氮卓斯汀对豚鼠哮喘的拮抗作用及相关机制

目的:研究组胺H1受体拮抗剂——氮卓斯汀(azelastine,AZT)对豚鼠哮喘的拮抗作用,探讨氮卓斯汀拮抗哮喘的可能机制。方法:以卵白蛋白致敏豚鼠,制备哮喘模型,通过豚鼠引喘潜伏期和跌倒率的变化评价氮卓斯汀对哮喘的拮抗作用;分别计数外周血和支气管肺泡灌洗液(BALF)中嗜酸性粒细胞的数量;采用ELISA法检测血清和BALF中IL-4和IL-5的质量浓度。结果:与模型组相比,氮卓斯汀能显著延长致敏豚鼠的引喘潜伏期,降低跌倒率;氮卓斯汀显著减少哮喘豚鼠血清和BALF中嗜酸性粒细胞的数量,降低血清和BALF中IL-4和IL-5的水平。结论:降低IL-4和IL-5的水平,减少血中嗜酸性粒细胞的数量及其在气道中的浸润,可能是组胺H1受体拮抗剂——氮卓斯汀拮抗哮喘的机制之一。     

Role of polymorphonuclear leukocytes in connective tissue breakdown during the reverse passive Arthus reaction

The reverse passive Arthus (RPA) reaction performed in the skin of rats was modified to allow for the determination of polymorphonuclear leukocyte (PMN) infiltration and hemorrhage, as well as changes in vascular permeability. After initiation of the RPA reaction, PMN infiltration, monitored by measurement of tissue myeloperoxidase (MPO, EC 1.11.1.7) content, increased dramatically with time. Depending on the experimental conditions used, PMN accumulation reached a maximum 2-10 hr after increased vascular permeability (125I-labeled albumin content) had peaked. Hemorrhage (59Fe-labeled erythrocyte accumulation) began to occur only after significant levels of PMN were reached and continued to increase proportionately to the level of PMN infiltration attained. Indomethacin administered 30 min prior to initiating the RPA reaction had no effect on vascular permeability increase but suppressed both PMN accumulation and hemorrhage development about 50%. When indomethacin was given 2 hr after the RPA reaction was begun, no effect on any of the RPA variables was noted. Dexamethasone suppressed the increase in vascular permeability (53%), PMN accumulation (78%), and hemorrhage (90%) when given 30 min prior to initiation of the reaction. Dexamethasone given 2 hr after initiating the RPA suppressed the entire reaction, but to a lesser extent. Catalase, as well as trasylol, alpha-1-antiproteinase and soybean trypsin inhibitor, inhibited PMN accumulation as well as hemorrhage when given intravenously at plus 2 hr. These results indicate that the damage to blood vessels during a severe RPA reaction is a direct consequence of PMN activity.     

Mechanism of the antitussive effect of azelastine in guinea pigs

In order to clarify the mechanism of the antitussive effects of azelastine hydrochloride (azelastine, CAS 790307-93-0), the cough responses to inhaled capsaicin and substance P (SP) were evaluated before and after the administration of azelastine in conscious guinea pigs. The concentrations of SP were also measured before and after the administration of azelastine by radioimmunoassay in anesthetized guinea pigs. Capsaicin and SP caused coughing in conscious guinea pigs in a dose-dependent fashion. After the treatment with azelastine, capsaicin-induced cough decreased significantly, and the dose-response curve to capsaicin was shifted to a higher concentration in comparison with the the controls. SP-induced cough was not inhibited by the treatment with azelastine, and the dose-response curves to SP did not change. The concentrations of SP recovered in bronchoalveolar lavage fluid and in the trachea were decreased statistically significantly in a dose-dependent manner after the treatment with azelastine, while the SP concentrations of the subjects not treated with azelastine were not inhibited. These results suggest that the antitussive effect of azelastine might be partly due to the inhibition of SP release from sensory nerves in guinea pigs.     

