halcinonide and Disease-Models--Animal

When Zika virus emerged as a public health emergency there were no drugs or vaccines approved for its prevention or treatment. We used a high-throughput screen for Zika virus protease inhibitors to identify several inhibitors of Zika virus infection. We expressed the NS2B-NS3 Zika virus protease and conducted a biochemical screen for small-molecule inhibitors. A quantitative structure-activity relationship model was employed to virtually screen ∼138,000 compounds, which increased the identification of active compounds, while decreasing screening time and resources. Candidate inhibitors were validated in several viral infection assays. Small molecules with favorable clinical profiles, especially the five-lipoxygenase-activating protein inhibitor, MK-591, inhibited the Zika virus protease and infection in neural stem cells. Members of the tetracycline family of antibiotics were more potent inhibitors of Zika virus infection than the protease, suggesting they may have multiple mechanisms of action. The most potent tetracycline, methacycline, reduced the amount of Zika virus present in the brain and the severity of Zika virus-induced motor deficits in an immunocompetent mouse model. As Food and Drug Administration-approved drugs, the tetracyclines could be quickly translated to the clinic. The compounds identified through our screening paradigm have the potential to be used as prophylactics for patients traveling to endemic regions or for the treatment of the neurological complications of Zika virus infection.

Topics: Animals; Antiviral Agents; Artificial Intelligence; Chlorocebus aethiops; Disease Models, Animal; Drug Evaluation, Preclinical; High-Throughput Screening Assays; Immunocompetence; Inhibitory Concentration 50; Methacycline; Mice, Inbred C57BL; Protease Inhibitors; Quantitative Structure-Activity Relationship; Small Molecule Libraries; Vero Cells; Zika Virus; Zika Virus Infection

Systemic or intraperitoneal administration of corticosteroids has been reported to have conflicting effects on the prevention of peritoneal adhesions. Painting corticosteroid cream directly on the likely site of adhesion formation, owing to its high concentrations and persistent effects, may be a promising approach to prevent peritoneal adhesion formation.. Adhesions were induced by abrading of the cecum, followed by dropping of 95% ethanol. Sixty Wistar rats were randomly allocated to two control groups with no further treatment of the cecum and to two therapy groups treated with 0.1% halcinonide cream painted directly on the damaged surface of the cecum. After 3 and 7 days, adhesion scores, adhesion incidence, and intraperitoneal leukocytes were evaluated.. On both postoperative days 3 and 7, halcinonide cream resulted in a significant decrease in mean adhesion scores (6.80 versus 0.67, 10.40 versus 1.26; P <0.001, P <0.001, respectively). The adhesion incidence was 43.3% for the therapy groups and 100% for controls (P <0.01). On day 3, the total numbers of intraperitoneal leukocytes were 120.73 +/- 24.01 millions for the therapy groups and 270.40 +/- 34.68 for controls (P <0.001).. Painting halcinonide cream directly on the damaged surface of the cecum could effectively reduce the severity and incidence of adhesion, possibly by suppression of early inflammatory exudate and of late fibroblast invasion and proliferation.

Topics: Abdomen; Administration, Topical; Animals; Anti-Inflammatory Agents; Digestive System Surgical Procedures; Disease Models, Animal; Female; Glucocorticoids; Halcinonide; Male; Random Allocation; Rats; Rats, Wistar; Tissue Adhesions