Mastoid pneumatization in children with congenital cholesteatoma: an aspect of the formation of open-type and closed-type cholesteatoma

We investigated the effect of spirulina on mast cell-mediated immediate-type allergic reactions. Spirulina dose-dependently inhibited the systemic allergic reaction induced by compound 48/80 in rats. Spirulina inhibited compound 48/80-induced allergic reaction 100% with doses of 100-1000 microg/g body weight, i.p. Spirulina (10-1000 microg/g body weight, i.p.) also significantly inhibited local allergic reaction activated by anti-dinitrophenyl (DNP) IgE. When rats were pretreated with spirulina at a concentration ranging from 0.01 to 1000 microg/g body weight, i.p., the serum histamine levels were reduced in a dose-dependent manner. Spirulina (0.001 to 10 microg/mL) dose-dependently inhibited histamine release from rat peritoneal mast cells (RPMC) activated by compound 48/80 or anti-DNP IgE. The level of cyclic AMP in RPMC, when spirulina (10 microg/mL) was added, transiently and significantly increased about 70-fold at 10 sec compared with that of control cells. Moreover, spirulina (10 microg/mL) had a significant inhibitory effect on anti-DNP IgE-induced tumor necrosis factor-alpha production. These results indicate that spirulina inhibits mast cell-mediated immediate-type allergic reactions in vivo and in vitro.     

Inhibition of immediate type allergic reactions by the aqueous extract of Kum-Hwang-San

We studied the effect of aqueous extract of Kum-Hwang-San (KHS) on mast cell-mediated immediate type allergic reactions. KHS (1-100 microg/site) inhibited concentration-dependently mast cell-dependent ear swelling response induced by compound 48/80 (200 microg/site) in mice by both topical and intradermal application. KHS (0.1-100 microg/site) inhibited concentration-dependently passive cutaneous anaphylaxis induced by anti-dinitrophenyl (DNP) IgE in rats by both topical and intradermal application. KHS also inhibited concentration-dependently the histamine release from the rat peritoneal mast cells (RPMC) by compound 48/80 and anti-DNP IgE. Moreover, KHS had a significant inhibitory effect on anti-DNP IgE-induced tumor necrosis factor-alpha (TNF-alpha) secretion from RPMC. These results indicate that KHS inhibits immediate type allergic reactions by inhibition of histamine release and TNF-alpha secretion from mast cells in vivo and in vitro.     

Effect of reference database on frequency estimates of polymerase chain reaction (PCR)-based DNA profiles

1. To assess the contribution of an aqueous extract of Ulmi radicis cortex (AEURC) in systemic anaphylaxis, compound 48/80 was used as a fatal anaphylaxis inducer in rats. 2. AEURC completely inhibited anaphylactic shock with a dose of 1.0 g/kg body weight (BW) 1 hr before injection of compound 48/80. 3. AEURC significantly inhibited serum histamine levels induced by compound 48/80. 4. AEURC (1.0 g/kg BW) also inhibited by 79.1% passive cutaneous anaphylaxis activated by anti-dinitrophenyl (DNP) IgE. 5. AEURC dose dependently inhibited the histamine release from the rat peritoneal mast cells (RPMCs) by compound 48/80. Moreover, AEURC had a significant inhibitory effect on anti-DNP IgE-induced histamine release and tumor necrosis factor-alpha production from RPMC. 6. The level of cAMP in RPMC, when AEURC was added, significantly increased compared with that of a normal control. 7. These results indicate that AEURC may possess strong antianaphylactic action.     

A novel embryogenetic mechanism for Currarino''s triad: inadequate dorsoventral separation of the caudal eminence from hindgut endoderm

We studied the effect of sulfasalazine on anaphylaxis. Sulfasalazine dose-dependently inhibited systemic anaphylaxis induced by compound 48/80 in rats. Sulfasalazine also inhibited local anaphylaxis activated by anti-dinitrophenyl (anti-DNP) IgE. Moreover, sulfasalazine dose-dependently inhibited histamine release in the peritoneal mast cells activated by compound 48/80 or anti-DNP IgE. All of these effects were comparable to those of the disodium cromoglycate (reference drug) tested. When sulfasalazine was added, the level of cAMP in rat peritoneal mast cells transiently and significantly increased about 6-fold compared with that of basal cells. Our studies provide evidence that sulfasalazine may be beneficial in the treatment of anaphylaxis.     