Antiallergic effect of 1-(2-ethoxyethyl)-2-(4-methyl-1-homopiperazinyl)benzimidaz ole difumarate (KB-2413)

Antiallergic effects of 1-(2-ethoxyethyl)-2-(4-methyl-1-homopiperazinyl)benzimidazol e difumarate (KB-2413) were investigated in immediate type hypersensitivities. KB-2413 (0.005-0.04 mg/kg p.o.) showed a marked inhibition on lethal anaphylaxis in guinea pigs induced by anti-egg albumin rabbit serum, and it was 30 and 1.6 times more potent than chlorpheniramine and ketotifen, respectively. KB-2413 (0.003-0.1 mg/kg p.o.) showed a dose-dependent inhibition on vascular permeability increase induced by 48 h homologous passive cutaneous anaphylaxis (PCA) and histamine in guinea pigs, being about 10-30 times and 3 times more potent than chlorpheniramine and ketotifen, respectively. All drugs did not completely inhibit 4 h heterologous PCA in guinea pigs induced by the anti-egg albumin rabbit serum in the doses used here, but KB-2413 was more effective than chlorpheniramine and ketotifen. No difference in inhibitory effect on the vascular permeability increase between the single and daily oral administration for 4 weeks of KB-2413 could be found. KB-2413, as well as chlorpheniramine and ketotifen, showed a dose-dependent inhibition on 48 h homologous PCA in rats at doses of 1-10 mg/kg p.o., and showed a concentration-dependent inhibition on Schultz-Dale reaction at 10(-8) - 10(-7) mol/l. KB-2413 (10(-5) - 10(-3) mol/l) showed a concentration-dependent inhibition of anaphylactic histamine release from isolated rat peritoneal mast cells which were passively sensitized by rat IgE. KB-2413 also inhibited compound 48/80-induced histamine release from rat peritoneal mast cells.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of azelastine on the down regulation of beta-adrenoceptors in guinea pig lung.

The new antiallergic drug azelastine (E-0659, Azeptin; CAS 58581-89-8) is used in the treatment of rhinitis and bronchial asthma. In the present study, the effect of azelastine on the regulation of the beta-adrenoceptors and the down regulation of beta-adrenoceptors by terbutaline, a beta-agonist, was investigated using guinea pig lungs. Guinea pigs were divided into four groups; (1) the control (saline-treated) group, (2) the terbutaline-treated group, (3) the azelastine-treated group, (4) terbutaline plus azelastine-treated group. Guinea pigs intramuscularly injected with each agent three times a day for successive 7 days. In the terbutaline-treated group, a 26% reduction in the number of beta-adrenoceptors compared with those of the control group was observed. In the azelastine-treated group, the number of beta-adrenoceptors increased by 24% compared with those of the control group. The number of the beta-adrenoceptors in the terbutaline plus azelastine-treated group was significantly increased compared with that of the terbutaline-treated group. These results suggest that azelastine may prevent the down regulation observed during beta-agonist administration by increasing the number of beta-adrenoceptors.     

Suppression of the Arthus reaction by Y-24180, a potent and specific antagonist of platelet-activating factor.

A novel and potent antagonist of platelet-activating factor (PAF), Y-24180 (4-(2-chlorophenyl)-2-[2-(4-isobutylphenyl)ethyl]-6,9-dimethyl-6H- thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4] diazepine) was investigated for the effects on the skin reactions induced by chemical mediators and the Arthus reactions. In the rat dorsal skin, Y-24180 (0.1-10 mg/kg, p.o.) inhibited increase in vascular permeability by the intradermal PAF injection in a dose dependent manner and the inhibitory activity was 60 times more potent than that of WEB 2086. While even at doses as large as 10 mg/kg, p.o., it had no effect on vascular permeability in the rat skin induced by histamine, serotonin, bradykinin and leukotriene D4. On a reversed passive Arthus reaction in rat dorsal skin, Y-24180 (0.1-1 mg/kg, p.o.) markedly inhibited vascular permeability in a dose dependent manner and the inhibitory activity was 15 times more potent than that of WEB 2086. Y-24180 also inhibited the Arthus dermal reaction in rabbits (0.03-0.3 mg/kg, p.o.) and guinea pigs (0.1-1 mg/kg, p.o.). In addition, Y-24180 (0.1-10 mg/kg, p.o.) significantly reduced the exudate volume and the number of infiltrated inflammatory cells in the reversed passive Arthus pleural reaction in rats. Furthermore, in rat passive Arthus pancreatitis, Y-24180 (0.3-10 mg/kg, p.o.) significantly inhibited the dye extravasation from the pancreas. These results provide strong evidence that endogenous PAF plays an important role as a mediator in the type III allergic inflammation.     

