gefarnate 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

We assessed the effects of some gefarnate analogs on gastric ulcer prophylaxis (adrenaline ulcers) and ulcer healing (acetic ulcers) and some secretory parameters in rats. Acute ulcers were induced in male Wistar rats by intraperitoneal injection of 2 mg/kg adrenaline hydrochloride. Rats were killed after 24 hours. Chronic gastric ulcers were induced in rats by application of 100% acetic acid to the serosal surface of the stomach on 60 sec. Gefarnate analogs introduced intraperitoneally or intragastrically. Gefarnate analogs dose-dependently increase the healing of gastric ulcers and have a marked prophylaxis effects especially in the case of adrenaline ulcers.

Topics: Animals; Anti-Ulcer Agents; Disease Models, Animal; Gastric Mucosa; Gefarnate; Male; Molecular Structure; Oxygen; Rats; Stomach Ulcer; Treatment Outcome; Wound Healing

To evaluate the effects of teprenone on acute gastritis, its inhibitory effects on gastric mucosal damage were compared to that of gefarnate in taurocholate/hydrochloric acid-induced acute gastric mucosal lesions in rats. After oral administration of 160 mM taurocholic acid and 250 mM hydrochloric acid, hemorrhage and erosion were macroscopically observed in the gastric mucosal surface layer. Edema in the submucosal tissue and decreased PAS staining in the mucosa were histomorphologically observed. Concerning macroscopic findings, pretreatment with teprenone at a dose of 50 mg/kg or more significantly reduced pathological changes in the mucosa of the fundic glandular area. However, gefarnate slightly inhibited these changes in at a dose of 50 mg/kg and significantly inhibited them at a dose of 200 mg/kg. With regards to histomorphological findings in the fundic glandular area, teprenone slightly inhibited erosion at a dose of 50 mg/kg, and it significantly and slightly inhibited the decrease in PAS staining in this area at doses of 50 and 200 mg/kg, respectively. Gefarnate at doses of 50 and 200 mg/kg showed significant inhibition of decreased PAS staining in the fundic glandular area. In the pyloric mucosa, decreased PAS staining was slightly inhibited by teprenone at both doses but not by gefarnate at either dose. The differences between teprenone and gefarnate observed in this model appear to be due to their differences in mucus production ability. These results suggest that teprenone was more effective than gefarnate for the treatment of gastritis.

Topics: Acute Disease; Animals; Anti-Ulcer Agents; Disease Models, Animal; Diterpenes; Dose-Response Relationship, Drug; Gastric Mucosa; Gastritis; Gefarnate; Hydrochloric Acid; Male; Mucus; Rats; Rats, Wistar; Taurocholic Acid