Presence of IgM antibodies to Trypanosoma cruzi urinary antigen in sera from patients with acute Chagas'' disease

We have investigated the ability of an antisense immunoglobulin E (IgE) receptor alpha-subunit oligodeoxynucleotide (Fc epsilon RI alpha ODN) specifically to inhibit IgE-mediated allergic reactions in the mouse. Synthetic antisense Fc epsilon RI alpha ODN dose-dependently inhibited passive cutaneous anaphylaxis and histamine release from the mouse peritoneal mast cells (MPMC) activated by anti-dinitrophenyl (DNP) IgE. Northern blot analysis showed that the mast cells treated with antisense Fc epsilon RI alpha ODN exhibited no detectable levels of L-histidine decarboxylase mRNA after anti-DNP IgE stimulation, whereas the cells treated with sense Fc epsilon RI alpha ODN possessed significant amounts of this mRNA. Examination of the elevation of cAMP levels in MPMC following the activation with anti-DNP IgE demonstrated a significant rise in activated cells, but not in the antisense Fc epsilon RI alpha ODN-treated cells. Moreover, antisense Fc epsilon RI alpha ODN had a significant inhibitory effect on anti-DNP IgE-induced tumour necrosis factor-alpha production. Our results demonstrated that antisense Fc epsilon RI alpha ODN inhibited the IgE-mediated allergic reaction in vivo and in vitro.     

Effect of an active metabolite of the antiallergic agent tazanolast on histamine release from rat mast cells

WP-871 (3'-(1H-tetrazol-5-yl)oxanilic acid monohydrate, CAS 114607-46-4) is a monohydrate of a main active metabolite of tazanolast (butyl 3'-(1H-tetrazol-5-yl) oxanilate, CAS 82989-25-1), an orally active antiallergic drug. WP-871 inhibited dose-dependently compound 48/80-induced histamine release from rat peritoneal mast cells. In a similar dose range, WP-871 was effective in inhibiting compound 48/80-induced 45Ca uptake into mast cells from extracellular medium and compound 48/80-induced translocation of protein kinase C from the cytosol to the membrane fraction of mast cells. WP-871 also inhibited inositol trisphosphate production but did not exhibit a direct inhibitory effect on phospholipase C in mast cells. WP-871 caused no increase in cAMP content in mast cells. These results suggest that WP-871 may inhibit histamine release mainly by preventing the increase in intracellular Ca2+ concentration, which is a critical event in signal transduction leading to histamine release in mast cells.     

Dual regulation of the Na+/H(+)-exchange in rat peritoneal mast cells: role of protein kinase C and calcium on pHi regulation and histamine release

