Modulation of T-cell function by (R)- and (S)-isomers of albuterol: anti-inflammatory influences of (R)-isomers are negated in the presence of the (S)-isomer

BACKGROUND: beta(2)-Adrenergic agonists interact with specific receptors on T lymphocytes to mediate anti-inflammatory activities. However, anti-inflammatory effects are not observed when beta(2)-adrenergic agonists are administered in vivo as racemates. OBJECTIVE: We hypothesized that anti-inflammatory influences are mediated by the (R)-isomer and are masked in the additional presence of the (S)-isomer. METHODS: Antigen-specific T-cell lines were generated in the presence of recombinant human IL-2 and tetanus with or without varying concentrations of (R)- and (S)-isomers of albuterol alone or in combination. Parallel lines were generated in the presence of propranolol. Cells were briefly pulsed with PHA and evaluated for proliferation, apoptosis, and cytokine secretion. RESULTS: (R)-Albuterol significantly inhibited T-cell proliferation (77.0% +/- 9.7% of control at 10(-8) mol/L and 61.1% +/- 9.0% at 10(-7) mol/L). No influence was observed with (S)-albuterol alone. However, the addition of (S)-albuterol to (R)-albuterol mediated a dose-dependent increase in proliferation. At equivalent concentrations of the 2 isomers, proliferation was unchanged from the control, whereas at 10(-6) mol/L (S)-albuterol, proliferation was enhanced. Both the inhibitory effects of (R)-albuterol alone and the stimulating influence of (R)- plus (S)-albuterol were blocked in the additional presence of propranolol. (R)-Albuterol at 10(-8) mol/L inhibited IL-2 and IFN-gamma production. Racemic albuterol (10(-8) mol/L each) had no influence on cytokine production; however, the combination of 10(-8) mol/L (R)-albuterol with 10(-6) (S)-albuterol stimulated production of IL-2 and IL-13. No effects were observed on apoptosis or cell viability. CONCLUSION: These studies confirm the beta-adrenergic receptor-specific anti-inflammatory effects of (R)-albuterol. The racemate had minimal influences on proliferation or cytokine production. The presence of excess (S)-albuterol resulted in proinflammatory influences. We hypothesize that the (S)-isomer functions as an inverse agonist to switch the function of the beta(2)-adrenergic receptor.     

Anti-inflammatory and anti-allergic effects of kefir in a mouse asthma model

Kefir is a microbial symbiont mixture that produces jelly-like grains. As a widely used neutraceutical, however, the therapeutic applicability of kefir is not certain. In order to investigate the pharmacological effects of kefir, we used a mouse asthma model, in which airway inflammation and airway remodeling was produced by ovalbumin sensitization and challenge. BALB/c mice sensitized and challenged to ovalbumin, were treated with kefir (50mg/kg administered by intra-gastric mode) 1h before the ovalbumin challenge. Kefir significantly suppressed ovalbumin-induced airway hyper-responsiveness (AHR) to inhaled methacholine. Intra-gastric administration of kefir significantly inhibited the increase in the total inflammatory cell count induced by ovalbumin, and the eosinophil count in bronchoalveolar lavage fluid (BALF). Type 2 helper T cell (Th2) cytokines, such as interleukin-4 and interleukin-13, and total immunoglobulin E (Ig E) levels, were also reduced to normal levels in bronchoalveolar lavage fluid. Histological studies demonstrate that kefir substantially inhibited ovalbumin-induced eosinophilia in lung tissue and mucus hyper-secretion by goblet cells in the airway. Kefir displayed anti-inflammatory and anti-allergic effects in a mouse asthma model and may possess new therapeutic potential for the treatment of allergic bronchial asthma.     

