The observed in vitro and in vivo benefit of combination treatment with anti-human immunodeficiency virus (HIV) agents prompted us to examine the potential of resistance development when two protease ...inhibitors are used concurrently. Recombinant HIV-1 (NL4-3) proteases containing combined resistance mutations associated with BMS-186318 and A-77003 (or saquinavir) were either inactive or had impaired enzyme activity. Subsequent construction of HIV-1 (NL4-3) proviral clones containing the same mutations yielded viruses that were severely impaired in growth or nonviable, confirming that combination therapy may be advantageous. However, passage of BMS-186318-resistant HIV-1 (RF) in the presence of either saquinavir or SC52151, which represented sequential drug treatment, produced viable viruses resistant to both BMS-186318 and the second compound. The predominant breakthrough virus contained the G48V/A71T/V82A protease mutations. The clone-purified RF (G48V/A71T/V82A) virus, unlike the corresponding defective NL4-3 triple mutant, grew well and displayed cross-resistance to four distinct protease inhibitors. Chimeric virus and in vitro mutagenesis studies indicated that the RF-specific protease sequence, specifically the Ile at residue 10, enabled the NL4-3 strain with the triple mutant to grow. Our results clearly indicate that viral genetic background will play a key role in determining whether cross-resistance variants will arise.
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BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
Rencofilstat (RCF) demonstrated antifibrotic effects in preclinical models and was safe and well tolerated in Phase 1 studies. The aim of this Phase 2a study was safety, tolerability, ...pharmacokinetics, and exploration of efficacy biomarkers in subjects with nonalcoholic steatohepatitis (NASH). This Phase 2a, multicenter, single‐blind, placebo‐controlled study randomized 49 presumed F2/F3 subjects to RCF 75 mg once daily (QD), RCF 225 mg QD, or placebo for 28 days. Primary safety and tolerability endpoints were explored using descriptive statistics with post hoc analyses comparing active to placebo groups. Pharmacokinetics were evaluated using population pharmacokinetics methods. Efficacy was explored using biomarkers, transcriptomics, and lipidomics. RCF was safe and well tolerated, with no safety signals identified. The most frequently reported treatment‐emergent adverse events were constipation, diarrhea, back pain, dizziness, and headache. No clinically significant changes in laboratory parameters were observed, and RCF pharmacokinetics were unchanged in subjects with NASH. Alanine transaminase (ALT) reduction was greater in active subjects than in placebo groups. Nonparametric analysis suggested that ALT reductions were statistically different in the 225‐mg cohort compared with matching placebo: −16.3 ± 25.5% versus −0.7 ± 13.4%, respectively. ProC3 and C6M reduction was statistically significant in groups having baseline ProC3 > 15.0 ng/ml. RCF was safe and well tolerated after 28 days in subjects with presumed F2/F3 NASH. Presence of NASH did not alter its pharmacokinetics. Reductions in ALT, ProC3, and C6M suggest direct antifibrotic effects with longer treatment duration. Reductions in key collagen genes support a mechanism of action via suppression and/or regression of collagen deposition. Conclusion: These results support advancement of rencofilstat into a larger and longer Phase 2b study.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Rencofilstat (RCF) is a novel cyclophilin inhibitor under development for the treatment of nonalcoholic steatohepatitis and hepatocellular carcinoma. This phase 1, randomized, open‐label study in ...healthy participants assessed the relative bioavailability of a single dose of RCF 225‐mg soft gelatin capsules in both fasted and high‐fat conditions. Forty‐four participants were enrolled to either the fasted (n = 24) or the high‐fat fed (n = 20) arm. Noncompartmental pharmacokinetics were evaluated following a single 225‐mg oral dose. Administration of RCF with a high‐fat meal led to increases in maximum concentration, area under the concentration–time curve (AUC) from time 0 to 24 hours, and AUC from time 0 to infinity fed‐to‐fasted geometric mean ratios of 102.2%, 114.5%, and 132.9%, respectively. All AUC geometric mean ratios were outside of the 80% to 125% range, suggesting that a high‐fat meal can increase the extent of RCF exposure. Time to maximum concentration increased from 1.5 to 1.8 hours in the fasted and high‐fat groups, respectively, suggesting slightly delayed absorption. High fat intake may delay gastric emptying while increasing the absorption and bioavailability of RCF. No treatment‐emergent adverse events were observed in the fasted group, and 1 treatment‐emergent adverse event occurred in the high‐fat meal group. The differences in observed whole‐blood concentrations are unlikely to have clinically relevant effects given the wide therapeutic index of RCF demonstrated in previous phase 1 studies.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
A series of HIV protease inhibitors containing a novel C2 symmetrical "aminodiol" core structure were prepared from amino acid starting materials. The ability of the aminodiols to inhibit HIV ...replication in cell culture is comparable to their ability to inhibit the isolated enzyme, a result compatible with good cell membrane penetration by this class of compounds. Optimization of the structure-activity in this series led to aminodiol 9a (Ki = 100 nM; ED50 (HIV-1) = 80 nM) containing P1/P1 benzyl and P2/P2 Boc substituents. Compound 9a is a selective inhibitor of HIV protease versus other aspartyl proteases such as human renin, human cathepsin D, and porcine pepsin. In addition, 9a is equipotent against HIV-1 and HIV-2 in cell culture and demonstrates similar activity in infected T-lymphocytes and PBMCs. After i.v. and oral administration in rats, 9a displayed significant oral bioavailability (ca. 40%) and a promising plasma elimination half-life (4 h).
In this qualitative study, I examined the role of a leader’s emotional intelligence in creating sustainable, K-12 independent schools. Grounded in interpretive traditions defined as knowledge gained ...through social constructions such as language, consciousness, and shared meanings, I applied the theoretical framework for this study as the leadership theory regarding the use of emotional intelligence by school leaders in creating a financially sustainable organization. Emotional intelligence is defined as the ability to identify and manage one’s emotions and the emotions of others. For data collection, I conducted 45-60 minute interviews with 10 people who are characterized as emotionally intelligent leaders of independent K-12 schools in the northeast region of the United States. Further, I analyzed publicly available and relevant documents, including school websites, newsletters and annual reports. In analyzing the data, I applied the methods of Saldana in coding the transcribed interviews. Based on data analysis, I identified three themes that answer my research question. The themes include (a) being an authentic school leader, (b) forming a client relationship with constituents, and (c) understanding the school’s culture. Authentic school leaders are transparent, expert communicators, and predictable leaders. They form client relationships by making meaningful connections, building trust, and sharing a vision. They demonstrate that they understand their school's culture by listening to people, enhancing the school’s program, and successfully navigating school politics.
A series of novel aminodiol inhibitors of HIV protease based on the lead compound 1 with structural modifications at P1‘ were synthesized in order to reduce the cytotoxicity of 1. We have observed a ...high degree of correlation between the lipophilicity and the cytotoxicity of this series of inhibitors. It was found that appropriate substitution at the para position of the P1‘ phenyl group of 1 resulted in the identification of equipotent (both against the enzyme and in cell culture) compounds (10l, 10m, 10n, and 15c) which possess significantly decreased cytotoxicity.
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