piperidines and Bronchial-Spasm

The development of beta2-specific sympathomimetic bronchodilators (rimiterol, salbutamol, terbutaline) has made the basic treatment of asthmatic patients more safe and effective. Despite that, the asthmatics should be under careful control and all patients should be taught the correct way to use their bronchodilator aerosols. If a sympathomimetic drug has lost its effectiveness, the patient should be able to have easy contact to the treating physician or outpatient department.

Topics: Adrenergic beta-Agonists; Aerosols; Animals; Asthma; Bronchial Spasm; Bronchodilator Agents; Catechols; Humans; 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

Topics: Administration, Oral; Aerosols; Albuterol; Animals; Anisoles; Asthma; Bronchi; Bronchial Spasm; Bronchodilator Agents; Catechols; Drug Evaluation, Preclinical; Ethanolamines; Hexoprenaline; Humans; Injections; Isoproterenol; Isoquinolines; Methanol; Piperidines; Resorcinols; Respiratory Therapy

AZD9164 has demonstrated potential as an inhaled, long-acting, muscarinic antagonist (LAMA) bronchodilator. However, in patients with COPD, but not in healthy subjects, a transient initial drop in FEV1 was observed following inhalation of nebulised doses of AZD9164 in citrate buffer.Two additional studies were conducted to further assess the safety and tolerability of multiple ascending doses of AZD9164 in 27 white and 18 Japanese healthy subjects and in 4 patients with COPD. In these studies, AZD9164 was inhaled via Turbuhaler™.. These were Phase I, randomised, double-blind, placebo-controlled, multiple ascending dose (MAD) studies conducted in Sweden and UK. Healthy subjects (mean age 25.9 yrs) and patients with COPD (mean age 66 yrs, mean post-bronchodilator FEV1 60.1% predicted normal value) were randomised 2:1 to active treatment (400, 1000 or 2800 μg delivered doses of AZD9164) or placebo.. No safety or tolerability concerns were identified in the healthy subjects at doses up to and including 2800 μg and both studies confirmed the bronchodilator effect of AZD9164. However, the first 3 patients in the COPD cohort who received AZD9164 (1000 μg) experienced a transient fall in FEV1 5 to 15 minutes after inhalation of AZD9164 while the patient receiving placebo did not. The study safety review process then resulted in cessation of further activities on AZD9164. Retrospective analysis showed that two healthy subjects had also had transient falls in FEV1 shortly after inhalation of AZD9164 400 and 2800 μg respectively, although neither reported any related respiratory symptoms or other AEs.. These results show that transient paradoxical bronchoconstriction can occur in some healthy subjects, in addition to patients with COPD, following inhalation of AZD9164 and that the citrate buffer used in the nebulised formulation cannot have been the only cause of the drop in FEV1 in previous studies. As preclinical data do not provide an explanation, the reasons for this brief post-dose drop in FEV1 remain unclear. However, these results highlight the importance of monitoring lung function immediately post-dose when investigating novel inhaled treatments, even when a rapid onset of effect is not expected.. Clinicaltrials.gov NCT01016951 and NCT01096563.

Topics: Administration, Inhalation; Adult; Bronchial Spasm; Bronchodilator Agents; Double-Blind Method; Female; Humans; Male; Muscarinic Antagonists; Piperidines; Pulmonary Disease, Chronic Obstructive; Quinuclidines; Retrospective Studies; Young Adult

Roxatidine acetate hydrochloride capsule is slowly absorbed from the gastrointestinal tract, and its acid suppressive effect on the stomach is long-lasting compared with other H2-blockers. The reduction of gastric juice in perioperative period is considered advantageous for patients not only because it decreases the risk for aspiration pneumonia but also because it reduces the risk of bronchial spasm induced by gastroesophageal reflux of acidic gastric content. The effects of single oral administration of roxatidine acetate hydrochloride 150 mg at night before the operation on the volume and pH of gastric juice were investigated during anesthesia using two types of anesthetic agents (isoflurane and propofol) in 93 patients of three age groups (group Y: age 20-40, group M: age 41-64, group O: age 65 <). The effect of roxatidine on reduction of gastric juice was found at the time of anesthetic induction and 2 hours after the induction in any age group with either anesthetic agent. The serum concentration of roxatidine at the time of induction was much higher in group O. The value of residual concentration of roxatidine 20 hours after oral intake was estimated from the intraoperative measurements of serum concentration. The results suggest that single administration at night before the operation is sufficient for the oldest group, but an additive dose is recommended for the younger groups.

Topics: Adult; Age Factors; Aged; Anesthesia, General; Bronchial Spasm; Delayed-Action Preparations; Depression, Chemical; Female; Gastric Acid; Histamine H2 Antagonists; Humans; Intraoperative Complications; Male; Middle Aged; Piperidines; Pneumonia, Aspiration; Preanesthetic Medication

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

UCB JO28 [( 2-[2-[4-(diphenylmethylene)-1-piperidinyl] ethoxy] ethoxy] acetic acid, hydrochloride) is derived from diphenylmethylene piperidine. Animal experiments have shown that it has spasmolytic properties for smooth muscle, particularly in the bronchi, as well as anti-Hl, anticholinergic and anti-serotonin activities. The degree of protection by JO28 against histamine and methacholine-induced bronchospasm has been investigated in 20 asthmatic patients with serious airways hyper-reactivity. Protection against histamine-induced bronchospasm was almost complete in 11 out of 12 patients, whereas protection against methacholine-induced bronchospasm, although clearly present in seven of eight patients, was less marked.