Anti-inflammatory effects of tilmicosin in a noninfectious mouse model of allergic asthma

Tilmicosin, a semi-synthetic tylosin-derived macrolide antibiotic commonly used by veterinarians, has been shown to possess anti-inflammatory activity. However, possible use in asthma treatment has not yet been studied. In this study, we investigated the anti-inflammatory properties of tilmicosin using a murine asthma model. BALB/c mice were sensitized and challenged by intraperitoneal (i.p.) or nasal administration of ovalbumin. Tilmicosin (10 and 20?mg/kg) treatment resulted in a marked reduction in the presence of several types of immune cells and cytokines in the bronchoalveolar lavage fluids of mice. Levels of ovalbumin-specific Immunoglobulin E (IgE) were significantly decreased following treatment with tilmicosin (10 and 20?mg/kg). Histological studies using H&E (haematoxylin and eosin) and AB-PAS (alcian blue-periodic acid-Schiff) staining demonstrated that tilmicosin substantially inhibited both ovalbumin-induced inflammatory cells in lung tissues and goblet cell hyperplasia in the airway. These findings provided new insight into the immunopharmacological role of tilmicosin in terms of its effects in a murine model of asthma.     

Anti-inflammatory effects of tilmicosin in a noninfectious mouse model of allergic asthma

Tilmicosin, a semi-synthetic tylosin-derived macrolide antibiotic commonly used by veterinarians, has been shown to possess anti-inflammatory activity. However, possible use in asthma treatment has not yet been studied. In this study, we investigated the anti-inflammatory properties of tilmicosin using a murine asthma model. BALB/c mice were sensitized and challenged by intraperitoneal (i.p.) or nasal administration of ovalbumin. Tilmicosin (10 and 20 mg/kg) treatment resulted in a marked reduction in the presence of several types of immune cells and cytokines in the bronchoalveolar lavage fluids of mice. Levels of ovalbumin-specific Immunoglobulin E (IgE) were significantly decreased following treatment with tilmicosin (10 and 20 mg/kg). Histological studies using H&E (haematoxylin and eosin) and AB-PAS (alcian blue-periodic acid-Schiff) staining demonstrated that tilmicosin substantially inhibited both ovalbumin-induced inflammatory cells in lung tissues and goblet cell hyperplasia in the airway. These findings provided new insight into the immunopharmacological role of tilmicosin in terms of its effects in a murine model of asthma.     

Anti-inflammatory effects of ivermectin in mouse model of allergic asthma

Background and objective  

Asthma is an inflammatory disease of the lungs that is characterised by increased inflammatory cell infiltration into the airways and poor respiratory function. Ivermectin is a semi-synthetic derivative of a family of macrocyclic lactones that shows broad-spectrum anti-parasitic activity. This drug has been shown to possess anti-inflammatory activity, but whether it can be used in asthma treatment has not yet been investigated. In this study, we aimed to investigate the inhibitory effects of ivermectin on allergic asthma symptoms in mice.     

金黄色葡萄球菌肠毒素对小鼠慢性哮喘模型的抗炎作用

目的：用金黄色葡萄球菌肠毒素A（SEA）和肠毒素B（SEB）干预幼年小鼠,观察它们对小鼠慢性哮喘气道炎症的影响以及对气道内相关细胞因子水平的调节作用。方法：实验组中BALB/c小鼠在出生后1周开始腹腔注射0.1 mL SEA或SEB（浓度1 mg/L）,隔天注射,共7次。其它小组注射相同剂量生理盐水对照。BALB/c 小鼠出生后4周建立哮喘模型,实验组和模型组分别在0、7和14 d用卵白蛋白（OVA）腹腔注射致敏,在28 d开始隔天OVA雾化激发哮喘,共7次,末次激发后24-48 h内取支气管肺泡灌洗液（BALF）,进行嗜酸性粒细胞和总白细胞计数,其余BALF离心-70 ℃冻存检测细胞因子,固定肺组织做病理切片分析。结果:SEA组和SEB组小鼠肺组织炎症反应轻于模型组,BALF中嗜酸性粒细胞数量少于模型组 (P＜0.05);SEA、SEB组BALF中Th1细胞因子干扰素-γ（IFN-γ）高于模型组(P＜0.05);而Th2细胞因子白细胞介素-4（IL-4）、白细胞介素-5（IL-5）和嗜酸性粒细胞趋化因子（eotaxin）均低于模型组(P＜0.01)。结论:早期感染 SEA、SEB可以减少小鼠慢性哮喘支气管肺泡灌洗液中嗜酸性粒细胞的数量,可能通过调节Th1/Th2细胞因子比值减轻气道中的哮喘炎症反应。     

Clinical comparability of albuterol delivered by the breath-actuated inhaler (Spiros) and albuterol by MDI in patients with asthma.

