allopurinol and Asthma

Topics: Animals; Asthma; Coordination Complexes; Enzyme Inhibitors; Gene Expression Regulation; Gold; Humans; Macrophages, Alveolar; Mice; Osteopontin; Pulmonary Disease, Chronic Obstructive; RANK Ligand; RNA, Messenger; Tartrate-Resistant Acid Phosphatase; Xanthine Oxidase

Nitrogen dioxide (NO2) is an environmental air pollutant and endogenously generated oxidant that contributes to the exacerbation of respiratory disease and can function as an adjuvant to allergically sensitize to an innocuous inhaled Ag. Because uric acid has been implicated as a mediator of adjuvant activity, we sought to determine whether uric acid was elevated and participated in a mouse model of NO2-promoted allergic sensitization. We found that uric acid was increased in the airways of mice exposed to NO2 and that administration of uricase inhibited the development of OVA-driven allergic airway disease subsequent to OVA challenge, as well as the generation of OVA-specific Abs. However, uricase was itself immunogenic, inducing a uricase-specific adaptive immune response that occurred even when the enzymatic activity of uricase had been inactivated. Inhibition of the OVA-specific response was not due to the capacity of uricase to inhibit the early steps of OVA uptake or processing and presentation by dendritic cells, but occurred at a later step that blocked OVA-specific CD4(+) T cell proliferation and cytokine production. Although blocking uric acid formation by allopurinol did not affect outcomes, administration of ultra-clean human serum albumin at protein concentrations equivalent to that of uricase inhibited NO2-promoted allergic airway disease. These results indicate that, although uric acid levels are elevated in the airways of NO2-exposed mice, the powerful inhibitory effect of uricase administration on allergic sensitization is mediated more through Ag-specific immune deviation than via suppression of allergic sensitization, a mechanism to be considered in the interpretation of results from other experimental systems.

Topics: Adaptive Immunity; Allergens; Allopurinol; Animals; Antigen Presentation; Asthma; Cytokines; Disease Models, Animal; Humans; Hypersensitivity; Lung; Mice; Mice, Inbred BALB C; Nitrogen Dioxide; Ovalbumin; Serum Albumin; Th2 Cells; Urate Oxidase; Uric Acid

Most asthma is mild and moderate and can be well controlled by low-dose inhaled steroid with or without bronchodilators. However, 5% to 10% of patients with asthma have more troublesome disease despite using such medication. Recent reports showed that nitrative stress induced tissue remodeling in vitro, which is associated with a component of refractoriness in asthma. However, there is no report that nitrative stress is involved in refractory asthma.. The aim of this study is to evaluate whether patients with refractory asthma have more nitrative stress.. Ten healthy subjects, 10 patients with well-controlled asthma, and 8 patients with refractory asthma took part in the current study. Exhaled nitric oxide, xanthine oxidase activity in the supernatant of the sputum, immunostaining for the inducible type of nitric oxide synthase, and 3-nitrotyrosine in induced sputum from the subjects were assessed.. All nitrative markers including exhaled nitric oxide (P < .01), immunopositivities for inducible nitric oxide synthase (P < .01), xanthine oxidase activities (P < .01), and 3-nitrotyrosine (P < .01) in sputum from the refractory asthma group were enhanced compared with the well-controlled group. All these nitrative markers in the sputum had a significant negative correlation with the %FEV(1) values (P < .01).. These results suggested that patients with refractory asthma have more nitrative stress in their airways compared with patients with well-controlled asthma.

Topics: Adult; Aged; Asthma; Biomarkers; Bronchodilator Agents; Drug Resistance; Exhalation; Female; Forced Expiratory Volume; Humans; Immunohistochemistry; Male; Middle Aged; Nitric Oxide; Nitric Oxide Synthase Type II; Sputum; Staining and Labeling; Steroids; Tyrosine; Vital Capacity; Xanthine Oxidase

The activity of the enzyme purine metabolism (5'-nucleotidase, adenosine deaminase, xanthine oxidase and the content of uric acid, i.e. the final product of the purine metabolism) were determined in lymphocytes, eosinophiles and blood serum of patients with bronchial asthma. The activity of 5'-nucleotidase in lymphocytes, eosinophiles and blood serum of patients with bronchial asthma was found to be reduced by 5-7-% as compared with the controls. The activity of adenosine deaminase in lymphocytes, eosinophiles and blood serum was found to be reduced in a majority of patients. An increased activity of adenosine deaminase was higher in lymphocytes and blood serum of 38% of the examined patients. The activity of xanthine oxidase in lymphocytes and eosinophiles of patients exceeded by 2.4 and 1.7 times the control value, respectively. The content of urine acid was found to be increased, in bronchial asthma, by 2.7 times. Consequently, the balance of enzyme reactions of the purine metabolism is impaired in bronchial asthma, and there is an accumulation of urine acid.