1. The purpose of this study was to compare the actions of phorbol 12-myristate 13-acetate (PMA) and ionomycin on Na+/H+ exchange activation and histamine release to that of compound 48/80 in order to study the possible relationship between pHi and secretion of histamine in rat peritoneal mast cells. 2. Resting pHi in mast cells suspended in a bicarbonate-free physiological salt solution amounted to 6.73 +/- 0.05 (mean +/- s.d., n = 52). 3. PMA (20 nM) induced a substantial but rather slow increase in pHi. This response was very sensitive to inhibition by staurosporine, very sensitive to inhibition by 5-(N,N-hexamethylene)amiloride (HMA), insensitive to the absence of extracellular calcium (without EGTA), and sensitive to partial depletion of intracellular calcium with EGTA. 4. Ionomycin (1 microM) induced a biphasic change in pHi that was sensitive to inhibition by HMA, insensitive to staurosporine. In the absence of extracellular calcium using EGTA, the biphasic response disappeared, leaving only a slow, and diminished change in pHi. 5. The effects of ionomycin and PMA on pHi were additive. 6. Addition of the secretagogue compound 48/80 (1 microgram ml-1) increased pHi, substantially, delta pHi amounting to 0.29 +/- 0.05 pH-units (n = 4). The biphasic pHi-response was insensitive to the absence of extracellular calcium (without EGTA). The initial fast response in pHi was, however, inhibited by HMA, not staurosporine. 7. The finding that staurosporine and HMA each inhibited approximately half of the compound 48/80-induced pHi-response, whereas both inhibitors completely abolished the compound 48/80-induced pHi-response seems to indicate that two independent pathways for the activation of the Na+/H+ exchange were stimulated by compound 48/80. 8. The histamine release induced via both PKC activation (using PMA) and calcium (using ionomycin) were much larger than the sum of each activation pathway, whereas in the absence of extracellular calcium using EGTA, the histamine release in response to PMA and ionomycin was completely abolished. 9. The compound 48/80-induced histamine release was partially sensitive to inhibition by HMA (approximately 30% inhibition) and partially sensitive to inhibition by staurosporine (approximately 50% inhibition). Preincubation with staurosporine and HMA before stimulation with compound 48/80 showed the same degree of inhibition as observed after staurosporine alone, even though this combination of drugs completely inhibited the pHi-response. Furthermore, compound 48/80-induced histamine release was not dependent on the presence of extracellular calcium (with and without EGTA). 10. In spite of the similarities in second messenger pathways for pHi regulation and histamine release, it is, however, not very likely that these two processes are directly related. It is, however, possible, that an increase in pHi plays a permissive, rather than an essential role for histamine release in rat peritoneal mast cells. This hypothesis was supported by the finding that preincubation with the Na+/H+ exchange-inhibitor HMA inhibited 30% of the compound 48/80-induced histamine secretion.     

Further studies on the anti-inflammatory effect of insulin

Experiments performed on rats showed that insulin, when applied i.v. or s.c., inhibited the foot edema induced by carrageenin, thermic effect of 45.7 degrees C, compound 48/80 and 5-HT, but moderately increased the paw swelling evoked by kallikrein, a kinin-forming enzyme. The increased vascular permeability elicited by intradermal injection of histamine, 5-HT, bradykinin, PGE1, carrageenin and compound 48/80 was also suppressed. The anti-inflammatory effect was not significantly altered by propranolol and adrenalectomy on the thermal and carrageenin edema, it was variably inhibited on the skin test, and was completely abolished on the paw swelling induced by 5-HT and compound 48/80. Since insulin had little or no effect on the vascular response when given topically together with the vasoactive agents, its complex effect on the acute inflammation appears to be brought about via indirect mechanisms.     

Inhibitory effects of methanolic extract from corydalis tuber against types I-IV allergic models

Methanolic extract (CM-ext) from tubers of Corydalis turtschaninovii forma yanhusuo has been screened for activity in experimental models of types I-IV allergy. In type I allergic models, CM-ext at doses of 200, 500 mg/kg, p.o. inhibited 48-h homologous passive cutaneous anaphylaxis (PCA) in rats which is related to IgE, and 4-h heterologous PCA in guinea pigs which is related to IgG. The inhibition of CM-ext on 48-h PCA was also recognized in adrenalectomized rats. CM-ext exhibited the inhibitory effect on formation of IgE antibody in BALB/c mice. In type II allergic model, it was found that CM-ext inhibits reversed cutaneous anaphylaxis (RCA). In type III allergic model, CM-ext showed the inhibitory effect on direct passive arthus reaction (DPAR) in rats. Furthermore, in type IV allergic model, CM-ext had the inhibitory effects on induction phase and effector phase in picryl chloride-induced contact dermatitis (PC-CD). It also showed therapeutic action on PC-CD. These results indicated that CM-ext not only inhibits antibody-mediated allergic reactions but also influences cell-mediated allergic reactions and should be recognized as a potent material for allergic reactions, although the mechanisms and active principles of CM-ext have not yet been completely determined.     

