 (carboxylic acid derivative) was measured using liquid chromatography‐tandem mass spectrometry. Pharmacokinetic parameters were determined by noncompartmental methods. Twelve subjects were enrolled, and the ratio of men to women was 5:1. Main pharmacokinetic parameters of EXP3174 after single and multiple doses of AI were a mean maximum concentration in plasma (Cmax) of 2242 ± 1037 ng/mL and median time to reach Cmax(Tmax) of 3.5 hours (2.5‐8 hours). The median Tmax,at steady state was 4.0 hours (1.5‐8 hours). The mean Cmaxat steady state (Cmax, SS) was 2047 ± 1050 ng/mL. In terms of EXP3174, there was no significant difference in the Cmax, SS, area under the curve from time zero to 24 hours of quantifiable concentration at steady state (AUC0–24 SS), and AUC0‐72after multiple doses of AI. Serious adverse events did not occur. These data suggest that AI is safe and well tolerated in healthy Chinese individuals at a single dose of 480 or 480 mg once daily for 7 days.

Acute liver failure (ALF) is a relatively rare liver disorder that leads to the massive death of hepatocytes. Our previous study reported that a novel small-molecule agent, (E)-5-(2,4-di-tert-butyl-6-((2,4-dioxothiazolidin-5-ylidene)methyl)phenyl)-5'-methyl-7,7'-dimethoxy-4,4'-bibenzo[d][1,3]dioxole-5,5'-dicarboxylate (7k), possessed potent anti-inflammatory activity. In the present study, we further evaluated the therapeutic effects of 7k on lipopolysaccharide (LPS)-induced ALF and investigated the mechanisms of action. Our results demonstrated that 7k inhibited the migration of RAW264.7 macrophages, blocked the activity of nuclear factor-κB protein, and dose-dependently down-regulated the production of interleukin (IL)-1β, tumor necrosis factor-α, and IL-6 as well as their corresponding mRNAs in RAW264.7 cells. Oral administration of 7k at a dose of 50 mg/kg significantly suppressed the serum level of enzyme activity and prevented the damage of liver tissue in D-galactosamine/LPS-induced ALF. Treatment with 7k also remarkably blocked the increase in the number of CD11b(+)- and CD68(+)-positive cells in the liver, and in vivo nuclear factor-κB activity, known to regulate inflammatory responses in many cell types, was effectively inhibited. The serum concentrations and hepatic mRNA expression of proinflammatory cytokines tumor necrosis factor-α, IL-1β, and IL-6 were markedly down-regulated in mice by the treatment of 7k. In summary, 7k alleviated the development and progression of D-galactosamine/LPS-induced ALF by inhibiting macrophage infiltration and regulating the expression of cytokines.

Abstract: Using the limit point formula of the Loop subdivision scheme, we propose a very simple and efficient method for constructing interpolation surface of triangular meshes by Loop subdivision scheme. The excellent properties of the method are: (1) Locality: the perturbation of a given vertex only influences the surface shape near this vertex. (2) Efficiency: the locations of new points can be computed with explicit formulae. (3) Easiness in implementation: only the geometric rule of the first step should be modified. (4) Freedom: for each edge, there is one degree of freedom to adjust the shape of the interpolation surface. (5) Easiness in generalization: it is easy to generalize our method to other approximation subdivision schemes with explicit formulae to compute limit point.