Topics: 5'-Nucleotidase; Adenosine Deaminase; Adolescent; Adult; Asthma; Eosinophils; Humans; Lymphocytes; Male; Middle Aged; Purines; Uric Acid; Xanthine Oxidase

Topics: Allopurinol; Aminophylline; Asthma; Benzbromarone; Bronchodilator Agents; Drug Therapy, Combination; Female; Gout; Humans; Middle Aged; Probenecid; Theophylline; Uric Acid; Uricosuric Agents

A high-performance liquid chromatographic method was developed for the determination of plasma purine nucleoside phosphorylase activity. In this method, the reaction mixture consisted of 15 microliters of plasma and 285 microliters of 50 mM phosphate buffer (pH 7.4) containing 3.8 mM inosine and 0.15 mM 2-(3-cyano-4-isobutoxyphenyl)-4-methyl-5-thiazolecarboxylic acid (strong xanthine oxidase inhibitor). After the reaction, the hypoxanthine produced was monitored to express plasma purine nucleoside phosphorylase activity. By this method, the activity of purine nucleoside phosphorylase was easily determined even with a small-volume plasma sample and despite its low activity in plasma. In addition, plasma purine nucleoside phosphorylase activity can be accurately determined even if the plasma is turbid. As a result, we were able to measure plasma purine nucleoside phosphorylase activity in patients with gout or asthma and healthy subjects, whereby it was demonstrated that plasma purine nucleoside phosphorylase activity was higher in patients with asthma than in either healthy subjects or patients with gout.

Topics: Adult; Aged; Asthma; Calibration; Chromatography, High Pressure Liquid; Febuxostat; Female; Gout; Gout Suppressants; Humans; Hypoxanthine; Hypoxanthines; Inosine; Male; Middle Aged; Purine-Nucleoside Phosphorylase; Thiazoles; Uric Acid; Xanthine Oxidase

Topics: Adrenal Cortex Hormones; Allopurinol; Angiotensin-Converting Enzyme Inhibitors; Asthma; Benzothiadiazines; Bronchodilator Agents; Calcium Channel Blockers; Contraindications; Diuretics; Drug Interactions; Gout; Humans; Hypertension; Male; Middle Aged; Sodium Chloride Symporter Inhibitors

Airway inflammation with human polymorphonuclear leukocytes (PMNs) may play an important role in the pathophysiology of bronchial asthma. Superoxide anion (O2-) and other active oxygen species derived from PMNs cause tissue damage. To evaluate the effects of antiasthma drugs on airway inflammation or antioxidative actions due to the inhibition of O2- generation, we investigated the effects of antiallergic drugs, beta-adrenergic agonists, theophylline and corticosteroids, on the in vitro generation of O2- by human PMNs, using a chemiluminescence (CL) method dependent on a Cypridina luciferin analog (MCLA), a highly sensitive and specific CL probe for O2-. We found that azelastine, one of the antiallergic drugs, and isoproterenol inhibited FMLP-induced O2- generation in a dose-dependent fashion, whereas the other drugs exhibited no such inhibitory action except at very high concentrations. Furthermore, we found that isoproterenol inhibited O2- generation from the hypoxanthine-xanthine oxidase system (an O2(-)-generating system) in a dose-dependent fashion, unlike azelastine and the other drugs. These results suggest that azelastine and isoproterenol inhibit the process of O2- generation from PMNs, while isoproterenol also scavenges O2-. These drugs may be beneficial in the treatment of airway inflammation due to O2- generation in bronchial asthma.

Topics: Adolescent; Asthma; Bronchodilator Agents; Child; Female; Free Radical Scavengers; Humans; Isoproterenol; Male; N-Formylmethionine Leucyl-Phenylalanine; Neutrophils; Phthalazines; Superoxides; Xanthine Oxidase

Chromatographic characteristics of urinary metabolites of theophylline were studied by two-dimensional thin-layer chromatography, high-performance liquid chromatography and gas chromatography--mass spectrometry. Quantitative date for the urinary metabolites of theophylline in asthmatic children are given. It was shown that 1,3-dimethyluric acid is the predominant excretory product. In addition, smaller amounts of 1-methyluric acid, 3-methylxanthine and unchanged theophylline were found. Excretory patterns after theophylline ingestion before and during the administration of allopurinol in asthma patients and in rats suggest the existence of three metabolic pathways of theophylline. The administration of this drug to a patient with xanthine oxidase of theophylline. The administration of this drug to a patient with xanthine oxidase deficiency resulted in the excretion of 1-methyluric acid in addition to 1,3-dimethyluric acid, 3-methylxanthine, 1-methylxanthine and unchanged theophylline. It was concluded that in man the oxidation of theophylline is not catalysed by xanthine oxidase.

Topics: Allopurinol; Animals; Asthma; Child; Chromatography, High Pressure Liquid; Chromatography, Thin Layer; Gas Chromatography-Mass Spectrometry; Humans; Male; Purines; Rats; Theophylline; Xanthine Oxidase

In order to examine the protective effect of allopurinol on experimental asthma produced by histamine aerosol in guinea pigs, allopurinol was administered intraperitoneally resulting in a significant prolongation of survival times. Significant elevation of blood ATP levels was shown in guinea pigs pretreated with allopurinol compared to the control guinea pigs. It is thought that this beneficial effect prevents the loss of functional purine base.

Topics: Adenine Nucleotides; Allopurinol; Animals; Asthma; Bronchodilator Agents; Guinea Pigs; Histamine; Lung; Male