Antiviral Therapy最新文献

Ebola virus is a member of the Filoviridae family, which causes hemorrhagic fever in primates, exhibiting a mortality rate that can reach up to 90%. The VP35 suppresses the host IFN-β/α production by disrupting the immune responses of the host during viral infection, making it a putative target for therapeutic intervention. Herein, the UMH SuperNatural II database was mined to identify prospective VP35 inhibitors employing advanced in silico approaches. Filtration of the UMH SuperNatural II database was first conducted based on drug-likeness features. These compounds were screened towards VP35, and those exhibiting docking scores lower than 1DK, a reference ligand, further underwent molecular dynamics simulations (MDS), followed by binding energy calculations. Upon the assessed binding energy throughout 200 ns MDS, UMHSN00005544 and UMHSN00005545 disclosed superior binding affinity against VP35 compared to 1DK, with ΔG_binding values of -35.5, -34.9, and -29.3 kcal/mol, respectively. Energetic and structural evaluations were conducted for the identified natural compounds in complex with VP35 over 200 ns MDS. Post-MD analyses demonstrated the significant constancy of the investigated complexes. RMSD values averaged 0.14, 0.13, and 0.12 nm for UMHSN00005544, UMHSN00005545, and 1DK bound to VP35 over 200 ns MDS, indicating stable protein-ligand conformations. Furthermore, the ADMET characteristics of the identified natural compounds were assessed, revealing favorable pharmacokinetic and non-toxicity profiles. Density functional theory computations unveiled the electronic stability and chemical reactivity of the identified natural compounds. The obtained outcomes affirmed the substantial therapeutic potential of UMHSN00005544 and UMHSN00005545 as prospective candidates for combating EBOV, thereby necessitating further experimental investigations.

BackgroundClass E (empty) capsid assembly modulators (CAM-Es) inhibit HBV capsid assembly, pregenomic RNA encapsidation preventing formation the establishment of covalently closed circular HBV DNA (ccDNA). ALG-000184 (pevifoscorvir sodium), is a prodrug of the Class E CAM ALG-001075.MethodsALG-000184-201 was a Phase 1 randomized, double-blind, placebo-controlled study to evaluate the safety, tolerability and pharmacokinetics of ALG-000184. Healthy participants (n = 8/cohort) received oral single-ascending doses (SAD) of ALG-000184 (40, 100, 250, and 500 mg) or placebo, and multiple-ascending daily doses (MAD) (150 mg and 250 mg) or placebo for 7 days.ResultsALG-000184 was well tolerated by 48 participants who received single doses up to 500 mg and multiple daily doses up to 250 mg for 7 days. ALG-000184 was rapidly converted to the active moiety, ALG-001075. ALG-001075 had dose-proportional increase in plasma exposure, low-to-moderate variability (18%-34% CV for AUC_0-24), rapid absorption (median t_max 1-3.5 h), and biphasic distribution/elimination with terminal t½ 7-8 h and minimal accumulation (∼30%). A major oxidative metabolite, ALG-000302, was identified in plasma (∼17%-24% of ALG-001075). A high-fat/high-calorie meal did not significantly impact the plasma pharmacokinetics. No differences in pharmacokinetics between Asian and non-Asian participants were observed. A concentration QT analysis indicated no statistically significant change in ΔΔQTcF with plasma ALG-001075. Urinary excretion of ALG-001075 was low following single or multiple ALG-000184 doses.ConclusionsALG-000184 demonstrated good tolerability, safety and pharmacokinetic properties in healthy participants. The pharmacokinetic profile suggests that a daily dose of 100 mg or higher will provide efficacious exposures in patients with chronic HBV infection.Clinical trial numberNCT04536337 (https://clinicaltrials.gov/study/NCT04536337).

Severe influenza infections involve an exacerbation of the pro-inflammatory response, which is influenced by both viral and host factors. Protectins PD1 and PDX previously demonstrated anti-influenza activity as well as anti-inflammatory properties. We recently reported that the combination of AN-137B, a molecular analogue of PDX, with oseltamivir or baloxavir provided synergism/additive effects against influenza, in vitro. Herein, we investigated potential benefits of the AN-137B-oseltamivir combination in mice infected with influenza A/Puerto Rico/8/1934 (H1N1) virus. Untreated animals and those that received single oseltamivir or AN-137B treatment showed mortality rates of 80%, 100% and 100%, respectively, whereas only 40% of mice that received the oseltamivir-AN-137B combination had to be euthanized. Body weight loss was also lower in the group of the combination. In the latter group, the mean lung viral titre (LVT), as determined by plaque assay (2.53 ± 0.63 × 10⁵ PFU/mL) and by qRT-PCR (2.39 ± 1.3 × 10⁸ copies/mL), was significantly lower than that of the untreated group (4.76 ± 0.9 × 10⁵ PFU/mL and 3.75 ± 0.86 × 10⁸ copies/mL (p < .05), contrasting with LVTs of animals that received single therapies. These in vivo results reinforce the potential of AN-137B when combined to a potent anti-influenza agent against severe influenza.