Human IgG monoclonal antibodies that modulate the binding of specific IgE to birch pollen Bet v 1

Birch pollen allergy is a very frequent pathology in Europe and North America. More than 95% of the tree pollen allergic patients display IgE reactivity against Bet v 1, the major birch pollen allergen. Starting with PBL from a patient desensitized by immunotherapy, we have generated five B cell lines (BAB1 to BAB5) that secrete human IgG mAbs of high affinity for Bet v 1. Although competition studies indicated that these human IgG mAb recognized different epitopes, broad cross-reactivity was found with Bet v 1 homologous allergens present in tree pollens and plant-derived foods. When tested for interference with allergic patients' IgE, BAB1 inhibited (by 80-100%) the binding of IgE to nitrocellulose-blotted Bet v 1, while BAB2 enhanced it. The biologic significance of the ability of BAB1 to interfere with patients' IgE binding is indicated by the finding that BAB1 completely inhibited Bet v 1-induced histamine release from allergic patients' basophils. Allergen-specific human IgG mAbs such as BAB1, which presents high blocking activity in both immunochemical and cellular IgE competition experiments, might have therapeutical application.     

The effects of anti-asthma drugs on mediator release from cultured human mast cells

BACKGROUND: A method for generating human mast cells in vitro was recently established. Little is known about the pharmacological profiles of allergic mediator release from cultured mast cells. OBJECTIVE: The main objective was to investigate the nature of cultured mast cells from a pharmacological point of view. We examined the effect of anti-asthma drugs on the release of histamine, sulfidoleukotrienes (LTs) and prostaglandin D2 (PGD2) from the cultured mast cells. METHODS: Using the method established by Saito et al. we cultured cord blood mononuclear cells in the presence of 80 ng/mL stem cell factor (SCF), 50 ng/mL interleukin-6 (IL-6) and 300 nmol/L prostaglandin E2 (PGE2), and obtained almost pure (> 99%) mast cells. We sensitized cultured mast cells with immunoglobulin E (IgE)-rich serum, and then treated them with some anti-asthma drugs before challenge with anti-human IgE. Released histamine, LTs and PGD2 were measured by high-performance liquid chromatography, commercial enzyme-linked immunosorbent assay (ELISA) and enzyme immunoassay (EIA) systems, respectively. RESULTS: The cultured mast cells released histamine, LTs and PGD2 following immunological stimulation through IgE. The mast cell stabilizing agents disodium cromoglycate (DSCG, 1 mmol/L) and azelastine (100 micromol/L) significantly inhibited the release of these three mediators. The beta-adrenoceptor agonists isoproterenol, salbutamol, and clenbuterol also inhibited all three mediators' release in a concentration-dependent manner. The non-selective and selective phosphodiesterase (PDE) inhibitors theophylline, rolipram, and cilostazol had no significant effect on mediator release at clinically useful concentrations. BAY x 1005 (a 5-lipoxygenase-activating protein inhibitor) inhibited the LTs release, whereas indomethacin (a cyclo-oxygenase I and II inhibitor) and NS-398 (a cyclo-oxygenase II inhibitor) inhibited PGD2 release. CONCLUSIONS: The present results indicate that cultured mast cells release histamine, LTs and PGD2 following IgE crosslinking. Anti-asthma drugs showed a characteristic suppression of the release of each mediator. The suppressive actions of these drugs are similar to their pharmacological actions on human lung mast cells. These results suggest that cultured mast cells are useful for the analysis of function and pharmacological profiles of lung mast cells.     

Inhibitory mechanisms of beta-adrenoceptor agonists for immunoglobulin E-mediated experimental allergic reactions in rats

