Reversion of methacholine induced bronchoconstriction with inhaled diazepam in patients with asthma.

BACKGROUND: Benzodiazepines have a direct bronchodilatory effect. Methacholine is a non-selective muscarinic receptor agonist causing bronchoconstriction. AIM: To examine the effects of inhaled benzodiazepines, modulating bronchoconstriction induced by methacholine in patients with asthma. PATIENTS AND METHODS: Twelve patients with well controlled asthma were studied. On the first day, after determining the initial values of pulmonary function, a dose response curve was carried out with progressive doses of methacholine. After the last dose, when at least a 20% drop of the initial forced expiratory volume in the first second (FEV1) was achieved, vital capacity (VC) and FEV1 were measured at 7, 15 and 30 minutes after provocation. On the second day a diazepam aerosol was inhaled by the patients prior to the same protocol with methacholine. RESULTS: In the first day of testing, methacholine inhalation (6 mg/mL) led to a significant drop in FEV1 from 2.98 to 1.69 L. On the second day of study, in the same patients, previous inhalation with diazepam reduced the changes of FEV1 after inhalation of methacholine. This parameter decreased from 2.48 to 2.21 L. CONCLUSIONS: Inhalation of benzodiazepines reduce bronchoconstriction after a methacholine challenge in patients with asthma.

Reversion of methacholine induced bronchoconstriction with inhaled diazepam in patients with asthma / Bloqueo de la respuesta bronco constrictora a metacolina con diazepam inhalado en pacientes con asma

Background: Benzodiazepines have a direct bronchodilatory effect. Methacholine is a non-selective muscarinic receptor agonist causing bronchoconstriction. Aim: To examine the effects of inhaled benzodiazepines, modulating bronchoconstriction induced by methacholine in patients with asthma. Patients and Methods: Twelve patients with well controlled asthma were studied. On the first day, after determining the initial values of pulmonary function, a dose response curve was carried out with progressive doses of methacholine. After the last dose, when at least a 20% drop of the initial forced expiratory volume in the first second (FEV1) was achieved, vital capacity (VC) and FEV1 were measured at 7, 15 and 30 minutes after provocation. On the second day a diazepam aerosol was inhaled by the patients prior to the same protocol with methacholine. Results: In the first day of testing, methacholine inhalation (6 mg/mL) led to a significant drop in FEV1 from 2.98 to 1.69 L. On the second day of study, in the same patients, previous inhalation with diazepam reduced the changes of FEV1 after inhalation of methacholine. This parameter decreased from 2.48 to 2.21 L. Conclusions: Inhalation of benzodiazepines reduce bronchoconstriction after a methacholine challenge in patients with asthma.

Antecedentes: Las benzodiacepinas tienen un efecto broncodilatador directo. La metacolina es un agonista muscarínico que causa bronco constricción. Objetivo: Evaluar el efecto modulador de la inhalación de diazepam sobre la bronco constricción inducida por metacolina. Pacientes y Métodos: Se estudiaron 12 pacientes con asma bien controlada. En el primer día, se determinó la curva dosis respuesta de parámetros de función pulmonar a una dosis progresiva de metacolina. Después de la última dosis, cuando se consiguió un 20% de reducción en la capacidad vital forzada en el primer segundo (FEV1), se midió FEV1 y la capacidad vital (CV) a los 7, 15 y 30 min después de la provocación. En el segundo día los pacientes se inhalaron con diazepam antes de hacer la prueba con metacolina. Resultados: En el primer día, el FEV1 bajo de 2,98 a 1,69 l con 6 mg/ml de metacolina. En el segundo día, la inhalación de diazepam redujo la respuesta a metacolina con una reducción de FEV1 de 2,48 a 2,21 L. Conclusiones: La benzodiacepinas reducen la respuesta de vasoconstricción a metacolina.

The orl rat is more responsive to methacholine challenge than wild type.

