Ibrutinib plus Bendamustine and Rituximab in Untreated Mantle-Cell Lymphoma.

BACKGROUND: Ibrutinib, a Bruton's tyrosine kinase inhibitor, may have clinical benefit when administered in combination with bendamustine and rituximab and followed by rituximab maintenance therapy in older patients with untreated mantle-cell lymphoma. METHODS: We randomly assigned patients 65 years of age or older to receive ibrutinib (560 mg, administered orally once daily until disease progression or unacceptable toxic effects) or placebo, plus six cycles of bendamustine (90 mg per square meter of body-surface area) and rituximab (375 mg per square meter). Patients with an objective response (complete or partial response) received rituximab maintenance therapy, administered every 8 weeks for up to 12 additional doses. The primary end point was progression-free survival as assessed by the investigators. Overall survival and safety were also assessed. RESULTS: Among 523 patients, 261 were randomly assigned to receive ibrutinib and 262 to receive placebo. At a median follow-up of 84.7 months, the median progression-free survival was 80.6 months in the ibrutinib group and 52.9 months in the placebo group (hazard ratio for disease progression or death, 0.75; 95% confidence interval, 0.59 to 0.96; P = 0.01). The percentage of patients with a complete response was 65.5% in the ibrutinib group and 57.6% in the placebo group (P = 0.06). Overall survival was similar in the two groups. The incidence of grade 3 or 4 adverse events during treatment was 81.5% in the ibrutinib group and 77.3% in the placebo group. CONCLUSIONS: Ibrutinib treatment in combination with standard chemoimmunotherapy significantly prolonged progression-free survival. The safety profile of the combined therapy was consistent with the known profiles of the individual drugs. (Funded by Janssen Research and Development and Pharmacyclics; SHINE ClinicalTrials.gov number, NCT01776840.).

Determinants of severity among hospitalised COVID-19 patients: Hospital-based case-control study, India, 2020.

BACKGROUND: Risk factors for the development of severe COVID-19 disease and death have been widely reported across several studies. Knowledge about the determinants of severe disease and mortality in the Indian context can guide early clinical management. METHODS: We conducted a hospital-based case control study across nine sites in India to identify the determinants of severe and critical COVID-19 disease. FINDINGS: We identified age above 60 years, duration before admission >5 days, chronic kidney disease, leucocytosis, prothrombin time > 14 sec, serum ferritin >250 ng/mL, d-dimer >0.5 ng/mL, pro-calcitonin >0.15 µg/L, fibrin degradation products >5 µg/mL, C-reactive protein >5 mg/L, lactate dehydrogenase >150 U/L, interleukin-6 >25 pg/mL, NLR ≥3, and deranged liver function, renal function and serum electrolytes as significant factors associated with severe COVID-19 disease. INTERPRETATION: We have identified a set of parameters that can help in characterising severe COVID-19 cases in India. These parameters are part of routinely available investigations within Indian hospital settings, both public and private. Study findings have the potential to inform clinical management protocols and identify patients at high risk of severe outcomes at an early stage.

Phytochemical Moieties From Indian Traditional Medicine for Targeting Dual Hotspots on SARS-CoV-2 Spike Protein: An Integrative in-silico Approach.

SARS-CoV-2 infection across the world has led to immense turbulence in the treatment modality, thus demanding a swift drug discovery process. Spike protein of SARS-CoV-2 binds to ACE2 receptor of human to initiate host invasion. Plethora of studies demonstrate the inhibition of Spike-ACE2 interactions to impair infection. The ancient Indian traditional medicine has been of great interest of Virologists worldwide to decipher potential antivirals. Hence, in this study, phytochemicals (1,952 compounds) from eight potential medicinal plants used in Indian traditional medicine were meticulously collated, based on their usage in respiratory disorders, along with immunomodulatory and anti-viral potential from contemporary literature. Further, these compounds were virtually screened against Receptor Binding Domain (RBD) of Spike protein. The potential compounds from each plant were prioritized based on the binding affinity, key hotspot interactions at ACE2 binding region and glycosylation sites. Finally, the potential hits in complex with spike protein were subjected to Molecular Dynamics simulation (450 ns), to infer the stability of complex formation. Among the compounds screened, Tellimagrandin-II (binding energy of -8.2 kcal/mol and binding free energy of -32.08 kcal/mol) from Syzygium aromaticum L. and O-Demethyl-demethoxy-curcumin (binding energy of -8.0 kcal/mol and binding free energy of -12.48 kcal/mol) from Curcuma longa L. were found to be highly potential due to their higher binding affinity and significant binding free energy (MM-PBSA), along with favorable ADMET properties and stable intermolecular interactions with hotspots (including the ASN343 glycosylation site). The proposed hits are highly promising, as these are resultant of stringent in silico checkpoints, traditionally used, and are documented through contemporary literature. Hence, could serve as promising leads for subsequent experimental validations.

Dual inhibition of COVID-19 spike glycoprotein and main protease 3CLpro by Withanone from Withania somnifera.

OBJECTIVE: To identify the safe and effective natural inhibitors of spike glycoprotein and main protease 3CLpro using potential natural antiviral compounds which are studied under various animal models and viral cell lines. METHODS: First, compounds were retrieved from the PubChem database and predicted for their druggability using the MolSoft web server, and compounds having drug-like property were predicted for major adverse drug reactions like cardiotoxicity, hepatotoxicity, arrhythmia, myocardial infarction, and nephrotoxicity using ADVERpred. Docking of nontoxic antiviral compounds with spike glycoprotein and main protease 3CLpro was performed using AutoDock vina by PyRx 0.8 version. The stability of compound-protein interactions was checked by molecular dynamic (MD) simulation using Schrodinger Desmond software. RESULTS: Based on the druggable and nontoxic profile, nine compounds were selected. Among them, Withanone from Withania somnifera showed the highest binding affinity and best fit at active sites 1 of spike glycoprotein (glycosylation site) and main protease 3CLpro via interacting with active site amino acid residues before and after MD simulation at 50 ns. Withanone, which may reduce the glycosylation of SARS-CoV-2 via interacting with Asn343 and inhibit viral replication. CONCLUSION: The current study reports Withanone as a non-toxic antiviral against SARS-CoV-2 and serve as a potential lead hit for further experimental validation.