STUDY OBJECTIVE: This study compares the efficacy and safety of one and two actuations of albuterol sulfate powder delivered via a breath-actuated, effort-assisted, investigational inhaler (Spiros, Dura Pharmaceuticals, Inc) and albuterol delivered via a conventional propellant-driven metered dose inhaler (Ventolin, Glaxo, Inc). DESIGN: Randomized, double-blind, placebo-controlled, 5-way crossover study. PARTICIPANTS: Sixty patients with mild-to-moderate asthma (FEV1 59% predicted) were enrolled and 44 completed the study. MEASUREMENTS AND RESULTS: FEV1 values over 6 hours were analyzed by ANCOVA and the Finney relative potency model. The relative potency of the inhalers (albuterol MDI: albuterol DPI) was 1.132 (90% CI, 0.680 to 2.252) indicating 1.132 actuations of albuterol MDI provided the same bronchodilation as one actuation of albuterol DPI. ANCOVA analyses further indicated that there were no significant differences between the two delivery systems with respect to FEV1, FVC, FEF25-75%, or PEF. Both inhalers had similar effects on serum potassium levels, QTc interval, blood pressure, and heart rate. CONCLUSIONS: In patients with mild-to-moderate asthma in this study, the albuterol DPI was determined to be therapeutically comparable to albuterol MDI in the delivery of one and two actuations of albuterol.     

Heme oxygenase-1 (HO-1) protein induction in a mouse model of asthma

BACKGROUND AND OBJECTIVE: Carbon monoxide (CO) is known to be present in measurable quantities in the exhalation of asthmatic patients. Corticosteroid treatment resulted in a decrease in exhaled CO levels in asthmatic patients, raising the possibility that an increase in exhaled CO concentration reflects inflammation of the asthmatic airway. Heme oxygenase-1 (HO-1) protein, also called HSP32, is the rate-limiting enzyme in the catabolism of heme to biliverdin, free iron and CO. However, it is unknown whether an expression of HO-1 within the lung tissue is related to allergic airway inflammation. We studied the expression of HO-1 in lung tissue and bronchoalveolar lavage cells in a mouse model of asthma. METHODS: Ovalbumin (OVA)-sensitized C57BL/6 mice were challenged with aerosolized OVA. HO-1 positive cells were identified by immunostaining in lung tissue and bronchoalveolar lavage fluid (BALF) after the challenge. RESULTS: HO-1 positive cell numbers increased in the subepithelium of the bronchi after OVA challenge. In cytospin preparations from BALF after OVA challenge, HO-1 was localized to alveolar macrophages. Inside the macrophages, HO-1 reactivity was expressed in the cytoplasm, and the perinuclear region in particular. CONCLUSION: The expression of HO-1 is increased within the lung tissue in allergic airway inflammation. Measurement of HO-1 activity may be clinically useful in the management of asthma.     

Evaluation of procaterol and albuterol (salbutamol) aerosol in the treatment of asthma.

Procaterol aerosol (10 micrograms/inhalation) was compared to albuterol (salbutamol) aerosol (100 micrograms/inhalation), two inhalations t.i.d. or q.i.d., in 333 outpatients with reversible bronchial airway obstruction over a 12-week period in a double-blind randomized and parallel study. Predose and postdose pulmonary function tests (PFTs) were performed initially and after 2, 4, 8, and 12 weeks of therapy. Patients maintained a daily diary of asthma symptom scores. A significantly higher percentage of patients receiving procaterol (59%) continued therapy on a t.i.d. schedule rather than a q.i.d. schedule compared with patients receiving albuterol (48%, P less than .05). Pulmonary function tests indicated similar improvement in both groups. Clinically significant improvement in mean FEV1 was maintained for four to seven hours postdose for procaterol and for three to six hours for albuterol. Adverse experiences were reported in 15% of procaterol-treated patients and 17% of albuterol-treated patients. Headache and tremor were most frequent, with no significant differences in frequencies between groups. Both procaterol and albuterol were highly effective in improving pulmonary function and controlling symptoms of asthma; both were well tolerated. Procaterol had a longer duration of action, and more patients were controlled on a t.i.d. dosage regimen.     

