loteprednol-etabonate 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

Loteprednol etabonate (LE) is the first, highly successful soft corticosteroid (SC) designed using the 'inactive metabolite' approach, starting with ∆. The new 6α, 9α, 16α and β 17α-dichloroacetyl 17β-esters were synthesized from the correspondingly substituted ∆. The 6α or 9α-fluoro substitution produced highly potent corticosteroids, but the 17α-dichloroacetyl substituent provided 'softness' in all cases. Local application of these steroids will significantly reduce systemic activity, due to the facile hydrolytic deactivation of these molecules.. A 17α-dichloroacetyl derivative of fluticasone (FLU) is highly potent but much safer than the currently used propionate or furoate ester.

Topics: Adrenal Cortex Hormones; Animals; Anti-Inflammatory Agents; Disease Models, Animal; Fluticasone; Lipopolysaccharides; Loteprednol Etabonate; Male; Ovalbumin; Rats; Rats, Inbred BN; Structure-Activity Relationship; Tumor Necrosis Factor-alpha

The aim of the current study is to compare the effects of two corticosteroids, prednisolone acetate 1% (PA) and loteprednol etabonate 0.5% (LE), for the treatment of benzalkonium chloride (BAC)-induced dry eye syndrome (DES) in rats.. DES was established by topical administration of 0.2% BAC, a commonly used preservative in ophthalmic drugs, for 1 week. Rats were divided into 3 groups just after establishment of DES: PA-treated (Group 1, n=10), LE-treated (Group 2, n=10), and vehicle-treated (Group 3, n=10). Rats were treated by topical administration of PA, LE, or vehicle twice daily for 1 week. The Schirmer test, break-up time score, Fluorescein staining, Rose Bengal staining, and inflammatory index scoring (IIS) tests were performed at all weeks. After the end of the study, eyes of the rats were enucleated and analyzed using light microscopy.. The mean aqueous tear volume was significantly increased in both PA- and LE-treated rats (P<0.05), although decreased in vehicle-treated rats (P>0.05). Histologically, diffuse inflammatory cell infiltration was observed in vehicle-treated rats, while inflammation induced by BAC was almost completely resolved in both PA- and LE-treated groups.. In the current study, we showed that both PA and LE are effective treatments in a rat model of BAC-induced DES, which is commonly observed in clinics. No significant differences were observed between the 2 corticosteroids in the efficacy of BAC-induced type of DES treatment.

Topics: Administration, Topical; Androstadienes; Animals; Benzalkonium Compounds; Disease Models, Animal; Dry Eye Syndromes; Inflammation; Loteprednol Etabonate; Male; Prednisolone; Preservatives, Pharmaceutical; Rats; Rats, Wistar; Tears

To investigate the ocular hypertensive response to topical dexamethasone (DEX), rimexolone (RIM), loteprednol etabonate (LOT) and fluorometholone (FML) in rabbits of different ages.. Seventy-five rabbits of three age groups (7 weeks, 6 months and 1-year old) received topical administration of 0.1% DEX, 1% RIM, 0.5% LOT, 0.1% FML or balanced salt solution four times daily for 1 month. Intraocular pressure (IOP) was monitored at regular time intervals. After a month, eyes were harvested for histological study with haematoxylin and eosin (H&E), periodic acid Schiff and Masson trichrome staining. Trabecular meshwork changes were graded by masked ocular pathologists.. Topical DEX caused the greatest increase in IOP, followed by RIM and FML. LOT caused the least IOP increase. Similar pattern of IOP response to the four corticosteroids was observed in the three studied age groups. Young rabbits (7 week) were the most responsive to corticosteroids among the age groups. Extracellular matrix thickening in the trabecular meshwork region and loss of trabecular meshwork cells were observed after DEX, FML or RIM treatments.. Young rabbits are more susceptible to steroid induced increase in IOP, even for milder steroids such as fluorometholone and rimexolone.

