cortodoxone 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

There is a major clinical need for new therapies for the treatment of chronic itch. Many of the molecular components involved in itch neurotransmission are known, including the neuropeptide NPPB, a transmitter required for normal itch responses to multiple pruritogens in mice. Here, we investigated the potential for a novel strategy for the treatment of itch that involves the inhibition of the NPPB receptor NPR1 (natriuretic peptide receptor 1). Because there are no available effective human NPR1 (hNPR1) antagonists, we performed a high-throughput cell-based screen and identified 15 small-molecule hNPR1 inhibitors. Using in vitro assays, we demonstrated that these compounds specifically inhibit hNPR1 and murine NPR1 (mNPR1). In vivo, NPR1 antagonism attenuated behavioral responses to both acute itch- and chronic itch-challenged mice. Together, our results suggest that inhibiting NPR1 might be an effective strategy for treating acute and chronic itch.

Topics: Animals; Behavior, Animal; Cell-Free System; Dermatitis, Contact; Disease Models, Animal; Ganglia, Spinal; Humans; Mice, Inbred C57BL; Mice, Knockout; Neurons; Pruritus; Receptors, Atrial Natriuretic Factor; Reproducibility of Results; Signal Transduction; Small Molecule Libraries

Topics: Animals; Anterior Chamber; Cortodoxone; Disease Models, Animal; Eye Diseases; Intraocular Pressure; Intraoperative Complications; Lens Capsule, Crystalline; Rabbits; Rupture; Vitreous Body

To develop a new technique to visualize vitreous body prolapsed in the anterior chamber using 11-deoxycortisol.. Experimental study.. An animal model of posterior capsule rupture was developed to investigate the usefulness of 11-deoxycortisol, a precursor of cortisol without steroid activity. After the intentional creation of posterior capsule rupture, the suspension of 11-deoxycortisol was injected into the anterior chamber of rabbit eyes. After gentle irrigation and aspiration, the vitreous body that had prolapsed into the anterior chamber was removed using an anterior vitrectomy cutter. To investigate the safety of 11-deoxycortisol, the biomicroscopic appearance, intraocular pressure (IOP), corneal endothelial count, and microstructure of the corneal endothelium were examined in the rabbits that received injections of 11-deoxycortisol in the anterior chamber.. In our posterior capsule rupture model, the vitreous in the anterior chamber became clearly visible, with 11-deoxycortisol showing white particles entrapped on its surface. The injection of 11-deoxycortisol facilitated the complete removal of the vitreous body from the anterior chamber. In intact rabbit eyes, most of the injected 11-deoxycortisol had disappeared from the anterior chamber by 12 hours after injection. The injection of 11-deoxycortisol had no effect on IOP, corneal endothelial density, or the microstructure of the corneal endothelium.. The injection of 11-deoxycortisol in the anterior chamber is useful in visualizing the vitreous body and has no significant side effects. This technique might reduce the intraoperative and postoperative complications of anterior vitrectomy after posterior capsule rupture.

Topics: Animals; Anterior Chamber; Cell Count; Cortodoxone; Disease Models, Animal; Endothelium, Corneal; Eye Diseases; Intraocular Pressure; Intraoperative Complications; Lens Capsule, Crystalline; Postoperative Complications; Prolapse; Rabbits; Rupture; Safety; Vitreous Body

We have reported previously that conjugated estrogens that are effective in shortening the prolonged bleeding time in uremic patients are also effective on bleeding time in a rat model of uremia. Using such a rat model we have recently demonstrated that nitric oxide (NO), an endothelium-derived vasodilator, is involved in mediating the bleeding tendency of uremia. With the present study we wanted to investigate whether conjugated estrogen mixture or its active component, 17 beta-estradiol, reduce uremic bleeding by interfering with the NO pathway. Our results showed that the shortening effect of conjugated estrogen and 17 beta-estradiol on bleeding time of uremic rats was completely reversed by giving the animals the NO precursor L-arginine, but not D-arginine, which is not a precursor of NO. Dexamethasone which at variance to progesterone inhibits the process of induction of NO-forming enzyme, shortened the prolonged bleeding time of uremic rats within 4 hours from injection. This effect was eliminated by L-arginine but not D-arginine administration. The glucocorticoid receptor antagonist cortexolone prevented the shortening of bleeding time induced by dexamethasone, suggesting that a receptor-mediated mechanism is involved in the hemostatic effect of dexamethasone as previously reported for estrogens. Unlike conjugated estrogens and dexamethasone, progesterone had no effect on bleeding time. All these findings would indicate that the effect of estrogens and dexamethasone on primary hemostasis in uremia might be mediated by changes in NO synthetic pathway.

Topics: Animals; Arginine; Bleeding Time; Cortodoxone; Dexamethasone; Disease Models, Animal; Estrogen Antagonists; Estrogens, Conjugated (USP); Male; Nitric Oxide; Rats; Rats, Inbred Strains; Uremia

An in vivo model of tumor-induced angiogenesis was used to monitor two known inhibitors of angiogenesis, protamine sulfate and the steroid tetrahydro S. Tumor cells entrapped in alginate beads were injected s.c. into mice. Blood vessel induction was measured by two quantitative methods: measurement of hemoglobin at the alginate pellet site, and pooling of radiolabeled RBC to the alginate pellet site. The two methods gave parallel results. Tetrahydro S with or without heparin inhibited blood vessel growth by 50%, and protamine sulfate inhibited blood vessel growth by 85%. These results were supported by gross morphology and histological analysis of the alginate pellet site.

Topics: Animals; Cortodoxone; Disease Models, Animal; Drug Synergism; Female; Heparin; Lung Neoplasms; Mice; Mice, Inbred BALB C; Neovascularization, Pathologic; Protamines

It is known that hydrocortisone can be converted to a potent angiogenesis inhibitor by coadministration with heparin or with a sulfated cyclodextrin. The activity of tetrahydrocortisol-S, a purely angiostatic corticosteroid, can be potentiated by beta-cyclodextrin tetradecasulfate as shown in this study. This drug "pair" and other pairs of corticosteroids and beta-cyclodextrin tetradecasulfate can be applied topically to inhibit corneal neovascularization. Endotoxin-induced corneal neovascularization in rabbits was treated with beta-cyclodextrin tetradecasulfate coadministered with either: hydrocortisone, tetrahydrocortisol-S, or 6-alpha-fluoro-17,21-dihydroxy-16-beta-methyl-pregna-4,9(11),diene,3, 20-dione. When optimal ratios of steroid and cyclodextrin were used, neovascularization was reduced to 13%, 26%, and 28% of untreated controls for the three steroids, respectively. Hydrocortisone-cyclodextrin drug pairs suppressed virtually all inflammatory cell infiltration (induced by endotoxin), whereas tetrahydrocortisol-cyclodextrin pairs only partially reduced inflammation. These results demonstrate that corneal neovascularization and corneal inflammation are separable processes and that the neovascularization may be treated specifically using angiostatic steroids without inflammatory activity.

Topics: Administration, Topical; Angiogenesis Inducing Agents; Animals; beta-Cyclodextrins; Betamethasone; Corneal Neovascularization; Cortodoxone; Cyclodextrins; Disease Models, Animal; Drug Synergism; Hydrocortisone; Male; Rabbits