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153. J Anim Sci. 2017 Sep;95(9):4018-4029. doi: 10.2527/jas2017.1522. Effects of a multi-strain Bacillus spp. direct-fed microbial and a protease enzyme on growth performance, nutrient digestibility, blood characteristics, fecal microbiota, and noxious gas emissions of grower pigs fed corn-soybean-meal-based diets-A meta-analysis. Payling L, Kim IH, Walsh MC, Kiarie E. Three studies involving 352 grower pigs were conducted to determine the effects of dietary supplementation with multistrain spp. direct-fed microbial (DFM) and protease, alone or in combination, on growth performance, nutrient digestibility, blood characteristics, fecal microbiota, and noxious gas emissions, and to use a meta-analysis to increase the reliability of the findings. Treatments ( = 4) were set up as a 2 × 2 factorial design with 2 levels of protease (0 and 5.000/6.000 units/kilogram of feed [U/KG]) and 2 levels of DFM (0 and 1.5 × 10 colony forming units/gram of feed [CFU/G]), plus a protease + DFM combination. Pigs were housed in groups of 3 or 4/pen with 8 replicate pens/treatment. Experimental diets were fed for 42 d and feed intake and BW were measured weekly. Fecal samples were collected at d 42 and analyzed to determine apparent total tract digestibility (ATTD). Fecal counts of and coliforms, and noxious gas emissions were measured. Blood samples were taken by anterior vena cava puncture to measure blood urea nitrogen (BUN) and creatinine. Data from the 3 studies were pooled and analyzed as a 2 × 2 factorial using the Fit Model platform of JMP 11 (SAS Inst. Inc., Cary, NC). Means separation was determined using Tukey's honest significant difference test. The main effect of protease and DFM increased: BW at 42 d, overall ADG, and overall G:F compared to the control ( < 0.04). There were no interactions between protease and DFM ( > 0.05); however, the protease + DFM combination was the only treatment to improve ADG and G:F in all phases compared to the control. The main effect of protease increased ATTD of DM, nitrogen (N), and ADF ( < 0.04). The main effect of DFM increased ATTD of DM, N, GE, DE, ADF, and fat ( < 0.02). There was a trend for an interaction between protease and

OBJECTIVE: As antiretroviral therapy (ART) expands for HIV-infected children, it is important to determine its impact on growth. We quantified growth and its determinants following ART in resource-limited (RLS) and developed settings. DESIGN: Systematic review and meta-analysis. METHODS: We searched publications reporting growth [weight-for-age (WAZ), height-for-age (HAZ), and weight-for-height (WHZ) z scores] in HIV-infected children following ART through August 2014. Inclusion criteria were as follows: younger than 18 years; ART; at least 20 patients; growth at ART; and post-ART growth. Standardized and overall weighted mean differences were calculated using random-effects models. RESULTS: A total of 67 articles were eligible (RLS = 54; developed settings = 13). Mean age was 5.8 years, and comparable between settings (P = 0.90). Baseline growth was substantially lower in RLS vs. developed settings (WAZ -2.1 vs. -0.5; HAZ -2.2 vs. -0.9; both P < 0.01). Rate of weight but not height reconstitution during 12 and 24 months was higher in RLS (12-month WAZ change 0.84 vs. 0.17, P < 0.01). Growth deficits persisted in RLS after 2 years ART (P = 0.04). Younger cohort age was associated with greater growth reconstitution. Protease inhibitor and nonnucleoside reverse-transcriptase inhibitor regimens yielded comparable growth. Adjusting for age and setting, cohorts with nutritional supplements had greater growth gains (24-month rate difference: WAZ 0.55, P = 0.03; HAZ 0.60, P = 0.007). Supplement benefits were attenuated after adjusting for baseline cohort growth. CONCLUSION: RLS children had substantial growth deficits compared with developed settings counterparts at ART; growth shortfalls in RLS persisted despite reconstitution. Earlier age and nutritional supplementation at ART may improve growth outcomes. Scant data on supplementation limit evaluation of impact and underscores need for systematic data collection regarding supplementation in pediatric ART programmes/cohorts.

Hepcidin is the central regulator of iron homeostasis, controlling iron sequestration and dietary iron absorption. Transmembrane serine protease 6 (TMPRSS6) suppresses hepcidin via the bone morphogenetic protein/small mothers against decapentaplegic (BMP/SMAD) pathway by cleaving the co-receptor hemojuvelin. DISC-3405 is a novel humanized monoclonal antibody that enhances hepcidin expression by inhibiting TMPRSS6, thereby promoting iron restriction. This Phase 1 study evaluated the safety/tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and immunogenicity of DISC-3405 or placebo in 56 healthy participants. DISC-3405 (37.5 to 300 mg) or placebo was administered subcutaneously (SC) or intravenously (IV). DISC-3405 was well tolerated. No deaths, serious adverse events, or participant discontinuations occurred. Most treatment-emergent adverse events were Grade 1 (mild) in severity, with 2 participants reporting Grade 2 (moderate) events following single dosing and no Grade 3/4 (severe/life-threatening) events reported. Median time to maximum plasma concentration was ≈96 to 168 h. Elimination half-life rose from 130 h at 37.5 mg to 265 h at 300 mg, with a clinically relevant half-life of ≈11 days. Absolute bioavailability was 39.7% (75 mg SC vs. IV). Minor accumulation occurred with repeat 4-week dosing of two doses, and PK was greater than dose proportional. DISC-3405 increased hepcidin-25 and reduced serum iron and transferrin saturation across dose levels. Single and repeated dosing of DISC-3405 produced reductions in reticulocyte hemoglobin, hemoglobin, and hematocrit. Overall, DISC-3405 was well tolerated with PK/PD data supporting further development for patients who could benefit from iron restriction, such as those with polycythemia vera. © 2026 American College of Clinical Pharmacology.