Topics: Administration, Topical; Age Factors; Androstadienes; Animals; Dexamethasone; Disease Models, Animal; Extracellular Matrix Proteins; Fluorometholone; Glucocorticoids; Intraocular Pressure; Loteprednol Etabonate; Male; Ocular Hypertension; Ophthalmic Solutions; Pregnadienes; Rabbits; Tonometry, Ocular; Trabecular Meshwork

The aim of this study was to compare the anti-inflammatory activities of ketorolac tromethamine 0.4% and 0.1%; diclofenac sodium 0.1%; and loteprednol etabonate 0.5% suspension in an animal model of ocular inflammation.. An ocular inflammatory response was induced in New Zealand White rabbits by the intravenous (i.v.) administration of 10 microg/kg lipopolysaccharide (LPS). In study animals, 1 eye was treated topically with 50 microL of study medication (n = 8 animals per drug) and the other eye was treated topically with a 50-microL vehicle (buffered saline). In control animals (n = 8), both eyes were treated with vehicle. All animals were treated twice: 2 h and 1 h before LPS challenge. The breakdown of the blood-aqueous barrier in the anterior chamber was measured by fluorophotometry (FITC-dextran 30 mg/kg, i.v. given immediately after LPS challenge). Aqueous prostaglandin E(2) (PGE(2)) levels were measured using an enzyme-linked immunosorbent assay (ELISA) immunoassay.. Ketorolac 0.4% resulted in a nearly complete inhibition of endotoxin-induced increases in FITC-dextran and PGE(2) synthesis (P < 0.001 vs. vehicle). Diclofenac 0.1% had much less of an effect on these parameters (P < 0.01 vs. ketorolac 0.4%). Loteprednol 0.5% was no more effective than vehicle at inhibiting increases in FITC-dextran.. Ketorolac has greater anti-inflammatory effects than diclofenac and loteprednol.

Topics: Androstadienes; Animals; Anti-Inflammatory Agents; Diclofenac; Disease Models, Animal; Endophthalmitis; Ketorolac Tromethamine; Loteprednol Etabonate; Rabbits

To validate pharmacologically the feline model of steroid-induced ocular hypertension.. Serial studies were conducted in domesticated adult female cats trained to accept topical ocular drug administration and pneumotonometry. To establish intraocular pressure (IOP) values for each study, measurements were performed at the same time of day for 6 consecutive days. Beginning on day 7, cats received either steroid or vehicle administered topically to both eyes three times a day for approximately 28 days. The IOP measurements were performed daily.. After 5 to 7 days of treatment with 0.1% dexamethasone or 1.0% prednisolone acetate, IOP began to increase, reaching peak values within 2 weeks. These values were sustained throughout dosing but declined rapidly to baseline upon cessation of treatment. Maximum IOPs for the dexamethasone- and prednisolone-treated groups averaged 4.5 +/- 0.3 mm Hg (n = 12) greater than the mean IOP value obtained in vehicle-treated cats. Cats treated with 0.25% fluorometholone, 1.0% loteprednol etabonate, and 1.0% rimexolone exhibited increases of 0.6, 1.2, and 1.7 mm Hg, respectively. These values were significantly lower than those observed following treatment with dexamethasone or prednisolone.. The ocular hypertensive effects of selected anti-inflammatory topical ocular steroids in this model are consistent with clinical findings.. This feline model is a useful tool for assessing the potential IOP liability of novel anti-inflammatory steroids.

Topics: Administration, Topical; Androstadienes; Animals; Cats; Dexamethasone; Disease Models, Animal; Female; Fluorometholone; Glucocorticoids; Humans; Intraocular Pressure; Loteprednol Etabonate; Ocular Hypertension; Ophthalmic Solutions; Prednisolone; Pregnadienes; Random Allocation; Reproducibility of Results; Tonometry, Ocular

Loteprednol etabonate (LE) is a novel steroid with a low tendency to raise IOP. It is metabolized in the eye to an inactive metabolite. The current study was undertaken to assess the intra-ocular anti-inflammatory activity of LE in two models of experimental uveitis in rabbits. In the endotoxin induced rabbit model, LE was effective at reducing measures of inflammation, but less so that either fluorometholone (FML) or dexamethasone. In the Freunds adjuvant chronic uveitis model, FML was also very effective with LE and dexamethasone showing similar activity. The data demonstrate that LE is effective at reducing intra-ocular inflammation.

Topics: Androstadienes; Animals; Anti-Inflammatory Agents; Chronic Disease; Dexamethasone; Disease Models, Animal; Fluorometholone; Intraocular Pressure; Loteprednol Etabonate; Ophthalmic Solutions; Rabbits; Uveitis, Anterior