Effect of Hepatic Impairment on the Pharmacokinetics of Grazoprevir, a Hepatitis C Virus Protease Inhibitor.

Grazoprevir (GZR) plus elbasvir is an approved treatment for chronic infection with hepatitis C virus (HCV) genotype 1 or 4. HCV infection complications include liver cirrhosis, end-stage liver disease, and hepatocellular carcinoma. The objective of this study was to evaluate the pharmacokinetics and safety of multiple-dose GZR (200, 100, or 50 mg) in non-HCV participants with mild, moderate, or severe hepatic impairment (HI), respectively, and in healthy matched controls (protocol MK-5172_p013; Merck & Co., Inc., Kenilworth, NJ). Participants with mild, moderate, or severe HI and controls (aged 18 to 65 years) matched for race, age, sex, and body mass index were enrolled in a 3-part, open-label, sequential-panel pharmacokinetic study. Participants received oral doses of GZR 200 mg (two 100-mg tablets), 100 mg (one 100-mg tablet), or 50 mg (two 25-mg tablets) once daily for 10 days. A total of 50 participants were enrolled: 8 with mild HI, 9 with moderate HI, 8 with severe HI, and a corresponding number of healthy matched controls for each hepatic cohort. Participants with HI demonstrated higher GZR exposure than healthy matched controls and showed an increase in exposure with increasing HI severity. The steady-state GZR AUC0-24 (area under the concentration-time curve from 0 to 24 h) for participants with mild, moderate, or severe HI was ≈2-, ≈5-, or ≈12-fold higher, respectively, than that for healthy matched controls. GZR was generally well tolerated in participants with HI. No dose adjustment is required for GZR in people with HCV with mild HI. GZR is contraindicated for those with moderate or severe HI (Child-Pugh class B or C), since they may have significantly increased GZR exposures that may lead to an increased risk of transaminase elevation.

Marine heatwaves modulate the genotypic and physiological responses of reef-building corals to subsequent heat stress.

Back-to-back marine heatwaves in 2016 and 2017 resulted in severe coral bleaching and mortality across the Great Barrier Reef (GBR). Encouragingly, some corals that survived these events exhibit increased bleaching resistance and may represent thermally tolerant populations that can better cope with ocean warming. Using the GBR as a natural laboratory, we investigated whether a history of minimal (Heron Island) or severe (Lizard Island) coral bleaching in 2016 and 2017 equates to stress tolerance in a successive heatwave (2020). We examined the genetic diversity, physiological performance, and trophic plasticity of juvenile (<10 cm) and adult (>25 cm) corals of two common genera (Pocillopora and Stylophora). Despite enduring greater cumulative heat stress (6.3°C week-1 vs. 5.6°C week-1), corals that experienced the third marine heatwave in 5 years (Lizard) exhibited twice as high survival and visual bleaching thresholds compared to corals that had not experienced significant bleaching in >10 years (Heron). Surprisingly, only one shared host-Symbiodiniaceae association was uncovered between locations (Stylophora pistillata-Cladocopium "C8 group") and there was no genetic overlap in Pocillopora-Cladocopium partnerships, suggesting turnover in species composition from recent marine heatwaves. Corals within the species complex Pocillopora that survived the 2016 and 2017 marine heatwaves at Lizard Island were the most resilient, exhibiting three times greater calcification rates than conspecifics at Heron Island. Further, surviving corals (Lizard) had distinct isotopic niches, lower host carbon, and greater host protein, while conspecifics that had not experienced recent bleaching (Heron) had two times greater symbiont carbon content, suggesting divergent trophic strategies that influenced survival (i.e., greater reliance on heterotrophy vs. symbiont autotrophy, respectively). Ultimately, while corals may experience less bleaching and survive repeated thermal stress events, species-specific trade-offs do occur, leaving open many questions related to the long-term health and recovery of coral reef ecosystems in the face of intensifying marine heatwaves.

Inorganic carbon uptake strategies in coralline algae: Plasticity across evolutionary lineages under ocean acidification and warming.