BACKGROUND: A randomized phase II screening trial of gemcitabine, nab-paclitaxel, and cisplatin with a medically supervised ketogenic diet (MSKD) versus usual diet (non-MSKD) was conducted in patients with treatment-naive metastatic pancreatic ductal adenocarcinoma (PDAC). METHODS: Patients with untreated metastatic PDAC were randomized 1:1 to MSKD or non-MSKD while receiving gemcitabine, nab-paclitaxel, and cisplatin on days 1 and 8 of a 21-day cycle. The MSKD was guided by a remote health care team and daily ketone (beta-hydroxybutyrate) levels, with goal beta-hydroxybutyrate of 0.5 to 3.0 mM. The primary endpoint was progression-free survival (PFS) using a one-sided alpha level of 0.20. Secondary endpoints included overall survival (OS), safety, and quality of life (QOL). Changes in microbiome were an exploratory endpoint. FINDINGS: Overall, there were 32 evaluable patients. In the MSKD arm, 15 of 16 patients achieved nutritional ketosis; the median proportion of days in ketosis was 39.4%. The median PFS was 8.5 months in MSKD patients and 6.2 months in non-MSKD patients: hazard ratio, 0.53 (95% CI, 0.21-1.37); one-sided p = .096. The median OS was 13.7 months with MSKD and 10.2 months in the non-MSKD arm: hazard ratio, 0.58 (95% CI, 0.25-1.37); one-sided p = .107). All MSKD-related adverse events were grade 1-2. There were no significant differences in grade ≥3 chemotherapy-related adverse events between the arms. MSKD patients had no decline in QOL and had significant enrichment of beneficial taxa in the microbiome (p < .05, log-fold change ≥2). CONCLUSIONS: The MSKD is feasible in patients with PDAC and, although not powered for definitive outcomes, shows trends in improved PFS and OS when combined with gemcitabine, nab-paclitaxel, and cisplatin, without added toxicity or detriment to QOL. Larger studies are required to confirm these findings and establish the value of the MSKD in pancreatic cancer treatment. © 2026 The Author(s). Cancer published by Wiley Periodicals LLC on behalf of American Cancer Society.

BACKGROUND: Children and adolescents with HIV have lower treatment success than adults. Suboptimal adherence and resistance to antiretroviral therapy (ART) are known aetiological factors. This preplanned analysis in the GIVE MOVE trial (NCT04233242) describes drug resistance patterns in children and adolescents in Lesotho and Tanzania. MATERIALS AND METHODS: GIVE MOVE randomized children and adolescents (6 months to below 19 years) with recent viraemia whilst taking ART to genotypic resistance testing (GRT)-informed care or usual care. Here, we conducted additional post-hoc GRT on stored samples from both groups and included participants with at least one successful resistance test. We assessed the number of drugs predicted to be active in participants' three-drug ART regimens and resistance-associated mutations. RESULTS: Amongst 137 participants, the majority were female (58%) and lived in Lesotho (77%). At their initial GRT, 69/137 (50%) were receiving protease inhibitor-based, 59/137 (43%) dolutegravir-based and 9/137 (7%) efavirenz-based ART. At that time, 80/137 (58%) participants had three, whilst 8/137 (6%) had two, 36/137 (26%) had one and 13/137 (9%) had no drugs predicted to be active in their regimens. Seventeen (12%) participants had resistance against their ART core agent, including one with high-level dolutegravir resistance.Across 312 detected resistance-associated mutations (222 major, 90 accessory), 146 conferred resistance to non-nucleoside reverse transcriptase inhibitors, 127 to nucleoside reverse transcriptase inhibitors, 28 to protease inhibitors and 11 to integrase strand transfer inhibitors. CONCLUSION: Given that more than half had an ART regimen predicted to be fully active, most viraemia in children and adolescents could not be explained by resistance.Registration: The GIVE MOVE trial was registered on Clinicaltrials.gov NCT04233242. © The Author(s) 2026. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy.

The objective of this study was to evaluate the potential applications of low-molecular-weight collagen peptides (LMWCPs), produced through enzymatic hydrolysis of fish skin-derived gelatin using a specific protease. LMWCP is enriched in Gly-X-Y tripeptide sequences, particularly Gly-Pro-Hyp (GPH). Preliminary human pharmacokinetic data showed that oral LMWCP markedly increased systemic exposure to GPH, yielding an approximately 54-fold higher area under the concentration-time curve from 0 to 2 h (3388 ± 1084 ng·h/mL) than general collagen. In a subsequent randomized, placebo-controlled trial, 114 women aged 20-50 years with thigh cellulite and self-reported hair thinning received either LMWCP (1000 mg/day) or placebo for 24 weeks. Efficacy endpoints included cellulite severity, dermal-subcutaneous border length, skin roughness, skin elasticity, and hair diameter. The LMWCP group demonstrated significant improvements in cellulite severity, dermal-subcutaneous border length, skin roughness, and skin elasticity at weeks 12 and 24 compared to the placebo group. Hair diameter also increased significantly at week 24, with a larger proportion of participants in the LMWCP group exhibiting measurable hair thickening. These findings indicate that LMWCP, characterized by high GPH content and enhanced systemic exposure resulting from targeted enzymatic hydrolysis, exerts beneficial effects on both skin and hair parameters. Daily intake of LMWCP for 24 weeks effectively reduces thigh cellulite and promotes hair thickness, supporting its potential as an orally administered functional ingredient for skin and hair health.

BACKGROUND AND PURPOSE: Overactivation of the alternative pathway (AP) underlies several diseases. Iptacopan is an oral, first-in-class, highly potent specific inhibitor of factor B, a key AP protease. EXPERIMENTAL APPROACH: The analysis included data from two phase 1 randomised, volunteer-blinded, placebo-controlled studies: Study 1, a single ascending dose (SAD; 5-400 mg), multiple ascending dose (MAD; 25-200 mg twice daily), and food effect study of iptacopan in healthy volunteers; Study 2, a SAD (25-400 mg) study of iptacopan in healthy Japanese males. The objectives were to evaluate the safety and tolerability of iptacopan, and the pharmacokinetics/pharmacodynamics of SAD and MAD doses. KEY RESULTS: In Study 1 (n = 100) and Study 2 (n = 30), iptacopan was rapidly absorbed; pharmacokinetic variability was low, with a half-life between 18.4 and 25.0 h across steady-state MAD doses, and iptacopan exhibited target-mediated drug disposition behaviour. Japanese and non-Japanese healthy volunteers had similar pharmacokinetics/pharmacodynamics. Food intake did not affect pharmacokinetics. Iptacopan 200 mg twice daily showed the highest and most persistent AP inhibition; ~67% AP inhibition remained 24 h after the last dose, while ex vivo classical complement pathway activation was not impaired. This dose also provided the highest proportion of volunteers achieving EC90 values for the complement biomarkers Wieslab® assay in serum, plasma Bb and sC5b-9. Iptacopan was well tolerated across doses. CONCLUSIONS AND IMPLICATIONS: These results characterise the pharmacokinetics/pharmacodynamics of iptacopan in healthy volunteers; the data helped build semi-mechanistic population pharmacokinetic/pharmacodynamic models, which guided the accelerated clinical development of iptacopan. © 2026 The Author(s). British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.