Antihistaminic and Antiallergic Properties of Dextro-mequitamium Iodide in Upper and Lower Guinea Pig Airways: Comparison with Azelastine

• 1.The ability of dextro-mequitamium iodide (d-Meq) to antagonize bronchomotor and inflammatory effects mediated by histamine and antigen challenge in the upper or lower guinea pig airways or both and its potential activity against the recruitment and activation of eosinophils in the bronchial wall have been evaluated in comparison with azelastine.
• 2.In receptor-binding studies, d-Meq displayed a nanomolar affinity for H1 and muscarinic receptors, and it was endowed with potent bronchodilating properties in the nanomolar range toward tonic contractions induced by histamine and carbachol.
• 3.d-Meq (100–1,000 nmol/guinea pig) and azelastine (100–5,000 nmol/guinea pig) administered by aerosol significantly inhibited histamine- and antigen-induced increases in insufflation pressure in sensitized animals.
• 4.d-Meq (1,000–6,000 nmol/kg IV) dose dependently inhibited the histamine- or antigen-induced increase in vascular permeability in the upper airways.
• 5.d-Meq was more effective against histamine than antigen challenge, and its potency was similar or greater than that of azelastine.
• 6.Aerosolized d-Meq (1,000 nmol/animal) reduced antigen-induced eosinophil accumulation in the bronchoalveolar lavage (BAL) fluid from sensitized guinea pigs.
• 7.Eosinophils recovered from the BAL fluid of antigen-challenged animals showed an increased chemotaxis in response to LTB₄ or platelet-activating factor. Both d-Meq and azelastine (300 nmol/animal) reduced this increase without affecting direct chemotaxis induced by leukotriene B₄ (LTB₄).
• 8.These findings provide evidence that local administration of d-Meq might be useful in the treatment of allergic disorders, such as rhinitis and asthma.

     

Cigarette smoke increases mucosal permeability in guinea pig trachea via tachykinin NK2 receptor activation

We investigated whether exposure to cigarette smoke increases the mucosal permeability in guinea pig trachea and if this effect could be mediated by tachykinin NK2 receptor activation. Guinea pigs were exposed to either three different doses of cigarette smoke or room air. Mucosal permeability was measured by monitoring the rate of appearance in the circulation of horseradish peroxidase (HRP) that had been instilled into the isolated tracheal segment. Exposure to 20 and 30 puffs but not 10 puffs of cigarette smoke increased the tracheal mucosal permeability. Pretreatment with the tachykinin NK2 receptor antagonist SR48,968 [(S)-N-methyl-N[4-(4-acetylamino-4-phenylpiperidino)-2-(3,4-dichlorophenyl)butyl]benzamide] completely inhibited the increase in the permeability of the tracheal mucosa induced by exposure to cigarette smoke, whereas the tachykinin NK1 receptor antagonist SSR240,600 [(R)-2-(1-{2-[4-{2-[3,5-bis(trifluoromethyl)phenyl]acetyl}-2-(3,4-dichlorophenyl)-2-morpholinyl]ethyl}-4-piperidinyl)-2-methylpropanamide] and the tachykinin NK3 receptor antagonist SR142,801 [(S)-(N)-(1-[3-(1-benzoyl-3(3,4-dichlorophenyl)piperidine-3-yl)propyl]-4-phenylpiperidin-4-yl)-N-methyl-acetamide] had no effect. It is concluded that endogenous tachykinins via NK2 receptor activation mediate the increase in the permeability of the tracheal mucosa induced by exposure to cigarette smoke in guinea pigs.     