Topics: Adolescent; Adult; Asthma; Bronchial Spasm; Clinical Trials as Topic; Female; Histamine; Humans; Male; Methacholine Chloride; Methacholine Compounds; Middle Aged; Piperidines; Prospective Studies

Parenterally administered diphemanil methylsulfate, a quarternary ammonium compound with both parasympatholytic and direct bronchial smooth muscle relaxing properties, has been found effective in the treatment of bronchial asthma. The present study was undertaken to test the effectiveness of inhaled diphemanil in preventing histamine induced bronchoconstriction in asymptomatic adult asthmatics. Twenty subjects, aged 19-40 years (average 25) were studied, each on three different days, observing an interval of at least 70 hours between testing. On day one, airway sensitivity to inhaled histamine was determined. On days two and three, histamine challenge was repeated 20 minutes after inhalation of either diphemanil (2 mg) or its vehicle in a double-blind crossover design. Airway sensitivity was assessed by determining cumulative log dose units of inhaled histamine required to provoke a 20% decline in FEV1 (log PD20 - FEV1). Diphemanil did not prevent histamine induced bronchoconstriction nor did it significantly affect log PD20 - FEV1 (p = 0.59). We conclude that a 2 mg dose of diphemanil, administered by oral inhalation 20 minutes before histamine challenge, is ineffective in protecting against induced bronchospasm in asymptomatic adult asthmatics.

Topics: Administration, Intranasal; Adult; Asthma; Bronchial Provocation Tests; Bronchial Spasm; Bronchodilator Agents; Female; Forced Expiratory Volume; Histamine; Humans; Male; Parasympatholytics; Piperidines

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: Animals; Asthma; Bronchial Provocation Tests; Bronchial Spasm; Histamine H1 Antagonists; Humans; Mast Cells; Passive Cutaneous Anaphylaxis; Piperidines; Rats; Tachyphylaxis; Thiophenes

Oral challenge tests with acetylsalicylic acid, tartrazine or benzoic acid were performed in 7 intolerant asthmatic patients after a 3-day treatment with either orally taken ketotifen (1 mg twice daily) or inhaled disodium cromoglycate (20 mg four times daily) at random. Protection was noted with ketotifen in 5, with DSCG in 3 patients. On the evaluation of the mean percentage of the maximum decline in the forced expiratory volume in 1 sec (FEV1) only ketotifen afforded significant protection statistically (p less than 0.05). All the intolerant asthmatics studies showed, as an immunological abnormity, a slight, but significant decrease of the C1-inhibitor levels. Moreover, in three out of these the alpha 1-antitrypsin serum values were under the lower normal range.

Topics: Adult; Aged; alpha 1-Antitrypsin; Aspirin; Asthma; Benzoates; Bronchial Spasm; Complement C1 Inactivator Proteins; Cromolyn Sodium; Female; Forced Expiratory Volume; Humans; Male; Middle Aged; Piperidines; Tartrazine; Thiophenes

Topics: Adult; Aged; Antitussive Agents; Bromhexine; Bronchial Diseases; Bronchial Spasm; Carbocysteine; Clinical Trials as Topic; Cough; Cysteine; Drug Combinations; Drug Evaluation; Female; Humans; Male; Middle Aged; Oxadiazoles; Piperidines

Pipoxizin is a new bronchodilator with the chemical name chlorhydrate-4-diphenyl-methylene-1-(2-/2-(2-hydroxy-ethoxy)-ethoxy/-ethyl/-ethyl)-piperidine. This substance exhibits powerful antihistaminic and antiserotonin properties but no parasympathetic or beta-adrenergic properties. The effects of Pipoxizin have been compared with those of the wellknown product hexoprenalin (Ipradol). Twelve male patients, each with bronchial obstruction, took part in the trials. Plethysmography before and after Alupent inhalation was carried out to determine the reversibility or irreversibility of the bronchial obstruction. On the following day, the plethysmorgraphic tests were repeated before and after intravenous injection of Pipoxizin, and on the third day, the tests were repeated again after intravenous injection of hexoprenalin. Pulse and blood pressure were monitored. Following the use of Pipoxizin, there was a significant decrease in the following parameters: RT, RE, RV, ITGV, pulse rate, and systolic blood pressure. A significant increase was found in FEV1. After hexoprenalin injection, there was a significant decrease only in RV and an increase in FEV1. A comparison of Pipoxizin and hexoprenalin shows a significant difference between the two products, Pipoxizin having the more favourable effect.

Topics: Bronchial Spasm; Bronchodilator Agents; Drug Evaluation; Hexoprenaline; Histamine H1 Antagonists; Humans; Male; Piperidines; Serotonin Antagonists

The protective anti-asthmatic effect of a new anti-allergic drug with histaminolytic and anti-anaphylactic properties was tested in various controlled clinical studies of induced bronchospasm in asthmatic patients (provocation tests using a histamine aerosol, and exercise-induced asthma using a bicycle ergometer). The drug, ketotifen (a cycloheptathiophene derivative) was compared with a classical antihistaminic (clemastine) and a known cell stabiliser (disodium cromoglycate). In both models ketotifen provided significant protection.

Topics: Adult; Asthma; Bronchial Spasm; Clemastine; Cromolyn Sodium; Histamine; Histamine H1 Antagonists; Humans; Physical Exertion; Piperidines; Spirometry; Thiophenes

A double-blind cross-over study showed that orally taken ketotifen and inhaled DSCG have a comparable protective effect on allergen-induced bronchoconstriction. Both drugs significantly inhibit the immediate bronchial reaction after a 3 day treatment with either 1 mg ketotifen or 20 mg DSCG four times daily. Late reactions, which occurred in three out of the ten patients, were inhibited in two of the three patients by ketotifen as by DSCG.