Inhibitory mechanisms of isoproterenol and clenbuterol for immunoglobulin E (IgE)-mediated experimental allergic reactions in rats were studied. IgE-mediated passive cutaneous anaphylaxis, histamine-induced cutaneous reaction and serotonin-induced cutaneous reaction were evoked at the same time in the same rats. Isoproterenol administered intravenously immediately before challenge inhibited all these reactions significantly. Clenbuterol administered intravenously 0-3 h before challenge also significantly inhibited the three cutaneous reactions. The inhibition was maximum when the drug was given 1 h before challenge. Passive cutaneous anaphylaxis was always inhibited more potently than histamine-induced cutaneous reaction and serotonin-induced cutaneous reaction by these beta-adrenoceptor agonists. Passive peritoneal anaphylaxis was caused by injecting an antigen intravenously. Isoproterenol administered intravenously immediately before challenge inhibited the reaction significantly. Clenbuterol administered intravenously 0-3 h before challenge also significantly inhibited passive peritoneal anaphylaxis, maximally so when given 1 h before challenge. In vitro IgE-dependent histamine release from sensitized peritoneal mast cells or mesenteric mast cells was not affected by isoproterenol and clenbuterol. Mouse monoclonal IgE, a foreign protein, administered intravenously decreased rapidly in the circulation. About 50% of the mouse IgE given disappeared in 20 min. The decrease of mouse IgE was partly but significantly inhibited by the beta-adrenoceptor agonists, and the inhibition was abolished by simultaneous treatment with propranolol. These results indicate that direct inhibition of mast cell activation does not contribute to the potent inhibition of in vivo allergic reactions in rats by beta-adrenoceptor agonists, and that inhibition of the allergic cutaneous reaction is partially explained by the inhibition of vascular permeability increases caused by mast cell mediators. Penetration of intravenously administered antigen from blood vessels to peripheral tissues to cause mast cell activation might be inhibited by beta-adrenoceptor agonists, and this could play some role in inhibiting intravenous antigen-induced allergic reactions in rats. Clenbuterol exhibited its maximum action with some latency in vivo, suggesting that some time-requiring process may be involved in the manifestation of its action.     

IgE antibody up-regulates high affinity IgE binding on murine bone marrow-derived mast cells

We have examined 3-week-old alcian blue positive cells (putatively mast cells) derived from mouse bone marrow for their expression of Fc epsilon RI. Using an indirect method of sensitizing the cells with immunoglobulin E (IgE) antibody (anti-DNP IgE) and detecting the level of bound IgE antibody by flow cytometry, we found that prolonged culture (1-5 days) with IgE, but not IgG, increased the total receptor density 6 +/- 1.9 fold. During the same period, histamine release in response to antigen (DNP-HSA) increased approximately 6-fold while the cell's response to either thrombin or ionomycin remained constant. The greatest up-regulation occurred in the first 2 days of culture. Using 2.4G2 to detect Fc epsilon RII RIII, we could not detect any up-regulation of this receptor. Culturing the cells for 1 h after sensitization did not result in any loss of cell surface IgE, suggesting a reasonably high affinity binding similar to that expected for Fc epsilon RI. This up-regulation was completely inhibited by co-culture with 2 micrograms/ml cycloheximide. These data suggest that IgE is capable of inducing a significant, protein synthesis, dependent up-regulation of its own high affinity receptor on mast cells/basophils.     

Expression of protein kinase C gene family members is temporally and spatially regulated during neural development in vitro

The dog mastocytoma BR cell line provides us with a permanent source of canine mast cells, allowing a characterization of secretory mediators that exert important effects in canine allergic and nonallergic diseases and in physiological processes. We studied the ultrastructural characteristics and histamine releasing activity after immunological and non-immunological stimuli of the dog mastocytoma BR cell line, and compared the cell line to normal skin mast cells enzymatically isolated from healthy dogs. The histamine content of BR cells was 0.04 +/- 0.002 pg/cell, approximately 100-fold less than that found in canine skin mast cells. Non-immunologic stimuli induced similar concentration-dependent histamine release from skin mast cells and BR cells: 29.3 +/- 0.9% vs. 12.7 +/- 0.7% (calcium ionophore A23187), 23.3 +/- 0.7% vs. 18.8 +/- 0.7% (substance P) and 12.5 +/- 0.3% vs. 12.1 +/- 0.9% (compound 48/80), respectively. Immunologic stimulation, however, was only effective on canine skin mast cells, causing 30.9 +/- 1.7%, 27.7 +/- 0.6% and 12.2 +/- 0.9% histamine release in response to anti-canine IgE, concanavalin A, and antigen Asc S 1, respectively. The absence of functional IgE receptors in BR cells was confirmed by the lack of response to anti-IgE and antigen Asc S 1 following passive sensitization with dog atopic serum and dog antigen sensitized serum. We conclude that BR cells are able to release histamine after non-immunologic stimulation in a similar manner to canine skin mast cells, but that there are morphological and functional differences possibly due to different states of maturity or differentiation. For this reason the study of the highly homogeneous BR cells could offer insights into dog mast cell biology in contexts where freshly isolated cells cannot be used because of low purity and recovery.     