Effect of in vitro and in vivo aerosolized treatment with geniposide on tracheal permeability in ovalbumin-induced guinea pigs.

The primary objective of this study was to investigate the effect of geniposide, a potent anti-inflammatory, on ovalbumin-antigen-induced tracheal permeability and transepithelial electrical resistance in guinea pigs. Two weeks after sensitization with ovalbumin (100 mg/ml), the permeability of guinea-pig tracheas was evaluated by flux measurements using the transcellular tracer, [(14)C]estradiol, and the paracellular tracer, [(14)C]mannitol. The effect of extracellular Ca(2+) with geniposide was also studied, using deletion of Ca(2+) in the donor chamber. The in vivo treatment effect of aerosolized geniposide on tracheal permeability in the ovalbumin-sensitized guinea pigs was also evaluated. The results indicate that tight junction permeability of ovalbumin-sensitized trachea was significantly dose dependent and decreased by geniposide (1-10 mM), as evidenced by substantial recovery of transepithelial electrical resistance and decreased transepithelial permeability of [(14)C]mannitol at (1.32+/-0.12) x 10(-5) cm/s. The effect of combination of the removal of extracellular Ca(2+) with geniposide had no effect on tight junction permeability of ovalbumin-sensitized trachea and revealed that transepithelial electrical resistance and junction permeability did not recover. In addition, the cAMP levels and phosphodiesterase activity were not significantly influenced in ovalbumin-sensitized tracheal tissues after geniposide treatment. Inhaled geniposide (50 mM, 30 min after ovalbumin sensitization) significantly restored junction permeability induced by ovalbumin (100 mg/ml, 2 min). Junction permeability did not recover on pretreatment with geniposide (50 mM for 30 min over 16 days consecutive before ovalbumin sensitization) after exposure of conscious guinea pigs to aerosol ovalbumin. In conclusion, geniposide has inhibitory effects on ovalbumin-induced junction permeability and recovery of transepithelial electrical resistance in guinea pig trachea, showing its potential as anti-asthma therapy.     

Studies on the mechanisms involved in the inflammatory response in a reversed passive Arthus reaction in guinea-pig skin: contribution of neutrophils and endogenous mediators.

1. Mediators of inflammation can increase vascular permeability in at least two different ways: by acting directly on endothelial cells or, indirectly, through an incompletely understood mechanism, dependent on circulating neutrophils. Neutrophil-dependent oedema formation has been described in the skin of rabbits, rats, hamsters, mice and man. In contrast, we presented evidence in a previous study that local oedema formation induced by i.d. injection of chemoattractants in guinea-pig skin was neutrophil-independent. In the present study, we sought evidence of neutrophil-dependent oedema formation in immune-complex-mediated vasculitis, the reversed passive Arthus (RPA) reaction, in guinea-pig skin. We also investigated whether haemorrhage in the RPA reaction was neutrophil-dependent (as it is in other species) and the role of endogenous mediators of inflammation (prostaglandins, nitric oxide, histamine, PAF and leukotrienes) in contributing to the local inflammatory response. 2. In the RPA reaction, most oedema formation occurred over the first 60 min whereas 111In-neutrophil accumulation was still increasing from 60 to 240 min. The different kinetics of these two events suggested that they may be dissociated. 3. Oedema formation was partially inhibited by a long-acting PAF antagonist (UK-74,505) and an H1 histamine receptor antagonist (mepyramine) but not by a 5-lipoxygenase inhibitor (ZM 230487). A nitric oxide synthesis inhibitor (NG-nitro-L-arginine methyl ester, L-NAME) suppressed oedema formation by 68% whereas a cyclo-oxygenase inhibitor suppressed oedema by 27%. 4. 111In-neutrophil accumulation in the RPA reaction was partially suppressed by UK-74,505. In contrast, ZM 230487 was without effect at doses which abrogated arachidonic acid-induced 111In-neutrophil accumulation. 5. The anti-CD18 monoclonal antibody, (mAb) 6.5E F(ab')2, effectively inhibited 111In-neutrophil accumulation induced by PAF, zymosan-activated plasma (ZAP) and in the RPA reaction. However, oedema formation measured in the same sites was not altered.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of azelastine on microviscosity of bronchial lavage fluid obtained from actively sensitized and challenged guinea pigs

