Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P15088 (mast cell)
 14,925 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Astemizole (0.5-5 mg/kg, p.o.) dose-dependently inhibited heterologous and homologous PCA reactions in rats at ID50 values of 1.48 mg/kg and 2.37 mg/kg, respectively. The inhibitory effect of astemizole on heterologous PCA was most remarkable when this compound was given p.o. 2 h prior to antigen challenge. Astemizole (0.1-5 mg/kg, p.o.) dose-dependently inhibited experimentally-induced asthma in guinea pigs at an ID50 of 0.86 mg/kg. Ex vivo, astemizole (0.5-5 mg/kg, p.o.) inhibited antigen-induced histamine release from lung pieces of sensitized guinea pigs. In in vitro experiments, the drug dose-dependently inhibited antigen-induced histamine and SRS-A releases from guinea pig lung pieces at concentrations of 0.05-10 microM. Furthermore, astemizole (0.1-10 microM) inhibited the histamine release induced by compound 48/80 and antigen-antibody reaction from rat peritoneal mast cells, and at 0.1-500 nM inhibited both leukotriene C4- and platelet-activating factor (PAF)-induced contraction of isolated guinea pig trachea at submicromolar concentrations. Astemizole not only inhibited 45Ca uptake into rat mast cells but also prevented the Ca2+ release from the intracellular Ca store induced by compound 48/80, although this compound did not affect the histamine release from permeabilized mast cells induced by Ca2+. Our results suggest that one of the antiallergic mechanisms of astemizole may be an inhibition of signal transduction from the mast cell membrane to the intracellular systems.
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PMID:Antiallergic effects of astemizole on immediate type hypersensitivity reactions. 170 34

Astemizole (Hismanal) is a chemically novel compound selected from a series of piperidinylaminobenzimidazoles. Further preclinical pharmacological investigations were initiated by experiences with other drugs in the same field. The aim of this review is to illustrate new pharmacological data on astemizole. Astemizole showed the lowest ED50 and the longest duration in mast cell-mediated shock. Binding characteristics to histamine H1 receptors were specificity, selectivity and long duration. Lack of effects on the wakefulness-sleep cycles was evidenced. An equal bioavailability of the drug was demonstrated with different formulations, dosing and food intake. High plasma levels of desmethylastemizole, the major metabolite, and longer half-life than for astemizole, contribute partly to the antihistamine activity. On chronic administration relative amounts of both molecules in the peripheral compartment are most likely responsible for the expected pharmacological effect. The time-course of kinetics shows, the peak plasma levels of the unchanged astemizole followed by a gradual take-over by desmethylastemizole. In patients with hepatic or renal insufficiency the pharmacokinetic background was similar to healthy volunteers.
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PMID:[Astemizole: its pharmacokinetics and pharmacologic properties]. 197 37

The effects of a series of analogues of the antiallergic drug astemizole on the exocytosis of the enzyme beta-hexosaminidase were studied in a mast cell model, the rat basophilic leukemia (RBL-2H3) cell. Besides differences in the effects on Fc epsilonRI receptor-stimulated exocytosis, changes were also observed in Ca2+ influx and in the perturbation of the cell membrane. A strong correlation was found between the effects on antigen- and thapsigargin-stimulated 45Ca2+ influx. Furthermore, the inhibition of 45Ca2+ influx was correlated with the inhibition of beta-hexosaminidase release and membrane stabilization. It is concluded that the astemizole analogues are capable of inhibiting mast cell beta-hexosaminidase release through inhibition of Ca2+-store-operated Ca2+ channels (SOC). Compounds with high lipophilicity also released Ca2+ from intracellular stores. Lowering of the hydrophobicity by introduction of nitrogens or truncation at different sites in the astemizole structure decreased inhibitory activity on SOC channels. The inhibition of SOC channels cannot completely be ascribed to non-specific membrane effects. The piperidinyl-benzimidazole moiety was found to be important for inhibition of SOC channels. The observed differences in activity possibly depend on the way the compounds penetrate the membrane bilayer. Astemizole is an interesting new tool to study SOC channels and can be a lead for the design of mast cell-stabilizing antiallergic drugs.
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PMID:Structure-activity relationships of astemizole derivatives for inhibition of store operated Ca2+ channels and exocytosis. 969 27