Repurposing old drugs as antiviral agents for coronaviruses.

BACKGROUND: New therapeutic options to address the ongoing coronavirus disease 2019 (COVID-19) pandemic are urgently needed. One possible strategy is the repurposing of existing drugs approved for other indications as antiviral agents for severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). Due to the commercial unavailability of SARS-CoV-2 drugs for treating COVID-19, we screened approximately 250 existing drugs or pharmacologically active compounds for their inhibitory activities against feline infectious peritonitis coronavirus (FIPV) and human coronavirus OC43 (HCoV-OC43), a human coronavirus in the same genus (Betacoronavirus) as SARS-CoV-2. METHODS: FIPV was proliferated in feline Fcwf-4 cells and HCoV-OC43 in human HCT-8 cells. Viral proliferation was assayed by visualization of cytopathic effects on the infected Fcwf-4 cells and immunofluorescent assay for detection of the nucleocapsid proteins of HCoV-OC43 in the HCT-8 cells. The concentrations (EC50) of each drug necessary to diminish viral activity to 50% of that for the untreated controls were determined. The viabilities of Fcwf-4 and HCT-8 cells were measured by crystal violet staining and MTS/PMS assay, respectively. RESULTS: Fifteen out of the 252 drugs or pharmacologically active compounds screened were found to be active against both FIPV and HCoV-OC43, with EC50 values ranging from 11 nM to 75 µM. They are all old drugs as follows, anisomycin, antimycin A, atovaquone, chloroquine, conivaptan, emetine, gemcitabine, homoharringtonine, niclosamide, nitazoxanide, oligomycin, salinomycin, tilorone, valinomycin, and vismodegib. CONCLUSION: All of the old drugs identified as having activity against FIPV and HCoV-OC43 have seen clinical use in their respective indications and are associated with known dosing schedules and adverse effect or toxicity profiles in humans. Those, when later confirmed to have an anti-viral effect on SARS-CoV-2, should be considered for immediate uses in COVID-19 patients.

Artificial intelligence approach fighting COVID-19 with repurposing drugs.

Background: The ongoing COVID-19 pandemic has caused more than 193,825 deaths during the past few months. A quick-to-be-identified cure for the disease will be a therapeutic medicine that has prior use experiences in patients in order to resolve the current pandemic situation before it could become worsening. Artificial intelligence (AI) technology is hereby applied to identify the marketed drugs with potential for treating COVID-19. Methods: An AI platform was established to identify potential old drugs with anti-coronavirus activities by using two different learning databases; one consisted of the compounds reported or proven active against SARS-CoV, SARS-CoV-2, human immunodeficiency virus, influenza virus, and the other one containing the known 3C-like protease inhibitors. All AI predicted drugs were then tested for activities against a feline coronavirus in in vitro cell-based assay. These assay results were feedbacks to the AI system for relearning and thus to generate a modified AI model to search for old drugs again. Results: After a few runs of AI learning and prediction processes, the AI system identified 80 marketed drugs with potential. Among them, 8 drugs (bedaquiline, brequinar, celecoxib, clofazimine, conivaptan, gemcitabine, tolcapone, and vismodegib) showed in vitro activities against the proliferation of a feline infectious peritonitis (FIP) virus in Fcwf-4 cells. In addition, 5 other drugs (boceprevir, chloroquine, homoharringtonine, tilorone, and salinomycin) were also found active during the exercises of AI approaches. Conclusion: Having taken advantages of AI, we identified old drugs with activities against FIP coronavirus. Further studies are underway to demonstrate their activities against SARS-CoV-2 in vitro and in vivo at clinically achievable concentrations and doses. With prior use experiences in patients, these old drugs if proven active against SARS-CoV-2 can readily be applied for fighting COVID-19 pandemic.

Inhibition of SARS-CoV-2 by Highly Potent Broad-Spectrum Anti-Coronaviral Tylophorine-Based Derivatives.