Fluorescence polarisation technique was adapted to measure microviscosity in the bronchoalveolar lavage fluid (BAL) of guinea pigs. In sensitized guinea pigs, 20 hours after antigen challenge, the microviscosity of BAL was increased by 86%, suggesting that antigen-induced bronchospasm is followed by inflammatory events. Pretreatment with azelastine (3 mg/kg, p.o., 2 hours prior to antigen challenge) tended to normalize microviscosity in the bronchoalveolar lavage fluid obtained from challenged guinea pigs. The present results suggest that azelastine inhibits the increase of microviscosity of BAL, a symptom of the late phase reactions.     

Effects of azelastine on contraction of guinea pig tracheal smooth muscle

Azelastine [4-(p-chlorobenzyl)-2-(hexahydro-1-methyl-1H-azepine-4-yl)-1(2H)-phthalazinone hydrochloride] is a new anti-asthmatic drug. We examined the mechanism of its inhibitory action on guinea pig tracheal smooth muscle contraction by measuring membrane potential and isometric force using intracellular microelectrodes and a micro-force transducer. The mean resting membrane potential of guinea pig tracheal muscle cells was -54 mV. Perfusion with 20 mM tetraethylammonium (TEA) caused membrane depolarization and elicited spontaneous action potentials. Azelastine (1-100 microM) suppressed both the amplitude and maximal rate of rise of the action potentials in a concentration-dependent manner. Complete abolition occurred at 100 microM. Similarly, azelastine (0.1-100 microM) inhibited and abolished 50 mM KCl-induced contractions. These results suggest that azelastine may inhibit voltage-dependent Ca2+ channels. Next, pretreatment of tracheal muscle (for 15 min) with azelastine (0.01-100 microM) inhibited subsequent acetylcholine (ACh) (0.01-100 microM)-induced contractions. Azelastine, 100 microM, completely abolished the ACh-induced contractions. In contrast, high concentrations of Ca2+ channel antagonists diltiazem (10-100 microM) or nifedipine (20 microM), and Ca2(+)-free solution, only partially depressed the ACh contractions suggesting that azelastine has an additional effect on intracellular Ca2+ release. In Ca2(+)-free solution (containing 0.5 mM EGTA), azelastine (1-100 microM) depressed and abolished the transient contractions induced by 10 microM ACh. We conclude that azelastine inhibits airway constriction by inhibiting both voltage-sensitive Ca2+ slow channels on the cell membrane and Ca2+ release from a intracellular storage site.     