Topics: Adult; Allergens; Asthma; Bronchi; Bronchial Spasm; Clinical Trials as Topic; Cromolyn Sodium; Double-Blind Method; Female; Forced Expiratory Volume; Humans; Male; Middle Aged; Piperidines; Thiophenes

Topics: Adrenergic beta-Agonists; Adult; Aerosols; Amino Alcohols; Bronchial Spasm; Butylamines; Catechols; Clinical Trials as Topic; Electrocardiography; Female; Heart Rate; Histamine; Humans; Isoproterenol; Male; Methanol; Phenethylamines; Piperidines; Respiration; Skin Temperature; Sympathomimetics; Vasodilator Agents

The aim was to evaluate the clinical profile and effectiveness of ECT in women. A retrospective chart review was carried out to identify female patients who had received ECT during the period September 2013-February 2015. Details regarding their sociodemographic, clinical, and treatment data were extracted from these records for the present study. The total number of patients, admitted to our psychiatry inpatient clinic during the survey period, was 802. During this period, 26 (3.24 %) female patients received ECT. Patients who received ECT were mostly in age group of 25-44 years (76.9 %). Twenty percent of patients were in the postpartum period. Psychotic disorders (46.1 %) was the most common diagnosis for which ECT was used, followed by bipolar affective disorder, current episode manic (19.2 %). At the end of ECT courses, 70 % of the patients showed good response with a CGI-I of 1 or 2, and 30 % showed minimal response with a CGI-I score of 3. The most common side effects were post-ECT confusion (15.4 %) and prolonged seizure (11.5 %). This rate of prolonged seizure was higher the rates reported in the literature. The bronchospasm related with remifentanil, post-ECT bradycardia, hypertensive crisis and oligohydramnios were also reported in one case each. ECT is a safe and effective treatment option in women with severe psychiatric disorders and disorders in the perinatal/postpartum period are a major area of ECT use. The female gender may be a contributing factor for the higher rates of prolonged seizure.

Topics: Adult; Aged; Anesthetics, Intravenous; Bipolar Disorder; Bradycardia; Bronchial Spasm; Depression, Postpartum; Depressive Disorder; Electroconvulsive Therapy; Female; Hospitals, Psychiatric; Humans; Hypertension; Middle Aged; Oligohydramnios; Piperidines; Pregnancy; Pregnancy Complications; Psychotic Disorders; Puerperal Disorders; Remifentanil; Retrospective Studies; Treatment Outcome; Turkey; Young Adult

We investigated the effects of nonselective muscarinic antagonist (atropine) and of selective muscarinic subtype 1 (M1), 2 (M2), 3 (M3) antagonists (VU0255035, methoctramine, pFHHSiD, respectively) on the contractions evoked by electrical field stimulation (EFS) or by exogenous ACh in isolated horse bronchial muscle. Atropine completely inhibited neurogenic contractions in a concentration-dependent fashion, whereas selective muscarinic antagonists induced relevant modifications only at the highest concentration tested. Experiments with selective muscarinic antagonists in combination showed that only the simultaneous blockade of M1 /M3 or M2 /M3 receptors was able to induce a nearly complete suppression of contractions. The contractions induced by exogenous ACh were competitively antagonized only by atropine (pA2 = 9.01 ± 0.05). M3 selective antagonist, up to 10(-6) m, caused a moderate concentration-dependent rightward shift of ACh curve (pA2 = 7.96 ± 0.10). These data show that M3 muscarinic receptors possess a central role in mediating cholinergic contraction of horse bronchi, while M1 and M2 receptors seem to have a cooperative role. Selective muscarinic antagonists seem unlikely to be useful against bronchoconstriction associated with airway diseases in horses. Conversely, compounds with selectivity for both M1 and M3 receptors could be as effective as traditional anticholinergics and induce fewer cardiac side effects.

Topics: Animals; Bronchi; Bronchial Spasm; Diamines; Gene Expression Regulation; Horses; Male; Parasympatholytics; Piperidines; Receptor, Muscarinic M1; Receptor, Muscarinic M2; Receptor, Muscarinic M3; Sulfonamides; Thiadiazoles

Bronchoscopy is generally a safe procedure, but the induction of anaesthesia can induce bronchospasm. Consequently we investigated the influence of propofol, remifentanil and lidocaine on the tone of the human bronchial smooth muscle.. The influence of propofol, remifentanil and lidocaine on the contractile response of human bronchial smooth muscle to electrical field stimulation (EFS) has been evaluated. The role of capsaicin-sensitive sensory nerves and of inducible nitric oxide synthase has also been assessed. Furthermore, the interaction between these three dugs has been measured by Bliss Independence (BI) theory. Statistical significance (P < 0.05) was assessed by Student's t test or ANOVA.. Propofol (1.3 μg ml(-1)) and lidocaine (1 mg ml(-1)) reduced the baseline tone of bronchial rings (-14.45 ± 4.53% and -33.40 ± 1.07%, respectively, P < 0.05), whereas remifentanil had not such effect. Aminoguanidine prevented the relaxant effect of propofol. Propofol did not alter the bronchial contractile response to EFS following 30 min of treatment, whereas remifentanil enhanced the bronchial tension (133.83 ± 9.38%, control 101.93 ± 6.82%, P < 0.05 P < 0.05) and lidocaine completely abolished the contractility at 1 mg ml(-1) (P < 0.05). The desensitization of capsaicin-sensitive sensory nerves normalized the hyperresponsiveness induced by remifentanil (-26.77 ± 1.68%, P < 0.05). Significant BI antagonism (P < 0.001) was detected for propofol and lidocaine on the bronchial hyperresponsiveness induced by remifentanil.. Propofol and remifentanil may be used safely for bronchoscopy, although remifentanil should be associated with propofol or lidocaine to prevent the potential opioid-mediated bronchospasm.