BACKGROUND: Doravirine and islatravir is an investigational, once-daily, single-tablet regimen containing two potent antiretrovirals with complementary mechanisms of action and resistance profiles. We aimed to evaluate the efficacy and safety of switching from stable, oral antiretroviral therapy (ART) to the fixed combination of doravirine (100 mg) and islatravir (0·25 mg) in virologically suppressed adults living with HIV-1. METHODS: This phase 3, randomised, active-controlled, open-label, non-inferiority trial was conducted at 53 research, community, and hospital-based clinics in eight countries: Australia, Canada, Colombia, Japan, South Africa, Switzerland, the UK, and the USA. Adults (aged ≥18 years) with a viral load of fewer than 50 copies of HIV-1 RNA per mL on any oral, two-drug or three-drug ART regimen for at least 3 months, with no history of treatment failure, known resistance to doravirine, or active hepatitis B infection, were randomly assigned (2:1) according to a computer-generated randomisation schedule (block size three) to receive oral doravirine (100 mg) and islatravir (0·25 mg) once daily or to continue baseline ART for 48 weeks. Randomisation was stratified by the anchor antiretroviral drug class (integrase strand-transfer inhibitor [INSTI], non-nucleoside reverse transcriptase inhibitor, or protease inhibitor) in the baseline regimen. The primary endpoint (assessed in all treated participants) was the percentage of participants with a viral load of 50 copies per mL or higher at week 48 (analysed according to the US Food and Drug Administration snapshot approach); non-inferiority would be concluded if the upper bound of the multiplicity-adjusted 95% CI for the treatment difference was less than 4%. The safety analysis population included all randomly assigned participants who received at least one dose of study treatment. The trial is registered at ClinicalTrials.gov, NCT05631093, and is ongoing but closed to enrolment. FINDINGS: Between Feb 20 and Oct 24, 2023, 614 individuals were screened for eligibility, of whom 553 were randomly assigned to receive doravirine and islatravir (n=368) or baseline ART (n=185). 551 participants received at

BACKGROUND: ODYSSEY trial showed superior efficacy of dolutegravir-based antiretroviral therapy (ART) versus then-current, non-dolutegravir standard of care over 96 weeks in children and adolescents living with HIV. The aim of this ancillary analysis was to compare anthropometric and body composition outcomes, including weight, height, BMI-for-age Z score, weight-for-age and height-for-age Z scores (<14 kg), mid-upper-arm circumference (MUAC), waist circumference, hip circumference, and body fat percentage, as well as metabolic outcomes (lipids and glucose), between dolutegravir and standard of care over approximately 5 years of follow-up. METHODS: In this open-label, randomised, non-inferiority trial, children (aged ≥4 weeks and <18 years), weighing 3 kg or more, starting first-line ART (ODYSSEY-A) or switching to second-line ART (ODYSSEY-B) were enrolled in 29 centres in Germany, Portugal, South Africa, Spain, Thailand, Uganda, Zimbabwe, and the UK in two cohorts (children weighing ≥14 kg and children weighing <14 kg). Treatment effects (dolutegravir vs standard of care) were estimated on randomised allocation, accounting for treatment switches (substantial in standard of care arm during extended follow-up) through censoring and inverse-probability-of-censoring-weights. Changes in continuous outcomes were compared using linear mixed models, accounting for correlated slope and baseline value. Proportions of participants with unfavourable outcomes were compared using logistic mixed models. ODYSSEY is registered with ClinicalTrials.gov, NCT02259127, EUDRACT, 2014-002632-14, and ISRCTN, ISRCTN91737921. FINDINGS: Between Sept 20, 2016, and Aug 26, 2019, 792 children were randomly assigned (392 to dolutegravir and 400 to standard of care). Of 707 children in the 14 kg or more cohort, 311 received first-line ART (ODYSSEY-A; 145 [92%] of 157 received efavirenz-based ART as standard of care) and 396 received second-line ART (ODYSSEY-B; 195 [98%] of 200 received boosted protease inhibitors as standard of care). Of 85 children in the less than 14 kg cohort, 72 received first-line ART (32 [74%] of 43 received lopinavir-ritonavir as first-line or second-line standard of ca

ASP1617 is a novel, highly selective inhibitor of cathepsin-S, an important protease for antigen peptide loading onto major histocompatibility complex class II molecules. Preclinically, ASP1617 prevented progression of lupus-like glomerulonephritis in an NZB/W F1 mouse model of systemic lupus erythematosus. In this double-blind, randomized, placebo-controlled, first-in-human study in healthy subjects, ASP1617 was generally well tolerated. Treatment-emergent adverse events of rash and throat tightness were reported in two subjects receiving the highest doses of 110 mg BID in multiple ascending dose (MAD) cohorts, leading to withdrawal of ASP1617 in both subjects. Mean elimination half-life was 10.4-15.9 h in single ascending dose (SAD) cohorts and 13.7-20.5 h in MAD cohorts. ASP1617 exposure increased slightly greater than dose proportionally between SAD cohorts and dose proportionally between MAD cohorts and was similar between Japanese and non-Asian subjects. A high-fat, high-calorie meal slightly decreased peak and total exposure and delayed absorption. Both single and multiple dosing of ASP1617 led to rapid and maximal inhibition (> 80% at 3 h post-dose) of cathepsin-S activity as well as the downstream increase of invariant chain p10 (Lip10) in B cells, indicating target engagement. However, in all MAD cohorts, cathepsin-S activity gradually rebounded during treatment, surpassing baseline levels after the last dose, and cathepsin-S mass increased significantly, fivefold above baseline, and prolonged after treatment. Due to the observed safety events, induction of the cathepsin-S target, and gradual loss of pharmacodynamic effects during repeated dosing, appropriate mitigation strategies are necessary for the further clinical development of ASP1617. Trial Registration: ClinicalTrials.gov Identifier: NCT04077879. © 2026 The Author(s). Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.

BACKGROUND: To date, clinical trials have been underpowered to assess which antiretrovirals perform best in people with advanced HIV disease. We aimed to investigate the efficacy and safety of an integrase inhibitor-containing versus a boosted protease inhibitor-containing regimen for this population. METHODS: In this open-label, multicentre, non-inferiority trial in seven European countries (Spain, France, Italy, Germany, Belgium, Ireland, and the UK), therapy-naive adults with advanced HIV disease were randomly allocated (1:1) to receive either bictegravir, emtricitabine, and tenofovir alafenamide (integrase inhibitor group) or darunavir, cobicistat, emtricitabine, and tenofovir alafenamide (boosted protease inhibitor group) for 48 weeks. Randomisation was computer generated in permuted blocks within strata with block sizes of four and stratified by country and baseline CD4 cell count. The primary composite outcome (time to first occurrence of specified virological or clinical events) and its components were evaluated by Kaplan-Meier and Cox regression analyses in both modified intention-to-treat (mITT) and per-protocol populations. The mITT population included all randomly allocated participants who received at least one dose of the study drug, whereas the per-protocol population excluded those who received incorrect treatment. Non-inferiority of the integrase inhibitor-based regimen versus the boosted protease inhibitor-containing regimen was declared if the upper limit of the 95% CI of the hazard ratio (HR) for the primary composite endpoint was less than 1·606, corresponding to a 12% difference in the cumulative probability of the composite primary endpoint. Adverse events, a secondary endpoint, were recorded at eight visits in all participants. This trial is registered with ClinicalTrials.gov, NCT03696160, and is completed. FINDINGS: Between May 13, 2019, and June 26, 2023, 222 people were randomly assigned to the integrase inhibitor group and 225 to the boosted protease inhibitor group. Of these 447 recruited participants, 442 (99%) participants with a median CD4 count of 41 cells per μL (IQR 17-79) received at least one dose. 358 (81%) of the 442 treate

