piperidines and Anaphylaxis

Topics: Alkaloids; Anaphylaxis; Azepines; Drug Eruptions; Drugs, Chinese Herbal; Gossypol; Heterocyclic Compounds, 4 or More Rings; Heterocyclic Compounds, Bridged-Ring; Humans; Lactones; Neuromuscular Depolarizing Agents; Piperidines

The substance 9,10-dihydro-10-(1-methyl-4-piperidylidene)-9-anthrol (WA 335) was examined for its antagonistic effects against histamine and serotonin, for its atropine-like properties as well as for a series of other qualities in comparison with cyproheptadine and pimethixene. The anti-histamine and anti-serotonin activities of compound WA 335 on the smooth muscle and the capillary do not only exceed that of cyproheptadine but also that of pimethixene. WA 335 shows an extremely strong binding to histamine and serotonin receptors. In the dose range in which it causes already an antamine effect, its oral absorption is very good. The anti-anaphylactic effect is much stronger than that of cyproheptadine. Like pimethixene and cyproheptadine, WA 335 has no distinct antagonistic qualities against bradykinin. The anticholinergic effects of WA 335 are dependent on the test object. In examinations on the bronchus of the guinea pig and the pupil of the mouse, the atropine-like efficiency corresponds to that of cyproheptadine; it is stronger on the stimulated vagus of the cat and less efficient than cyproheptadine on the stomach of the rat. WA 335 has distinct central atropine-like properties. It possesses a strong surface anesthetic activity. The effects of WA 335 on circulation are dependent on species. In contrast to pimethixene, compound WA 335 like cyproheptadine potentiates the effects of norepinephrine in cats. The reduction of the carotid sinus reflex in the cat is more distinct after WA 335 than after pimethixene and corresponds to that produced by cyproheptadine. Higher doses of WA 335 than are necessary to demonstrate antaminic effects are needed to provoke central nervous effects. WA 335 shows no analgesic potency in mice. The influence on body temperature in the rat is similar to that of cyproheptadine. WA 335 is equally efficient as pimethixene with regard to the inhibition of spontaneous motility and prolongation of barbiturate sleep in mice, and shows the same anti-emetic activity as does chlorpromazine in dogs. In contrast to chlorpromazine the behaviour of dogs and cats is distinctly altered already by doses of WA 335 which cause a slight sedation.

Topics: Analgesics; Anaphylaxis; Animals; Anthracenes; Asthma; Behavior, Animal; Blood Pressure; Bronchial Spasm; Cats; Dogs; Drug Evaluation, Preclinical; Edema; Female; Gastric Juice; Gastrointestinal Motility; Guinea Pigs; Histamine H1 Antagonists; In Vitro Techniques; Lethal Dose 50; Male; Mice; Muscle Contraction; Muscle, Smooth; Piperidines; Pupil; Rabbits; Rats; Receptors, Drug; Serotonin Antagonists; Uterine Contraction

At therapeutic dosage, cetirizine and ebastine induce significant inhibition of skin reactivity to histamine. The consistency of their efficacy, that is, efficacy with the least interindividual variability among subjects, has not been carefully assessed, however.. To compare the consistency and efficacy of these antihistamines on skin reactivity.. Twenty-four healthy volunteers participated in a randomized double-blind crossover study. The areas of wheals and flares induced by increasing (0, 5, 10, 50, 100, 200, and 300 mg/mL) histamine concentrations, administered by prick tests, were measured before and four hours after intake of 10 mg of each antihistamine, allowing concentration-response curves to be established. The threshold histamine concentrations inducing wheal areas of 3 mm2 (positivity) were calculated by interpolation. The coefficient of variation (SD/mean %) was used to evaluate the consistency of the response.. Pretreatment concentration-response curves were similar, and threshold concentrations identical (0.29 mg/mL and 0.34 mg/mL for cetirizine and ebastine, respectively). For both, curves were lower after treatment than before. After cetirizine, the threshold concentration was significantly higher (217 mg/mL) than after ebastine (0.82 mg/mL) (P < .001), and total inhibition of the wheal reaction was observed in 21 of 24 patients at the lowest histamine concentration and in 17 of 24 at the highest. Ebastine never totally inhibited reaction, even to 5 mg/mL of histamine. Over the entire concentration-response curve, the coefficient of variation for the wheal reaction was 6.3% for cetirizine and 72.6% for ebastine, and, for flares, 11.0% and 83.7%, respectively. Hence, variability was much lower after cetirizine.. Our study shows clearly that the efficacy of a single therapeutic dosage of cetirizine is consistently good for suppression of cutaneous reactivity to histamine in healthy volunteers. The need for ebastine to metabolize into the active carebastine might explain its lesser consistency.

Topics: Adult; Anaphylaxis; Butyrophenones; Cetirizine; Cross-Over Studies; Dermatitis, Allergic Contact; Dose-Response Relationship, Drug; Double-Blind Method; Female; Histamine; Histamine H1 Antagonists; Humans; Male; Piperidines; Safety; Skin; Skin Tests

Ebastine is a nonsedating histamine H-1 antagonist undergoing evaluation for treatment of allergic rhinitis and urticaria.. To compare the suppression of prick and intradermal skin reactions to histamine over a period of 24 hours produced by a single dose of ebastine. Also to record side effects and assess changes in the electrocardiogram, particularly the QTc interval.. Single doses of 1, 3, 10, and 30 mg of ebastine or placebo were administered double-blind at approximately 8 AM after baseline measurement of the reaction to intradermal testing with 5 micrograms histamine base and prick skin testing with three concentrations of histamine. Intradermal testing with histamine was repeated hourly for four hours, every two hours for eight hours, and after 24 hours. Titrated prick skin testing with histamine was performed at 6, 12, and 24 hours. Potential side effects were recorded each time skin testing was performed. Electrocardiograms were repeated at 4 and 24 hours.. Intradermal skin test reactions were suppressed between 4 and 24 hours and prick skin tests to 10 mg/mL histamine base were suppressed between 6 and 24 hours with all doses of ebastine. Prick skin test reactions were significantly smaller at 12 and 24 hours in the group receiving the 30 mg dose of ebastine than in all other groups.. Ebastine is a potent antihistamine that suppresses skin reactions to histamine for 24 hours following single doses in the doses tested (1 to 30 mg). No differences from placebo were noted in either the incidence of side effects or in the QTc intervals of serial electrocardiograms.

Topics: Adult; Anaphylaxis; Butyrophenones; Dermatitis, Allergic Contact; Dose-Response Relationship, Drug; Double-Blind Method; Female; Histamine H1 Antagonists; Humans; Male; Middle Aged; Piperidines; Skin; Skin Tests

1. The rate of onset and magnitude of the effect of levocabastine, a potent H1-receptor antagonist, in reversing histamine-induced bronchoconstriction were determined in a double-blind cross-over trial against saline placebo. Histamine was administered by nebuliser so that forced expiratory volume in 1 second (FEV1) was reduced to 80-75% of baseline FEV1 in 10 men with mildly or moderately responsive airways and the effects of intravenous injection of saline or saline + 200 micrograms levocabastine were studied. 2. The maximum rate of recovery of FEV1 was 7[2-10]% min-1 (median [range]) in the first 5 min after levocabastine injection, but only 4[1-7]% min-1 after saline alone (P less than 0.05). 3. The median area under the recovery curve of FEV1 from 0 to 30 min after injection was 405 [228-498]% basal FEV1 X min after levocabastine and 301[98-502]% basal FEV1 X min after saline alone (P less than 0.002). 4. FEV1 returned to 90% of baseline within 30 min in all subjects after levocabastine, but not after saline alone (P less than 0.002). 5. Histamine-induced bronchoconstriction was relieved more quickly by levocabastine than saline alone. This model may have application to the study of drugs used in the treatment of anaphylaxis.