BACKGROUND: This study presents an animal model of native airway hyperresponsiveness (AHR). AHR is a fundamental aspect of asthma and reflects an abnormal response characterized by airway narrowing following exposure to a wide variety of non-immunological stimuli. Undescended testis (UDT) is one of the most common male congenital anomalies. The orl rat is a Long Evans substrain with inherited UDT. Since boys born with congenital UDT are more likely to manifest asthma symptoms, the main aim of this study was to investigate the alternative hypothesis that orl rats have greater AHR to a methacholine aerosol challenge than wild type rats. METHODS: Long Evans wild type (n = 9) and orl (n = 13) rats were anesthetized, tracheostomized, and mechanically ventilated at 4 weeks of age. Escalating concentrations of inhaled methacholine were delivered. The methacholine potency and efficacy in the strains were measured. Respiratory resistance was the primary endpoint. After the final methacholine aerosol challenge, the short-acting ß2-adrenoceptor agonist albuterol was administered as an aerosol and lung/diaphragm tissues were assayed for interleukin (IL)-4, IL-6, and tumor necrosis factor (TNF)-α. Histological and histomorphometrical analyses were performed. RESULTS: The methacholine concentration-response curve in the orl group indicated increased sensitivity, hyperreactivity, and exaggerated maximal response in comparison with the wild type group, indicating that orl rats had abnormally greater AHR responses to methacholine. Histological findings in orl rats showed the presence of eosinophils, unlike wild type rats. ß2-Adrenoceptor agonist intervention resulted in up-regulation of IL-4 diaphragmatic levels and down-regulation of IL-4 and IL-6 in the lungs of orl rats. CONCLUSION: orl rats had greater AHR than wild type rats during methacholine challenge, with higher IL-4 levels in diaphragmatic tissue homogenates. Positive immunostaining for IL-4 was detected in lung and diaphragmatic tissue in both strains. This model offers advantages over other pre-clinical murine models for studying potential mechanistic links between cryptorchidism and asthma. This animal model may be useful for further testing of compounds/therapeutics options for treating AHR.

Effect of IL-1ß and TNF-α vs IL-13 on bronchial hyperresponsiveness, ß2-adrenergic responses and cellularity of bronchial alveolar lavage fluid.

1 Levels of IL-13, IL-1ß and TNF-α are increased in bronchial lavage fluid of asthmatics and induce certain significant features of bronchial asthma including airway hyper-responsiveness (AHR). In this study, we have investigated the effect of these cytokines in naïve mice and those sensitized to ovalbumin (OVA) on bronchoconstrictions to methacholine (MCh) and the functional antagonism induced by ß2 -adrenoceptor agonism. 2 Naïve or OVA-sensitized mice were treated for 3 days with IL-1ß (250 U), TNF-α (150 ng), IL-13 (5 µg) or combinations of IL-1ß with TNF-α or IL-1ß with IL-13. MCh-induced bronchoconstriction and its sensitivity to albuterol, a ß2-adrenoceptor agonist, was assessed 24 h after the last cytokine administration. 3 In naïve mice, responsiveness to MCh was significantly increased by the combination of IL-1ß and TNF-α, IL-13 alone or in combination with IL-1ß, but not by treatment with IL-1ß or TNF-α alone. Similar results were obtained in OVA-sensitized mice except that treatment with IL-13 alone did not increase sensitivity to MCh. 4 In naïve mice, albuterol sensitivity was only significantly attenuated by treatment with IL-1ß and TNF-α in combination. In mice sensitized to OVA, albuterol sensitivity was significantly attenuated by treatment with TNF-α, IL-13 or IL-13 in combination with IL-1ß. 5 Inflammatory cell influx was increased by all cytokines and combinations except IL-13 in OVA-sensitized mice. 6 Our data do not support a link between inflammatory cell influx and AHR. In addition, the mechanism of IL-13-induced AHR might involve decreased ß2-adrenoceptor responsiveness.

The i.v. infusion of mannitol decreases airway responsiveness to methacholine in asthma.