Topics: Bronchi; Bronchial Spasm; Electric Stimulation; Female; Humans; Hypnotics and Sedatives; In Vitro Techniques; Lidocaine; Male; Middle Aged; Muscle Contraction; Muscle, Smooth; Nitric Oxide Synthase; Piperidines; Propofol; Remifentanil; Sensory Receptor Cells

Topics: Adult; Anesthesia, General; Anesthetics, Intravenous; Bradycardia; Bronchial Spasm; Cholinesterase Inhibitors; Drug Interactions; Drug Therapy, Combination; Humans; Hypotension; Male; Myasthenia Gravis; Piperidines; Preanesthetic Medication; Propofol; Pyridostigmine Bromide; Remifentanil; Thymectomy

We set out to establish the in vivo histamine H(1) receptor antagonistic (antihistaminic) and antiallergic properties of bilastine.. In vivo antihistaminic activity experiments consisted of measurement of: inhibition of increase in capillary permeability and reduction in microvascular extravasation and bronchospasm in rats and guinea pigs induced by histamine and other inflammatory mediators; and protection against lethality induced by histamine and other inflammatory mediators in rats. In vivo antiallergic activity experiments consisted of measurement of passive and active cutaneous anaphylactic reactions as well as type III and type IV allergic reactions in sensitised rodents.. In the in vivo antihistaminic activity experiments, bilastine was shown to have a positive effect, similar to that of cetirizine and more potent than that of fexofenadine. The results of the in vivo antiallergic activity experiments showed that the properties of bilastine in this setting are similar to those observed for cetirizine and superior to fexofenadine in the model of passive cutaneous anaphylactic reaction. When active cutaneous anaphylactic reaction experiments were conducted, bilastine showed significant activity, less potent than that observed with cetirizine but superior to that of fexofenadine. Evaluation of the type III allergic reaction showed that of the antihistamines only bilastine was able to inhibit oedema in sensitised mice, although its effect in this respect was much less potent than that observed with dexamethasone. In terms of the type IV allergic reaction, neither bilastine, cetirizine nor fexofenadine significantly modified the effect caused by oxazolone.. The results of our in vivo preclinical studies corroborate those obtained from previously conducted in vitro experiments of bilastine, and provide evidence that bilastine possesses antihistaminic as well as antiallergic properties, with similar potency to cetirizine and superior potency to fexofenadine.

Topics: Animals; Benzimidazoles; Bradykinin; Bronchial Spasm; Capillary Permeability; Cetirizine; Dermatitis; Dose-Response Relationship, Drug; Guinea Pigs; Histamine; Histamine Antagonists; Hypersensitivity; Male; Mice; Molecular Structure; Oxazolone; Piperidines; Rats; Rats, Wistar; Receptors, Histamine H1; Serotonin; Structure-Activity Relationship; Terfenadine; Time Factors

Ebastine (CAS 90729-43-4), cetirizine (CAS 83881-51-0) and loratadine (CAS 79794-75-5) are second generation H1-antihistamines of proven efficacy for treating allergy. Recent clinical studies have found ebastine to be more effective than cetirizine or loratadine in alleviating the symptoms of seasonal allergic rhinitis. The objective of this study was to compare the efficacy of these compounds in three guinea-pig modeles of bronchoconstriction, elicited either by histamine, allergen or leukotriene C4 in order to shed light onto the mechanisms that might explain differences found in clinical studies. In the present experiments, ebastine and cetirizine were equipotent against aerosol histamine-induced bronchospasm in guinea pigs (ED50 115 and 100 micrograms/kg p.o., respectively), while loratadine was three-fold less potent. In the same model the effects of ebastine, loratadine and cetirizine lasted 21, 19 and 15 h, respectively. Ebastine (ED50 334 micrograms/kg p.o.) was the most potent compound in inhibiting allergen-induced bronchospasm in conscious guinea pigs. In vitro studies in tracheally perfused guinea pig lungs demonstrated that ebastine and loratadine inhibited with equal potency the bronchoconstriction induced by leukotriene C4 whilst cetirizine was significantly less potent. Finally, in another in vivo study, ebastine reverted the changes in pulmonary resistance induced by leukotriene C4 in anaesthetised guinea pigs, whereas cetirizine and loratadine were devoid of activity in this model. In accordance with the clinical data, ebastine proved to be the substance with the widest range of application in animal experiments, too.

Topics: Aerosols; Airway Resistance; Algorithms; Animals; Anti-Allergic Agents; Bronchial Spasm; Butyrophenones; Cetirizine; Guinea Pigs; Histamine; Histamine H1 Antagonists; Leukotriene C4; Loratadine; Male; Ovalbumin; Piperidines