Effect of KC-404 on allergic reactions types I-IV

The effects of 3-isobutyryl-2-isopropylpyrazolo [1,5-a] pyridine (KC-404), a new anti-allergic agent, on type I to IV allergic reactions were investigated. KC-404 administered orally inhibited heterologous and homologous passive cutaneous anaphylaxis (PCA) reactions in guinea pigs and homologous PCA in rats; the minimum effective doses were 50, 12.5 and 3 mg/kg, respectively. However, the inhibition of PCAs by KC-404 was incomplete so that only 50 to 60% inhibitions were obtainable even at the highest doses used. KC-404 had no effect on increased vascular permeability by chemical mediators other than SRS-A and hardly affected antigen-induced degranulation of the sensitized mesenteric mast cells in vitro. These results suggest that KC-404 exerts its effect conceivably through inhibition of the SRS-A-mediated component of PCA. KC-404 had no effect on type II allergic reaction as estimated by its failure to inhibit reversed cutaneous anaphylaxis in rats and the Forssman systemic reaction in guinea pigs. Also, no influence on complement activity was observed in vitro and in vivo. KC-404 (100 approximately 200 mg/kg, p.o.) produced a marked inhibition of passive and active Arthus reactions in guinea pigs and rabbits, respectively. The tuberculin reaction in guinea pigs was not affected by KC-404. These results suggest that KC-404 inhibits PCAs mediated by IgE as well as IgG antibodies probably through a unique mechanism of action. KC-404 was shown to be effective also on type III allergic reaction.     

Effects of TAK-427 on acute nasal symptoms and nasal obstruction in guinea pig model of experimental allergic rhinitis

TAK-427 (2-[6-[[3-[4-(diphenylmethoxy)piperidino]propyl]amino]imidazo[1,2-b]pyridazin-2-yl]-2-methylpropionic acid dihydrate) is a novel anti-allergic agent that has both histamine H1-receptor antagonist and anti-inflammatory activities. In this study, we evaluated the efficacy of TAK-427 on acute nasal responses and nasal obstruction using various guinea pig models of allergic rhinitis. TAK-427 inhibited the histamine-induced nasal reactions with an ID50 value of 0.633 mg/kg, p.o. TAK-427 (0.1-10 mg/kg, p.o.) and most histamine H1-receptor antagonists tested inhibited the increase in intranasal pressure, nasal hypersecretion, sneezing and nasal itching caused by a single antigen challenge in sensitized guinea pigs. In addition, TAK-427 (0.3, 30 mg/kg, p.o.) significantly inhibited the development of nasal obstruction when sensitized guinea pigs were repeatedly challenged via inhalation with Japanese cedar pollen, whereas the histamine H1-receptor antagonist, azelastine (1 mg/kg, p.o.), and ketotifen (1 mg/kg, p.o.) were without effect. These results suggest that TAK-427 might not only suppress acute nasal symptoms but also ameliorate nasal obstruction via the effects other than those as a histamine H1-receptor antagonist.     

Antigenicity studies on catena-(S)-[mu-[N alpha-(3-aminopropionyl)histidinato(2-)-N1,N2,O:N tau]-zinc]

The antigenicity of Z-103 (catena-(S)-[mu[N alpha-(3-aminopropionyl) histidinato(2-)-N1,N2,O:N tau]-zinc], CAS 107667-60-7) was evaluated using the following assay procedures: 1. active systemic anaphylaxis (ASA) in guinea pigs. 2. passive cutaneous anaphylaxis (PCA) in guinea pigs with serum from guinea pigs sensitized with Z-103, 3. delayed type skin reaction (Maximization Test) in guinea pigs, 4. passive cutaneous anaphylaxis (PCA) in rats with serum from mice sensitized with Z-103 and 5. passive hemagglutination (PHA) with serum from mice sensitized with Z-103. In each test except for Maximization Test, the sera obtained 1 or 6 h (hereinafter designated as 1-h-sera or 6-h-sera) after a single oral administration of 500 mg/kg of Z-103 to the unused rats, guinea pigs or rabbits, were used as the challenge antigen. 1. ASA in guinea pigs: No anaphylaxis reaction was observed in any of the sensitized guinea pigs by elicitation with challenge antigen. 2. PCA in guinea pigs: PCA titer of sera from all the sensitized animals was less than 1 in elicitation with the challenge antigen. 3. Delayed type skin reaction test: No skin reaction was observed in sensitized guinea pigs after intradermal injection or dermal application of Z-103. 4. PCA in rats: PCA titer of sera from BALB/c and C3H/He mice sensitized with Z-103 was less than 5 in elicitation with the challenge antigen. 5. PHA reaction: When erythrocytes coated with challenge antigen were added to sensitized sera, the hemagglutination titer was less than 1.(ABSTRACT TRUNCATED AT 250 WORDS)     