Bronchial asthma and chronic obstructive pulmonary disease (COPD) are characterized by airway inflammation and oedema. The oedema of the airway wall may contribute to airway narrowing and hyperresponsiveness by increasing airway wall thickness, by altering airway compliance, or by impairing the transmission of the lung elastic recoil to the airway smooth muscle (ASM). We hypothesized that the i.v. infusion of mannitol, an osmotic diuretic, would reduce the water content of the airway wall in asthma and COPD, thus decreasing airway responsiveness to methacholine (MCh). In eight asthmatic and in six COPD patients, airway responsiveness to MCh, lung volumes and lung mechanics were measured before and after infusion of mannitol. In the asthmatics, mannitol decreased airway responsiveness to MCh and lung elastic recoil. In the COPD patients, no differences were recorded after mannitol infusion. These data suggest that the airway wall oedema, in asthma, has an impact on airway responsiveness to MCh. The differential effect of mannitol in asthma versus COPD, may relate to the specific pathologic features of the diseases.

Suppression of histamine-induced tachypnoea in the rhesus monkey by sibenadet: no role for dopamine D2 receptors.

1. Sibenadet (Viozan), a dual dopamine D(2)/beta(2)-adrenoceptor agonist, suppresses histamine-induced tachypnoea in the dog by activating dopamine D(2) receptors. We here compare the effects of sibenadet and formoterol, a selective beta(2)-adrenoceptor agonist, on histamine-induced tachypnoea in the rhesus monkey. 2. Anaesthetized, spontaneously breathing, rhesus monkeys were set up for measuring airways resistance, respiratory rate, blood pressure and heart rate. 3. Both sibenadet and formoterol administered by aerosol, induced inhibition of the bronchoconstrictor response to aerosolized methacholine accompanied by tachycardia. Sibenadet, but not formoterol, also reduced blood pressure. 4. Administration of histamine by inhalation induced tachypnoea which was accompanied by bronchoconstriction. Tachypnoea to histamine was suppressed by both sibenadet and formoterol at doses which manifest anti-bronchoconstrictor activity. These effects and the accompanying tachycardia but not the hypotension induced by sibenadet were abolished by pretreatment with propranolol. 5. The dopamine D(2) receptor agonist, quinagolide, did not suppress tachypnoea to histamine despite inducing a fall in blood pressure indicating activation of dopamine D(2) receptors. 6. Thus, both sibenadet and formoterol suppress histamine-evoked tachypnoea in the rhesus monkey. The effect arises exclusively through activation of beta(2)-adrenoceptors and probably reflects the anti-bronchoconstrictor effects of these agents. The results reveal a fundamental difference in the role of dopamine receptors in the airways of dog and rhesus monkey.

Relaxant effects of carvacrol on guinea pig tracheal chains and its possible mechanisms.

The bronchodilatory effects of three cumulative volumes (0.02, 0.04, and 0.08 ml) of 1/100 diluted carvacrol were examined by their relaxant effects on tracheal chains of guinea pigs precontracted by 60 mM KCl (group 1) and 10 microM methacholine in two different conditions including: non-incubated tissues (group 2) and incubated tissues with 1 microM propranolol and 1 microM chlorpheniramine (group 3), (for each group, n = 5). The relaxant effects of all three volumes of carvacrol were significantly higher than those of ethanol and even theophylline in all three groups of experiments (p < 0.05 to p < 0.001). There were positive correlations between the relaxant effect of carvacrol and incremental volume (p < 0.05 to p < 0.001). These results indicated that carvacrol has a potent relaxant effect on tracheal chains of guinea pigs which is not due to beta2-adrenergic stimulatory, histamine H1, and muscarinic blocking effect.

A comparison of salmeterol and formoterol in attenuating airway responses to short-acting beta2-agonists.