Topics: Adult; Anaphylaxis; Bronchial Spasm; Double-Blind Method; Forced Expiratory Volume; Histamine; Histamine H1 Antagonists; Humans; Kinetics; Male; Middle Aged; Piperidines; Random Allocation

The protective effect of ketotifen was examined by an open assessment trial in 261 asthmatics of variable types, a double blind trial comparing ketotifen and inert placebo in 189 asthmatics of extrinsic type including pure atopic asthma and asthma with atopic and infectious components (mixed type or combined type), and a double blind trial comparing ketotifen and disodium cromoglycate (DSCG) by double placebo technique in 132 asthmatics of a pure atopic type. The open clinical assessment trial suggested that ketotifen was most effective in atopic asthmatics having moderate and severe as well as mild asthmatic episodes. Efficacy increased with prolonged administration; 1 mg twice daily was better than a 1 mg daily dose. In the placebo-controlled double blind trial, the efficacy of ketotifen was demonstrated by the reduction of concomitant anti-asthmatic therapy. The results of the double blind trial comparing ketotifen and DSCG are not fully reported. However, preliminary data showed that the efficacy of both drugs was equivalent or that ketotifen was slightly superior to DSCG. Safety of ketotifen was confirmed by the three trials, transient day-time sedation being the major side effect of this agent. In conclusion, ketotifen is a promising drug for the prophylaxis of asthma.

Topics: Adult; Anaphylaxis; Asthma; Basophils; Cromolyn Sodium; Double-Blind Method; Humans; Hypersensitivity, Immediate; Japan; Ketotifen; Mast Cells; Piperidines; Placebos; Thiophenes

We studied the preventive effect of ketotifen, an oral drug with antianaphylactic and antihistaminic properties on methacholine-induced bronchoconstriction in controlled cross-over experiments in twenty-six adult patients with extrinsic asthma. Both a single dose of 1 mg ketotifen and 4 weeks treatment of ketotifen, 1 mg twice daily, failed to reduce the methacholine-induced drop in peak expiratory flow. The spirometric findings remained unchanged during ketotifen treatment. There was no difference between treatments with ketotifen and placebo with regard to the patients assessment of the severity of asthma or airway sensitivity to tobacco smoke, fumes or dusts, or exercise. The results suggest that treatment during 4 weeks with ketotifen does not reduce unspecific broncial hyperreactivity in patients with extrinsic asthma.

Topics: Adolescent; Adult; Anaphylaxis; Asthma; Bronchial Spasm; Dose-Response Relationship, Drug; Double-Blind Method; Histamine H1 Antagonists; Humans; Methacholine Compounds; Middle Aged; Piperidines; Spirometry; Thiophenes

Topics: Anaphylaxis; Brentuximab Vedotin; Humans; Immunoconjugates; Piperidines

Mast cells play an important role in inflammatory and allergic diseases. MAS-related G protein-coupled receptor X2 (MRGPRX2) is a novel G protein-coupled receptor in mast cells that mediates drug-induced anaphylactoid reactions. Piperine has been reported to have anti-inflammatory and anti-allergic pharmacological activities. However, whether the pharmacological effects are regulated by MRGPRX2 has not yet been reported. The purpose of this study was to assess the anti-anaphylactoid effect of Piperine and to explore its potential mechanism. The anti-anaphylactoid effect of Piperine was assessed by an in vivo mouse hindpaw extravasation model. Mast cell intracellular calcium mobilization was measured by a calcium imaging assay. An enzyme immunoassay was used to evaluate the release of pro-inflammatory factors from stimulated mast cells. Activated mast cell related signals were assessed by western blot. A cell membrane chromatography assay was used to determine the binding characteristics of Piperine and MRGPRX2. The results showed that Piperine suppressed mast cell intracellular Ca

Topics: Alkaloids; Anaphylaxis; Animals; Benzodioxoles; Disease Models, Animal; Humans; Male; Mast Cells; Mice; Piperidines; Polyunsaturated Alkamides; Receptors, G-Protein-Coupled

We report here a case of rocuronium-induced anaphylactic shock in a 41-year-old woman. She was scheduled for partial hepatectomy due to liver metastasis of a pheochromocytoma. Anesthesia was induced with propofol, remifentanil, and rocuronium. Bag-mask ventilation was difficult, and her blood pressure fell to around 40 mmHg just after induction. Subsequently, her trachea was intubated and adrenaline was injected. However, due to the subsequent persistence of severe hypotension and hypoxia, cardiopulmonary resuscitation was necessary. Suspecting the development of pulmonary embolism or anaphylaxis, we performed transesophageal echography; however, no evidence of right heart dilatation was observed, indicating a low possibility of pulmonary embolism. Although her general condition was stabilized, surgery was canceled. Blood tests showed high serum histamine and tryptase levels, suggesting an Ig-E mediated allergic reaction. A skin test performed five weeks after anesthesia suggested that she had suffered from rocuronium-induced anaphylaxis. A skin test also showed cross-reactivity between rocuronium and vecuronium. Therefore, we did not use any neuromuscular agent for the subsequent surgery, which was completed uneventfully. Determining the drug responsible for anaphylaxis helps to prevent recurrence of anaphylaxis.

Topics: Adult; Anaphylaxis; Androstanols; Anesthesia, General; Female; Humans; Neoplasm Recurrence, Local; Neuromuscular Blocking Agents; Piperidines; Propofol; Pulmonary Embolism; Remifentanil; Rocuronium; Skin Tests; Tryptases

Topics: Analgesics, Opioid; Anaphylaxis; Anesthesiology; Anesthetics; Anesthetics, Inhalation; Anesthetics, Intravenous; Child; Child, Preschool; Drug Therapy, Combination; Humans; Hypnotics and Sedatives; Infant; Intubation, Intratracheal; Laryngismus; Lidocaine; Methyl Ethers; Neuromuscular Blocking Agents; Pediatrics; Piperidines; Propofol; Remifentanil; Sevoflurane

Adults suffering from wheat-dependant, exercise-induced anaphylaxis (WDEIA) develop IgE directed against wheat omega5-gliadins (major allergens for this allergy) and against wheat low-molecular weight glutenin subunits (LMW-GS). However, the ability of LMW-GS to trigger an inflammatory response is still unknown. It also remains to be determined if IgE from these patients bind the same epitopes on LMW-GS and omega5-gliadins or if the epitopes are independent.. WDEIA patients were selected and skin prick tests (SPTs) were performed on them using commercial gluten, wheat flour extracts, prolamin fractions and a purified natural LMW-GS P42. The IgE-binding ability of natural and recombinant wheat prolamins was verified by immunoblot experiments. Cross-reactivity between LMW-GS and omega5-gliadins was studied by immunoblot inhibition experiments, using purified natural omega5-gliadin as an inhibitor.. Patients developed positive SPTs with natural LMW-GS fractions and/or with the purified LMW-GS P42. Natural and recombinant LMW-GS were highly reactive with patient IgE in immunoblot experiments, as was omega5-gliadin. However, differences in reactivity were evident within the LMW-GS group. Except for one recombinant LMW-GS (P73), IgE cross-reactivity between LMW-GS and natural omega5-gliadin was only partial.. LMW-GS are able to promote local inflammation and they share common epitopes with omega5-gliadins. The nature of these epitopes is discussed. LMW-GS also carried specific epitopes, completely independent from the omega5-gliadin epitopes. Thus, LMW-GS behaved partly as independent allergens.