Tylophorine-based compounds and natural cardiotonic steroids (cardenolides and bufadienolides) are two classes of transmissible gastroenteritis coronavirus inhibitors, targeting viral RNA and host cell factors, respectively. We tested both types of compounds against two types of coronaviruses, to compare and contrast their antiviral properties, and with view to their further therapeutic development. Examples of both types of compounds potently inhibited the replication of both feline infectious peritonitis virus and human coronavirus OC43 with EC50 values of up to 8 and 16 nM, respectively. Strikingly, the tylophorine-based compounds tested inhibited viral yields of HCoV-OC43 to a much greater extent (7-8 log magnitudes of p.f.u./ml) than the cardiotonic steroids (about 2-3 log magnitudes of p.f.u./ml), as determined by end point assays. Based on these results, three tylophorine-based compounds were further examined for their anti-viral activities on two other human coronaviruses, HCoV-229E and SARS-CoV-2. These three tylophorine-based compounds inhibited HCoV-229E with EC50 values of up to 6.5 nM, inhibited viral yields of HCoV-229E by 6-7 log magnitudes of p.f.u./ml, and were also found to inhibit SARS-CoV-2 with EC50 values of up to 2.5-14 nM. In conclusion, tylophorine-based compounds are potent, broad-spectrum inhibitors of coronaviruses including SARS-CoV-2, and could be used for the treatment of COVID-19.

Assessment of respiratory drive with esophageal diaphragmatic electromyography in patients with acute respiratory distress syndrome treated with prone position ventilation.

BACKGROUND: Prone position ventilation (PPV) is an important strategy for patients with severe acute respiratory distress syndrome (ARDS). This prospective study investigated the use of electromyography of the diaphragm (EMGdi) for monitoring respiratory drive in patients with moderate to severe ARDS during long-term PPV. METHODS: An integrated nostril-gastric feeding tube containing an esophageal electrode and balloon was placed in 14 patients with severe ARDS prior to PPV. EMGdi and trans-pulmonary pressure (∆PL) data were collected before PPV (baseline), every 2 h during PPV, and 2 h after the restoration of supine position ventilation (post-2 h SPV). RESULTS: In ARDS patients, the static compliance of the chest wall was significantly decreased after PPV. EMGdi levels were slightly lower in the early, middle, and late stages of PPV compared with baseline. Patients who received neuromuscular blocker experienced a greater drop in EMGdi from baseline than those who did not. CONCLUSIONS: For ARDS patients, EMGdi was slightly decreased after prolonged PPV. This is contrary to the change in diaphragm electromyography during normal body position changes. Monitoring EMGdi regularly during PPV in ARDS patients is feasible and can be used as a reference for lung protective ventilation strategies.

Risk factors for dysphagia after anterior cervical spine surgery: A meta-analysis.

BACKGROUND: Dysphagia is a well-known complication following anterior cervical spine surgery. Although risk factors for dysphagia have been reported in the literature, they still remain controversial. This study aims to investigate the risk factors associated with dysphagia following anterior cervical spinal surgery. METHODS: PubMed, EMBASE, and The Cochrane Library were searched up to June 2016 for studies examining dysphagia following anterior cervical spinal surgery. Risk factors associated with dysphagia were extracted. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated for outcomes. Data analysis was conducted with RevMan 5.3 and STATA 12.0. RESULTS: The final analysis includes a total of 18 distinct studies. The pooled analysis reveals that there are significant differences in female gender (OR = 2.30, 95% CI: 1.76-2.99, P < 0.001), the use of anterior cervical plate (OR = 1.66, 95% CI: 1.05-2.62, P = 0.03), more than 1 surgical level (OR = 2.07, 95% CI: 1.62-2.66, P < 0.001), the upper surgical level at C3/4 (OR = 3.08, 95% CI: 1.44-6.55, P = 0.004), and the use of bone morphogenetic protein-2 (rhBMP-2) (OR = 5.52, 95% CI: 2.16-14.10, P < 0.001). However, no significant difference is found in revision surgery (OR = 1.67, 95% CI: 0.60-4.68, P = 0.33), the type of fusion (OR = 1.02, 95% CI: 0.62-1.67, P = 0.95), and cervical disc arthroplasty (OR = 1.37, 95% CI: 0.75-2.51, P = 0.30). CONCLUSION: Female gender, the use of anterior cervical plate, more than 1 surgical level, the upper surgical level at C3/4, and the use of rhBMP-2 are the risk factors for dysphagia following anterior cervical spinal surgery. However, revision surgery, the type of fusion, and cervical disc arthroplasty are unassociated with dysphagia. Considering the limited number of studies, this conclusion should be interpreted cautiously, and larger scale studies are required.

Factors predicting venous thromboembolism after spine surgery.

