Rajat Pareek

RATIONALE: Respiratory syncytial virus (RSV) is the leading cause of childhood lower respiratory infection, yet viable therapies are lacking. Two major challenges have stalled antiviral development: ethical difficulties in performing pediatric proof-of-concept studies and the prevailing concept that the disease is immune-mediated rather than being driven by viral load. OBJECTIVES: The development of a human experimental wild-type RSV infection model to address these challenges. METHODS: Healthy volunteers (n = 35), in five cohorts, received increasing quantities (3.0-5.4 log plaque-forming units/person) of wild-type RSV-A intranasally. MEASUREMENTS AND MAIN RESULTS: Overall, 77% of volunteers consistently shed virus. Infection rate, viral loads, disease severity, and safety were similar between cohorts and were unrelated to quantity of RSV received. Symptoms began near the time of initial viral detection, peaked in severity near when viral load peaked, and subsided as viral loads (measured by real-time polymerase chain reaction) slowly declined. Viral loads correlated significantly with intranasal proinflammatory cytokine concentrations (IL-6 and IL-8). Increased viral load correlated consistently with increases in multiple different disease measurements (symptoms, physical examination, and amount of nasal mucus). CONCLUSIONS: Viral load appears to drive disease manifestations in humans with RSV infection. The observed parallel viral and disease kinetics support a potential clinical benefit of RSV antivirals. This reproducible model facilitates the development of future RSV therapeutics.

Background Respiratory syncytial virus ( RSV ) viral load and disease severity associate, and the timing of viral load and disease run in parallel. An antiviral must be broadly effective against the natural spectrum of RSV genotypes and must attain concentrations capable of inhibiting viral replication within the human respiratory tract. Objectives We evaluated a novel RSV fusion inhibitor, MDT ‐637, and compared it with ribavirin for therapeutic effect in vitro to identify relative therapeutic doses achievable in humans. Method MDT ‐637 and ribavirin were co‐incubated with RSV in HE p‐2 cells. Quantitative PCR assessed viral concentrations; 50% inhibitory concentrations ( IC 50 ) were compared to achievable human MDT ‐637 and ribavirin peak and trough concentrations. Results and conclusions The IC 50 for MDT ‐637 and ribavirin (against RSV ‐A Long) was 1.42 and 16 973 ng/mL, respectively. The ratio of achievable peak respiratory secretion concentration to IC 50 was 6041‐fold for MDT ‐637 and 25‐fold for aerosolized ribavirin. The ratio of trough concentration to IC 50 was 1481‐fold for MDT ‐637 and 3.29‐fold for aerosolized ribavirin. Maximal peak and trough levels of oral or intravenous ribavirin were significantly lower than their IC 50 s. We also measured MDT ‐637 IC 50 s in 3 lab strains and 4 clinical strains. The IC 50 s ranged from 0.36 to 3.4 ng/mL. Achievable human MDT ‐637 concentrations in respiratory secretions exceed the IC 50 s by factors from hundreds to thousands of times greater than does ribavirin. Furthermore, MDT ‐637 has broad in vitro antiviral activity on clinical strains of different RSV genotypes and clades. Together, these data imply that MDT ‐637 may produce a superior clinical effect compared to ribavirin on natural RSV infections.

Aim To estimate the ABO blood groups from saliva samples and to correlate with the secretor status. Materials and methods A sample size of 300 individuals was selected from the outpatient department of Surendera Dental College & Research Institute, Sriganganagar, India, and from dental camps organized by the college in the near vicinity. Informed consent was obtained from selected individuals to collect their blood and saliva samples. Salivary samples were evaluated for ABO blood groups by the absorption-inhibition method. The indicator erythrocytes were prepared after blood group confirmation from serum. It was used to identify the blood group antigens in saliva to confirm the secretor status. The results were tabulated and the Pearson's chi-squared test was performed for statistical analysis using SPSS 15.0 (SPSS Inc., Chicago, IL). Results The present study showed that 282 subjects (94%) were Rhesus positive and 18 subjects (6%) were Rhesus negative. Two-hundred-and-fifty subjects (83.3%) were secretors of antigens in saliva. Non-secretors were 50 subjects (16.7%). We identified that 250/300 were secretors and the majority were in AB & A group. Conclusion Blood groups could not be detected from the saliva of subjects who were non-secretors. In contrast, blood types could be accurately identified from the saliva of those subjects who were secretors of antigen.

Introduction: Therapeutic options for RSV, a leading cause of lower respiratory infection in children and adults, are suboptimal. Ribavirin has antiviral effect but its controversial mild clinical therapeutic benefit and environmental contamination issues preclude its routine use. MDT-637 is a novel RSV fusion inhibitor not yet evaluated for therapeutic effect in man. The extent to which the achievable human concentration of an antiviral exceeds its invitro viral inhibitory concentration, can predict its clinical efficacy. Methods: RSV A-long (MOI=0.001) was co-incubated in duplicate with ascending concentrations of ribavirin or MDT-637, added to HEp-2 cells and incubated x 72 hrs. Viral concentrations were then assessed by quantitative PCR (qPCR). 50% Inhibitory Concentrations (IC50) were measured and compared to achievable human MDT-637 and ribavirin peak and trough concentrations. For calculations, measured MDT-637 concentrations in human respiratory secretions were extrapolated based on known solubility in simulated lung fluid. Achievable human ribavirin concentrations were from the literature. Genotypic diversity was based on RSV G-protein. Results: The IC50 for MDT-637 and ribavirin (against RSV A-long) was 2.1 and 16,973ng/ml respectively representing >7,000x greater potency of MDT-637. Using RSV A-long, the ratio of achievable peak respiratory secretion concentration to IC50 was 86,000x for MDT- 637 and 25x for ribavirin. The ratio of trough concentration to IC50 was 18,000x for MDT-637 and 1.6x for ribavirin. MDT-637 IC50s were also measured vs. 3 lab strains [RSV-ALong (ATCC-VR26, clade NH/A1), RSV-A2 (VR-1540), RSV-B (VR-955)] and 7 clinical strains [clades NH/A2, NH/A4, NH/B2, NH/B3, BE/GB2]. The IC50s ranged from 0.50-7.37ng/ml. Conclusions: MDT-637 is several thousand times more potent invitro compared to ribavirin. Achievable human MDT-637 concentrations in respiratory secretions exceed the IC50s by factors thousands of times greater than does ribavirin. Furthermore, MDT-637 has broad invitro antiviral activity on clinical strains of different RSV genotypes and clades. Together, this data implies that MDT-637 may produce a superior clinical effect compared to ribavirin on natural RSV infections.

With the growing understanding of coronavirus disease-2019 (COVID-19) pathogenesis, different therapeutic targets are being considered for the management of COVID-19 The development of new drugs is a time-consuming process;hence, many drugs acting on similar therapeutic targets/sites in the COVID-19 treatment are repurposed in COVID-19 In this article, an expert panel deliberated on the existing evidence on the immunopathogenesis, therapeutic targets under consideration for treatment of COVID-19, and the place of mefenamic acid in the therapy landscape of COVID-19 The expert panel has also provided recommendations regarding the dose and regimen of mefenamic acid in different phases of the COVID-19 disease