A safe and effective ultra-short-acting nondepolarizing neuromuscular blocking agent is required to block nicotinic receptors to facilitate intubation. Rapacuronium, which sought to fulfill these criteria, was withdrawn from clinical use due to a high incidence of bronchospasm resulting in death. Understanding the mechanism by which rapacuronium induces fatal bronchospasm is imperative so that newly synthesized neuromuscular blocking agents that share this mechanism will not be introduced clinically. Selective inhibition of M2 muscarinic receptors by muscle relaxants during periods of parasympathetic nerve stimulation (e.g., intubation) can result in the massive release of acetylcholine to act on unopposed M3 muscarinic receptors in airway smooth muscle, thereby facilitating bronchoconstriction.. Competitive radioligand binding determined the binding affinities of rapacuronium, vecuronium, cisatracurium, methoctramine (selective M2 antagonist), and 4-diphenylacetoxy-N-methylpiperidine methiodide (4-DAMP; selective M3 antagonist) for M2 and M3 muscarinic receptors.. Rapacuronium competitively displaced 3H-QNB from the M2 muscarinic receptors but not from the M3 muscarinic receptors within clinically relevant concentrations. Fifty percent inhibitory concentrations (mean +/- SE) for rapacuronium were as follows: M2 muscarinic receptor, 5.10 +/- 1.5 microm (n = 6); M3 muscarinic receptor, 77.9 +/- 11 microm (n = 8). Cisatracurium and vecuronium competitively displaced 3H-QNB from both M2 and M3 muscarinic receptors but had affinities at greater than clinically achieved concentrations for these relaxants.. Rapacuronium in clinically significant doses has a higher affinity for M2 muscarinic receptors as compared with M3 muscarinic receptors. A potential mechanism by which rapacuronium may potentiate bronchoconstriction is by blockade of M2 muscarinic receptors on prejunctional parasympathetic nerves, leading to increased release of acetylcholine and thereby resulting in M3 muscarinic receptor-mediated airway smooth muscle constriction.

Topics: Animals; Atracurium; Binding, Competitive; Bronchial Spasm; Cell Membrane; CHO Cells; Cricetinae; Diamines; Indicators and Reagents; Muscarinic Antagonists; Neuromuscular Nondepolarizing Agents; Piperidines; Quinuclidinyl Benzilate; Radioligand Assay; Receptor, Muscarinic M2; Receptor, Muscarinic M3; Receptors, Muscarinic; Vecuronium Bromide

Smoking marijuana or administration of its main active constituent, delta9-tetrahydrocannabinol (delta9-THC), may exert potent dilating effects on human airways. But the physiological significance of this observation and its potential therapeutic value are obscured by the fact that some asthmatic patients respond to these compounds with a paradoxical bronchospasm. The mechanisms underlying these contrasting responses remain unresolved. Here we show that the endogenous cannabinoid anandamide exerts dual effects on bronchial responsiveness in rodents: it strongly inhibits bronchospasm and cough evoked by the chemical irritant, capsaicin, but causes bronchospasm when the constricting tone exerted by the vagus nerve is removed. Both effects are mediated through peripheral CB1 cannabinoid receptors found on axon terminals of airway nerves. Biochemical analyses indicate that anandamide is synthesized in lung tissue on calcium-ion stimulation, suggesting that locally generated anandamide participates in the intrinsic control of airway responsiveness. In support of this conclusion, the CB1 antagonist SR141716A enhances capsaicin-evoked bronchospasm and cough. Our results may account for the contrasting bronchial actions of cannabis-like drugs in humans, and provide a framework for the development of more selective cannabinoid-based agents for the treatment of respiratory pathologies.

Topics: Animals; Arachidonic Acids; Axons; Bronchi; Bronchial Spasm; Bronchoconstriction; Cannabinoids; Capsaicin; Cough; Endocannabinoids; Guinea Pigs; Lung; Muscle Contraction; Muscle, Smooth; Piperidines; Polyunsaturated Alkamides; Pyrazoles; Rats; Rats, Wistar; Receptors, Cannabinoid; Receptors, Drug; Rimonabant

The major pulmonary effects of tachykinins, including bronchoconstriction, are mediated by activation of both neurokinin-1 (NK(1)) and neurokinin-2 (NK(2)) receptors. In guinea-pigs NK(1)and NK(2)receptor antagonists interact synergistically to inhibit the bronchoconstriction induced by neurokinin-A (NKA). However, the effect of combined NK(1)and NK(2)receptor antagonists on tachykinin-induced bronchoconstriction in most other species has not been evaluated. In this study, the interactive effects of CP 99994, an NK(1)receptor antagonist and SR 48968, an NK(2)receptor antagonist, were evaluated against NKA-induced brochospasm in dogs. Pulmonary resistance (R(L)) and dynamic lung compliance (C(Dyn)) were measured in anesthetized, spontaneously breathing dogs to measure the bronchoconstrictor response to aerosolized NKA (1%). Mean arterial blood pressure (MAP) and minute volume (MV) were also measured to assess the NK(1)receptor mediated cardiorespiratory response to substance P (100 ng/kg, iv). Pretreatment with SR 48968 (0.3-3 mg/kg, po) in the presence of an NK(1)antagonist dose of CP 99994 (10 mg/kg, po) inhibited the NKA-induced bronchospasm. However, the inhibition produced by SR 48968 plus CP 99994 was no greater than that previously shown for SR 48968 alone. Therefore, dual NK(1)/NK(2)receptor antagonists do not interact synergistically against NKA-induced bronchospasm in dogs. This may relate to the fact that dogs, like humans, have the NK(2)receptor as the predominant receptor subtype producing bronchoconstriction.