In vitro data suggest that salmeterol, contrary to formoterol, can partly antagonise the effect of short-acting beta(2)-agonist rescue medication. To explore whether this occurs in vivo, we compared the effects of increasing doses (200-3200 microg) of fenoterol on the recovery of methacholine induced bronchoconstriction as well as PD(20) methacholine in 23 asthmatic patients, during two-week treatment periods with placebo, and standard doses of salmeterol or formoterol in a double blind, double-dummy, crossover study. Salmeterol showed a slightly higher propensity for the development of bronchodilator tolerance. The recovery of methacholine induced bronchoconstriction was more complete during regular use of formoterol relative to salmeterol. During regular use of both long-acting beta(2)-agonists the bronchoprotective efficacy of fenoterol was attenuated, but this was more pronounced during salmeterol than during formoterol. The mean maximum increase in PD(20) metacholine after the highest dose of fenoterol was 3.97 DD during placebo, 2.47 DD during formoterol (p<0.001) and 1.81 DD during salmeterol treatment (p<0.001). We conclude that in asthmatic patients the efficacy of short-acting beta(2)-adrenoceptor agonists can be significantly attenuated during regular use of long-acting beta(2)-agonists. In this respect, differences were observed between salmeterol and formoterol that may represent the expression of partial antagonism by salmeterol.

Adenosine-mediated bronchoconstriction and lung inflammation in an allergic mouse model.

In this study, we studied the role of adenosine on airway responsiveness and airway inflammation using an allergic mouse model. Mice were sensitized by two i.p. injections of ragweed and three consecutive ragweed aerosol challenges. It was found that inhalation of adenosine causes a dose-related bronchoconstriction in this model. Ragweed sensitized and challenged mice showed increased sensitivity to airway challenge to adenosine compared to control animals. Theophylline, a non-selective adenosine receptor antagonist, blocked adenosine-induced bronchoconstriction, but was unable to inhibit bronchoconstrictor response to methacholine. Mice systemically sensitized and airway challenged with allergen showed a marked airway inflammation manifesting increases in eosinophils, lymphocytes and neutrophils, and decrease in macrophages. Twenty-four hours after airway challenge with allergen, aerosolization of adenosine further potentiated the allergen-induced airway inflammation. Cells in bronchoalveolar lavage fluid after adenosine aerosolization increased by 3.07-fold as compared to control mice, and by 1.8-fold compared to ragweed sensitized and challenged mice. The increases in eosinophils, lymphocytes, and neutrophils caused by allergen were potentiated after adenosine challenge. Unexpectedly, macrophages significantly decreased after adenosine challenge. Theophylline attenuated adenosine-enhanced airway inflammation, but could not reverse allergen-induced airway inflammation. These findings suggested that specific adenosine receptors contribute to airway responsiveness and airway inflammation associated with this model of allergic asthma.

Comparison of relaxant effects of propofol on methacholine-induced bronchoconstriction in dogs with and without vagotomy.

Propofol has been suggested to have in vivo airway relaxant effects, although the mechanism is still unclear. In this study, we determined whether propofol could antagonize methacholine-induced bronchoconstriction and determined whether vagotomy modifies this relaxant effect. Fourteen mongrel dogs anaesthetized with pentobarbital and pancuronium were assigned to a control group (n=7) and a vagotomy group (n=7). The trachea was intubated with a special endotracheal tube that had a second lumen for insertion of the bronchoscope. Bronchial cross-sectional area, which was monitored continuously through the bronchoscope, was measured with image analysis software. Bronchoconstriction was elicited with methacholine (0.5 microg kg(-1) + 5.0 microg kg(-1) min(-1)) until the end of the experiment. Thirty minutes after the start of methacholine infusion, propofol 0, 0.2, 2.0 and 20 mg kg(-1) was administered. Changes in bronchial cross-sectional area were expressed as percentages of the basal area. Plasma concentrations of propofol and catecholamine were measured by high-performance liquid chromatography. Maximal inhibition (bronchoconstriction = 0%, baseline = 100%) and IC50 (concentration producing 50% inhibition of maximal effect) produced by propofol was obtained from each concentration-response curve using a curve-fitting program. Methacholine decreased bronchial cross-sectional area to 49.3% (95% confidence interval 38.5-60.1%) and 45.3% (34.8-55.7%) of the baseline value. Propofol 20 mg kg(-1) significantly reversed this effect: bronchial cross-sectional area was reduced to 77.8% (66.2-89.6%) and 75.9% (64.0-87.9) in the control and vagotomy groups respectively. The two groups did not differ significantly in the maximal inhibitory effect of propofol [control group, 61.1% (46.3-75.9%), vagotomy group, 64.2% (40.1-88.3%)] or pIC50 [control group 5.03 (4.55-5.51), vagotomy group 4.86 (4.49-5.24)]. Therefore, the relaxant effects of propofol on methacholine-induced bronchoconstriction may not be mediated centrally. Propofol may relax airway smooth muscles directly or through the peripheral vagal pathway.

