levocetirizine 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

Both glucocorticoids and H1-antihistamines were widely used on patients with allergic rhinitis (AR) and obstructive airway diseases. However, their direct effects on airway smooth muscle were not fully explored. In this study, we tested the effectiveness of prednisolone (Kidsolone) and levocetirizine (Xyzal) on isolated rat trachea submersed in Kreb's solution in a muscle bath. Changes in tracheal contractility in response to the application of parasympathetic mimetic agents were measured. The following assessments of the drug were performed: (1) effect on tracheal smooth muscle resting tension; (2) effect on contraction caused by 10(-6) M methacholine; (3) effect of the drug on electrical field stimulation (EFS) induced tracheal smooth muscle contractions. The result revealed sole use of Kidsolone or Xyzal elicited no significant effect or only a little relaxation response on tracheal tension after methacholine treatment. The tension was 90.5 ± 7.5 and 99.5 ± 0.8 % at 10(-4) M for Xyzal and 10(-5) M for Kidsolone, respectively. However, a dramatically spasmolytic effect was observed after co-administration of Kidsolone and Xyzal and the tension dropped to 67.5 ± 13.6 %, with statistical significance (p < 0.05). As for EFS-induced contractions, Kidsolone had no direct effect but Xyzal could inhibit it, with increasing basal tension. In conclusion, using glucocorticoids alone had no spasmolytic effect but they can be synergized with antihistamines to dramatically relax the trachea smooth muscle within minutes. Therefore, for AR patients with acute asthma attack, combined use of those two drugs is recommended.

Topics: Animals; Cetirizine; Cholinergic Agents; Disease Models, Animal; Drug Synergism; Electric Stimulation; Glucocorticoids; Histamine Antagonists; Humans; Lung Diseases, Obstructive; Male; Methacholine Chloride; Muscle Contraction; Muscle, Smooth; Prednisolone; Rats; Rhinitis, Allergic; Trachea; Treatment Outcome

Substantial evidence implicates mast cells and their main constituent histamine in the pathogenesis of visceral hypersensitivity. We explored the specific contribution of histamine H4 (H4R) and H1 (H1R) receptors to visceral hypersensitivity in a postinflammatory rat model.. Trinitrobenzenesulfonic acid (TNBS)-colitis was monitored individually by colonoscopy: first on day 3 to confirm the presence of colitis and then every 4 days, starting from day 10, to monitor convalescence and determine the exact timepoint of endoscopic healing in each rat. Experiments were performed 3 days after endoscopic resolution of colitis. Visceral sensitivity was assessed by quantifying visceromotor responses (VMRs) to colorectal distension. Colonic mast cell numbers, histamine release and H4R and H1R mRNA expression were quantified. JNJ7777120 (H4R antagonist) and/or levocetirizine (H1R antagonist) were administered 30 min prior to VMR assessment or histamine release assay.. Postcolitis rats displayed a higher number of colonic mast cells, excessive histamine release and significantly enhanced VMRs. Heightened VMRs were dose-dependently reduced by JNJ7777120 and levocetirizine; combined administration of JNJ7777120 and levocetirizine potentiated the antinociceptive effect. In the colon, both H4R and H1R mRNA were present; in the dorsal root ganglia, only H1R mRNA was found. Only colonic H4R mRNA expression was increased in postcolitis rats. Excessive histamine release in postcolitis rats was attenuated by the highest dose of JNJ7777120.. H4R and H1R antagonists dose-dependently reduce and even normalise postinflammatory visceral hypersensitivity via different underlying mechanisms but with a synergistic effect. Both receptor subtypes represent promising targets for the treatment of postinflammatory visceral hypersensitivity.

Topics: Animals; Cetirizine; Colitis; Colonoscopy; Convalescence; Disease Models, Animal; Histamine; Histamine H1 Antagonists, Non-Sedating; Histamine Release; Hypersensitivity; Indoles; Intestinal Mucosa; Male; Mast Cells; Piperazines; Rats; Rats, Sprague-Dawley; Receptors, G-Protein-Coupled; Receptors, Histamine; Receptors, Histamine H1; Receptors, Histamine H4; Regeneration; Trinitrobenzenesulfonic Acid

Allergy is thought to be one of the etiologic factors in otitis media. The purpose of this study was to determine the histopathologic effects of H1 histamine receptor antagonists in an experimental histamine-induced middle ear inflammation model. In group A (20 rabbits), histamine challenge followed a 3-day intramuscular pretreatment with a single dose of 0.1 ml hydroxyzine hydrochloride (50 mg/ml) per day. In group B (20 rabbits), histamine challenge followed a 3-day pretreatment with a single dose 1.2 mg desloratadine per day orally. In group C (20 rabbits), histamine challenge followed a 3-day pretreatment with a single dose 1.2 mg levocetirizine per day orally. On the fourth day after baseline otomicroscopy 0.5 ml histamine 20 mg/ml was injected transtympanically on the right. Middle ear mucosa was removed and the following parameters were assessed: edema, vascular dilatation and congestion, inflammation, acute inflammatory component, presence of eosinophils, activity of the inflammation and fibrosis. A semi-quantitative grading system of 0-3 was used for grading of all parameters and statistical analysis performed by using the Mann-Whitney non-parametric test. Group A mucosae showed lower grades of all the parameters evaluated compared with those of group B. Histopathology of the mucosae of group C showed lower grade of inflammation compared with group B with significant statistical difference for the seven parameters tested. Our data validate the use of antihistamines in the treatment of refractory OME of allergic origin. Oldest H1 antagonists can be replaced by the newest agents who counteract successfully histamine effects, without any interactions or adverse effects from central nervous system.

Topics: Animals; Cetirizine; Disease Models, Animal; Ear, Middle; Female; Histamine H1 Antagonists, Non-Sedating; Loratadine; Male; Mucous Membrane; Otitis Media with Effusion; Rabbits