小剂量哌替啶对香烟烟雾致豚鼠急性肺气道反应的影响

目的研究小剂量阿片受体激动剂哌替啶(Peth)对香烟烟雾吸入引起的豚鼠急性气道收缩反应和炎性反应的影响。方法观察Peth0.01,0.1和1mg.kg-1对豚鼠自主吸入75%香烟烟雾(含25%O2)60mL后,气道阻力和肺动态顺应性变化的影响及气道组织血管通透性变化的影响;观察Peth0.1mg.kg-1对豚鼠2h内分6次吸入(共360mL)75%浓度的香烟烟雾后,支气管肺泡灌洗液(BALF)中白细胞总数和分类计数改变的影响,测定BALF中一氧化氮(NO)含量。结果Peth能减轻或明显抑制香烟烟雾刺激后气道阻力增高和肺动态顺应性下降的反应,抑制气道组织各段微血管通透性增加的反应,降低BALF中的白细胞总数和中性粒细胞比例,降低BALF中NO的含量。结论小剂量Peth对豚鼠急性神经源性气道收缩反应和炎性反应具有抑制作用。     

Effects of azelastine hydrochloride, a new antiallergic drug, on the gastrointestinal tract

Effects of 4-(p-chlorobenzyl)-2-(hexahydro-1-methyl-1H-azepin-4-yl)-(2H)-phthalazinone hydrochloride (azelastine hydrochloride), a new antiallergic drug, on the gastrointestinal tract were experimentally studied in comparison with diphenhydramine and clemastine. In the isolated guinea pig ileum, the dose-response curve for histamine was shifted to the right by 10(-8) mol/l of diphenhydramine, clemastine or azelastine to the same degree. Clemastine and azelastine reduced the maximum response in the dose-response curve, while diphenhydramine caused a parallel shift. In addition to the potent antihistamine action, azelastine at higher dose antagonized serotonin action and clemastine markedly inhibited the contractile responses of isolated intestinal preparations to acetylcholine and bradykinin. Azelastine and clemastine (50 mg/kg intraduodenally) reduced gastric secretion in pylorus ligated rats. Azelastine (5 mg/kg i.v.), clemastine (1 mg/kg i.v.) and diphenhydramine (1 mg/lg i.v.) depressed gastrointestinal motility in conscious rats. Biliary and pancreatic secretions of anesthetized rats were not affected by 1 mg/kg i.v. of azelastine or clemastine.     

Biochemical and pharmacological characterization of ICI 198,615: a peptide leukotriene receptor antagonist

ICI 198,615 is one representative of a new chemical class of peptide leukotriene receptor antagonists that are the most potent and selective described to date. ICI 198,615 antagonized LTC4-, LTD4- and LTE4-induced increases in cutaneous vascular permeability in the guinea pig, with i.v. ED50 values of 0.083, 0.11 and 0.067 mumol/kg, respectively. Against LTD4, ICI 198,615 was 615 and 415 times more potent than LY 171883 and FPL 55712, respectively. L-Serine borate, an inhibitor of the metabolism of LTC4 to LTD4, did not influence the antagonism by ICI 198,615 of LTC4-induced increases in cutaneous vascular permeability. The compound both inhibited and reversed aerosol ovalbumin antigen-induced increases in pulmonary resistance in passively sensitized guinea pigs, but demonstrated little ability to inhibit or reverse ovalbumin antigen-induced decreases in dynamic lung compliance. At concentrations ranging from 10(-8) to 10(-5) M, ICI 198,615 had no significant effect on either the spontaneous or ovalbumin antigen-induced release of histamine, peptide leukotrienes, thromboxane B2 or 6-keto-prostaglandin F1 alpha from chopped guinea pig lung. At 10 microM, the compound did not inhibit 5-, 12- or 15-lipoxygenase. Finally, ICI 198,615 antagonized LTD4-induced increases in TxB2 release from chopped guinea-pig lung.     