Comparison of the anti-bronchoconstrictor activities of inhaled formoterol, its (R,R)- and (S,S)-enantiomers and salmeterol in the rhesus monkey.

The principle objective of this study was to define the anti-bronchoconstrictor effects of inhaled racemic formoterol and its (R,R)- and (S,S)-enantiomers in a new model of methacholine-induced bronchoconstriction in the rhesus monkey. A second long-acting beta(2)agonist, salmeterol, was included for comparison. Anaesthetized, spontaneously breathing rhesus monkeys were set up for measuring airway resistance. Blood pressure, heart rate and serum potassium concentrations were measured concomitantly to gauge systemic exposure and the potential for side effects. Formoterol, 0.14, 0.34 and 1.15 microg/kg, administered by aerosol, induced rapidly developing, sustained, dose-related inhibition of the bronchoconstrictor responses to aerosolised methacholine (maximum 76%) accompanied by sustained, dose-related tachycardia. (R,R)-formoterol, 0.56 microg/kg, induced anti-bronconstrictor effects and an associated tachycardia which corresponded closely to the effects seen following twice the dose of the racemate. (S,S)-formoterol, 0.54 microg/kg, was inactive. Salmeterol, 1.4 microg/kg, had no significant anti-bronchoconstrictor effect whereas doses of 5.5 and 30 microg/kg produced quantitatively similar but submaximal anti-bronchoconstrictor effects (maximum 47%). Sustained dose-dependent tachycardia was seen with salmeterol over the full dose range. Thus, the anti-bronchoconstrictor activity of formoterol resides in the (R,R) enantiomer and the (S,S) enantiomer does not interfere with the activity when present in the racemic form. Furthermore, the data indicate that the present model of methacholine-induced bronchospasm in the rhesus monkey could be useful in defining the key properties of beta(2)agonist bronchodilators such as relative potency, efficacy, duration of action and potential for systemic side effects.

A comparison of the relaxant effects of olprinone and aminophylline on methacholine-induced bronchoconstriction in dogs.

UNLABELLED: IV aminophylline, a nonselective phosphodiesterase (PDE) inhibitor, is often used to treat an asthma attack during anesthesia. However, in some instances, aminophylline-resistant attacks are observed. Selective PDE3 inhibitors are now clinically available and have been reported to produce bronchodilation. Thus, we compared the relaxant effects of olprinone, a novel PDE3 inhibitor, and aminophylline on methacholine-induced bronchoconstriction. Dogs were anesthetized with pentobarbital. Bronchoconstriction was elicited with methacholine (0.5 microg/kg + 5.0 microg. kg(-1). min(-1)) and assessed as percentage of changes in the bronchial cross-sectional area (BCA; basal = 100%) monitored by bronchoscope. Initially, the relaxant effects of olprinone (n = 8; 0-1000 microg/kg) and aminophylline (n = 8; 0-50 mg/kg) were compared. The bronchial cross-sectional areas were assessed before and 30 min after methacholine infusion began and 5 min after each dose of olprinone or aminophylline. We then determined whether propranolol (0.4 mg/kg) reversed the relaxation induced by olprinone (1000 microg/kg) and aminophylline (50 mg/kg). Olprinone and aminophylline dose-dependently antagonized bronchoconstriction by 56.2% +/- 21.3% (SD) and 68.0% +/- 30.3% with -log 50% effective dose (mean) of 4.80 +/- 0.38 (15.8) microg/kg and 1.96 +/- 0.42 (10.9) mg/kg, respectively. Aminophylline 50 mg/kg significantly increased plasma epinephrine, whereas olprinone did not. In addition, propranolol significantly reduced aminophylline-induced relaxation, but not olprinone-induced relaxation. Therefore, the relaxant effects of olprinone are independent of plasma epinephrine, whereas aminophylline effects may partially result from increased circulating concentrations of epinephrine. IMPLICATIONS: We compared the relaxant effects of olprinone and aminophylline on methacholine-induced bronchoconstriction in dogs. The relaxant effects of olprinone are independent of plasma epinephrine, whereas the aminophylline effects may be partly caused by an increase in plasma epinephrine.

