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As the SARS-CoV-2 pandemic remains uncontrolled owing to the continuous emergence of variants of concern, there is an immediate need to implement the most effective antiviral treatment strategies, especially for risk groups. Here, we evaluated the therapeutic potency of nirmatrelvir, remdesivir, and molnupiravir and their combinations in SARS-CoV-2-infected K18-hACE2 transgenic mice. Systemic treatment of mice with each drug (20 mg/kg) resulted in slightly enhanced antiviral efficacy and yielded an increased life expectancy of only about 20-40% survival. However, combination therapy with nirmatrelvir (20 mg/kg) and molnupiravir (20 mg/kg) in lethally infected mice showed profound inhibition of SARS-CoV-2 replication in both the lung and brain and synergistically improved survival times up to 80% compared to those with nirmatrelvir (P= 0.0001) and molnupiravir (P= 0.0001) administered alone. This combination therapy effectively reduced clinical severity score, virus-induced tissue damage, and viral distribution compared to those in animals treated with these monotherapies. Furthermore, all these assessments associated with this combination were also significantly higher than that of mice receiving remdesivir monotherapy (P= 0.0001) and the nirmatrelvir (20 mg/kg) and remdesivir (20 mg/kg) combination (P= 0.0001), underscored the clinical significance of this combination. By contrast, the nirmatrelvir and remdesivir combination showed less antiviral efficacy, with lower survival compared to nirmatrelvir monotherapy, demonstrating the inefficient therapeutic effect of this combination. The combination therapy with nirmatrelvir and molnupiravir contributes to alleviated morbidity and mortality, which can serve as a basis for the design of clinical studies of this combination in the treatment of COVID-19 patients. IMPORTANCESince SARS-CoV-2 spread rapidly with the emergence of new variants of concerns, it is necessary to develop effective treatment strategies to treat elderly individuals and those with comorbidities. Antiviral therapy using a combination of drugs is more effective in eradicating viruses and will undoubtedly improve the clinical outcome and survival probability of hospitalized SARS-CoV-2 patients. In the current study, we observed three FDA-approved antivirals nirmatrelvir, remdesivir, and molnupiravir have therapeutic significance with moderate survival for their monotherapies against SARS-CoV-2 infected K18-hACE2 mouse model. The combination of nirmatrelvir and molnupiravir showed significant antiviral activity and a higher survival rate of approximately 80%, providing in vivo evidence of the potential utility of this combination. In contrast, nirmatrelvir and remdesivir combination showed less antiviral potency and emphasized the ineffective significance with less survival. The current study suggests that the nirmatrelvir and molnupiravir combination is an effective drug regimen strategy in treating SARS-CoV-2 patients.
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Background@#Delirium is a neuropsychiatric disorder characterized by sudden impairments in consciousness, attention, and perception. The evidence of successful pharmacological interventions for delirium is limited, and medication recommendations for managing delirium are not standardized. This study aimed to provide evidence of antipsychotics for symptomatic treatment of delirium in cancer patients receiving palliative care. @*Methods@#We retrospectively reviewed adult cancer patients in palliative care who received antipsychotic delirium treatment at Severance Hospital between January 2016 and June 2019. The efficacy was evaluated primarily by resolution rates. The resolution of delirium was defined as neurological changes from drowsiness, confusion, stupor, sedation, or agitation to alertness or significant symptomatic improvements described in the medical records. The safety was studied primarily by adverse drug reaction incidence ratios. @*Results@#Of the 63 enrolled patients, 60 patients were included in the statistical analysis and were divided into three groups based on which antipsychotic medication they were prescribed [quetiapine (n=27), haloperidol (n=25) and co-administration of quetiapine and haloperidol (n=8)]. The resolution ratio showed quetiapine to be more effective than haloperidol (p=0.001). No significant differences were seen in adverse drug reaction rates among the three groups (p=0.332). @*Conclusions@#Quetiapine was considered the most effective medication for delirium, with no significant differences in adverse drug reaction rates. Therefore, quetiapine may be considered a first-line medication for treating delirium in cancer patients receiving palliative care. However, further studies comparing more diverse antipsychotics among larger populations are still needed.
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OBJECTIVE: Necrotising soft tissue infection is a rare surgical emergency, which requires immediate and aggressive surgical debridement. Following control of the infection, patients are often left with large defects, with wound reconstruction and closure creating significant challenges. Here we describe a case of extensive thoracoabdominal necrotising soft tissue infection and provide a discussion on the standard of care and treatment based on a current literature review. METHOD: A 53-year-old female presented with bilious and feculent discharge from her surgical incision two weeks after a total abdominal hysterectomy. She was found to have two enterocutaneous fistulae and an extensive abdominal wall necrotising soft tissue infection extending to the lower thorax. Wide excision and debridement were performed, leaving a large triangular defect. Following serial washouts and debridements, a biologic mesh with openings for the enterocutaneous fistulae was used to cover the fascial defect Results: Postoperatively, the patient was discharged to a nursing facility where she remained on total parenteral nutrition due to high fistula output. She subsequently underwent fistulectomy nine months later followed by skin grafting. To date, she has not had any recurrent fistulae or infection. CONCLUSION: Necrotising soft tissue infection resulting in a large abdominal wall defect secondary to enterocutaneous fistulae poses a significant challenge for source control and abdominal wall reconstruction. After serial debridements, use of biologic mesh for temporary closure followed by staged resection of the bowel with abdominal wall reconstruction can be performed. DECLARATION OF INTEREST: The authors have no personal financial or institutional interest in any of the drugs, materials, or devices used.
