Vaccines and drugs have helped reduce disease severity and blunt the spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, ongoing virus transmission, continuous evolution, and increasing selective pressures have the potential to yield viral variants capable of resisting these interventions. Here, we investigate the susceptibility of natural variants of the main protease [M ^pro ; 3C-like protease (3CL ^pro )] of SARS-CoV-2 to protease inhibitors. Multiple single amino acid changes in M ^pro confer resistance to nirmatrelvir (the active component of Paxlovid). An additional clinical-stage inhibitor, ensitrelvir (Xocova), shows a different resistance mutation profile. Importantly, phylogenetic analyses indicate that several of these resistant variants have pre-existed the introduction of these drugs into the human population and are capable of spreading. These results encourage the monitoring of resistance variants and the development of additional protease inhibitors and other antiviral drugs with different mechanisms of action and resistance profiles for combinatorial therapy.

Rocuronium, like other steroidal nondepolarizing muscle relaxants, may in part be eliminated by the liver. To determine the influence of liver disease on its neuromuscular blocking effect, we studied the pharmacokinetics and pharmacodynamics of rocuronium in patients with cirrhosis. Eighteen patients undergoing elective surgery, 10 with cirrhosis and 8 with normal liver function, were studied. Anesthesia was induced with intravenous thiopental 5-7 mg.kg-1 and maintained with 60% nitrous oxide in oxygen and repeated doses of fentanyl 2 micrograms.kg-1. The force of thumb adduction in response to supramaximal ulnar nerve stimulation was monitored and recorded. An intravenous bolus of rocuronium 0.6 mg.kg-1 was administered and venous blood sampled at frequent intervals for 6 h. Plasma concentrations of rocuronium was measured by high-pressure liquid chromatography. Data were fitted to both a pharmacokinetic and a pharmacodynamic model by using a two-compartment open model and an effect compartment model. Data were analyzed by least-squares regression. The onset of neuromuscular blockade was longer (P < 0.01) in patients with cirrhosis (158 +/- 56 s) than in normal patients (108 +/- 33 s). Recovery of the thumb twitch to 75 and 90% of its control value was 77 +/- 25 and 88 +/- 29 min in cirrhotic patients versus 57 +/- 11 and 64 +/- 13 min, respectively, in normal patients (P < 0.05). The central volume of distribution of rocuronium was 104 +/- 21 in cirrhotic patients and 78 +/- 24 ml.kg-1 in normal patients (P < 0.05). No significant difference in elimination kinetics was observed between the two groups. The elimination half-life was 87.5 +/- 17.5 min in normal patients and 96.0 +/- 36.8 min in cirrhotic patients (difference not significant). This increased onset time was linearly correlated to the increased central volume of distribution of rocuronium in cirrhosis. Rocuronium onset time is longer in cirrhotic patients than in those with normal liver function; this can be explained by an increase in the volume in which rocuronium initially distributes. Although elimination kinetics are unchanged in patients with cirrhosis, rocuronium recovery time is prolonged in cirrhotic patients.

Targeting host factors exploited by multiple viruses could offer broad-spectrum solutions for pandemic preparedness. Seventeen candidates targeting diverse functions emerged in a screen of 4,413 compounds for SARS-CoV-2 inhibitors. We demonstrated that lapatinib and other approved inhibitors of the ErbB family of receptor tyrosine kinases suppress replication of SARS-CoV-2, Venezuelan equine encephalitis virus (VEEV), and other emerging viruses with a high barrier to resistance. Lapatinib suppressed SARS-CoV-2 entry and later stages of the viral life cycle and showed synergistic effect with the direct-acting antiviral nirmatrelvir. We discovered that ErbB1, ErbB2, and ErbB4 bind SARS-CoV-2 S1 protein and regulate viral and ACE2 internalization, and they are required for VEEV infection. In human lung organoids, lapatinib protected from SARS-CoV-2–induced activation of ErbB-regulated pathways implicated in non-infectious lung injury, proinflammatory cytokine production, and epithelial barrier injury. Lapatinib suppressed VEEV replication, cytokine production, and disruption of blood-brain barrier integrity in microfluidics-based human neurovascular units, and reduced mortality in a lethal infection murine model. We validated lapatinib-mediated inhibition of ErbB activity as an important mechanism of antiviral action. These findings reveal regulation of viral replication, inflammation, and tissue injury via ErbBs and establish a proof of principle for a repurposed, ErbB-targeted approach to combat emerging viruses.

The present study carried out to clarify the impact of heavy metals (Fe, Zn, Cu, Mn and Cd) pollution of Rosetta Branch on the antioxidant defence system activities and lipid peroxidation indicator MDA levels in O. niloticus tissues (liver and white muscles) collected from three stations from Rosetta Branch of River Nile in summer2014 and winter 2015. Rosetta Branch of River Nile exposed to high input of agricultural drainage water, sewage and industrial waste water which influence the living organisms especially fish. In the present study results revealed that the concentration of heavy metals (Fe, Zn, Cu, Mn and Cd) in water and fish samples increased in station II and III, especially in winter. In muscles of O. niloticus, the accumulation patterns of heavy metals were in the following order: Fe > Zn > Mn > Cu and Cd. The bioaccumulation factor (BAF) in winter was higher than summer. Antioxidant enzymes (SOD, CAT, GPx, GST and GR) activities and the indicator of lipid peroxidation MDA levels showed a significant increase in liver and white muscles of O. niloticus, in stations II and III, especially in winter. Moreover, the antioxidant enzymes activities and MDA levels were higher in liver than white muscles.