Relaxant effect of Pimpinella anisum on isolated guinea pig tracheal chains and its possible mechanism(s).

We have studied the relaxant effect of Pimpinella anisum on isolated guinea pig tracheal chains and its possible mechanism(s). The bronchodilatory effects of aqueous and ethanol extracts and essential oil were examined on precontracted isolated tracheal chains of the guinea pig by 10 microM methacholine in two different conditions including: non-incubated tissues (group 1) and incubated tissues with 1 microM propranolol and 1 microM chlorpheniramine (group 2). In addition, the anticholinergic effects of essential oil and 10 nM atropine were tested by comparing the cumulative log concentration-response curves of methacholine induced contraction of tracheal chains and the effective concentration of methacholine, causing 50% of maximum response (EC(50)) in the presence of essential oil or atropine. Aqueous and ethanol extracts, essential oil and theophylline (1 mM) showed significant relaxant effects compared to those of controls. Although relaxant effect of essential oil was lower than theophylline, there was no significant difference between the effect of aqueous and ethanol extracts and that of theophylline. There was also no significant difference between the relaxant effects obtained in group 1 and 2 experiments. The results also showed parallel rightward shifts of methacholine-response curves and significant increase in EC(50) with the presence of atropine or essential oil. These results indicated bronchodilatory effects of essential oil, aqueous, and ethanol extracts from P. anisum. The results also showed that the relaxant effect of this plant is not due to an inhibitory effect of histamine (H(1)) or stimulatory effect of beta(2)-adrenergic receptors, but due to inhibitory effects on muscarinic receptors.

Functional antagonism with formoterol and salmeterol in asthmatic patients expressing the homozygous glycine-16 beta(2)-adrenoceptor polymorphism.

BACKGROUND: Formoterol and salmeterol differ in their relative intrinsic activity at airway beta(2)-adrenoceptors, with formoterol being a full agonist. The homozygous glycine-16 polymorphism of the beta(2)-adrenoceptor occurs in approximately 40% of patients and is known to predispose to agonist-induced downregulation and desensitization. OBJECTIVES: To evaluate possible differences in intrinsic beta(2)-adrenoceptor agonist activity between salmeterol and formoterol in terms of their functional antagonism against methacholine-induced bronchoconstriction (the primary end point) in genetically susceptible patients who exhibited the homozygous glycine-16 polymorphism. METHODS: Eighteen patients with mild-to-moderate persistent asthma receiving inhaled corticosteroid who expressed the homozygous glycine-16 genotype were randomized to completion (mean [SEM] age, 35.8 [3.2] years; mean FEV(1), 76.9 [2. 5]% predicted). Patients received three different treatments for 1 week in randomized, double-blind, crossover fashion, with a 1-week washout period between treatments: formoterol, 12 microg bid; salmeterol, 50 microg bid; and placebo. For each of the randomized treatment periods, there were three separate methacholine challenges: baseline after washout, 12 h after the first dose, and 12 h after the last dose. RESULTS: Both salmeterol and formoterol exhibited significantly (p < 0.05) greater bronchoprotection than placebo for their effects after single or repeated dosing, although there was no significant difference between the two drugs. The geometric mean fold protection vs placebo (95% confidence interval [CI]) for the first dose was 1.6-fold (95% CI, 1.1 to 2.2) for salmeterol and 1.9-fold (95% CI, 1.1 to 3.2) for formoterol, and for last dose was 1.6-fold (95% CI, 1.2 to 2.3) for salmeterol and 1. 9-fold (95% CI, 1.2 to 2.8) for formoterol. Salmeterol and formoterol produced significant (p < 0.05) increases in FEV(1) and forced expiratory flow after 25 to 75% of vital capacity has been expelled, after the first but not the last dose compared to placebo, while there were significant (p < 0.05) improvements in domiciliary peak flows during treatment with both drugs. CONCLUSION: Our results showed no difference between formoterol and salmeterol in the degree of functional antagonism against methacholine-induced bronchoconstriction at the end of a 12-h dosing interval in patients who expressed the homozygous glycine-16 genotype. There was a significant residual degree of bronchoprotection after 1 week of treatment, which was not significantly different compared to the first-dose effect.