Comparative study of acute effects of albuterol and isoproterenol sulphate aerosols in bronchial asthma.

Albuterol, a new bronchodilator drug known to cause beta2-adrenergic receptor stimulation, was compared with isoproterenol sulphate for their pulmonary and cardiovascular effects in patients suffering from bronchial asthma. In a double-blind manner 24 patients received as aerosol 170 micrograms of Albuterol or 150 micrograms of Isoproterenol or placebo on three different days. Spirometric, plethysmographic, heart rate and blood pressure measurements were made at 1, 5, 15, 30, 60, 90, 120, 300 and 360 minutes after drug inhalation. Baseline values for the various indices were not significantly different before administration of the drugs. Results demonstrate that Albuterol is an effective bronchodilator and its bronchodilating effect is significantly superior and of longer duration than that of Isoproterenol. Albuterol did not produce any significant changes in blood pressure and pulse rate, thus confirming its selectivity for beta2 receptors.     

A comparison of inhaled fenoterol and albuterol in asthma

In 24 adult asthmatics the effects of clinically recommended doses of fenoterol (320 micrograms) and albuterol (180 micrograms) were compared to placebo in a double-blind, crossover trial. Bronchodilation in FEV1 was significantly greater than placebo for both active drugs: two hours on albuterol and five hours on fenoterol. Results of FEF25-75% were similar. There were no significant changes in pulse rate, blood pressure and electrocardiogram, but 11 patients had mild subjective side-effects on fenoterol.     

Detection of chemical mutagens using Muta(R) Mouse: a transgenic mouse model

A transgenic mouse strain with a high copy number of rescuablelac Z sequences was evaluated for its effectiveness in detectinglacZ^– mutations in selected tissues. Procarbazine, cyclophosphamide,ethylnitrosourea, 7, 12-dimethylbenz [a] anthracene (DMBA),acrylamide and chlorambucil were tested following either singleor repeated dosing regimens. Bone marrow, liver, skin and testistissues were selected to assess as target sites for mutation.Bone marrow, liver and testis tissues were examined for mutationfollowing exposures to ethylnitrosourea and chlorambucil. Increasedmutant frequencies were found for both chemicals in all threetissues. Bone marrow tissue was examined for mutation followingprocarbazine, cyclophosphamide and acrylamide exposures, andskin was examined for mutation following dermal applicationof DMBA. Mutation induction was observed in all cases. The resultsbtained from this investigation demonstrate the applicabilityof this transgenic mouse as an effective model to detect andanalyze gene mutation in selected organs including germinaltissues. Studies of organotrophic chemical mutagens and carcinogensare possible with this model as are studies of the susceptibilityof germinal tissues to mutagen exposures. ²To whom correspondence should be addressed     

Comparison of inhaled albuterol powder and aerosol in asthma

In this multicenter, randomized, double-blind study comparing the efficacy and safety of aerosolized albuterol with the dry powder formulation, 231 patients with chronic reversible obstructive airway disease were randomly allocated to receive either placebo albuterol aerosol followed immediately by active albuterol powder (200 micrograms) or active albuterol aerosol (two puffs, 180 micrograms) followed immediately by placebo lactose powder four times a day for a period of 12 weeks. No statistically significant differences were found between the powder and aerosol formulations with respect to pulmonary function, length of time mean FEV1 remained greater than or equal to 15% above baseline, physicians' assessments of patients' clinical response, or patients' subjective symptom scores. There were also no significant differences between treatment groups in cardiovascular effects, laboratory values, or adverse events. Among patients who expressed a preference for one of the delivery systems, half preferred using the powder. Results of this study demonstrate that 200 micrograms of albuterol powder is as safe and effective as 180 micrograms of albuterol aerosol.     