Dissolved inorganic carbon (DIC) assimilation is essential to the reef-building capacity of crustose coralline algae (CCA). Little is known, however, about the DIC uptake strategies and their potential plasticity under ongoing ocean acidification (OA) and warming. The persistence of CCA lineages throughout historical oscillations of pCO2 and temperature suggests that evolutionary history may play a role in selecting for adaptive traits. We evaluated the effects of pCO2 and temperature on the plasticity of DIC uptake strategies and associated energetic consequences in reef-building CCA from different evolutionary lineages. We simulated past, present, moderate (IPCC RCP 6.0) and high pCO2 (RCP 8.5) and present and high (RCP 8.5) temperature conditions and quantified stable carbon isotope fractionation (13ε), organic carbon content, growth and photochemical efficiency. All investigated CCA species possess CO2-concentrating mechanisms (CCMs) and assimilate CO2 via diffusion to varying degrees. Under OA and warming, CCA either increased or maintained CCM capacity, which was associated with overall neutral effects on metabolic performance. More basal taxa, Sporolithales and Hapalidiales, had greater capacity for diffusive CO2 use than Corallinales. We suggest that CCMs are an adaptation that supports a robust carbon physiology and are likely responsible for the endurance of CCA in historically changing oceans.

Demonstration of a genetic therapeutic index for tumors expressing oncogenic BRAF by the kinase inhibitor SB-590885.

Oncogenic BRAF alleles are both necessary and sufficient for cellular transformation, suggesting that chemical inhibition of the activated mutant protein kinase may reverse the tumor phenotype. Here, we report the characterization of SB-590885, a novel triarylimidazole that selectively inhibits Raf kinases with more potency towards B-Raf than c-Raf. Crystallographic analysis revealed that SB-590885 stabilizes the oncogenic B-Raf kinase domain in an active configuration, which is distinct from the previously reported mechanism of action of the multi-kinase inhibitor, BAY43-9006. Malignant cells expressing oncogenic B-Raf show selective inhibition of mitogen-activated protein kinase activation, proliferation, transformation, and tumorigenicity when exposed to SB-590885, whereas other cancer cell lines and normal cells display variable sensitivities or resistance to similar treatment. These studies support the validation of oncogenic B-Raf as a target for cancer therapy and provide the first evidence of a correlation between the expression of oncogenic BRAF alleles and a positive response to a selective B-Raf inhibitor.

A Single-Dose Bioequivalence and Food Effect Study With Aprepitant and Fosaprepitant Dimeglumine in Healthy Young Adult Subjects.

Fosaprepitant dimeglumine, a lyophilized prodrug, is rapidly converted to aprepitant, a substance P/neurokinin 1 (NK1 ) receptor antagonist. Intravenous (IV) fosaprepitant and oral aprepitant are used in combination with other antiemetics to prevent chemotherapy-induced nausea and vomiting. This randomized, phase 1 study was designed to assess the aprepitant area under the curve (AUC0-∞ ) equivalence of a single, oral 165-mg or 185-mg dose of aprepitant to a single 150-mg fosaprepitant IV dose infused over 20 minutes, and to evaluate the effect of food on the bioavailability of the oral 165-mg and 185-mg aprepitant doses. Plasma samples were analyzed for aprepitant, and linear mixed-effects models were applied to natural log-transformed aprepitant AUC data. A 2 one-sided tests procedure was used to evaluate bioequivalence; the adjusted P values for the AUC0-∞ of both oral doses versus the IV dose were < .05, supporting the hypothesis that each single, oral dose of aprepitant is equivalent to the AUC0-∞ of a single IV infusion of fosaprepitant. Food effect results suggest that dose adjustment would not be necessary with a single oral dose of aprepitant. Single-dose administration of oral 165 mg and 185 mg aprepitant and IV 150 mg fosaprepitant was generally well tolerated.

Orally active 4-amino-5-diarylurea-furo[2,3-d]pyrimidine derivatives as anti-angiogenic agent inhibiting VEGFR2 and Tie-2.

During our effort to develop dual VEGFR2 and Tie-2 inhibitors as anti-angiogenic agents for cancer therapy, we discovered 4-amino-5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)- aminocarbonylamino)phenyl)furo[2,3-d]pyrimidine (8a) possessing strong inhibitory activity at both the enzyme and cellular level against VEGFR2 and Tie-2. Compound 8a demonstrated high pharmacokinetic exposure through oral administration, and showed marked tumor growth inhibition and anti-angiogenic activity in mouse HT-29 xenograft model via once-daily oral administration.