Variability in lung deposition of inhaled drug, within and between asthmatic patients, with a pMDI and a dry powder inhaler, Turbuhaler.

In vitro analysis of inhaled formulations measures, among other parameters, the variability in delivered dose, while a corresponding in vivo analysis also includes the variability caused by patient performance and distribution of drug between the oropharynx and the lungs. In vitro, the dose variability is higher for Turbuhaler(R) than for the corresponding pMDI, whereas in vivo, the converse is true: the variability in lung deposition is significantly higher, both between and within subjects, for pMDI than for Turbuhaler. The observation can be due to several factors such as the non-continuous working principle of inhalation via pMDI as opposed to the continuous working principle of inhalation via Turbuhaler.

Inhibitory effects of azelastine hydrochloride in alcohol-induced asthma.

BACKGROUND: Alcohol-induced bronchoconstriction is due to high blood concentrations of acetaldehyde, a metabolic product of ethanol, which lead to the release of histamine from basophils and mast cells. OBJECTIVE: We examined the inhibitory effects of azelastine hydrochloride, which inhibits histamine release and blocks H1 receptors, in alcohol-induced asthma. METHODS: Subjects were 13 Japanese asthmatic patients. We measured the change in FEV1 after ingestion of 30 g of pure ethanol. Blood ethanol, acetaldehyde, histamine, leukotriene C4 (LTC4), and thromboxane B2 (TXB2) concentrations were also measured. Alcohol challenge test was repeated in responders after administration of azelastine for 1 week at 4 mg/day. RESULTS: Of 13 asthmatic patients, five (38.5%) tested positive during an ethanol challenge test, represented by a fall more than 20% in FEV1. The responders had a high blood ethanol, and showed a rise in blood acetaldehyde and histamine concentrations, but not in LTC4 or TXB2. After azelastine treatment, there was no significant fall in FEV1 among responders. Neither the rise in blood ethanol nor blood acetaldehyde levels were blunted by treatment with azelastine, but the rise in blood histamine was blunted by this treatment. CONCLUSION: Our results suggest that antihistamine agents may be effective against alcohol-induced asthma by both blocking H1 receptors and inhibiting histamine release.

Surface-modified antiasthmatic dry powder aerosols inhaled intratracheally reduce the pharmacologically effective dose.