Topics: Animals; Benzamides; Bronchial Spasm; Bronchoconstriction; Disease Models, Animal; Dogs; Male; Neurokinin-1 Receptor Antagonists; Piperidines; Receptors, Neurokinin-1; Receptors, Neurokinin-2; Tachykinins

1. IRL 1620 (0.01-0.1 mg kg-1, i.v.), a selective endothelin B (ETB) receptor agonist, induced a dose-dependent biphasic increase in total lung resistance and a decrease in dynamic compliance in anaesthetized and artificially ventilated guinea-pigs. After intravenous injection of IRL 1620 (0.03 mg kg-1), the first phase was observed within 2 min whereas the second phase started between 5 and 10 min after injection and was long lasting. 2. In order to characterize which endothelin receptors are involved in both phases of bronchoconstriction, we studied the effect of ETA and ETB receptor antagonists (BQ 123 and BQ 788, respectively). BQ 788 (0.1-1 mg kg-1, i.v.) inhibited, in a dose-dependent manner, both phases of bronchoconstriction. BQ 123 (3 mg kg-1, i.v.) markedly inhibited (by 76%) the second phase of bronchoconstriction but had no effect on the early component of the response. 3. The effect of atropine, neurokinin-I (NK1) and neurokinin-2 (NK2) receptor antagonists (SR140333 and SR48968, respectively) were tested to investigate the possible involvement of cholinergic and sensory nerve activation, respectively, in the response to IRL 1620. Likewise, the role of arachidonic acid metabolites (leukotriene D4 antagonist, ONO-1078 and thromboxane A2 (TXA2) inhibitor, OKY-046) in this response was also investigated. OKY-046 (1 mg kg-1, i.v.) and atropine (1 mg kg-1, i.v.) partially inhibited the first phase (by 80% and 20%, respectively) without affecting the late phase of bronchoconstriction. Neither ONO-1078 (1 mg kg-1, i.v.) nor the combination of SR140333 (0.2 mg kg-1, i.v.) and SR 48968 (0.2 mg kg-1, i.v.) modified IRL 1620-induced bronchoconstriction. 4. A low dose of IRL 1620 (0.005 mg kg-1, i.v.) induced a monophasic bronchoconstriction. Pretreatment by phosphoramidon (100 mumol kg-1, i.v.) restored the second phase of bronchoconstriction. In this condition, BQ 123 (3 mg kg-1, i.v.) was able to inhibit partially the second phase of bronchoconstriction. 5. These results suggest that both phases of bronchoconstriction induced by IRL 1620 were mediated primarily by ETB receptor activation, the first phase being a consequence of TXA2 and acetylcholine release. The inhibition by an ETA receptor antagonist and the restoration by a neutral endopeptidase (NEP) inhibitor of the second phase of bronchoconstriction suggests that primary activation of ETB receptors leads to autocrine/paracrine endothelin-1 (ET-1) release that would subsequently cause profound b

Topics: Animals; Atropine; Bronchial Spasm; Bronchodilator Agents; Endothelin Receptor Antagonists; Endothelin-1; Endothelins; Female; Guinea Pigs; In Vitro Techniques; Male; Methacrylates; Neurokinin-1 Receptor Antagonists; Oligopeptides; Peptide Fragments; Peptides, Cyclic; Piperidines; Receptors, Endothelin; Receptors, Neurokinin-2; Thromboxane A2; Thromboxane-A Synthase

Topics: Adult; Anti-Ulcer Agents; Bronchial Spasm; Cisapride; Female; Humans; Male; Middle Aged; Piperidines

The present study characterized neurokinin receptor-mediated bronchoconstrictor responses in anesthetized guinea pigs. Thus, we have compared the actions of the selective neurokinin 1 (NK1) (CP-99,994) and neurokinin 2 (NK2) (SR-48,968) receptor antagonists against dose-response curves (DRC) induced by intravenously administered substance P (SP), neurokinin A (NKA), neurokinin B (NKB), beta Ala8-NKA (4-10),Sar9-Met(O2)11SP, and single dose (intravenous) challenge with resiniferatoxin (RTX), a capsaicin-like sensory neurotoxin, leukotriene D4 (LTD4) and antigen. The rank order of potency of the neurokinins for inducing bronchoconstriction was beta Ala8-NKA(4-10) > NKA > Sar9-Met(O2)11Sp > SP >> NKB. The DRC to the selective NK1 agonist Sar9-Met(O2)11SP was shifted to the right 10-fold by the selective NK1 antagonist, CP-99,994 (1 mg/kg, intravenously), but was not shifted by SR-48,968 (3 mg/kg, intravenously). The DRC to the selective NK2 agonist beta-Ala8-NKA(4-10) was shifted to the right 82-fold by the NK2 antagonist, SR-48,968 (1 mg/kg), but was not shifted by CP-99,994 (3 mg/kg, intravenously). SR-48,968 (1 mg/kg) also blocked NKA (3-fold shift) but did not block SP. CP-99,994 failed to produce a significant rightward shift of the DRC to either SP or NKA. However, the combination of 1 mg/kg CP-99,994 and 1 mg/kg SR-48,968 produced significant shifts of the DRCs to SP (> 5-fold) and NKA (> 300-fold). Hypotension induced by NKA and SP was also blocked by this combination.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Benzamides; Bronchial Spasm; Bronchoconstriction; Diterpenes; Dose-Response Relationship, Drug; Drug Interactions; Guinea Pigs; Male; Neurokinin A; Peptide Fragments; Piperidines; Receptors, Neurokinin-1; Receptors, Neurokinin-2; Substance P; Tachykinins