Inhibitory effect of epinastine on the type II-IV allergic reactions in mice, rats and guinea pigs.

The inhibitory effect of epinastine (WAL 801 CL, CAS 80012-43-7) on types II, III and IV allergic reactions was studied. Epinastine caused an inhibition of type II allergic reactions: 1. the swelling of rat foot pad induced by a subcutaneous injection of anti-rat rabbit antiserum, and 2. lethality induced by an intravenous injection of anti-SRBC (sheep red blood cells) rabbit serum into guinea pigs (Forssman systemic reaction). The drug also caused an inhibition of the early phase in active Arthus reaction in guinea pigs (type III reactions). However, no significant inhibition was detected in the delayed-hypersensitivity reaction (type IV allergic response) induced by sheep red blood cells or picryl chloride in mice.     

GR46611 potentiates 5-HT1A receptor-mediated locomotor activity in the guinea pig.

5-HT(1B/D) receptor agonists such as GR46611 (3-[3-(2-Dimethylaminoethyl)-H-indol-5-yl]-N-(4-methoxybenzyl)acrylamide ) are known to lower body temperature in guinea pigs. Although stimulation of their functional analogs in rats, the 5-HT1B receptor induces hyperlocomotion, this effect has yet to be demonstrated with 5-HT(1B/D) receptor agonists in the guinea pig. Previous studies have shown that 5-HT1A agonists increase locomotor activity in guinea pigs. The current study set out to examine the effects of 5-HT(1B/D) receptor stimulation on locomotor activity in the guinea pig and to examine the interaction between 5-HT1A and 5-HT(1B/D) receptor stimulation on locomotor activity in that species. The full agonist at 5-HT1A receptors, 8-OH-DPAT (R(+)-8-Hydroxy-dipropylaminotetralin HBr) dose-dependently increased locomotor activity in guinea pigs (0.3-1.25 mg kg(-1) s.c.), as to a lesser extent, did the partial agonist, buspirone (8-[4-[4-(2-Pyramidinyl)-1-piperazinyl]butyl]-8-azaspiro[4.5 ]decane-7,9-dione HCl) (5.0-20.0 mg kg(-1) s.c.). The 5-HT(1B/D) receptor agonist GR46611 had no effect on locomotor activity in guinea pigs at doses up to 40 mg kg(-1) s.c. 8-OH-DPAT-induced behavioural activation was reversed by the selective 5-HT1A receptor antagonist WAY100635 (N-[-2-[4-(-methoxyphenyl)-1-piperazinyl]ethyl]-N-(pyrinidyl) cyclo hexanocarboxamide trihydro-chloride), with a minimum effective dose of 0.006 mg kg(-1), but not by the 5-HT(1B/D) receptor antagonist GR127935 (2'-methyl-4-(5-methyl-[1,2,4]oxadiazol-3-yl)-biphenyl-4-carboxyli c acid [4-methoxy-3-(4-methyl-piperazin-1-yl)phenyl]-amide) (0.25-1.0 mg kg(-1)). GR46611, at doses that were without effect given alone (0.5-2.5 mg kg(-1)), significantly enhanced the locomotor response to subthreshold doses of 8-OH-DPAT (0.5 mg kg(-1)) and buspirone (10 mg kg(-1)). The effect of GR46611 on 8-OH-DPAT-induced hyperactivity was reversed by pretreatment with GR127935 and with WAY 100635 indicating that activation of both receptors was required for the expression of locomotor hyperactivity. These findings suggest that activation of 5-HT(1B/D) receptors alone may not stimulate locomotor activity but it does potentiate the locomotion induced by 5-HT1A receptor stimulation in guinea pigs.