PURPOSE: The aim of this study was to construct a reliable dry powder inhalation (DPI) testing system for use in guinea pigs. Using this system, we were able to demonstrate the superiority of pulmonary administration of hydrophilically surface-modified pranlukast hydrate powder (SM-DP) over IV and PO administration as reflected in improved pharmacological action. Our ultimate aim is the development of an ideal treatment system for bronchial asthma involving topical administration to the lung. METHODS: The reliability of the present DPI system was validated by continuously monitoring the concentration and particle size distribution of aerosols generated with an ambient particulate monitor and an Andersen air sampler, respectively. The pharmacological effect of SM-DP intratracheally administered to guinea pig was investigated by measuring the degree of bronchoconstriction and microvascular leakage induced by leukotriene D4. RESULTS: The mass concentration of aerosols generated by the DPI system was stable and the mass median aerodynamic diameter of aerosols insufflated from the respirator of the DPI system ranged from 1.4 to 1.7 microm, within respirable limits. Inhibition of bronchoconstriction and airway microvascular leakage induced by leukotriene D4 was achieved successfully with a dramatically lower dose of DP, or a further lower dose of SM-DP, comparable with that of the drug solution injected intravenously. The plasma pranlukast hydrate level with SM-DP at 50% inhibition of bronchoconstriction and airway microvascular leakage was reduced to 1/10 or less that following IV and PO administration. CONCLUSIONS: The hydrophilically surface-modified pranlukast hydrate powders were ideally aerosolized by the present DPI system, and were uniformly deposited in the lung lobes after inhalation. The pulmonary administration system with SM-DP is strongly recommended as an ideal system for the treatment of bronchial asthma in order to avoid systemic side-effects due to a dramatically reduced ED50, comparable with or lower than IV, and the low plasma concentration of drug, 1/12 or less than that following IV and PO administration.

Pharmacology of airway smooth muscle.

Airway smooth muscle contributes to changes in airway caliber not only through the variations in its tone but also through its contribution to thickness of the airway wall. Until recently, most attention was paid to the agents that altered airway smooth muscle tone, their receptors, the signal transduction pathways they activated, and the mechanisms of contraction and relaxation themselves. Lately, the regulation of smooth muscle proliferation has received increasing attention, and, most recently, the possible role of smooth muscle as a source of inflammatory mediators has been recognized. Airway smooth muscle cells are now seen as playing an important interactive role with inflammatory and structural cells in the response to injury and repair of the airways.

[Effect of amrinone and vagotomy on airway constriction in dogs: analysis by respiratory system impedance method].

Amrinone, a selective phosphodiesterase III inhibitor, is a positive inotropic agent with vasodilating effect which is attributable to an increase in cyclic AMP in vascular smooth muscle. Little is known about the effect of amrinone on airway mechanics. The purpose of this study was to clarify the bronchodilating effect of amrinone in dogs, when bronchoconstriction was induced by methacholine infusion. We also evaluated the effect of amrinone on bronchoconstriction in vagotomized dogs. To evaluate the effect of amrinone on respiratory function, the total respiratory system impedance was measured using forced oscillation method by imposing a random noise. The analysis was performed by dynamic models and a second-order system curve fitting. From the study, we conclude that amrinone 0.5 mg.kg-1.1.0 mg.kg-1 or 2.0 mg.kg-1 attenuates methacholine-induced bronchoconstriction in a dose-related manner. In vagotomized dogs, amrinone also had the same effect on methacholine induced bronchoconstriction.

Effects of inhaled budesonide on allergen-induced airway responses and airway inflammation.

Allergen inhalation by sensitized subjects results in acute bronchoconstriction, which can be followed by a later bronchoconstrictor response, allergen-induced airway hyperresponsiveness, and increases in airway inflammatory cells. Treatment with inhaled glucocorticosteroids attenuates allergen-induced asthmatic airway responses. The purpose of this study was to determine whether a 1-wk pretreatment with inhaled budesonide influences allergen-induced changes in inflammatory cells in blood and induced sputum. Seven subjects with mild atopic asthma were treated in a double-blind, placebo-controlled, randomized, crossover fashion with either inhaled budesonide 400 microg/d, or placebo for 7 d. Allergen challenges were carried out the morning after treatment was discontinued and sputum samples were obtained 7 h after allergen inhalation. Methacholine airway responsiveness was measured, and blood and sputum samples were obtained 24 h post-allergen. Budesonide treatment attenuated the magnitude of both the early and the late asthmatic response, reduced allergen-induced methacholine airway hyperresponsiveness, and attenuated allergen-induced increases in total eosinophils and activated eosinophils. These results suggest that the effects of inhaled glucocorticosteroids on allergen-induced airway responses may be mediated through their inhibition of allergen-induced eosinophil migration and activation.