Topics: Adult; Allergens; Amino Acid Sequence; Anaphylaxis; Antigens; Bridged Bicyclo Compounds, Heterocyclic; Cross Reactions; Exercise; Gliadin; Glutens; Humans; Immunoglobulin E; Middle Aged; Piperidines; Recombinant Proteins; Skin Tests; Triticum; Wheat Hypersensitivity; Young Adult

Allergies to iron salts are seldom reported. We studied a patient with iron-deficiency anemia who had suffered anaphylactic reactions caused by oral iron salts. An allergy study was performed using single-blind, placebo-controlled oral challenge and skin tests with various iron salts as well as excipients in commercial formulations. Oral challenges were positive for 2 of the commercial formulations of iron salts. Intradermal tests with ferrous sulphate and ferrous lactate also showed positive results. All of the cutaneous tests using the excipients were negative. A desensitization protocol was designed which enabled us to readminister ferrous sulphate, although antihistamines were necessary to guarantee good tolerance to iron salts. We report a patient with allergy to iron salts, positive skin tests, and positive controlled challenge. We highlight the desensitization protocol designed to complete the therapeutic management of the anemia.

Topics: Aged; Anaphylaxis; Butyrophenones; Chlorpheniramine; Desensitization, Immunologic; Drug Hypersensitivity; Female; Ferrous Compounds; Histamine H1 Antagonists; Humans; Lactates; Piperidines

The Tako-Tsubo syndrome (or transient left ventricular apical balloning) is a new clinical entity, very similar to acute myocardial infarction, but different by its excellent short-term prognosis. It has been reported after a physical or an emotional stress, and it is diagnosed by a coronary angiogram and a left ventriculography. We report here a case of Tako-Tsubo syndrome related to an anaphylactic shock caused by succinylcholine during general anaesthesia of a female patient, wearing an unadjustable gastric band.

Topics: Anaphylaxis; Anesthesia, General; Anesthesia, Intravenous; Diabetes Mellitus, Type 2; Female; Gastroplasty; Heart Arrest; Humans; Intraoperative Complications; Laparoscopy; Middle Aged; Neuromuscular Depolarizing Agents; Obesity; Pelvic Floor; Piperidines; Postoperative Complications; Propofol; Pulmonary Edema; Remifentanil; Succinylcholine; Takotsubo Cardiomyopathy; Ventricular Fibrillation

Tecastemizole, a major metabolite of astemizole, is a potent and selective H1 receptor antagonist. Evidence suggests that this and certain other H1 receptor antagonists may possess anti-inflammatory effects that are, in some cases, independent of H1 receptor antagonism. Objective The aim of this study was to investigate the anti-inflammatory effects of tectastemizole in models of allergic inflammation.. Effects of tecastemizole were assessed in a murine model of allergic lung inflammation, in passive cutaneous anaphylaxis (PCA) responses in guinea-pig skin and in in vitro assays measuring endothelial adhesion molecule expression and leucocyte-endothelial adhesion.. Tecastemizole inhibited antigen-induced eosinophil recruitment to the lungs of allergic mice in a dose-dependent manner. Furthermore, combination of a sub-effective dose of tecastemizole, combined with a sub-effective dose of dexamethasone inhibited eosinophil accumulation in this model. Plasma extravasation in PCA reactions was inhibited by tecastemizole, although by a mechanism that would appear to be H1 receptor-dependent. Cytokine-induced endothelial intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 expression, as well as mononuclear cell adhesion to human umbilical vein endothelial cells was inhibited by tecastemazole in a manner independent of H1 receptor antagonism.. These data suggest that tecastemizole may have H1 receptor-independent effects in inhibiting late-phase inflammatory responses, while acute responses appear to be inhibited in a H1 receptor-dependent manner. Furthermore, our data suggest an important potential steroid-sparing role for such drugs in the treatment of allergic inflammatory conditions.

Topics: Anaphylaxis; Animals; Anti-Inflammatory Agents; Astemizole; Benzimidazoles; Cell Adhesion; Cell Adhesion Molecules; Cell Movement; Dermatitis, Atopic; Dexamethasone; Disease Models, Animal; Endothelium, Vascular; Eosinophils; Guinea Pigs; Histamine H1 Antagonists; Humans; Inflammation; Intercellular Adhesion Molecule-1; Male; Mice; Mice, Inbred BALB C; Piperidines; Receptors, Histamine H1; Respiratory Hypersensitivity; Umbilical Veins; Vascular Cell Adhesion Molecule-1

Clinical doses of available H(1) antihistamines are limited mainly by sedative side effects. However, higher doses are often required to obtain optimal therapeutic activity, especially in dermatology. We report the synthesis of three norpiperidine imidazoazepines representative of a new class of selective and nonsedating H(1) antihistamines. The compounds were at least as potent as cetirizine and loratadine as measured by H(1) receptor binding affinity, by protection against compound 48/80- and histamine-induced lethality in rats and guinea pigs, respectively, and by skin reaction tests in rats, guinea pigs, and dogs. The compounds, in particular 3a, were less prone than the reference compounds to penetrate the brain and to occupy central H(1) receptors, suggesting absence of sedative side effects. In vitro and in vivo cardiovascular safety tests showed that 3a had no intrinsic potential to prolong ventricular repolarization or induce cardiac arrhythmias. Compound 3a has been selected for further clinical development, mainly for application in dermatology.

Topics: Anaphylaxis; Animals; Arrhythmias, Cardiac; Benzazepines; Blood-Brain Barrier; CHO Cells; Cricetinae; Cricetulus; Dermatitis; Dermatologic Agents; Dogs; Drug Stability; Female; Guinea Pigs; Histamine H1 Antagonists, Non-Sedating; Hydrogen-Ion Concentration; Imidazoles; In Vitro Techniques; Male; Passive Cutaneous Anaphylaxis; Piperidines; Radioligand Assay; Rats; Rats, Wistar; Solubility; Spiro Compounds; Structure-Activity Relationship; Ventricular Function

To study the effects of ketotifen fumarate, olopatadine, and levocabastine on ocular active anaphylaxis in guinea pigs and on ocular immediate hypersensitivity in albino rats.. Clinical grading scores and Evans blue dye leakage to eyelids and to eyeballs were assessed in five treatment groups (n = 10): ketotifen fumarate 0.025%, olopatadine 0.1%, levocabastine 0.05%, negative control, and positive control.. At 20 minutes after challenge, edema scores for ketotifen-treated guinea pigs were statistically significantly lower than those for levocabastine or olopatadine. Active treatment significantly reduced vascular leakage in both models. Ketotifen significantly reduced vascular leakage in eyelids compared with the other drugs. In guinea pigs, vascular leakage in eyeballs was significantly reduced with ketotifen fumarate compared with olopatadine and levocabastine.. In the guinea pig model, ketotifen was more effective than olopatadine and levocabastine at reducing conjunctival edema and vascular permeability in eyelids and eyeballs. In the rat model, ketotifen was more effective at reducing vascular permeability in eyelids than olopatadine and levocabastine.