Effect of betotastine besilate (TAU-284), a novel anti-allergic agent, on experimental allergic rhinitis

We investigated the effect of betotastine besilate (betotastine) on the experimental allergic rhinitis. The oral administration of betotastine (1, 3 and 10 mg/kg) inhibited the increase in dye leakage during and after the nasal perfusion of antigen in actively sensitized rats. It also prevented the increase in intranasal pressure induced by topically applied histamine in non-sensitized guinea pigs. Cetirizine and terfenadine dose-dependently inhibited the increase in a similar manner. Ketotifen (0.01-0.3 mg/kg, p.o.) inhibited the increase more than 50% at 0.01 mg/kg. The ID50s of ketotifen, cetirizine, betotastine and terfenadine for this model were more than 0.01 mg/kg, 0.01 mg/kg, 0.03 mg/kg and 0.5 mg/kg, respectively. Furthermore, in actively sensitized guinea pigs, nasal airway resistance showed a biphasic increase after the topical antigen challenge to the nasal cavity; the first peak at 0.5 hr and a second peak at 4 hr. Both the responses of first and second peaks were significantly inhibited by orally administered betotastine besilate, and its inhibitory effect on the second peak was the strongest among drugs tested. Since betotastine showed significantly inhibitory effects in experimental allergic rhinitis models, it was suggested to show a good efficacy for the treatment of allergic rhinitis clinically.     

A shock reaction from insect bites in patients with urticaria pigmentosa

The examination of 11 urticaria pigmentosa (UP) patients included allergological history, skin prick, scarification tests and intracutaneous tests with noninfectious and bee poison allergens, total and specific serum IgE measurements, in vitro reaction of histamine release from peripheral blood basophils induced by bee poison. The response of mastocytosis patients to insect sting was characterized by a rapid (within 5 min) development of severe systemic reactions or shock. The skin reactions and serum antibodies to bee poison were not registered in 9 of 11 patients. They also had a negative reaction of allergen-specific histamine release from basophils. This gives evidence for nonimmunological, pseudoallergic mechanism of the shock reaction. The latter can be prevented by bee poison immunotherapy. IgE-antibody-mediated allergic reaction to bee sting could not be excluded in 2 patients. For them specific immunotherapy with bee poison, possibly with purified poison preparations containing the allergens alone, are indicated.     

The role of mast cell-derived histamine in the closure of an in vitro wound

We have previously reported that mast cells (MC) stimulate 3T3 fibroblast migration and proliferation into an in vitro model of wound obtained by producing in a confluent 3T3 monolayer, a midline cut and by scraping the cells from half of the monolayer. The purpose of the present study was to determine the contribution of mast cell-derived histamine to this MC increasing effect. Histamine levels in supernatants of MC/ 3T3 cultures unactivated or activated with either compound 48/80 or anti-IgE antibodies (10 min) did not correlate to the degree of fibroblast migration and proliferation into the wound space (42 h). Various concentrations of histamine were added to 3T3 fibroblast monolayers in the absence of cocultured MC, and fibroblasts beyond the wound line were counted (42 h). Addition of 100 ng/ml histamine had the highest stimulating effect on fibroblast numbers. This effect was abrogated by the addition of cimetidine (an H-2 antagonist). Addition of cimetidine to unactivated MC/ 3T3 cultures did not affect the increasing activity of MC presence on the wounded monolayer, although it diminished the enhancing effect obtained after MC activation with compound 48/80. These results indicate that histamine is partially responsible for the mast cell enhancing effect on fibroblast migration and proliferation in an in vitro model of wound.     

