prostaglandin-d2 and oxatomide

Oxatomide (OXA), a histamine H1 receptor antagonist, is effective in the treatment of patients with allergic rhinitis, some allergic skin disorders, and bronchial asthma. We have characterized the effect of OXA on the immunologic release of preformed (histamine and tryptase) and de novo synthesized mediators (leukotriene C4:LTC4 and prostaglandin D2:PGD2) from human basophils and mast cells purified (from 10 to 82%) from human lung parenchyma (HLMC) and skin tissue (HSMC). Preincubation (15 min, 37 degrees C) of basophils with OXA (10(-7)-10(-5) M) before Der p I antigen or anti-IgE challenge concentration-dependently (10-40%) inhibited the immunologic release of histamine and LTC4. OXA (10(-7)-10(-5) M) also inhibited (10-40%) histamine, tryptase and LTC4 release from HLMC activated by anti-IgE. In addition, OXA caused a concentration-dependent inhibition of histamine, tryptase and PGD2 release from HSMC immunologically challenged with a monoclonal antibody against the alpha chain of the high affinity receptor for IgE (anti-Fc epsilon RI) or anti-IgE. These results demonstrate that OXA exerts anti-inflammatory activities by inhibiting the release of preformed and de novo synthesized mediators from human basophils and mast cells.

Topics: Adult; Basophils; Cells, Cultured; Chymases; Histamine H1 Antagonists; Histamine Release; Humans; Leukotriene C4; Lung; Mast Cells; Middle Aged; Piperazines; Prostaglandin D2; Serine Endopeptidases; Skin; Tryptases

Recently, mast cell stabilizers, so called antiallergic drugs, that also have blocking effects on receptors for chemical mediators (CM) have been developed. The present study investigated the effects of a new antiallergic drug, epinastine (3-amino-9,13b-dihydro-1H-dibenz[c,f]imidazol [1,5-a]azepine hydrochloride, WAL 810 CL; CAS 80012-43-7) on the in vivo bronchoconstriction (BC) induced by several CM as compared with those of other antiallergic drugs such as ketotifen, azelastine and oxatomide. Male Hartley guinea pigs were used. The BC was measured with a modified Konzett-Rössler method and expressed as a change in ventilation overflow (VO) under anesthesia. Antiallergic drugs were given orally 1 h before i.v. administration of CM. I.v. administrations of histamine (His), U-46619 (thromboxane A2 mimetic), leukotriene D4 (LTD4), prostaglandin D2 (PGD2), substance P (SP), neurokinin A (NKA), bradykinin (BK) and endothelin-1 (ET-1) increased VO in a dose dependent manner. The potency was as follows; ET-1 greater than LTD4 greater than NKA much greater than U-46619 greater than SP greater than His greater than BK much greater than PGD2. All the antiallergic drugs used markedly inhibited the His-induced BC. Epinastine, ketotifen and azelastine also significantly inhibited the BK-induced BC; epinastine had the strongest anti-BK effect among them. On the other hand, the four antiallergic drugs did not inhibit the BC induced by the other CM except for His and BK. Based on the above results, it is suggested that epinastine possesses anti-His and BK effects, and therefore could be promising as a new antiallergic drug without sedative effect.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Bradykinin; Bronchoconstriction; Dibenzazepines; Guinea Pigs; Histamine; Histamine H1 Antagonists; Imidazoles; Ketotifen; Male; Neurokinin A; Phthalazines; Piperazines; Prostaglandin D2; Prostaglandin Endoperoxides, Synthetic; SRS-A; Substance P

The effect of oxatomide, an orally active antiallergic drug, on immunoreactive LTC4 (iLTC4) production has been studied in rat peritoneal exudate cells (PEC) and guinea-pig lung fragments using the calcium ionophore A23187 and specific antigen in vitro. Oxatomide (10(-5) M) inhibited iLTC4 release by 70% with A23187 from rat PEC, and by 48% with antigen from guinea-pig lung. Oxatomide is supposed to affect the biosynthesis pathway of leukotrienes, because oxatomide inhibits 5-lipoxygenase from guinea-pig peritoneal leukocytes with an IC50 17 microM. Oxatomide also depressed the release of PGD2 from rat peritoneal mast cells stimulated by A23187 (IC50 4.2 microM). The effects of oxatomide on iLTC4 and PGD2 release were more potent than other antiallergic drugs (DSCG, ketotifen, tranilast).

Topics: Animals; Arachidonate 5-Lipoxygenase; Calcimycin; Cromolyn Sodium; Guinea Pigs; Ketotifen; Lung; Mast Cells; ortho-Aminobenzoates; Piperazines; Prostaglandin D2; Prostaglandin-Endoperoxide Synthases; Prostaglandins D; Rats; SRS-A