Topics: Anaphylaxis; Animals; Capillary Permeability; Conjunctivitis, Allergic; Dibenzoxepins; Disease Models, Animal; Edema; Eyelids; Guinea Pigs; Histamine H1 Antagonists; Ketotifen; Male; Olopatadine Hydrochloride; Ophthalmic Solutions; Ovalbumin; Piperidines; Rats

We report on a patient who suffered an anaphylactoid reaction because of moxifloxacin.

Topics: Adult; Anaphylaxis; Anti-Infective Agents; Aza Compounds; Butyrophenones; Female; Fluoroquinolones; Humans; Moxifloxacin; Otitis; Piperidines; Quinolines

A 47-year-old woman with Cushing's syndrome suffered a severe anaphylactic reaction on induction of anaesthesia, resulting in circulatory arrest. A spontaneous cardiac output appeared after 25 minutes of chest compression and she regained consciousness three hours later, with no neurological deficit. A Bispectral Index monitor demonstrated values greater than 40 throughout the whole period of resuscitation. Possible implications for this observation are discussed.

Topics: Anaphylaxis; Cardiopulmonary Resuscitation; Electroencephalography; Female; Heart Arrest; Humans; Middle Aged; Monitoring, Intraoperative; Piperidines; Propofol; Remifentanil; Vecuronium Bromide

In anaphylactic shock (AS), the relative effects of the autacoids including histamine, prostaglandins, and leukotrienes on causing cardiovascular collapse and the extent to which receptor blocking agents and pathway inhibitors may prevent this collapse are not clear. In a ragweed model of anaphylaxis, we examined whether pretreatment with H1, H2, H3 receptor blockers, and cyclooxygenase and leukotriene pathway inhibitors was useful in preventing the depression in left ventricular (LV) contractility known to occur in this model. The dose of allergen was varied to produce similar degrees of shock between treatments. The animals were studied under pentobarbital anesthesia in which the treatment studies were approximately 3 wk apart. LV volumes were measured by sonomicrometric techniques. During challenge, mean arterial blood pressure (Pa), cardiac output (Q), and LV end-diastolic pressure (LVEDP) decreased approximately 50% compared with preshock values in all treatments. Histamine H3 receptor blockade was associated with higher heart rates (HR) and higher stroke work (SW) (p < 0.05) as compared with the other treatment studies. We conclude that histamine H3 activation by inhibiting adrenergic neural norepinephrine release contributes to cardiovascular collapse in AS.

Topics: Anaphylaxis; Animals; Chlorpheniramine; Cyclooxygenase Inhibitors; Dogs; Hemodynamics; Histamine; Histamine Antagonists; Histamine H1 Antagonists; Histamine H2 Antagonists; Indoles; Indomethacin; Leukotrienes; Lipoxygenase Inhibitors; Myocardial Contraction; Piperidines; Prostaglandins; Quinolines; Ranitidine; Receptors, Histamine H3; Stroke Volume; Ventricular Function, Left

In anaphylactic shock (AS), the relative effects of the autacoids including histamine, prostaglandins (prost), and leukotrienes (leuk) on causing cardiovascular collapse and the extent to which receptor blocking agents and pathway inhibitors may prevent this collapse are not clear.. In randomized design, we investigated whether blockade of histamine H1, H2, and H3 receptors or inhibition of the cyclooxygenase (cyclo) and lipoxygenase pathways (lipox) prevented AS in ragweed sensitized dogs. Seven dogs were studied under pentobarbital anesthesia in which the treatment studies were approximately 2 weeks apart.. During H1 receptor blockade, the decreases in blood pressure and cardiac output otherwise observed in AS were attenuated (P < 0.05) and the release of prost, thromboxanes, and leuk were reduced as compared with nontreatment studies. Cyclo inhibition also attenuated cardiovascular collapse and mediator release in AS, but the other treatments showed no effects.. H1 receptor blockade and cyclo may attenuate cardiovascular shock in AS. These agents inhibit autacoid release from mast cells in addition to any specific receptor blocking and pathway inhibition effects.

Topics: Analysis of Variance; Anaphylaxis; Animals; Cardiovascular System; Cyclooxygenase Inhibitors; Dogs; Hemodynamics; Histamine Antagonists; Histamine H1 Antagonists; Histamine H2 Antagonists; Indoles; Indomethacin; Inflammation Mediators; Lipoxygenase Inhibitors; Piperidines; Quinolines; Random Allocation; Ranitidine; Receptors, Histamine H3

The basic mechanisms of food allergies are still unknown. The aims of this study were to investigate whether endothelins (ETs) in the intestinal mucosa are involved in the pathogenesis of intestinal anaphylaxis.. Sprague-Dawley rats were sensitized to chicken egg albumin (EA) by intraperitoneal injection. Fourteen days after sensitization, EA was administered in the jejunal segments to induce intestinal anaphylaxis. Net water outflux and histamine release into loops and serum concentrations of rat mast cell protease II (RMCP-II) were determined. ET-1 and ET-3 concentrations in the jejunal mucosa were determined, and expression of the corresponding messenger RNAs was examined by competitive polymerase chain reaction.. In sensitized animals, challenge with intraluminal antigen caused a significant increase in net water outflux and histamine release together with an elevation of serum RMCP-II concentrations. Mucosal concentrations of ET-1 and ET-3 and expression of their messenger RNAs were significantly increased in sensitized animals after EA challenge. Treatment with an ETA-receptor antagonist, but not an ETB-receptor antagonist, attenuated the increase in net water outflux, histamine release, and serum RMCP-II concentrations in rats with EA-induced intestinal anaphylaxis.. Release of ETs in the intestinal mucosa increased in sensitized animals after EA challenge. ETs may play a significant role in the development of intestinal anaphylaxis via an ETA receptor.

Topics: Albumins; Anaphylaxis; Animals; Bosentan; Cell Line; Chickens; Eggs; Endothelin Receptor Antagonists; Endothelin-1; Endothelin-3; Histamine; Intestinal Mucosa; Intestines; Oligopeptides; Peptides, Cyclic; Piperidines; Rats; Rats, Sprague-Dawley; Serine Endopeptidases; Sulfonamides

The effect of 2-[2-[4-(diphenylmethyl)-1-piperadinyl]ethoxy] benzoic acid maleate (ZCR-2060) on passive systemic anaphylaxis (PSA) and antigen-induced immediate- and late-phase increase in airway resistance (Rrs) in either passively or actively sensitized guinea pigs were investigated. ZCR-2060 inhibited PSA in guinea pigs. ID50 values of ZCR-2060, ketotifen, terfenadine and cetirizine on PSA were 0.03, 0.02, 0.8 and 0.3 mg/kg, respectively, when administered orally 1 h before the antigen challenge. The protective effect of ZCR-2060 was observed until 12 h before the antigen challenge. Aeroantigen-induce immediate increase in Rrs in passively sensitized guinea pigs with and without metyrapone treatment was inhibited by ZCR-2060, ketotifen, terfenadine and cetirizine. In contrast, prednisolone did not affect the aeroantigen-induced immediate increase in Rrs in animals not treated with metyrapone, but significantly inhibited the metyrapone-induced enhanced immediate response. In actively sensitized animals, the immediate- and late-phase increases in Rrs were observed within 30 min and between 3 and 8 h after the aeroantigen challenge. Pretreatment with metyrapone accelerated both antigen-induced responses. ZCR-2060 (1 mg/kg) significantly inhibited both responses. Ketotifen (1 mg/kg), terfenadine (10 mg/kg) and prednisolone (10 mg/kg) significantly the inhibited the late-phase response, but did not affect the immediate-phase response. In contrast, Cetirizine (10 mg/kg) did not affect either response. The effect of ZCR-2060 on late-phase response was stronger than that of ketotifen, terfenadine and cetirizine, and was almost the same as that of prednisolone. These results suggest that ZCR-2060 has a potent protective effect on immediate- and late-phase increases in Rrs.

