calcimycin and pemirolast

Although acyclovir (9-(2-hydroxyethoxymethyl) guanine) is an antiviral drug that inhibits DNA polymerase of herpes virus, we have had the experience of an asthmatic patient's peak flow rate being improved by oral administration of acyclovir.. The aim of this experiment is whether acyclovir has anti-asthma effects using an asthma model in guinea-pigs.. The airway response was induced by a single inhalation of calcium ionophore A23187 (2 mg/mL). The airway obstruction was estimated by the ratio of expiration to inspiration time (E/I). The peribronchial eosinophil infiltration and eosinophil influx into bronchoalveolar lavage (BAL) fluid 7 h after the inhalation were also examined. To assess the effects of acyclovir (1, 10, and 100 mg/kg), aminophylline (20 mg/kg) and pemirolast potassium (TBX, 20 mg/kg) on A23187-induced asthmatic response, the drugs were intraperitoneally administered before the inhalation.. The immediate airway obstruction was significantly suppressed by acyclovir (10 mg/kg) and aminophylline, whereas different doses of acyclovir (1 and 100 mg/kg) and TBX showed only a small inhibitory effect on the airway obstruction. On the other hand, the peribronchial eosinophilia was most successfully inhibited by TBX. Acyclovir (10 mg/kg) and aminophylline also suppressed the eosinophilia significantly. Furthermore, acyclovir significantly suppressed eosinophil influx into BAL fluid, whereas aminophylline and TBX weakly suppressed the influx.. These results suggest that acyclovir exhibits not only antiviral but also antiasthma activity.

Topics: Acyclovir; Aminophylline; Animals; Anti-Asthmatic Agents; Antiviral Agents; Asthma; Bronchi; Bronchoalveolar Lavage Fluid; Bronchoconstriction; Calcimycin; Eosinophils; Guinea Pigs; Histamine Antagonists; Humans; Male; Middle Aged; Peak Expiratory Flow Rate; Pyridines; Pyrimidinones; Time Factors

To determine whether pemirolast, a new antiallergic drug, inhibits the activation of eosinophils, we investigated the effect of pemirolast on the release of leukotriene C4 (LTC4) and eosinophil cationic protein (ECP) from human eosinophils. Calcium ionophore A23187 caused both LTC4 and ECP release from human eosinophils, whereas PAF and FMLP induced only ECP release from the eosinophils. Pemirolast (10(-6) to 10(-3) M) inhibited A23187-induced LTC4 release from the eosinophils in a dose-dependent fashion with 77% inhibition at 10(-3) M. Pemirolast (10(-5) to 10(-3) M) inhibited A23187-induced ECP release from the eosinophils in a dose-dependent fashion with 42% inhibition at 10(-3) M. Pemirolast (10(-4) and 10(-3) M) also inhibited PAF-induced and FMLP-induced ECP release from the eosinophils. We conclude that pemirolast prevents the activation of human eosinophils to inhibit LTC4 and ECP release. These results suggest that pemirolast might be useful in controlling allergic diseases by inhibiting eosinophil activation.

Topics: Asthma; Blood Proteins; Calcimycin; Eosinophil Granule Proteins; Eosinophils; Humans; In Vitro Techniques; Leukotriene C4; N-Formylmethionine Leucyl-Phenylalanine; Platelet Activating Factor; Pyridines; Pyrimidinones; Ribonucleases; Secretory Rate

Phosphatidylinositol (PtdIns) is the key precursor of phosphoinositide-derived intracellular mediators. The effects of changing the rate of PtdIns synthesis on mitogenic activity of human amnion-derived WISH cells were investigated. Incubation of the cells with [3H]inositol caused a time- and dose-dependent PtdIns labeling. Exogenous Ca2+ inhibited [3H]inositol incorporation in a dose-dependent fashion; half-maximal inhibition occurred with 0.3-1.0 mM Ca2+. In contrast, removal of cytosolic Ca2+ by ionophore A23187 and 1 mM EGTA induced enhancement of the PtdIns labeling as a function of A23187 concentration, perhaps through release of inhibitory effects of endogenous Ca2+. The A23187-stimulated PtdIns labeling with [3H]inositol was not abolished by additional unlabeled inositol, suggesting that [3H]inositol labeling of PtdIns occurred mainly through de novo synthesis catalyzed by PtdIns synthase (EC 2.7.8.11). In cells with PtdIns synthase activity decreased by exogenous Ca2+, [3H]thymidine incorporation was also inhibited, while A23187 caused dose-dependent enhancement of thymidine incorporation. The changes in PtdIns synthase activity occurred in parallel with changes in mitogenic activity caused by increasing the dose of exogenous Ca2+ or A23187. A similar lowering of mitogenic activity was observed upon suppression of PtdIns synthase by pemirolast potassium (9-methyl-3-1H-tetrazol-5yl-4H-pyrido[1,2-a]pyridin-4-one potassium) via a Ca(2+)-independent mechanism. These data demonstrate that changes in PtdIns synthase activity by some agents acting via different mechanisms are associated with parallel changes in thymidine incorporation, and suggest that PtdIns production is tightly coupled to cell proliferation in human amnion cells.

Topics: Amnion; Calcimycin; Calcium; CDP-Diacylglycerol-Inositol 3-Phosphatidyltransferase; Cell Division; Cell Line; DNA; Dose-Response Relationship, Drug; Egtazic Acid; Gene Expression; Histamine Antagonists; Humans; Inositol; Magnesium; Membrane Proteins; Phosphatidylinositols; Phosphotransferases; Pyridines; Pyrimidinones; Time Factors; Transferases (Other Substituted Phosphate Groups)

The ability of 9-methyl-3-(1H-tetrazol-5-yl)-4H-pyrido[1,2-a]pyrimidin-4-one potassium salt (TBX) to inhibit histamine release from both peritoneal exudate cells (PEC) containing mast cells and lung fragments of rats was investigated in vitro. Low concentrations of TBX dose-dependently inhibited IgE-mediated histamine release from PEC of passively sensitized animals; its IC50 was 5.1 x 10(-9) g/ml. When TBX was added simultaneously with the antigen challenge, the highest inhibition was obtained. In contrast, extension of preincubation time with the agent resulted in a marked decrease in the inhibition of histamine release. The potent inhibition of histamine release by TBX was observed equally in glucose-free as well as complete Tyrode's solution, whereas TBX reduced its inhibitory action in Ca2+-free or D2O-supplemented medium. In addition, TBX inhibited compound 48/80- but not calcium ionophore A23187-induced histamine release from normal PEC. With regard to the intracellular cyclic AMP level in normal PEC, it was significantly enhanced by a high concentration of TBX (10(-3) g/ml). TBX also inhibited antigen-induced histamine release from lung fragments of actively immunized animals. Interestingly, TBX displayed non-competitive inhibition of cyclic AMP-dependent phosphodiesterase derived from lung homogenates; its K1 value was 8.70 x 10(-4) M.

Topics: 3',5'-Cyclic-AMP Phosphodiesterases; Animals; Antigens; Calcimycin; Cromolyn Sodium; Cyclic AMP; Histamine Release; In Vitro Techniques; Lung; Male; Mast Cells; p-Methoxy-N-methylphenethylamine; Peritoneal Cavity; Pyridines; Pyrimidinones; Rats; Rats, Inbred Strains