BACKGROUND: Dietary unsaturated fat, protein, and carbohydrate have well-established effects on HDL (high-density lipoprotein) cholesterol levels, but whether these effects are connected causally to coronary heart disease (CHD) has been called into question. Protein-based minor HDL subspecies are emerging as novel and likely causal biomarkers, direct or inverse, for risk of CHD, diabetes, and other conditions. HDL-raising drugs such as CETP (cholesteryl ester transfer protein) inhibitors raise certain HDL subspecies that have adverse effects on CHD risk. We hypothesize that dietary unsaturated fat, protein, and carbohydrate differentially affect 15 minor protein-based HDL subspecies with diverse functionality in lipid metabolism, antioxidation, immunity, hemostasis, and protease inhibition. METHODS: We analyzed the apo (apolipoprotein) A1 concentrations of 15 minor HDL subspecies after 4 weeks on each diet in 141 participants in the OmniHeart trial (Optimal Macronutrient Intake Trial to Prevent Heart Disease), a randomized 3-period crossover, controlled feeding study. The diet rich in carbohydrate contained 58% carbohydrate, 27% fat, and 15% protein, and the diets rich in unsaturated fat and protein replaced 10% of carbohydrate with unsaturated fat or protein, respectively. RESULTS: Unsaturated fat replacing dietary carbohydrate increased concentrations of apoA1 in lipid metabolism subspecies including HDL that contains apoA2, apoE, or apoC1 that has been associated with reduced risk of CHD. Protein replacing carbohydrate increased apoE HDL, consistent with lower CHD risk, and decreased concentrations of several other HDL subspecies that were associated with higher risk of CHD including HDL that contains PLMG (plasminogen), A2M (alpha-2-macroglobulin), or apoL1. Network analysis showed connections between functional groups of HDL subspecies that are quantitatively affected by dietary macronutrients. CONCLUSIONS: Replacing dietary carbohydrate with unsaturated fat or protein raised levels of protein-based HDL subspecies associated with lower risk of CHD or lowered the levels of those associated with higher risk of CHD. Minor HDL subspecies with diverse functions

RATIONALE: Non-small cell lung cancer (NSCLC) continues to impose a significant global mortality burden, due to limited therapies, drug resistance, and treatment-related toxicity. Exosomes offer promise for the targeted delivery of therapeutic agents. METHODS: Exosomes were isolated from bovine colostrum and characterized for size, polydispersity index, and surface charge. Celastrol (CEL) was loaded onto exosomes (ExoCEL), and Folic Acid (FA)-functionalized exosomes (FA-ExoCEL) and validated using fluorescence quenching and protease sensitivity assay. Anticancer activity was assessed in NSCLC cell lines using colony formation, cell migration and uptake assays. Transcriptomic (RNA-seq) and protein analysis were performed to analyze gene expression changes. Biodistribution, oral uptake and potential toxicity were evaluated in wild-type mice, while oral antitumor efficacy was tested in orthotopic lung tumor models comparing CEL, ExoCEL and FA-ExoCEL. Synergistic activity with paclitaxel was assessed in chemoresistant cells. RESULTS: Exosomes were isolated, characterized and efficiently loaded with CEL. ExoCEL demonstrated superior antiproliferative effects in NSCLC cell lines and enhanced potency in drug-resistant A549TR cells compared to free CEL. ExoCEL significantly inhibited colony formation and cell migration in a dose-dependent manner. RNA Seq and protein analyses showed that CEL and ExoCEL reversed TGF-β-induced EMT, restored epithelial markers, suppressed mesenchymal, oncogenic and extracellular matrix related markers. In orthotopic lung tumor models, FA-ExoCEL achieved approximately 80-90% tumor inhibition, outperforming both free CEL and ExoCEL. Oral delivery of FA-ExoCEL resulted in efficient gastrointestinal uptake, selective tumor targeting, recovery of exosomal markers in circulation and no observed systemic toxicity. CEL exhibited strong synergy with paclitaxel, with exosomal delivery further enhancing paclitaxel efficacy in resistant cells. CONCLUSIONS: FA-ExoCEL represents a safe, scalable, and effective oral therapeutic strategy for NSCLC. By combining exosome-mediated delivery with folate-targeted tumor accumulation, this platform enhances CEL bi

14. Neotrop Entomol. 2026 Apr 15;55(1):29. doi: 10.1007/s13744-026-01377-8. Synergistic Action of Alpha-cypermethrin, Propolis Nanoemulsions and Other Activator Adjuvants for Peach Fruit Fly, Bactrcera zonata Management. Romeh AA(1), El-Nagar HM(2), Romeh ZAA(1), Ismail AM(3), Al-Kahtani SN(4),

Rhodesain is a cysteine protease that plays a key role in the life cycle of Trypanosoma brucei rhodesiense, an endemic parasite in sub-Saharan Africa and responsible for Human African Trypanosomiasis (HAT), a disease that can be fatal if not treated promptly. Due to the limitations associated with current HAT pharmacological therapy, the search for new targets for the development of antitrypanosomal agents is urgently needed; in this context, rhodesain represents a promising therapeutic target. In this study, new chalcones were synthesized and tested against rhodesain. Given their affinity for the trypanosomal cysteine protease (Ki values in the micromolar range), chalcone 1a was selected to evaluate its effect in combination with the nutraceutical curcumin. The Combination Index (CI) was calculated using Chou and Talalay's method. The analysis of the CI calculated at different fa values of enzyme inhibition for the combination curcumin + 1a showed promising results. For all fa values, the CI is less than one, indicating a synergistic effect when chalcone 1a is combined with curcumin. In particular, at the most significant fa value (0.90), corresponding to 90% of enzyme inhibition, the CI value is 0.1781, indicating a strong synergism between the synthetic drug and the nutraceutical. The combined use of curcumin and chalcone 1a led to an enhancement of rhodesain inhibitory activity, resulting in a strong synergistic effect and supporting further investigation of this combination.