Topics: Airway Resistance; Anaphylaxis; Animals; Benzoates; Bronchi; Cetirizine; Female; Guinea Pigs; Ketotifen; Metyrapone; Ovalbumin; Piperidines; Prednisolone; Terfenadine

The effect of bilateral vagal stimulation on aerosolized antigen-induced responses was examined in the sensitized, perfused guinea pig lung. Vagal stimulation in the sensitized, perfused lung resulted in bronchoconstriction (peak response 160 +/- 18% above baseline) that was unaffected by either atropine (1 microM), a muscarinic receptor antagonist, or CP 96,345 (1 microM), a NK-1 receptor antagonist, but was transiently augmented in the presence of physostigmine (1 microM), a cholinesterase inhibitor, through an atropine-sensitive mechanism. However, SR 48968 (1 microM), a NK-2 receptor antagonist, and SR 48968 + CP 96,345 reduced by approximately 50 and 90%, respectively, vagally mediated increases in intratracheal pressure in the perfused lung. Simultaneous challenge with vagal stimulation and aerosolized antigen in the sensitized perfused lung resulted in a significant (p < 0.01) increase in intratracheal pressure (Pi), pulmonary arterial pressure (Ppa), and lung weight (LW) compared with either vagal stimulation or aerosolized antigen alone. Increases in Pi, Ppa, and LW in response to vagal stimulation + aerosolized antigen were associated with elevated venous effluent concentrations of thromboxane A2 (TXA2), prostacyclin, leukotriene C4, and histamine. Vagally mediated potentiation of aerosolized antigen-induced increases in Pi, Ppa, and LW was unaffected by atropine or CP 96,345 but was inhibited by the NK-2 receptor antagonist, SR 48968. These data suggest that vagally mediated (predominantly NK-2) potentiation of aerosolized antigen-induced increases in Pi, Ppa, and LW is characterized by elevated venous effluent concentrations of eicosanoids and histamine.

Topics: Anaphylaxis; Animals; Atropine; Benzamides; Biphenyl Compounds; Bronchoconstriction; Electric Stimulation; Guinea Pigs; Hypnotics and Sedatives; Lung; Male; Neurokinin A; Organ Size; Physostigmine; Piperidines; Trachea; Vagus Nerve; Vasoconstriction

Anaphylactic histamine release from isolated rat peritoneal mast cells was concentration-dependently blocked by a 5-min treatment with exogenous histamine at 0.9 and 9 microM and enhanced by a 20- to 30-min treatment with thioperamide (H3-antagonist) at 3 microM with significance, but little affected by mepyramine (H1-antagonist) and cimetidine (H2-antagonist) at the cell concentration of 10(6) mast cells/ml. At a low concentration of mast cells (10(4) mast cells/ml), (R)-alpha-methylhistamine (alpha-MH), an H3-agonist, at 0.9-90 microM also inhibited the release in a concentration-dependent fashion. Thioperamide, but neither mepyramine nor cimetidine, significantly restored the decreased release by alpha-MH. However, the complete restoration by thioperamide could not be achieved because the drug itself slightly but concentration-dependently inhibited anaphylactic histamine release. On the other hand, not only betahistine and dimaprit but also alpha-MH did not suppress histamine release from the mast cells induced by compound 48/80. In rat plasma, considerable levels of histamine were detected. From these results, it is strongly suggested that histamine H3-like receptors are largely responsible for the negative feedback regulation of the anaphylactic histamine release from rat peritoneal mast cells.

Topics: Anaphylaxis; Animals; Anticonvulsants; Chromatography, High Pressure Liquid; Cimetidine; Dimaprit; Dose-Response Relationship, Drug; Histamine; Histamine Agonists; Histamine Antagonists; Histamine Release; In Vitro Techniques; L-Lactate Dehydrogenase; Male; Mast Cells; Methylhistamines; p-Methoxy-N-methylphenethylamine; Peritoneal Cavity; Peritoneum; Piperidines; Pyrilamine; Rats; Rats, Wistar; Receptors, Histamine H3

1. In the present study, we have investigated the role of kinins in allergen-induced bronchoconstriction. 2. Anaesthetized guinea-pigs were sensitized to ovalbumin, ventilated artificially, pretreated with atropine (1.4 mumol kg-1, i.v.) and total pulmonary resistance (RL) measured. In preliminary studies in the presence of the neutral endopeptidase inhibitor, phosphoramidon (4.5 mumol kg-1, i.v.), the bradykinin B2 receptor antagonist Hoe 140 (0.1 mumol kg-1, i.v.) completely abolished the increase in RL following aerosolized bradykinin (1 mM, 40 breaths), but had no effect on the increase in RL following aerosolized neurokinin A (NKA, 10 microM, 40 breaths). On the other hand, a combination of the NK1 (CP-96,345, 2 mumol kg-1, i.v.) and NK2 (SR 48968, 0.3 mumol kg-1, i.v.) tachykinin receptor antagonists abolished completely the increase in RL produced by NKA and partially inhibited the increase in RL produced by bradykinin. These results confirm previous studies that suggest that bradykinin induces the release of tachykinins from sensory nerves in guinea-pig airways. 3. Aerosolized ovalbumin (0.5%, 5 breaths) increased RL in sensitized guinea-pigs pretreated with atropine (1.4 mmol kg-1, i.v.), an effect that began within 2 min and reached a maximum within 5 min; RL remained above baseline at 20 min. Pretreatment with the bradykinin B2 receptor antagonist, Hoe 140, decreased the bronchoconstrictor effect of ovalbumin markedly at 10 to 20 min. In the presence of phosphoramidon (4.5 mumol kg-1, i.v.) the inhibition induced by Hoe 140 was apparent earlier and remained over the 20 min period of study. 4. Pretreatment with a combination of NK1 (CP-96,345) and NK2 (SR 48968) tachykinin receptor antagonists also markedly inhibited ovalbumin-induced bronchoconstriction; addition of the bradykinin B2 receptor antagonist to the NK1 and NK2 tachykinin receptor antagonists had no additional inhibitory effect on antigen-induced bronchoconstriction.5. These findings confirm that activation of sensory nerves to release tachykinins in guinea-pig airways contribute to antigen-induced bronchoconstriction, and provide evidence that tachykinin release is due to kinins generated during the allergic response.