Extrapulmonary effects of maintenance therapy with theophylline and inhaled albuterol in patients with chronic asthma

The extrapulmonary effects of slow-release theophylline and an inhaled beta 2-agonist (albuterol) were examined separately and in combination among 18 adults and adolescents with asthma during a 3-month randomized, double-blind, crossover trial. Although neither global impressions nor daily diaries revealed differences in adverse effects, a structured questionnaire completed at the end of each regimen suggested a small but statistically significant increase in nausea and depressive and caffeine-like symptoms during the theophylline-containing regimens. Theophylline was also associated with improved verbal learning but decreased motor steadiness. Metabolic effects associated with theophylline included lower serum bicarbonate, greater urinary calcium excretion, and higher serum calcium, uric acid, and creatinine. Albuterol was associated with lower neutrophil counts and lower serum theophylline concentrations. There were no drug-induced effects on cardiac rhythm.     

Macrocyclic peptides, 8. Enantiomeric differentiations of various (R)- and (S)- ammonium and (R)- and (S)-α-amino acid ester salts by macrocyclic pseudopeptides

The interactions of the hydrobromides of (R)- and (S)-alanine-N-methylanilides ( 1 ) with 24-, 27- and 36-membered ring pseudopeptides ( H-24, H-27 and H-36 , respectively) derived from glycine and (2S,3′ S)-4-methyl-2-(2′-oxo-3′-isobutyl-1′-piperazinyl)pentanoic acid were studied by means of ¹H and ¹³C NMR measurements in CDCl₃. It was found from these results that H-24 and H-27 distinguished (R)- and (S)-isomers of 1 , while H-36 did not entirely. Moreover, the enantioface-differentiating abilities of these cyclic peptides were investigated by means of ¹H NMR measurements in CDCI₃ using (R)- and (S)-1-phenylethylammonium and (R)- and (S)-p-methoxy-1-phenylethylammonium bromides as the substrates, showing that the enantio-selectivity of H-36 is superior to those of H-24 and H-27 . Also, the chiral recognition ability of H-24 for the hydrochlorides of (R)- and (S)-alanine (Ala), -leucine (Leu), -methionine (Met), -phenylalanine (Phe), -proline (Pro) and -valine (Val) methyl esters were examined by ¹H and ¹³C NMR measurements in CDCl₃. Among these hydrochlorides, HCl · Phe? OCH₃ was distinguished more effectively with H-24 .     

Effects of albuterol and procaterol on exercise-induced asthma

Procaterol and albuterol, beta agonists, were studied using a placebo-controlled, repeated exercise challenge design in order to assess their duration of effectiveness in both bronchodilation and in modifying exercise-induced asthma (EIA). Fifty-three subjects aged 12 to 50 years who had at least a 20% drop in FEV1 during a screening exercise tolerance test were entered. Subjects took two inhalations of procaterol (10 micrograms/inhalation), albuterol (90 micrograms/inhalation), or placebo. Thirty minutes later they exercised on a treadmill at a workload sufficient to induce greater than or equal to 80% aerobic O2 consumption for six minutes. Pulmonary function was measured before and serially for 30 minutes after exercise. The same exercise challenge was repeated three, six, and nine hours after drug administration. Both procaterol and albuterol bronchodilated and modified EIA at 30 minutes and three hours, mean drops in FEV1 being 8.2 and 9.7% respectively at 30 minutes and 16.8 and 16.3% at three hours. This was compared with placebo falls of 30% and 26%. At six hours the subjects' response was similar after both procaterol and albuterol, and fewer subjects had a 20% fall in FEV1 than with placebo, although protection afforded by both beta agonists was substantially less than at three hours. Both drugs were tolerated well.     

Comparison of albuterol and isoproterenol aerosols in bronchial asthma.

Albuterol and isoproterenol aerosols were compared with placebo in a double-blind manner in 18 patients with bronchial asthma. Both drugs elicited significant improvement in flow rates and vital capacity. Duration of action was longer with albuterol than with isoproterenol. Neither was associated with significant increases in heart rate or blood pressure.