BACKGROUND: Solid organ transplantation (SOT) in patients living with HIV (PLWH) has transitioned from a relative contraindication to standard practice following the widespread use of effective antiretroviral therapy (ART). Although patient and graft survival increasingly parallel those of HIV-negative recipients, optimizing immunosuppressive therapy-particularly tacrolimus-remains a major clinical challenge in this population. OBJECTIVES: This review examines the mechanisms and clinical consequences of ART-tacrolimus drug-drug interactions, evaluates the role of therapeutic drug monitoring (TDM), and highlights emerging strategies to improve attainment of target tacrolimus trough levels in PLWH undergoing transplantation. CONTENTS: Tacrolimus has a narrow therapeutic index and is highly susceptible to cytochrome P450 3A4-mediated interactions with ART, especially protease inhibitor- and cobicistat-based regimens. These interactions often necessitate extreme dose reductions, result in marked pharmacokinetic variability, and complicate maintenance of stable trough concentrations. Subtherapeutic exposure is associated with increased rejection risk, whereas supratherapeutic levels increase nephrotoxicity and infection. While integrase strand transfer inhibitor-based regimens reduce interaction burden, many PLWH remain on boosted ART, underscoring the importance of intensive TDM. This review also discusses tacrolimus formulation choice as a modifiable factor, with growing evidence supporting liquid tacrolimus to enable micro-dose titration and improve time in therapeutic range. Emerging pharmacometric approaches, including population pharmacokinetic modeling and Bayesian dosing, offer additional opportunities for precision immunosuppression. IMPLICATIONS: Optimizing tacrolimus exposure-rather than HIV status itself-is central to transplant outcomes in PLWH. Integrating ART-informed dosing, formulation flexibility, and advanced TDM strategies may reduce variability, improve graft outcomes, and inform future guideline development for this expanding transplant population. © 2026 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

The continuous evolution of coronaviruses compromises the efficacy of existing therapeutic antibodies and replication inhibitors, necessitating antiviral strategies that are resilient to viral escape. Distinct from conventional antibody cocktails that remain vulnerable to spike protein mutations, we evaluated a multi-mechanistic therapy targeting three discrete stages of the viral life cycle: receptor binding, membrane fusion, and viral replication. Using pseudotyped and authentic human coronaviruses (HCoVs), including SARS-CoV-2 and HCoV-OC43, in cell culture models, we demonstrated that combining the pan-coronavirus fusion inhibitor EK1 with a receptor-binding domain-specific broadly neutralizing antibody (bnAb) and/or a main protease (Mpro) inhibitor yields synergistic inhibition. Collectively, our findings establish a conceptual framework for a trident antiviral regimen that theoretically restricts the evolutionary space for viral escape, although clinical translation will require optimizing delivery strategies to reconcile the distinct pharmacokinetic profiles of these agents.IMPORTANCEThe continuous emergence of highly transmissible and immune-evasive SARS-CoV-2 variants highlights an urgent need for broad-spectrum antiviral approaches capable of countering rapid viral evolution and future coronavirus outbreaks. Here, we designed a dual- or triple-stage antiviral strategy centered on the membrane fusion inhibitor EK1, in combination with a receptor-binding domain-targeting antibody and/or a small-molecule viral replication inhibitor (Mpro inhibitor). In cell culture models, our results demonstrate marked synergy between EK1 and the antibody and/or the replication inhibitor. These combinations not only enhance antiviral potency but are also anticipated to maintain efficacy against emerging variants. By targeting non-overlapping stages of the viral life cycle, this approach theoretically raises the genetic barrier to resistance. While clinical translation will require reconciling the distinct pharmacokinetic profiles of these components, our study provides a conceptual framework for developing a trident anti-coronavirus therapy.

The COVID-19 pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has underscored the need for broad and potent antiviral agents. Although overall disease severity has diminished, the persistent risk of reinfection highlights the continued demand for novel therapeutic options. In this study, we performed an image-based high-throughput screening campaign of 11,030 small molecules-including nucleoside analogs, known antivirals, and diverse bioactives-to identify inhibitors of SARS-CoV-2 infection. Using an immunofluorescence assay that quantified viral proteins and assessed cell viability by Hoechst nuclear staining, we identified 97 primary hits in infected Vero cells. Dose-response evaluation confirmed 18 compounds active against both ancestral and Omicron variants, and subsequent validation in human lung cell lines (A549-hACE2-TMPRSS2 and Calu-3) highlighted multiple cysteine protease inhibitors as strong antiviral candidates. Among these, MG-101 emerged as a potent cysteine protease inhibitor with favorable pharmacokinetics, metabolic stability, and robust in vivo antiviral efficacy. Docking analysis and enzymatic assays demonstrated that MG-101 inhibits the SARS-CoV-2 3CL protease, and combination studies revealed in vitro synergistic antiviral activity with remdesivir. Together, these findings establish MG-101 as a potential therapeutic lead for COVID-19 and illustrate the value of image-based high-throughput screening for accelerating antiviral drug discovery.

PURPOSE OF REVIEW: To summarize recent advances in drug-resistant tuberculosis (DR-TB) treatment for people with HIV (PWH), including drug-drug interactions, investigational medications and host-directed therapy, as well as emerging evidence on novel treatment regimens, post-TB complications, and DR-TB medication resistance among PWH. RECENT FINDINGS: Treatment for DR-TB has evolved to shorter, all-oral regimens with reduced drug-drug interactions. However, emerging dolutegravir resistance may necessitate protease inhibitor-based ART regimens resulting in interactions that complicate DR-TB management. Investigational TB medications including BTZ-043, sutezolid, and delpazolid demonstrate promising bactericidal activity in early phase trials. Several clinical trials have demonstrated the efficacy of 6-9 month DR-TB regimens and have included PWH; however, all successful shortened regimens currently contain bedaquiline, which limits options for PWH in areas with emerging bedaquiline resistance. While treatments targeting Mycobacterium tuberculosis are the mainstay of treatment, host-directed therapy is being evaluated both as an intervention for treatment and for the prevention of immune reconstitution inflammatory syndrome and post-tuberculosis lung disease. SUMMARY: Treatment options for DR-TB have improved dramatically with less toxic, more effective regimens, but managing HIV-associated DR-TB continues to require careful attention to drug-drug interactions and HIV related co-morbidities. Research into novel DR-TB regimens, especially for people with bedaquiline resistance, and host-directed therapies are critical to realize continued improvement in HIV-associated DR-TB outcomes.