Topics: Adrenergic beta-Antagonists; Airway Resistance; Anaphylaxis; Animals; Benzamides; Biphenyl Compounds; Bradykinin; Bronchoconstriction; Glycopeptides; Guinea Pigs; Hypnotics and Sedatives; Kinins; Male; Neprilysin; Neurokinin-1 Receptor Antagonists; Piperidines; Receptors, Neurokinin-2; Tachykinins

A series of [(3-pyridylalkyl)piperidylidene]- and (nicotinoylpiperidylidene)benzocycloheptapyridine derivatives, Ia,b, were prepared and evaluated for PAF antagonist and H1 antihistamine activity. PAF antagonist activity was investigated by the in vitro PAF-induced platelet aggregation assay (PPA) and the in vivo PAF-induced hypotension test in rats (PH) and mortality test in mice (PM). For the evaluation of H1 antihistamine activity, the in vitro histamine-induced contraction of the guinea-pig ileum assay (HC) and the in vivo histamine-induced hypotension test (HH) in normotensive rats were used. The potential antiallergic activity of the compounds was evaluated using the active anaphylactic shock test in mice. These compounds are structurally related to loratadine (1) and were generated by replacement of the ethoxycarbonyl group of 1 with substituted 3-pyridylmethyl and nicotinoyl moieties. Both anti-PAF and H1 antihistamine activities have shown a high dependence on the exact nature and position of the substituent in the pyridine ring. Optimum structure 19 (UR-12592) incorporating a (5-methyl-3-pyridyl)methyl radical displayed an unique dual activity inhibiting both PAF-induced effects (PPA, IC50 = 3.7 microM; PH, ID50 = 0.44 mg/kg iv; PM, ID50 = 1.9 mg/kg po) and histamine-induced effects (HC, IC50 = 3.9 nM; HH, ID50 = 1.4 mg/kg iv). Furthermore, 19 was highly active in the passive cutaneous anaphylactic shock in rats (ID50 = 1.2 mg/kg po) and strongly protected mice and rats from mortality induced by endotoxin (ID50 = 1.2 and 0.5 mg/kg iv, respectively). Compound 19 showed itself to be devoid of CNS depressant effects, neither modifying spontaneous motor activity nor prolonging barbiturate-sleeping time in mice at a dose of 100 mg/kg po, and is now under development.

Topics: Anaphylaxis; Animals; Benzocycloheptenes; Blood Pressure; Guinea Pigs; Histamine; Histamine H1 Antagonists; Ileum; In Vitro Techniques; Indicators and Reagents; Magnetic Resonance Spectroscopy; Male; Mice; Molecular Structure; Muscle Contraction; Muscle, Smooth; Piperidines; Platelet Activating Factor; Platelet Aggregation Inhibitors; Rabbits; Rats; Rats, Sprague-Dawley; Structure-Activity Relationship

Levocabastine hydrochloride (R50 547, CAS79516-68-0) caused no inhibitory effect on the histamine release from rat peritoneal mast cells induced by compound 48/80, A23187 and concanavalin A. However, the drug inhibited histamine release from passively sensitized mast cells and passive peritoneal anaphylaxis in rats, though higher concentrations or doses were required. Moreover, levocabastine provided a relatively potent inhibitory effect on histamine release from lung pieces of actively sensitized guinea pigs exposed to antigen, and simultaneously the drug prevented a decrease in the cyclic AMP (cAMP) content. Levocabastine potently inhibited histamine-induced cutaneous reactions in rats and the drug also prevented histamine-induced contraction of isolated guinea pig ileum. Levocabastine did not induce any significant changes in platelet aggregation or in the contraction of guinea pig ileum induced by platelet activating factor (PAF). However, the drug inhibited eosinophil migration induced by PAF. The chemotaxis of neutrophils induced by N-formyl-methionyl-leucylphenylalanine (fMLP) was also inhibited by levocabastine in a dose-dependent fashion. Levocabastine has no influence on the order parameter tested with liposomes, suggesting that the drug provides no significant effect on the membrane fluidity of lipid bilayer. These results seem to indicate that the antiallergic effect of levocabastine is mainly dependent on its potent antihistaminic activity.

Topics: Anaphylaxis; Animals; Chemotaxis, Leukocyte; Complement Inactivator Proteins; Cyclic AMP; Guinea Pigs; Histamine; Histamine H1 Antagonists; Histamine Release; Hypersensitivity; Immunoglobulin E; In Vitro Techniques; Lung; Male; Mast Cells; Mice; Mice, Inbred BALB C; Muscle, Smooth; Piperidines; Platelet Aggregation; Prostaglandins E; Rabbits; Rats; Rats, Wistar; Skin Tests

Whether anaphylactic histamine release from rat peritoneal mast cells is influenced by betahistine, a histamine H1-receptor agonist/H3-antagonist, and dimaprit, an H2-agonist, was examined. Treatment with dimaprit at 6 and 60 microM for 20 min significantly inhibited the anaphylactic histamine release, whereas betahistine at up to 80 microM under the same conditions did not affect it. Treatment with dimaprit at 6 and 60 microM for 1 to 20 min and for 5 to 20 min, respectively, caused a time-dependent inhibition of the release, but up to 30 min treatment with 8 and 80 microM betahistine had no effect. The decreased histamine release induced by dimaprit was recovered by neither mepyramine nor cimetidine. However, thioperamide, an H3-selective antagonist, dose-dependently restored the diminished release. From these results, the inhibition of anaphylactic histamine release by dimaprit is not produced by the stimulation of H2-receptors, but involves the stimulation of H3-like receptors or H3-subtype receptors, which are distinct from the H3-receptors located in brain, and suggests that the receptor plays an important role in the negative feedback regulation of histamine release.

Topics: Anaphylaxis; Animals; Anticonvulsants; Betahistine; Cimetidine; Dimaprit; Histamine H2 Antagonists; Histamine Release; In Vitro Techniques; Indicators and Reagents; Male; Mast Cells; Piperidines; Pyrilamine; Rats; Rats, Wistar

Levocabastine, selected from a series of cyclohexylpiperidine derivatives protects rats from compound 48/80-induced anaphylactic shock for at least 16 h at the oral dose of 0.0015 mg/kg. At the same dose histamine skin reactions and at slightly higher doses passive cutaneous anaphylactic reactions are inhibited. Blockade of passive cutaneous anaphylactic reactions is obtained with levocabastine, despite absence of peripheral serotonin antagonism and any other known non-specific action that may facilitate inhibition of passive anaphylaxis. In dogs allergic reactions are inhibited at oral doses 40 times lower than ketotifen. In guinea-pigs orally and topically administered levocabastine are remarkably effective against allergic conjunctivitis.