This study has examined the abilities of (+/-)-CP96345 and (+/-)-SR48968, nonpeptide antagonists selective for the tachykinin NK1 and NK2 receptors, respectively, to block bronchoconstriction caused by intravenous administration of direct-acting receptor agonists and the indirect-acting mimetics capsaicin, serotonin and 2-methyl-serotonin in the anesthetized guinea pig. The NK1 antagonist (+/-)-CP96345 was found to cause, at a maximally tolerated dose of 9 mumol/kg, an approximate 10-fold rightward shift of the dose-response curves for selective NK1 agonists substance P (SP), [Sar9,Met(O2)11]SP and Ac-[Arg6,Sar9,Met(O2)11]SP6-11 without altering responses to selective NK2 agonists neurokinin A (NKA), [Nle10]NKA4-10 or [beta-Ala8]NKA4-10. The NK2 antagonist (+/-)-SR48968 caused dose-dependent rightward shifts of the dose-response curves for the NK2 but not the NK1 agonists. Results using combinations of the receptor antagonists indicate that the NK2 agonists could cause bronchoconstriction by acting on the NK1 receptors at large doses relative to those used without antagonists. Of the agonists used here, [beta-Ala8]NKA4-10 appeared to be the most selective for the NK2 receptors. When used alone, only (+/-)-SR48968 was found to block bronchoconstriction caused by capsaicin, serotonin (after blockade of 5-HT2 receptors by LY53857) and 2-methyl-serotonin. When (+/-)-CP96345 was also given, larger additional blockade was seen with capsaicin than with serotonin or 2-methyl-serotonin as mimetic substance. Atropine caused small and variable degrees of blockade of serotonin and 2-methyl-serotonin but not of capsaicin after combinations of the two antagonists.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Amino Acid Sequence; Anesthesia; Animals; Benzamides; Biphenyl Compounds; Bronchial Spasm; Bronchoconstriction; Capsaicin; Guinea Pigs; Hypnotics and Sedatives; Injections, Intravenous; Male; Molecular Sequence Data; Neurokinin A; Piperidines; Receptors, Tachykinin; Serotonin

Multiple mediators are involved in the pathophysiology of allergic and inflammatory disorders. Drugs that affect the action of more than one mediator may, therefore, be particularly effective in these disorders. Two such mediators are platelet-activating factor (PAF) and histamine. From a structural series with documented antihistamine activity, Sch 37370 has been identified as a dual antagonist of PAF and histamine. In vitro, Sch 37370 selectively inhibits PAF-induced aggregation of human platelets (IC50 = 0.6 microM) and also competes with PAF binding to specific sites in membrane preparations from human lungs (IC50 = 1.2 microM). Sch 37370 also blocks the binding of [3H]pyrilamine to histamine H1 receptors in rat brain membranes. In guinea pigs, orally administered Sch 37370 is effective against bronchospasm to histamine (ED50 = 2.4 mg/kg), PAF (ED50 = 6.0 mg/kg) or serotonin (ED50 = 9.6 mg/kg). In contrast, it only weakly antagonizes methacholine-induced bronchospasm (ED50 = 51 mg/kg) and is totally inactive at 50 mg/kg against bronchospasm due to leukotriene C4 or substance P. Sch 37370 blocks hypotension in rats and a cutaneous reaction in monkeys induced by either PAF or histamine, as well as PAF-induced edema in the rat pleural cavity. In addition, Sch 37370 blocks bronchospasm induced by either antigen in sensitized guinea pigs or hyperventilation in nonsensitized guinea pigs. Sch 37370 also inhibits antigen-induced lung eosinophilia in sensitized guinea pigs and a reverse passive Arthus reaction in rats. Although Sch 37370 is not the most potent PAF antagonist or antihistamine, it is the first compound that combines these pharmacologically relevant activities and may offer important advantages over currently available antihistamine therapies.

Topics: Animals; Antigens; Bronchial Spasm; Guinea Pigs; Histamine Antagonists; Humans; Hyperventilation; Loratadine; Male; Piperidines; Platelet Activating Factor; Platelet Aggregation; Platelet Aggregation Inhibitors; Rats; Rats, Inbred Lew

Platelet-activating factor (PAF) and histamine are potent bronchospastic agents and possess additional properties such as induction of vasopermeability and activation of inflammatory cells that are consistent with their ability to mediate allergic and inflammatory responses. From a structural series with anticipated antihistamine activity, Sch 37370 (1-acetyl-4(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2- b]pyridine-11-ylidine)piperidine) has been identified as a dual antagonist of PAF and histamine in vitro and in vivo and has been compared with several selective antagonists of PAF and histamine. Sch 37370 selectively inhibits PAF-induced aggregation of human platelets (IC50 = 0.6 microM) and also competes with PAF binding to specific sites in membrane preparations from human lungs (IC50 = 1.2 microM). Sch 37370 blocks the binding of [3H]pyrilamine to histamine-H1 receptors in rat brain membranes. Administered i.v. to guinea pigs, Sch 37370 is an equipotent antagonist of PAF and histamine-induced bronchospasm (ED50 = 0.6-0.7 mg/kg). Orally in guinea pigs, Sch 37370 is somewhat more effective against bronchospasms to histamine (ED50 = 2.4 mg/kg) than against PAF (ED50 = 4.1-6.0 mg/kg) or serotonin (ED50 = 9.6 mg/kg). Sch 37370 only weakly antagonizes methacholine-induced bronchospasm (ED50 = 51 mg/kg) and is completely inactive at 50 mg/kg against leukotriene C4 or substance P. Sch 37370 blocks hypotension in rats and a cutaneous reaction in monkeys induced by either PAF or histamine, as well as PAF-induced lethality in mice.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Administration, Oral; Animals; Binding, Competitive; Brain; Bronchial Spasm; Female; Guinea Pigs; Histamine; Histamine Antagonists; Humans; Loratadine; Lung; Macaca fascicularis; Male; Mice; Piperidines; Platelet Activating Factor; Platelet Aggregation; Pyrilamine; Rats

Ketotifen administered prior to aspirin offered protection against bronchoconstriction in 13 of 14 patients with aspirin-sensitive asthma. In four other subjects, suffering from urticaria/angioedema following ingestion of aspirin-like drugs, pretreatment with ketotifen resulted in total prevention of the adverse reactions. These results support the suggestion of a common pathogenetic mechanism operating in two distinct clinical patterns of idiosyncrasy to aspirin and other cyclo-oxygenase inhibitors. They also indicate that ketotifen might find application in treatment of adverse reactions to aspirin.