Urokinase plasminogen activator receptor-associated protein (uPARAP) is a collagen-internalizing receptor with emerging relevance as a therapeutic target. The involvement of uPARAP in extracellular matrix turnover and stromal remodeling within the tumor microenvironment (TME) makes it an especially promising target in tumors with a high stromal component. Mesothelioma, characterized by its unique complex TME, is a highly refractory cancer type for which no effective targeted therapy exists. uPARAP has been shown to be expressed across all subtypes of mesothelioma, especially in the sarcomatoid and biphasic subtypes, suggesting that a uPARAP-targeted therapy may benefit a specific patient population. In this study, we utilized an antibody-drug conjugate (ADC) comprising an anti-uPARAP mAb conjugated to monomethyl auristatin E via a protease-sensitive linker for preclinical studies on mesothelioma treatment. Using mouse xenograft models with a human mesothelioma cell line or a patient-derived mesothelioma cell isolate, we demonstrated a strong anticancer effect following treatment with the uPARAP-targeting ADC. IHC studies revealed this to be the case, even in tumors exhibiting a heterogeneous expression of uPARAP, suggesting that uPARAP-expressing cancer-associated fibroblasts also play a role in the anticancer effect through a bystander mechanism. Furthermore, we show that combination treatment with cisplatin, commonly used in first-line mesothelioma therapy, leads to a strongly enhanced anticancer effect relative to treatment with either drug alone. Our study demonstrates the potential utility of a uPARAP-targeted ADC as a therapeutic option for mesothelioma, alone or in combination with chemotherapeutics. This perspective is particularly emphasized by a recently initiated clinical trial with a humanized anti-uPARAP ADC for the treatment of other malignancies. SIGNIFICANCE: This study highlights the translational promise of a uPARAP-targeted ADC for the treatment of mesothelioma, a cancer lacking effective therapies. Demonstrating potent preclinical efficacy and synergy with cisplatin, our findings support the clinical advancement of a uPARAP-directed ADC strat

BACKGROUND: Resistance to docetaxel (DTX), a frontline chemotherapeutic agent for prostate cancer (PC), remains a major therapeutic challenge, often driven by impaired apoptosis and enhanced metastatic potential. Calebin A (CA), a natural polyphenol derived from turmeric, has demonstrated anticancer properties in various malignancies. This study investigated the individual and combined effects of CA and DTX on proliferation, apoptosis, cell cycle progression, migration, and gene expression in human PC3 prostate cancer cells. METHODS: PC3 cells were treated with varying concentrations of CA and DTX, alone or in combination. Cell viability was assessed using the MTT assay, and drug interactions were evaluated using the combination index (CI) analysis. Flow cytometry was employed to analyze apoptosis and cell cycle distribution. Gene expression of Bax, Bcl-2, MMP-2, and MMP-9 was quantified using qRT-PCR, while gelatin zymography and wound healing assays evaluated protease activity and migratory behavior, respectively. RESULTS: Both CA and DTX exhibited time- and dose-dependent cytotoxicity, with combination treatment producing synergistic effects (CI < 1). Co-treatment significantly increased apoptotic cell populations and induced marked sub-G1 and G2/M cell cycle arrest. The combination therapy upregulated the pro-apoptotic Bax/Bcl-2 ratio and downregulated MMP-2 expression, with modest reductions in MMP-2 and MMP-9 enzymatic activities. Furthermore, migratory capacity was significantly diminished under combinatorial treatment compared to monotherapies. CONCLUSION: CA enhances the antitumor efficacy of DTX by potentiating apoptosis, inhibiting migration, and modulating gene expression associated with metastasis and survival. These findings suggest CA as a promising adjuvant to overcome chemoresistance and improve therapeutic outcomes in prostate cancer. © 2025. The Author(s), under exclusive licence to Tehran University of Medical Sciences.

BackgroundRAY1216 is an alpha-ketoamide-based peptide inhibitor of severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) major protease (Mpro). This study evaluated the absorption, distribution, metabolism and excretion of [14C]-labelled RAY1216 by oral administration.Research design and methodsThis phase Ι study was designed to assess the pharmacokinetics, mass balance and metabolic pathways in 6 healthy Chinese adult men after a single fasting oral administration of 240 mL (containing 400 mg/100 μCi) [14C] RAY1216.ResultsRAY1216 absorbed rapidly in the plasma, with a Cmax of 1796.83 ng/mL, tmax of 1.42 h and t1/2 of 5.97 h. RAY1216 is mainly excreted through feces and a small amount through urine, indicating that the excretion of RAY1216 occurs through the fecal route, within 96 h after administration, the majority (>90%) of the radioactive substances were excreted 104.17% of the metabolites were identified in urine and fecal samples. The radioactive transformation pathways suggest that RAY1216 has multiple metabolic pathways, including Oxidation-dealkylation, Mono-oxidation, Hydrolysis, and Urea binding. There were no reports of death, serious adverse events (SAEs), or withdrawals related to SAEs.ConclusionThe overall recovery rate data of radioactive substances in the excreta of all 6 subjects indicate that favourable mass balance recovery. The overall safety profile is favourable, and it demonstrates promising potential in mitigating both the duration and severity of COVID-19, and the comprehensive clinical safety and therapeutic effect are significantly superior to those of similar COVID-19 treatment drugs. RAY1216 can be referred to and further verified for the Phase II and Phase III clinical trials for the treatment of COVID-19.

BACKGROUND: In the REPRIEVE trial of statin therapy in people with HIV, pitavastatin reduced major adverse cardiovascular events (MACE) among those with low-to-moderate risk of cardiovascular disease (CVD). We aimed to investigate associations between former and current use of antiretroviral therapy (ART) on entry into the REPRIEVE trial and the development of MACE. METHODS: This longitudinal cohort analysis was a prespecified secondary analysis of the REPRIEVE trial, a double-blind, placebo-controlled, multicentre, phase 3 randomised trial conducted at 137 sites in 12 countries. REPRIEVE enrolled people with HIV aged 40-75 years, currently on ART, with a CD4 count of more than 100 cells per μL and low-to-moderate CVD risk, and randomly assigned them to receive pitavastatin or placebo. For this secondary analysis, participants' history of ART use, including lifetime exposure to selected agents, was collected at baseline. The primary outcome of interest was time-to-first MACE. Stratified Cox proportional hazards models were used to estimate the relative hazards of MACE associated with ART exposures. Effects of no previous exposure, former exposure, and current exposure to ART at entry to the study were compared using models unadjusted and adjusted for entry risk factors and ART regimen at entry. All analyses were conducted in the intention-to-treat population. The REPRIEVE trial is registered at ClinicalTrials.gov, NCT02344290, and is complete. FINDINGS: Between March 26, 2015, and July 31, 2019, 7769 participants were enrolled into the REPRIEVE trial. 2419 (31·1%) of 7769 participants were assigned female at birth and 5350 (68·9%) were assigned male at birth. 3208 (41·3%) of 7769 participants were Black or African American, 2704 (34·8%) were White, 1138 (14·6%) were Asian, and 719 (9·3%) were of other races. Participants had a median age of 50·0 years (IQR 45·0-55·0), LDL cholesterol concentration of 106 mg/dL (86-128), 10-year atherosclerotic cardiovascular disease risk score of 4·5% (2·1-7·0), and CD4 cell count of 621 cells per μL (448-827). 5867 (97·8%) of 5997 participants for whom data on this measure were available had an HIV-1 viral load of less than 400