Topics: Anaphylaxis; Animals; Ascaris; Conjunctivitis, Allergic; Dogs; Guinea Pigs; Histamine; Histamine H1 Antagonists; Hypersensitivity; p-Methoxy-N-methylphenethylamine; Passive Cutaneous Anaphylaxis; Piperidines; Rats

Topics: Aged; Analgesics; Anaphylaxis; Benzophenones; Dipyrone; Drug Combinations; Drug Therapy, Combination; Emergencies; Female; Humans; Male; Middle Aged; Penicillin G; Penicillin G Benzathine; Penicillin G Procaine; Piperidines

AHR-13268D (4-[3-[4-[Bis(4-fluorophenyl)hydroxymethyl]-1- piperidinyl]propoxy]benzoic acid, sodium salt) is a potent, long-acting water soluble, antiallergic and antihistaminic agent. AHR-13268D protects sensitive guinea pigs from collapse induced by aerosolized antigen; 1, 5, and 24 h ED50s in the test were 0.27, 0.25, 0.93 mg/kg, PO, respectively. AHR-13268D was also active when given as an aerosol, the 1 h ED50 = 0.29%. In the rat passivefoot anaphylaxis test. AHR-13268D was slightly more active (1.55 times) than AHR-5333B when given orally 1 h prior to challenge and equipotent to cromolyn when given intravenously immediately prior to challenge. AHR-13268D displayed potent, long-acting antihistaminic activity in naive guinea pigs; the 1, 5, and 24 h oral ED50s being in the range of 0.3 mg/kg. AHR-13268D (10 to 20 mg/kg, PO) attenuated the skin responses to ascaris antigen in sensitive dogs and did not alter the EEG pattern or sleep/wake patterns of cats at doses in vast excess of its antihistaminic activity. In vitro, AHR-13268D was a potent inhibitor of histamine release from rat peritoneal mast cells (IC50 = 0.51 nM) and was as potent as the reference 5-LO inhibitor phenidone in inhibiting antigen-induced contractions of guinea pig ileum in the presence of pyrilamine, atropine, and imidazole (IC50 approximately 300 microM). AHR-13268B was bioavailable (approximately 88%) from capsules or from oral solutions.

Topics: Aerosols; Anaphylaxis; Animals; Antigens; Ascaris; Benzoates; Biological Availability; Electroencephalography; Female; Food Hypersensitivity; Guinea Pigs; Histamine; Histamine H1 Antagonists; Hypersensitivity; Immunoglobulin E; Lung; Male; Piperidines; Rats; Rats, Inbred Strains; Skin Tests

Intracellular signal transduction during anaphylactic contractions of smooth muscle and the site of signal generation, or antigen-antibody reaction, participating in the appearance of these contractions were studied. The taenia coli was removed from a guinea-pig which had previously been sensitized with anti-egg albumin (EA) rabbit serum or anti-EA rabbit immunoglobulin G (IgG) fraction. Dispersed smooth muscle cells, obtained after enzymatic digestion, were used as the specimen. The dispersed single smooth muscle cells sensitized with anti-EA rabbit IgG fraction showed anaphylactic contractions in response to antigen administration. The method using enzyme-linked antibody revealed binding of IgG by these single muscle cells. Anaphylactic contractions of the single cells were not inhibited by antihistamines or anti-5-hydroxy-tryptamine (5HT) agents, but they were suppressed by Y-19,432 [1-butyl-5-hydroxy-2-methyl-N-[1-(2-phenylethyl)-4-piperidyl] indole-3-carboxamide hydrochloride hydrate], an inhibitor of 5-lipoxygenase. The anaphylactic contractions of the single smooth muscle cells of the guinea-pig taenia coli appear to be initiated in response to IgG binding with the antigen bound to the smooth muscle plasma membrane. For contraction development, the lipoxygenase pathway was shown to participate as a part of the intracellular signal transduction.

Topics: Anaphylaxis; Animals; Female; Guinea Pigs; Immunoglobulin G; In Vitro Techniques; Indoles; Lipoxygenase Inhibitors; Muscle Contraction; Muscle, Smooth; Piperidines

A series of 4-(diarylhydroxymethyl)-1-[3-(aryloxy)propyl]piperidines was synthesized and evaluated for antiallergy activity. Several analogues had potent activity in the passive foot anaphylaxis (PFA) assay, an IgE-mediated model useful in the detection of compounds possessing antiallergic activity. In particular 1-[4-[3-[4-[bis(4-fluorophenyl)hydroxymethyl]-1-piperidinyl] propoxy]-3-methoxyphenyl]ethanone (1, AHR-5333) was more potent than oxatomide and terfenadine in this assay.

Topics: Anaphylaxis; Animals; Benzhydryl Compounds; Chemical Phenomena; Chemistry; Drug Evaluation, Preclinical; Guinea Pigs; Hypersensitivity; Male; Passive Cutaneous Anaphylaxis; Piperazines; Piperidines; Rats; Rats, Inbred Strains; Structure-Activity Relationship; Terfenadine

Pipethiadene, a prophylactic of vasomotoric headaches of the series of 4,9-dihydrothieno(2,3-c)-2-benzothiepine derivatives, shows a peripheralpharmacological profile of an antiallergic agent. The experiments in rats showed a high antianaphylactic effect of pipethiadene in the passive cutaneous anaphylaxis (PCA) test. Pipethiadene also exerted intensive antianaphylactoid action in rats on the liberator of histamine, compound 48/80, on dextran, and in the use of a combination of ovalbumin with indomethacin. In comparative pharmacological experiments with pizotifen and cyproheptadine an attempt was made to estimate the relative role of histamine and 5-hydroxytryptamine 5-HT) mediators in the employed experimental procedures in rats.

Topics: Anaphylaxis; Animals; Cyproheptadine; Female; Guinea Pigs; Mice; Migraine Disorders; Passive Cutaneous Anaphylaxis; Piperidines; Pizotyline; Rats

AHR-5333 [1-[4-[3-[4-[bis(4-fluorophenyl)hydroxymethyl]-1-piperidinyl] propoxy]-3-methoxyphenyl]ethanone] possessed potent, long-acting activity in rat and guinea pig in vivo models of immediate hypersensitivity: AHR-5333 was more potent than azatadine (2 X), ketotifen (approximately 3 X), oxatomide (approximately 5 X), albuterol (6 X) and aminophylline (approximately 50 X) in a passive, foot anaphylaxis model in rats and more potent than diphenhydramine (approximately 237 X), oxatomide (approximately 5.6 X) and theophylline (approximately 295 X) in guinea pigs challenged with aerosolized antigen. A long duration of action was noted after oral dosing of guinea pigs (24 h PD50, 0.78 mg/kg). Administration by aerosol (1%) to sensitized, spontaneously breathing, conscious guinea pigs protected against antigen-induced anaphylactic collapse; this protection persisted through 8 h. When administered prior to antigen challenge, AHR-5333 (10 mg/kg, p.o.) effectively inhibited ascaris antigen-induced skin hypersensitivity reactions in both dogs and cynomolgus monkeys.

Topics: Administration, Oral; Anaphylaxis; Animals; Antigens, Helminth; Ascaris; Dogs; Female; Guinea Pigs; Histamine H1 Antagonists; Hypersensitivity, Immediate; Macaca fascicularis; Male; Piperidines; Rats; Skin Tests

Topics: Anaphylaxis; Animals; Arthus Reaction; Histamine H1 Antagonists; Hypersensitivity; Lipoxygenase Inhibitors; Piperidines

The preparation of several derivatives to oxatomide (A), with the benzimidazolinone moiety replaced by another heterocyclic residue is described. In some cases changes to the basic chain of (A) were also considered. All the new compounds were evaluated as antihistaminics (H1) and antianaphylactics. The derivatives where the heterocyclic moiety was an unsubstituted or phenylsubstituted 2-pyrrolidone or 2-piperidone residue showed antihistaminic and antianaphylactic activities similar to those of oxatomide while modification of the basic side chain with elimination of the benzhydryl group, gave a complete loss of activity. The pharmacological screening was completed by the evaluation of the barbiturate induced sleep prolongation and of acute toxicity.

