allopurinol and Lung-Diseases--Obstructive

Advances have recently been made in understanding the pharmacokinetics of theophylline. To correlate the new knowledge of theophylline pharmacokinetics with the drug's current status in therapy, we have critically reviewed the relevant investigations of the last 5 years. We consider data on its presumed mechanisms of action, factors affecting its clearance, its use in pregnancy, treatment of overdoses, and important drug interactions. Theophylline clearance is decreased by concomitant use of erythromycin, cimetidine, high-dose allopurinol, oral contraceptives, and caffeine. Clearance is increased by concomitant use of phenobarbital and phenytoin. Newly discovered actions of theophylline include dose-dependent improvement of diaphragmatic contractility, augmentation of ventilatory response to hypoxia, and sleep disturbances (especially with high-dose treatments). Points clinically relevant to the daily use of theophylline derivatives and the importance of sustained-release preparations are discussed. Theophylline continues to play a major role in therapy for reactive airways disease.

Topics: Acidosis; Aging; Allopurinol; Animals; Anti-Bacterial Agents; Breast Feeding; Bronchodilator Agents; Caffeine; Contraceptives, Oral; Cooking; Cystic Fibrosis; Drug Interactions; Erythromycin; Female; Heart Diseases; Histamine H2 Antagonists; Humans; Hypoxia; Infections; Kinetics; Liver Diseases; Lung Diseases, Obstructive; Maternal-Fetal Exchange; Phenobarbital; Phenytoin; Pregnancy; Respiration Disorders; Sleep; Smoking; Theophylline

In the present study, we hypothesized that exhaustive exercise in patients with chronic obstructive pulmonary disease (COPD) results in glutathione oxidation and lipid peroxidation and that xanthine oxidase (XO) contributes to free radical generation during exercise. COPD patients performed incremental cycle ergometry until exhaustion with (n = 8) or without (n = 8) prior treatment with allopurinol, an XO inhibitor. Reduced (GSH) and oxidized glutathione (GSSG) and lipid peroxides [malondialdehyde (MDA)] were measured in arterial blood. In nontreated COPD patients, maximal exercise (approximately 75 W) resulted in a significant increase in the GSSG-to-GSH ratio (4. 6 +/- 0.9% at rest vs. 9.3 +/- 1.7% after exercise). In nontreated patients, MDA increased from 0.68 +/- 0.08 nmol/ml at rest up to 1. 32 +/- 0.13 nmol/ml 60 min after cessation of exercise. In contrast, in patients treated with allopurinol, GSSG-to-GSH ratio did not increase in response to exercise (5.0 +/- 1.2% preexercise vs. 4.6 +/- 1.1% after exercise). Plasma lipid peroxide formation was also inhibited by allopurinol pretreatment (0.72 +/- 0.15 nmol/ml preexercise vs. 0.64 +/- 0.09 nmol/ml 60 min after exercise). We conclude that strenuous exercise in COPD patients results in blood glutathione oxidation and lipid peroxidation. This can be inhibited by treatment with allopurinol, indicating that XO is an important source for free radical generation during exercise in COPD.

Topics: Adenosine Triphosphate; Allopurinol; Exercise Test; Female; Glutathione; Glutathione Disulfide; Humans; Lipid Peroxidation; Lung Diseases, Obstructive; Male; Malondialdehyde; Middle Aged; Oxidative Stress; Physical Exertion; Rest; Xanthine Oxidase

Xanthine oxidase (xanthine: oxygen oxidoreductase, EC 1.1.3.22), a molybdenum-containing hydroxylase that produces superoxide and uric acid from purine substrates and molecular oxygen, is involved in the oxidative stress underlying several human pathologies including lung diseases. An enzymatic activity similar to xanthine oxidase was previously reported in bronchoalveolar lavage fluid of patients with chronic obstructive pulmonary disease (COPD-BAL), by fluorometric analysis of DNA unwinding and cytochrome c reduction kinetics. Here we report the detection of xanthine oxidase activity products by electron paramagnetic resonance (EPR) in presence of the spin-trap 5,5-dimethyl-1-pyrroline N-oxide (DMPO) and reversed-phase high-performance liquid chromatography (RP-HPLC) in COPD-BAL (n = 14, average age of patients 65 years, range 38-81) and BAL from healthy nonsmoker controls (n = 6, average age 64 years, range 44-73). Superoxide DMPO adducts were detected in COPD-BAL and in an in vitro system containing xanthine and xanthine oxidase (XA/XO), but not in BAL controls and when superoxide dismutase (SOD, 1000 I.U./ml) was added to COPD-BAL. The HPLC analyses after addition of xanthine showed production of uric acid in COPD-BAL and in the XA/XO system but not in BAL controls. These results support the involvement of xanthine oxidase in the mechanisms of superoxide production by BAL supernatant, which increases oxidative stress in chronic obstructive pulmonary disease.

Topics: Adult; Aged; Aged, 80 and over; Bronchoalveolar Lavage Fluid; Chromatography, High Pressure Liquid; Cyclic N-Oxides; Cytochrome c Group; Electron Spin Resonance Spectroscopy; Electrophoresis, Polyacrylamide Gel; Female; Humans; Lung Diseases, Obstructive; Male; Middle Aged; Oxidative Stress; Spin Labels; Superoxides; Xanthine Oxidase

Chronic obstructive pulmonary disease (COPD) is a serious respiratory pathology characterized by irreversible limitation of expiratory flow and includes chronic obstructive bronchitis, chronic airflow limitation, and emphysema. To determine whether xanthine oxidase activity increased in the airspaces of COPD patients, we examined bronchoalveolar lavage fluid (BAL) from COPD patients recruited during a 2-year clinical study. Filtered BAL supernatant from COPD patients and healthy nonsmoking controls was examined by fluorometric analysis of DNA unwinding (FADU) and spectrophotometric assays (cytochrome c reduction kinetics and uric acid kinetics). Compared to controls, filtered BAL supernatant of subjects with COPD exhibited a detectable clastogenic activity probably related to superoxide production. The method of BAL preparation as an acellular system strongly suggests that superoxide production may be due to xanthine oxidase activity.

Topics: Adult; Aged; Aged, 80 and over; Bronchoalveolar Lavage Fluid; Cytochrome c Group; DNA; DNA Damage; Female; Humans; Kinetics; Lung Diseases, Obstructive; Male; Middle Aged; Mutagens; Oxidation-Reduction; Spectrometry, Fluorescence; Superoxides; Uric Acid; Xanthine Oxidase

Topics: Aged; Allopurinol; Erythrocytes; Humans; Lung Diseases, Obstructive; Middle Aged; Oxygen Inhalation Therapy