BACKGROUND: Analyses of genomic and proteomics data in prospective biobank studies in diverse populations may discover novel or repurposing drug targets for stroke. METHODS: We extracted individual cis-protein quantitative trait locus for 2923 proteins measured using Olink Explore panel from a genome-wide association study in prospective China Kadoorie Biobank and UK Biobank, both established ≈20 years ago. These cis-protein quantitative trait loci were used in ancestry-specific 2-sample Mendelian randomization analyses of ischemic stroke (IS) in East Asians (n=22 664 cases) and Europeans (n=62 100 cases). We further undertook colocalization analyses to examine the shared causal variants of cis-protein quantitative trait locus with stroke, along with various downstream analyses (eg, phenome-wide association study, drug development lookups) to clarify mechanisms of action and druggability. RESULTS: In Mendelian randomization analyses, the genetically predicted plasma levels of 10 proteins were significantly associated with IS in East Asians (n=2) and Europeans (n=9), with 6 proteins (FGF5 [fibroblast growth factor 5], TMPRSS5 [transmembrane protease serine 5], FURIN, F11 [coagulation factor XI], ALDH2 [aldehyde dehydrogenase 2], and ABO [histo-blood group ABO system transferase]) showing positive and 4 (GRK5 [G protein-coupled receptor kinase 5], KIAA0319 [dyslexia-associated protein KIAA0319], PROCR [endothelial protein C receptor], and MMP12 [macrophage metalloelastase 12]) showing inverse associations, all directionally consistent between East Asians and Europeans. Colocalization analyses provided strong evidence (posterior probabilities for the H4 hypothesis ≥0.7) of shared genetic variants with IS for 9 out of 10 proteins (except ABO). Moreover, 8 proteins were also causally associated, in the expected directions, with systolic blood pressure (positive/inverse: 4/2), low-density lipoprotein cholesterol (1 positive), body mass index (1 inverse), type 2 diabetes (2/1), or atrial fibrillation (3/1). Phenome-wide association study analyses and lookups in knock-out mouse models confirmed their importance for IS or stroke-related traits (eg, hematologic phenotypes

This study evaluated the safety and pharmacokinetics (PK) of a single dose of leritrelvir, a novel inhibitor of 3-chymotrypsin-like cysteine protease (3CLpro), in patients with hepatic impairment versus healthy participants with normal hepatic function. Eight participants with mild (Child-Pugh A) hepatic impairment, eight with moderate (Child-Pugh B) hepatic impairment, and eight healthy matched control participants were enrolled in this open-label, parallel clinical trial. After administration of leritrelvir of 400 mg, PK parameters were calculated and compared across groups. In total, 24 participants were enrolled and completed the study. Leritrelvir was generally well tolerated, with no serious adverse events or deaths reported during the study. Compared to the group with normal hepatic function, the geometric least-squares mean ratios (90% confidence intervals) for Cmax, AUC0-t, and AUC0-∞ of leritrelvir in participants with mild hepatic impairment were 96.9% (69.3%, 135%), 92.2% (69.6%, 122%), and 92.1% (69.7%, 122%), respectively. For moderate hepatic impairment, the corresponding ratios were 91.6% (61.7%, 136%), 113% (80.0%, 160%), and 113% (80.0%, 159%). Leritrelvir exposures were comparable among the three groups. Overall, there was no clinically relevant difference in leritrelvir exposure in participants with hepatic impairment compared to normal controls. No dose adjustment is required for leritrelvir in patients with mild or moderate hepatic impairment.CLINICAL TRIALSThis study is registered with ClinicalTrials.gov as NCT06161259.

GST-HG171 is a potent, broad-spectrum, orally bioavailable small-molecule 3C-like (3CL) protease inhibitor that was recently approved for treating mild to moderate coronavirus disease 2019 patients in China. Since cytochrome P450 (CYP) enzymes, primarily CYP3A, are the main metabolic enzymes of GST-HG171, hepatic impairment may affect its pharmacokinetic (PK) profile. Aiming to guide clinical dosing for patients with hepatic impairment, this study, using a non-randomized, open-label, single-dose design, assessed the impact of hepatic impairment on the PK, safety, and tolerability of GST-HG171. Patients with mild and moderate hepatic impairment along with healthy subjects were enrolled (n = 8 each), receiving a single oral dose of 150 mg GST-HG171, with concurrent administration of 100 mg ritonavir to sustain CYP3A inhibition before and after GST-HG171 administration (-12, 0, 12, and 24 hours). Compared to subjects with normal hepatic function, the geometric least-squares mean ratios (90% confidence intervals) for GST-HG171's maximum plasma concentration (Cmax), area under the concentration-time curve up to the last quantifiable time (AUC0-t), and area under the plasma concentration-time curve from time 0 extrapolated to infinity (AUC0-∞) in subjects with mild hepatic impairment were 1.14 (0.99, 1.31), 1.07 (0.88, 1.30), and 1.07 (0.88, 1.29), respectively. For moderate hepatic impairment, the ratios were 0.87 (0.70, 1.07), 0.82 (0.61, 1.10), and 0.82 (0.61, 1.10), respectively. Hepatic impairment did not significantly alter GST-HG171's peak time (Tmax) and elimination half-life (T1/2). GST-HG171 exhibited good safety and tolerability in the study. Taken together, mild to moderate hepatic impairment minimally impacted GST-HG171 exposure, suggesting no need to adjust GST-HG171 dosage for patients with mild to moderate hepatic impairment in the clinic.Clinical TrialsRegistered at ClinicalTrials.gov (NCT06106113).

Ensitrelvir fumaric acid (Xocova® hereafter ensitrelvir) is a novel anti-SARS-CoV-2 drug for COVID-19. Hokkaido University and Shionogi & Co., Ltd. engaged in joint research targeting SARS-CoV-2 3C-like (3CL) protease at an early stage and started clinical trials in July 2021. In February 2022, an application was filed for manufacture and sales approval for the indication of "SARS-CoV-2 infection,". Ensitrelvir recieved the first emergency regulatory approval from the Ministry of Health, Labour and Welfare (MHLW) in Japan in November 2022, and has obtained standard approval in March 2024. This emergency approval was based on the confirmed safety in a Phase 2/3 study (T1221) conducted in Japan and other Asian countries (Korea and Vietnam) in patients with mild/moderate COVID-19 and the presumed efficacy in Phase 3 Part (SCORPIO-SR), and the standard approval is based on efficacy from the Phase 3 part. In the Phase 3 part, ensitrelvir administered orally 375/125 ‍mg once daily for five days, in patients with irrespective of risk factors for severe complications and vaccination status, demonstrating a significant reduction vs placebo in the time to resolution of five typical Omicron-related symptoms (stuffy or runny nose, sore throat, cough, feeling hot or feverish, and low energy or tiredness), and also showed a significant reduction in viral RNA on day 4 relative to placebo (P < 0.001). In the Phase 2/3 study, there were no serious adverse events or deaths, indicating good tolerability and safety. We hope that ensitrelvir will contribute as a new treatment option for patients suffering from COVID-19 symptoms.

