ovalbumin and 3-5-bis(acetoxyacetylamino)-4-chlorobenzonitrile

1. The effect of TYB-2285 on the antigen-induced accumulation of eosinophils into the airway was investigated in two models (inhalant sensitization and noninhalant sensitization) using Brown Norway (BN) rats. 2. In the method of inhalant sensitization, BN rats were sensitized by weekly exposure to ovalbumin (OA). The accumulation of eosinophils was inhibited by the oral administration of TYB-2285 for the first 2 days of each sensitization in a dose-dependent manner. 3. With noninhalant sensitization, BN rats were sensitized by i.m. injection of OA and i.p. injection of killed Bordetella pertussis. The accumulation of eosinophils was inhibited by TYB-2285 in a dose-dependent manner, when TYB-2285 is given p.o. 5 mm before and 5 hr after the antigen exposure. Moreover, this accumulation of eosinophils was inhibited by a single administration of TYB-2285 5 hr after the antigen exposure, presumably when the mast cell degranulation was already finished. 4. In the method with noninhalant sensitization, the accumulation of eosinophils was not inhibited by mast cell stabilizers such as ketotifen, tranilast, or DSCG. 5. The present study demonstrates that TYB-2285, unlike other mast cell stabilizers, inhibits the antigen-induced accumulation of eosinophils into the airway. It also suggests that this drug might be effective in asthmatic patients.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Antigens; Bordetella pertussis; Bronchoalveolar Lavage Fluid; Dose-Response Relationship, Drug; Eosinophils; Female; Male; Mast Cells; Nitriles; Ovalbumin; Rats; Rats, Inbred BN

1. We examined the effect of TYB-2285 on the acute phase and the late phase of lung anaphylaxis in rats. 2. TYB-2285 (3-30 mg/kg PO) inhibited antigen-induced bronchoconstriction and TxB2 production during the acute phase of lung anaphylaxis in a dose-dependent manner. 3. Ketotifen fumarate (30 mg/kg p.o.) inhibited bronchoconstriction and TxB2 production less potently than TYB-2285. 4. TYB-2285 (30 mg/kg p.o.) inhibited the accumulation of neutrophils during the late phase of lung anaphylaxis significantly without a significant change in total cells. 5. Hydrocortisone acetate (100 mg/kg p.o.) inhibited the accumulation of total cells as potent as neutrophils.

Topics: Anaphylaxis; Animals; Anti-Inflammatory Agents; Anti-Inflammatory Agents, Non-Steroidal; Antigens; Bronchoconstriction; Hydrocortisone; Ketotifen; Lung; Male; Neutrophils; Nitriles; Ovalbumin; Rats; Thromboxane B2

1. TYB-2285 (1-30 mg/kg p.o.) inhibited ovalbumin (OA)- and dinitrophenyl-Ascaris (DNPAs)-induced passive cutaneous anaphylaxis (PCA) in a dose-dependent manner. 2. The ED50 of TYB-2285 and ketotifen fumarate on OA-induced PCA were 0.5 and 3.9 mg/kg, respectively. The ED50 of TYP-2285 and amlexanox on DNP-As-induced PCA were 3.5 and 0.9 mg/ kg, respectively. 3. TYB-2285 (3-30 mg/kg p.o.) inhibited histamine consumption at the PCA site. 4. Unlike cyproheptadine or amlexanox, TYB-2285 (30 mg/kg p.o.) did not inhibit histamine-, serotonin-, ascites-, 48/80-, or A23187-induced capillary permeability. It inhibited dextran-induced capillary permeability slightly. 5. These results demonstrate that TYB-2285 inhibits PCA by inhibiting histamine release, although it does not inhibit capillary permeability.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Antigens, Helminth; Ascaris suum; Capillary Permeability; Dinitrobenzenes; Dose-Response Relationship, Drug; Histamine; Male; Nitriles; Ovalbumin; Passive Cutaneous Anaphylaxis; Rats; Time Factors

The effect of a new anti-asthmatic drug, TYB-2285 (3,5-bis(acetoxyacetylamino)-4-chlorobenzonitrile), was investigated in ovalbumin-sensitized guinea-pigs. When guinea-pigs were pretreated with TYB-2285 (300 mg kg-1, p.o., single dose or consecutively for 7 days), the immediate asthmatic response was inhibited as demonstrated by diminished cyanosis, but not the bronchoconstriction. TYB-2285, given singly or consecutively, inhibited the appearance of late asthmatic response and the infiltration of inflammatory cells, such as eosinophils, into the airway. Additionally, airway hyper-responsiveness was also reversed by the single administration of TYB-2285. Luminol-dependent chemiluminescence of airway-infiltrated cells stimulated with A23187 was inhibited by TYB-2285 in a dose-dependent manner. The present study suggests that TYB-2285 inhibits late asthmatic response and airway hyperresponsiveness by inhibiting the accumulation of eosinophils and other inflammatory cells into the airway, and also by inhibiting the production of oxygen radicals from airway-infiltrated cells.

Topics: Animals; Asthma; Bronchoalveolar Lavage Fluid; Calcimycin; Dose-Response Relationship, Drug; Guinea Pigs; Histamine; Luminescent Measurements; Luminol; Male; Nitriles; Ovalbumin; Respiratory Function Tests; Respiratory Hypersensitivity