Topics: Anaphylaxis; Animals; Barbiturates; Chemical Phenomena; Chemistry; Female; Guinea Pigs; Histamine Antagonists; Male; Mice; Mice, Inbred Strains; Piperidines; Piperidones; Pyrrolidinones; Rats; Sleep

Calves were sensitized with horse plasma (H.P.), 0.2 ml/kg, i.v., and H.P. (0.2 ml/kg) in Freund's complete adjuvant, s.c. The latter injection was repeated 1 week later and the animals were killed 10 days after the second injection. Spirally cut strips of pulmonary artery and vein and the trachealis muscle from the sensitized calves contracted to 5-hydroxytryptamine (5-HT) and specific antigen (horse plasma). Antigen-induced contractions of the pulmonary smooth muscles were significantly blocked (P less than 0.05) by the 5-HT antagonists, methysergide and ketanserin. The trachea, however, appeared less sensitive to the antagonists than the pulmonary vessels. The results suggest that 5-HT participates in the pulmonary anaphylactic reactions of cattle and that ketanserin may be useful in suppressing bovine pulmonary hypersensitivities.

Topics: Anaphylaxis; Animals; Cattle; Horses; In Vitro Techniques; Ketanserin; Lung; Methysergide; Muscle Contraction; Muscle, Smooth; Piperidines; Pulmonary Artery; Pulmonary Veins; Serotonin Antagonists; Trachea; Tryptamines

Ketotifen is a compound with strong anti-anaphylactic and anti-histaminic properties both in experimental mental animals and man. In this paper pharmacological experiments are presented which show that these two activities are independent. In the rat, the two actions of ketotifen differ markedly in their time course. The ability of ketotifen to prevent a passive cutaneous anaphylactic reaction is of short duration and is already abolished at times when the compound still fully prevents the cutaneous reaction to histamine. Two anti-histamines, clemastine and mepyramine, were compared with ketotifen. All three compounds prevented the wheal and flare induced by intracutaneous administration of histamine, but only ketotifen also prevented passive cutaneous anaphylaxis. Accordingly, concomitant administration of the anti-histamine clemastine with ketotifen resulted in enhanced histamine-blocking effects but did not influence the anti-anaphylactic action of ketotifen. Finally, clemastine and mepyramine differed from ketotifen in their activities in a model of anaphylactically-induced bronchospasm. Ketotifen prevented the bronchospasm, dyspnea and respiratory arrest in dose-dependent fashion, while the two reference anti-histamines were virtually inactive.

Topics: Airway Resistance; Anaphylaxis; Animals; Antigens; Clemastine; Female; Histamine H1 Antagonists; Ketotifen; Piperidines; Pyrilamine; Rats; Skin Tests; Thiophenes

In a multicentre, double-blind trial, the steroid sparing effect of a new anti-anaphylactic agent ketotifen was assessed against placebo in eighty-six steroid-dependent asthmatics. Mean reduction in total daily prednisolone dosage in patients on ketotifen was 4.0 +/- 3.6 mg compared to 1.7 +/- 2.8 mg on placebo, a result significantly in favour of the active drug (P < 0.01). This suggests that ketotifen has a place similar to that of disodium cromoglycate or steroid aerosols in the managment of steroid-dependent asthmatics. It has the advantage of requiring only twice-daily oral administration.

Topics: Adult; Aged; Anaphylaxis; Asthma; Cromolyn Sodium; Double-Blind Method; Female; Humans; Ketotifen; Male; Middle Aged; Peak Expiratory Flow Rate; Piperidines; Placebos; Prednisolone; Substance-Related Disorders; Thiophenes

Topics: Anaphylaxis; Anesthetics, Local; Animals; Cats; Central Nervous System Agents; Dogs; Female; Guinea Pigs; Haplorhini; Hemodynamics; Histamine Antagonists; Histamine H1 Antagonists; In Vitro Techniques; Kidney; Macaca mulatta; Male; Mice; Parasympatholytics; Phosphodiesterase Inhibitors; Piperidines; Rats; Serotonin Antagonists; Thiophenes

Topics: Albuterol; Anaphylaxis; Animals; Anura; Bronchial Spasm; Cardiovascular System; Chlorpheniramine; Dogs; Drug Evaluation, Preclinical; Female; Gastric Juice; Guinea Pigs; Histamine H1 Antagonists; Inflammation; Male; Mice; Muscle, Smooth; Piperidines; Pizotyline; Rats; Respiration; Stomach Ulcer; Thiophenes

Topics: Anaphylaxis; Animals; Clemastine; Cromolyn Sodium; Dose-Response Relationship, Drug; Histamine H1 Antagonists; Histamine Release; Ovalbumin; p-Methoxy-N-methylphenethylamine; Passive Cutaneous Anaphylaxis; Piperidines; Rats; Thiophenes

1-Phenethyl-4-hydroxy-salicylamido-4-methylpiperidine-hydrochloride (S 1592) markedly inhibits coughing induced in laboratory animals by chemical or mechanical irritation of respiratory tract or by electrical stimulation of the superior laryngeal nerve. The drug has low acute toxicity in mice and rats. The new compound possesses bronchodilating and antianaphylactic properties and does not affect gastrointestinal propulsion. Cardiovascular effects are absent.

Topics: Analgesia; Anaphylaxis; Animals; Antitussive Agents; Body Temperature; Bronchi; Cats; Cough; Dogs; Gastrointestinal Motility; Guinea Pigs; Hemodynamics; Lethal Dose 50; Male; Mice; Motor Activity; Motor Skills; Muscle Contraction; Muscle Tonus; Muscle, Smooth; Piperidines; Rats; Respiration; Salicylamides; Seizures; Sleep

Topics: Anaphylaxis; Animals; Asthma; Dose-Response Relationship, Drug; Glucocorticoids; Guinea Pigs; Histamine; Histamine H1 Antagonists; Hydrocortisone; Male; Mice; Oxazoles; Piperidines; Rats; Serum Albumin, Bovine; Spiro Compounds

Topics: Analgesics; Anaphylaxis; Animals; Bile; Biopharmaceutics; Brain Chemistry; Central Nervous System; Chromatography, Thin Layer; Histamine H1 Antagonists; Kidney; Liver; Lung; Male; Myocardium; Piperidines; Protein Binding; Rats; Spleen; Taurine

Topics: Anaphylaxis; Animals; Chlorpheniramine; Clemastine; Diphenhydramine; Histamine; Histamine H1 Antagonists; Maleates; Piperidines; Promethazine; Pyrrolidines; Rats; Serotonin Antagonists; SRS-A

Topics: Administration, Oral; Analgesics; Anaphylaxis; Animals; Anti-Inflammatory Agents; Arthritis; Edema; Fever; Fluorine; Graft Rejection; Humans; Ketones; Mice; Piperidines; Rabbits; Rats

Topics: Adult; Analgesics; Anaphylaxis; Drug Hypersensitivity; Female; Humans; Piperidines; Resuscitation

Topics: Anaphylaxis; Animals; Anti-Allergic Agents; Bradykinin; Guinea Pigs; Histamine H1 Antagonists; Intestines; Muramidase; Muscle, Smooth; Ovalbumin; Pharmacology; Piperidines; Prednisone; Rabbits; Research; Selective Serotonin Reuptake Inhibitors; Serotonin; Thioxanthenes; Xanthenes