Enteroviruses can cause severe, chronic infections in patients with primary and secondary humoral immunodeficiencies. These patients may benefit from anti-enteroviral therapy. Here, we report a patient with mantle cell lymphoma treated with chemotherapy followed by autologous stem cell transplantation and rituximab maintenance therapy, who presented with echovirus 7-associated deafness and myositis leading to severe disability. She showed marked clinical improvement and enterovirus clearance from faeces and blood after treatment with intravenous immunoglobulins (IVIgs) followed by remdesivir. We demonstrated efficacy of IVIg and remdesivir against echovirus 7 using virus neutralization and cell culture assays, which supports a potential contribution to the treatment success for both therapies.

BackgroundRAY1216 is an alpha-ketoamide-based peptide inhibitor of severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) major protease (M^pro). 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 C_max of 1796.83 ng/mL, t_max of 1.42 h and t_1/2 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.

BackgroundHepatitis D virus (HDV) represents the most severe form of human viral hepatitis, associated with rapid progression to cirrhosis and increased liver-related mortality. Globally, an estimated 9-19 million individuals are anti-HDV positive. To ensure early detetion, current guidelines recommend screening all HBsAg-positive individuals or, at a minimum, those with defined risk factors.MethodsThis expert consensus paper updates the current landscape of HDV management. Recommendations were derived from a structured expert panel discussion, incorporating recent evidence and clinical guideline developments, with a focus on screening, diagnosis, and antiviral therapy.ResultsThe panel emphasized the importance of systematic HDV screening in HBsAg-positive individuals. Therapeutic strategies aim at sustained HDV-RNA suppression and, ideally, HBV surface antigens (HBsAg) loss. Bulevirtide was recommended as a long-term monotherapy. Pegylated interferon alpha (PEG-IFNα), if used, should be limited to 48 weeks and tailored based on viral response and tolerability. Combination therapy with bulevirtide and PEG-IFNα may be considered in selected cases.ConclusionThis consensus provides updated recommendations for the screening, diagnosis, and treatment of HDV infection, highlighting the role of bulevirtide and individualized therapeutic approaches. As the treatment landscape continues to evolve, combination regimens and novel agents currently under investigation may offer additional options in the near future.

BackgroundPorcine reproductive and respiratory syndrome virus (PRRSV) is a pathogen that affects swine and causes substantial economic losses in the global pig industry. Despite the availability of vaccines, it remains crucial to explore innovative therapeutic strategies to control PRRSV infections. Magnolol, a bioactive compound extracted from the root and bark of Magnolia officinalis, has demonstrated broad-spectrum antiviral activity in previous studies.MethodsThe cytotoxicity of magnolol was determined by the CCK-8 method. RT-qPCR, western blot, and immunofluorescence were used to study the inhibitory effect of magnolol on PRRSV N gene and protein expression through antiviral assay and viral attachment, internalization, replication and release assays. The effect of magnolol on immune-related gene expression was analysed by RT-qPCR.ResultsWe found magnolol hinders multiple facets of the PRRSV lifecycle, encompassing the stages of viral attachment and replication. Furthermore, magnolol enhances the expression of pivotal cytokines, including interleukin-6 (IL-6), interleukin-8 (IL-8), and tumour necrosis factor-α (TNF-α), during PRRSV infection, thereby reinforcing the host cells' capacity to mount an effective antiviral defence. Additionally, it exerts inhibitory effects on PRRSV replication by upregulating the expression of a disintegrin and metalloprotease 17 (ADAM17) at both the protein and mRNA levels.ConclusionsIn this study, we provide evidence demonstrating the potent efficacy of magnolol in inhibiting PRRSV replication within Marc-145 cells. Our findings underscore the potential of magnolol as a novel antiviral agent for the PRRSV control.