Role of nitric oxide in pathogenesis of gastric mucosal damage induced by compound 48/80 in rats

We examined the effects of various nitric oxide synthase (NOS) inhibitors on development of gastric lesions induced by compound 48/80 (48/80) in rats and investigated the roles of NO and inducible NOS (iNOS) in inflammatory gastric responses. Animals were given 48/80 (1 mg/kg, i.p.) once daily for 4 days, and the stomachs were examined for lesions 24 h after the final administration. NOS inhibitors such as L-NAME, L-NMMA, aminoguanidine or dexamethasone were administered for 4 days during 48/80 treatment. The repeated administration of 48/80 caused damage in the stomach with severe edema in the submucosa. These lesions induced by 48/80 were dose-dependently prevented by concurrent administration of L-NAME. The protective effect of L-NAME on 48/80-induced gastric lesions was mimicked by L-NMMA, aminoguanidine as well as dexamethasone, and significantly antagonized by co-administration of L-arginine but not by D-arginine. Acid secretion was slightly decreased after 48/80 treatment, but was significantly augmented by the combined administration of L-NAME with 48/80. The mucosal MPO activity, TBA reactants and vascular permeability in the stomach were all increased after 48/80 treatment, but these changes were also significantly mitigated by co-administration of L-NAME. The Ca(2+)-independent NOS activity in the mucosa was increased four times during 48/80 treatment, and this change was also inhibited by dexamethasone. These results suggest that: 1) the repeated administration of 48/80 induced inflammatory gastric lesions in the rat stomach; 2) the pathogenic mechanism of these lesions involves endogenous NO produced by iNOS, in addition to oxyradical formation; and 3) the deleterious role of NO during 48/80 treatment may be accounted for by a cytotoxic action of peroxynitrite, which is formed in the presence of NO and superoxide radicals.     

Antiallergic action of betotastine besilate (TAU-284) in animal models: A comparison with ketotifen

The effects of betotastine besilate (betotastine: TAU-284), a novel antiallergic drug, on homologous passive cutaneous anaphylaxis (PCA), mediator-induced cutaneous reaction, antigen-induced asthmatic responses and platelet-activating factor (PAF)-induced airway eosinophilia in several animal models, were compared to ketotifen. Betotastine (0.1 mg/kg, p.o.) and ketotifen (1 mg/kg, p.o.) inhibited both rat PCA and histamine-induced cutaneous reaction, whereas they showed little effect on serotonin-induced cutaneous reaction. Betotastine (0.3 mg/kg, p.o.) and ketotifen (1 mg/kg, p.o. ) significantly inhibited antigen-induced bronchoconstriction in guinea pigs which had been passively sensitized with guinea pig IgE antibody. In actively sensitized guinea pigs, the immediate and late phase increase in airway resistance (Rrs) were observed within 5 min and between 4 and 7 h after the aeroantigen challenge. Betotastine (1 mg/kg, p.o.) inhibited both responses. Ketotifen (1 mg/kg, p.o.) inhibited the immediate phase response, but did not affect the late phase response. Exposure of guinea pigs to aerosolized PAF increased the number of eosinophils in bronchoalveolar lavage fluid 24 h after the stimulation. Betotastine (3-10 mg/kg, p.o.) dose-dependently inhibited PAF-induced accumulation of eosinophils in the bronchoalveolar cavity. In contrast, cetirizine (10 mg/kg, p.o.) showed a tendency to inhibit eosinophil accumulation, and ketotifen (10 mg/kg, p.o.) and terfenadine (10 mg/kg, p.o.) did not have any affect. These results indicate that betotastine could be useful in the treatment of allergic disease such as bronchial asthma.     

The effect of mepyramine and 48/80 on the histamine content of pleural exudates in the rat

The influence of pretreatment with the antihistaminic, mepyramine, or with the histamine liberator 48/80 was studied on the volume and the histamine content of pleural exudates induced in rats by intrapleural injection of turpentine, silver nitrate or carrageenan. The fluorometric determination of histamine was performed in the exudates collected at different times after injection of the irritant. In control animals the histamine levels were different from those previously found by the authors using biological assays. In rats pretreated with mepyramine or compound 48/80, the effects observed varied according to the nature of the irritant used to induce pleurisy.