ETHNOPHARMACOLOGICAL RELEVANCE: The rhizome of Dryopteris crassirhizoma Nakai (Dryopteridaceae, RDC), a traditional East Asian herbal medicine, possesses a broad spectrum of medicinal properties, including anti-inflammatory, anticancer, antibacterial, and antiviral activities. AIM OF THE STUDY: This study investigates the 30% ethanolic extract of RDC's antiviral potential against human coronavirus OC43 (HCoV-OC43), severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and its variants infections. MATERIALS AND METHODS: A 30% ethanolic extract of RDC or its components, filixic acid ABA (PubChem CID: 15081408) and dryocrassin ABBA (PubChem CID: 3082025) were treated with Human Coronavirus infection (HCoV-OC43, SARS-CoV-2 and its variants). The base peak chromatogram of RDC was evaluated using UPLC-Q/TOF Mass to identify the RDC, and the quantitative analysis of RDC compounds was performed using LC-MS/MS. A cytopathic effect (CPE) reduction assay, Western blot, immunofluorescence staining of viral protein expression, and qRT-PCR were performed to quantify the viral RNA copy numbers and determine the antiviral activity. The time-of-addition assay, the virus attachment, penetration, and virucidal assays, and SARS-CoV-2 Mpro and PLpro activity assay were used to elucidate the mode of action. RESULTS: RDC exhibited dose-dependent inhibition of HCoV-OC43-induced cytopathic effects, reducing viral RNA copy numbers and viral protein levels. Time-of-addition assays indicated that RDC targets the early stages of the HCoV-OC43 life cycle, inhibiting virion attachment and penetration with virucidal activity. Notably, filixic acid ABA and dryocrassin ABBA, constituents of RDC, reduced HCoV-OC43 viral RNA loads. Furthermore, RDC effectively blocked viral entry in pseudotyped lentivirus assays, involving spike proteins of SARS-CoV-2 Delta plus and South Africa variants, as well as control lentiviral particles expressing vesicular stomatitis virus glycoprotein G. Additionally, RDC demonstrated inhibition of SARS-CoV-2 infection and its variants by targeting viral proteases, namely main protease (Mpro) and papain-like protease (PLpro). CONCLUSIONS: These findings underscor

Comment in Korean J Intern Med. 2023 Jul;38(4):454-455. doi: 10.3904/kjim.2023.248. BACKGROUND/AIMS: Despite the availability of direct-acting antivirals (DAAs) for chronic hepatitis C virus (HCV) infection in Korea, need remains for pangenotypic regimens that can be used in the presence of hepatic impairment, comorbidities, or prior treatment failure. We investigated the efficacy and safety of sofosbuvir-velpatasvir and sofosbuvir-velpatasvir-voxilaprevir for 12 weeks in HCV-infected Korean adults. METHODS: This Phase 3b, multicenter, open-label study included 2 cohorts. In Cohort 1, participants with HCV genotype 1 or 2 and who were treatment-naive or treatment-experienced with interferon-based treatments, received sofosbuvir-velpatasvir 400/100 mg/day. In Cohort 2, HCV genotype 1 infected individuals who previously received an NS5A inhibitor-containing regimen ≥ 4 weeks received sofosbuvir-velpatasvir-voxilaprevir 400/100/100 mg/day. Decompensated cirrhosis was an exclusion criterion. The primary endpoint was SVR12, defined as HCV RNA < 15 IU/mL 12 weeks following treatment. RESULTS: Of 53 participants receiving sofosbuvir-velpatasvir, 52 (98.1%) achieved SVR12. The single participant who did not achieve SVR12 experienced an asymptomatic Grade 3 ASL/ALT elevation on day 15 and discontinued treatment. The event resolved without intervention. All 33 participants (100%) treated with sofosbuvir-velpatasvir-voxilaprevir achieved SVR 12. Overall, sofosbuvir-velpatasvir and sofosbuvir-velpatasvir-voxilaprevir were safe and well tolerated. Three participants (5.6%) in Cohort 1 and 1 participant (3.0%) in Cohort 2 had serious adverse events, but none were considered treatment-related. No deaths or grade 4 laboratory abnormalities were reported. CONCLUSION: Treatment with sofosbuvir-velpatasvir or sofosbuvir-velpatasvir-voxilaprevir was safe and resulted in high SVR12 rates in Korean HCV patients.

BACKGROUND: Management of drug-drug interactions (DDIs) for ensitrelvir, a novel 3-chymotrypsin-like protease inhibitor of SARS-CoV-2 infection is crucial. A previous clinical DDI study of ensitrelvir with midazolam, a clinical index cytochrome P450 (CYP) 3A substrate, demonstrated that ensitrelvir given for 5 days orally with a loading/maintenance dose of 750/250 mg acted as a strong CYP3A inhibitor. OBJECTIVES: The objectives of this study were to investigate the effect of ensitrelvir on the pharmacokinetics of CYP3A substrates, dexamethasone, prednisolone and midazolam, and to assess the pharmacokinetics, safety, and tolerability of ensitrelvir following multiple-dose administration of ensitrelvir. METHODS: This was a Phase 1, multicenter, single-arm, open-label study in healthy Japanese adult participants. The effects of multiple doses of ensitrelvir in the fasted state on the pharmacokinetics of dexamethasone, prednisolone, and midazolam were investigated. Ensitrelvir was administered from Day 1 through Day 5, with a loading/maintenance dose of 750/250 mg for the dexamethasone and prednisolone cohorts whereas 375/125 mg for the midazolam cohort. Either dexamethasone, prednisolone, or midazolam was administered alone (Day - 2) or in combination with ensitrelvir (Day 5) in each of the cohorts. Additionally, dexamethasone or prednisolone was administered on Days 9 and 14. The pharmacokinetic parameters of ensitrelvir, dexamethasone, prednisolone, and midazolam were calculated based on their plasma concentration data with non-compartmental analysis. In safety assessments, the nature, frequency, and severity of treatment-emergent adverse events were evaluated and recorded. RESULTS: The area under the concentration-time curve (AUC) ratio of dexamethasone on Day 5 was 3.47-fold compared with the corresponding values for dexamethasone alone on Day - 2 and the effect diminished over time after the last dose of ensitrelvir. No clinically meaningful effect was observed for prednisolone. The AUC ratio of midazolam was 6.77-fold with ensitrelvir 375/125 mg suggesting ensitrelvir at 375/125 mg strongly inhibits CYP3A similar to that at 750/250 mg. No new safety signals w