ObjectiveThe bioequivalence of the simplified protease-inhibitor-based HIV-1 antiretroviral regimen darunavir/cobicistat (DRV/COBI) 600/90-mg fixed-dose combination (FDC) tablet dispersed in water was evaluated in healthy adults and swallowability in children living with HIV aged >3 years and weighing ≥15 to <25 kg, respectively.MethodsIn the bioequivalence study 32 healthy adult participants received either a single oral dose of the DRV/COBI-600/90-mg FDC tablet dispersed in water (test) or the separate formulations (DRV 100-mg/mL at a dose of 600-mg and COBI 90-mg tablet: reference) separated by ≥ 7 days of washout. In a separate acceptability study children living with HIV-1, aged ≥3 years and weighing ≥15 to <25 kg, received a single oral dose of the dispersed DRV/COBI-600/90-mg FDC tablet. Acceptability questionnaires were completed by observers, participants and caregivers.ResultsThe bioequivalence study indicated that the geometric mean ratios for DRV maximum plasma concentration and area under the concentration-time curve of the dispersed DRV/COBI-600/90-mg FDC tablet versus the separate formulations fell within the 80-125% bioequivalence limits. In the acceptability study in children, per independent observers 83% (10/12) of the children were able to swallow the dispersion completely and rated the dispersed FDC tablet as "ok" to "very easy" to swallow.ConclusionThe DRV/COBI 600/90-mg FDC tablet dispersed in water was bioequivalent to coadministration of the separate formulations and was acceptable for long-term daily use in the intended pediatric population.

BackgroundThis study aims to evaluate the cost-effectiveness of tenofovir alafenamide fumarate (TAF) versus tenofovir disoproxil fumarate (TDF) for chronic hepatitis B treatment from a payer's perspective in a limited-income context like Vietnam.MethodsA Markov model was developed to estimate the lifetime cost and effectiveness (measured in quality-adjusted life year, QALY) of TAF compared to TDF in the HbeAg+ patient population. Efficacy data came from clinical trials, and costs were based on 2023 data from an exit survey of 94 inpatients and 464 outpatients in Bach Mai hospital. Other clinical data were also sourced from CHB patients at Bach Mai hospital. Along with deterministic analysis, two-way sensitivity analysis, probabilistic sensitivity analysis, threshold, and budget impact analysis were performed.ResultsCompared to TDF, TAF yielded an additional cost of USD 3,983 and an additional QALY gained of 0.14, resulting in the incremental cost-effectiveness ratio (ICER) of USD 32,090 per QALY gained. The ICER exceeds the cost-effective threshold of three-time gross domestic product (GDP) per capita, that is, USD 11,348, by 2.8 times. According to one-way sensitivity analysis, ICERs were driven mainly by transition probabilities and TDF/ TAF prices. TAF would be cost-effective compared to TDF at the three-time GDP per capital threshold if TAF price were reduced by 33.4%.ConclusionsTAF is not cost-effective compared to TDF for treating chronic hepatitis B in HBeAg+ patients. The study offers relevant evidence for policymakers to consider including TAF in the social health insurance package, with a focus on price negotiation. Future updates are needed as new evidence on the effectiveness and costs of treating chronic hepatitis B emerges.

BackgroundDrug-resistant Mycobacterium tuberculosis strains have challenged efforts to combat tuberculosis (TB), a major global killer. C-reactive protein (CRP) shows promise as a biomarker for TB screening, particularly in HIV-positive cases, with demonstrated sensitivity and specificity in meta-analyses.MethodsWe performed a meta-analysis to assess the accuracy of CRP for screening HIV-associated PTB in outpatients, combining the sensitivities and specificities of diagnostic tests. PubMed, Web of Science, and SCOPUS were searched for articles that were published until April 2024. Quality assessment was done using the QUADAS-2 scale, and analysis was conducted using the random-effect model in STATA 17.ResultsEighteen studies, primarily from Africa (2013-2023), were analysed from an initial pool of 1186. These studies included 5625 HIV patients, 1248 of whom had PTB coinfection. Using a CRP threshold of 10 mg/L, 17 studies (5109 patients) showed 84% sensitivity (95% CI: 72%-91%) and 67% specificity (95% CI: 52%-79%) with I² = 84.91%. At 8 mg/L, nine studies (3631 patients) reported 77% sensitivity (95% CI: 65%-86%) and 81% specificity (95% CI: 69%-89%) with I² = 86.75%.ConclusionsOur study showed that CRP may aid in screening for PTB in PLHIV but requires clinical assessment and additional tests. Its high sensitivity can rule out PTB, but low specificity necessitates further investigation.