BACKGROUND: A meta-analysis was performed to explore predicted factors of venous thromboembolism (VTE) after surgery in the treatment for spine degeneration diseases. SUMMARY OF BACKGROUND DATA: Many scholars have focused on VTE after spine surgery, but as for the risk factors of VTE have not reached a consensus. METHODS: An extensive search of literature, "spine or spinal," "degeneration," "after surgery or postoperation," and "venous thromboembolism" as key words, was performed in PubMed/MEDLINE, Embase, the Cochrane library, CNKI, and WANFANG databases. The following variables were extracted: wearing elastic stocking, hypertension (HT), heart disease, diabetes, drinking, anticoagulant therapy, walking disability preoperation, smoking, sex, age, surgical duration, fusion versus nonfusion (lumbar fusion vs lumbar discectomy), surgical site (cervical vs lumbar), blood loss, and body mass index. Data analysis was conducted with RevMan 5.3 and STATA 12.0. RESULTS: A total of 12 studies were identified, including 34,597 patients of whom 624 patients had VTE, and the incidence of VTE was 2% in all patients who underwent spine surgery. The incidence of VTE for Asian patients was 7.5%, compared with 1% VTE for Occidental patients; the difference was significant (P < 0.0001). The pooled analysis showed that there were significant differences regarding wearing elastic stocking (odds ratio [OR] = 11.71, 95% confidence interval [CI] [1.46, 94.00], P = 0.02), walking disability preoperation (OR = 4.80, 95% CI [2.53, 9.12], P < 0.00001), surgical site (lumbar surgery) (OR = 0.23, 95% CI [0.20, 0.27], P < 0.00001), HT (OR = 1.59, 95% CI [1.21, 2.10], P = 0.001), and diabetes (OR = 2.12, 95% CI [1.09, 4.10], P = 0.03). However, there were no significant differences in blood loss, heart disease, smoking, sex, surgical duration, body mass index, surgical duration, anticoagulant therapy, wearing elastic stocking, fusion versus nonfusion, drinking, and age (all P > 0.05). CONCLUSIONS: Based on our meta-analysis, Asian patients, patients with walking disability preoperation, patients wearing elastic stocking, patients having undergone lumbar surgery, patients with a history of HT, and patients experiencing diabetes have a higher incidence of VTE after spine surgery.

[Effects of shenshuning recipe on expression of hepatocyte growth factor in rats with glomerulosclerosis].

OBJECTIVE: To investigate the effects of Shenshuning Recipe (SSNR) on gene expression of hepatocyte growth factor (HGF) in renal tissues in rats with glomerulosclerosis. METHODS: Glomerulosclerosis was induced in 42 rats by unilateral nephrectomy and intravenous injection of doxorubicin. Then these 42 rats were randomly divided into three groups: untreated group, SSNR-treated group and benazepril-treated group. Another eight rats were included into sham-operation group. The rats in the SSNR-treated group and the benazepril-treated group were fed SSNR or benazepril respectively for 8 weeks. The levels of 24 h urine protein (Upr), serum creatinine (Cr) and blood urea nitrogen (BUN) of rats in each group were examined. The renal morphological changes were observed under microscope, and the diameter of glomerular capillary, mesangial matrix and glomerulosclerosis index were analyzed by image analysis software. Reverse transcription-polymerase chain reaction (RT-PCR) method was used to detect the gene expression of HGF in the renal tissues. RESULTS: The levels of 24 h Upr, serum Cr and BUN in the untreated group were remarkably increased than those in the sham-operation group (P<0.01). The pathological morphological changes in the untreated group showed that the glomerulosclerosis was diffused around the renal tissue and the capillaries were shrunk. The expression level of mesangial matrix was up-regulated and the glomerulosclerosis index was 3.32+/-0.35. The expression level of HGF mRNA in the untreated group was obviously lower than that in the sham-operation group (P<0.05). The levels of 24 h Upr, serum Cr and BUN in the SSNR-treated group and the benazepril-treated group were remarkably decreased as compared with those in the untreated group, while the expression levels of HGF mRNA were both obviously higher than that in the untreated group (P<0.01). The pathological morphological changes in the SSNR-treated group and the benazepril-treated group were both alleviated. There was no significant difference in therapeutic effect between the SSNR-treated group and the benazepril-treated group. CONCLUSION: Shenshuning Recipe can up-regulate the expression of HGF mRNA, decrease the mesangial matrix, and improve the renal function, so that it may retard the development of glomerulosclerosis.