Topics: Adult; Aspirin; Asthma; Bronchi; Bronchial Spasm; Drug Hypersensitivity; Female; Histamine H1 Antagonists; Humans; Ketotifen; Male; Middle Aged; Piperidines; Placebos; Thiophenes

Topics: Adult; Aspirin; Asthma; Bronchial Spasm; Drug Hypersensitivity; Humans; Ketotifen; Piperidines; Thiophenes

Rimiterol hydrobromide (Pulmadil) has been shown to have a dose-related bronchodilator effect; the optimum dose by inhalation appears to lie between 200 and 1,000 microgram. When given to a group of asthmatic patients at 'recommended' and 5--10 times 'recommended' dose by aerosol, cardiovascular effects were minimal and of a magnitude similar to that of salbutamol given in the same dosages to the same patients. The very rapid bronchodilator effect of rimiterol would appear to make the drug particularly suitable for the treatment of patients with intermittent asthmatic attacks, before exercise in patients with exercise-induced asthma and for bronchodilatation before using inhaled sodium cromoglycate or corticosteroid aerosols.

Topics: Aerosols; Albuterol; Asthma; Blood Pressure; Bronchial Spasm; Catechols; Heart Rate; Humans; Peak Expiratory Flow Rate; Piperidines

Topics: Acetylcholine; Aerosols; Antigens; Aspirin; Benzoates; Bronchial Spasm; Double-Blind Method; Histamine; Histamine H1 Antagonists; Humans; Physical Exertion; Piperidines; Placebos; Tartrazine; Thiophenes

W10,294A (1,2,3,4-tetrahydro-8,9-dimethoxy-3(2-piperidinoethyl)-5H-[1] benzopyrano [3,4-c] pyridin-5-one dihydrochloride) is a potent antagonist of the bronchoconstriction induced by histamine, methacholine or acetylcholine. In vitro evaluation on guinea pig trachea indicated that W10,294A had both direct smooth muscle relaxant activity and modest antihistaminic properties. Resistance and dynamic compliance measurements in anesthetized dogs indicated that W10,294A prevented or reversed bronchoconstriction due to histamine or pilocapine. Bronchodilator activity of long duration was observed in dogs after oral administration. W10,294A was compared with aminophylline in several tests. W10,294A was 6 times more potent than aminophylline in relaxing isolated guinea-pig trachea. In the anesthetized dog W10,294A was more potent and longer acting than aminophylline in reversing pilocarpine-induced bronchospasm. The bronchodilator activity of W10,294A was not blocked by the beta adrenoceptor antagonist bunolol. Comparative studies in dogs and guinea pigs, using identical doses, showed that W10,294A had considerably less effect on the cardiovascular system than did aminophylline.

Topics: 3',5'-Cyclic-AMP Phosphodiesterases; Acetylcholine; Airway Resistance; Animals; Barium; Bronchial Spasm; Bronchodilator Agents; Coumarins; Dogs; Female; Guinea Pigs; Heart Rate; Histamine H1 Antagonists; In Vitro Techniques; Lung; Lung Compliance; Male; Methacholine Compounds; Muscle Contraction; Muscle, Smooth; Pilocarpine; Piperidines

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

To investigate the role of bronchoconstriction in the cough reflex, we compared antitussive effects of several drugs with their ability to effect the respiratory tract (i.e. bronchodilation vs. bronchoconstriction). Antitussive activities of five drugs administered either intravenously or orally on electrically-induced cough were evaluated in the non-anesthetized dog. The antitussive activities were as follows: morphine, 0.1 mg/kg (i.v.) and 0.5 mg/kg (p.o.); codeine, 1.0, 4.0; picoperidamine, 2.0, 9.8; piclobetol, 7.6, 9.0; HH-197, 12.5, 143.0, respectively. Morphine, codeine and HH-197 caused bronchoconstriction, but picoperidamine and picrobetol caused bronchodilation. The antitussive and bronchodilatation effects of isoproterenol were abolished by propranolol. Each bronchoconstricting drug (i.e. morphine, codeine and HH-197) was administered concurrently with isoproterenol (10 mug/kg, i.v., and non-antitussive activity), and the cough reflex was observed. Compared with the single administration of each drug, respiratory resistance was decreased and the antitussive effect was increased. These results indicate a strong correlation between bronchodilatation and increased antitussive activity.

Topics: Airway Resistance; Animals; Antitussive Agents; Bronchi; Bronchial Spasm; Bronchodilator Agents; Codeine; Cough; Dogs; Ethanolamines; Female; Isoproterenol; Male; Morphine; Phenylacetates; Picolines; Piperidines; Propranolol

Topics: Aminophylline; Analgesics; Animals; Atropine; Blood Pressure; Bronchial Spasm; Epinephrine; Fibrinolysin; Histamine H1 Antagonists; Humans; Hypertension, Pulmonary; Injections, Intravenous; Iproniazid; Methods; Morphine; Muscles; Nitroglycerin; Papaverine; Phenothiazines; Piperidines; Pulmonary Circulation; Rats; Reserpine; Serotonin Antagonists; Vascular Resistance; Vasodilator Agents