To study whether theophylline inhibits airway hyperresponsiveness in a dose-dependent fashion, we performed inhalation challenges with histamine and methacholine in 9 asthmatic patients. On 4 separate days, 3 consecutive histamine or methacholine tests were carried out, each of them 20 min after saline (placebo) and after 100, 100, and 200 mg intravenous theophylline ethylenediamine given in a cumulative fashion. Airway responsiveness was expressed as the provocative dosage of histamine or methacholine necessary to increase specific airway resistance by 100% (PD100SRaw). After placebo PD100SRaw for histamine showed a small but significant (p less than 0.01) increase not observed after methacholine. Theophylline markedly attenuated airway reactivity in a dose-dependent manner. At a mean (SD) serum concentration of 6.14 (0.30) mg/L, theophylline increased geometric mean PD100SRaw for histamine from 2.76 to 6.07 units (p less than 0.01) and for methacholine from 1.52 to 2.60 units (p less than 0.05). At a mean (SD) serum concentration of 12.9 (0.70) mg/L, theophylline increased geometric mean PD100SRaw for histamine from 2.70 to 17.1 units (p less than 0.01) and for methacholine from 1.28 to 4.98 units (p less than 0.01). Thus, there was a protective effect of theophylline on histamine and methacholine responsiveness in patients with bronchial asthma at "subtherapeutic" serum theophylline concentrations with increasing efficacy at higher serum theophylline concentrations. These observations may have therapeutic implications in the treatment of patients with mild asthma.
Since the calcium antagonists nifedipine and verapamil have been shown to diminish exercise induced asthma, the effect of oral diltiazem, a calcium channel blocker not previously investigated in this context, was studied. Ten patients with bronchial asthma were given 60 mg diltiazem or placebo four hours before the challenge in a double blind, randomised, crossover fashion. Exercise was performed on a cycle ergometer while the subjects were breathing cold air, resulting in a respiratory heat exchange which was similar at the two study sessions. FEV, and specific conductance (sGaw) were recorded before and three, 10, 15, and 30 minutes after the challenge. No significant differences were found between placebo and diltiazem days in the fall of FEV, or sGaw after exercise. Thus unlike other calcium antagonists diltiazem, in a dose of 60 mg given orally four hours before exercise, failed to protect against exercise induced asthma.Exercise induced asthma can be completely or partially inhibited by oral nifedipine'-3 or by inhaled verapamil.4 We have investigated another calcium channel blocker, diltiazem, as no study on its ability to influence exercise induced asthma has previously been reported. As respiratory heat exchange is considered to be an initiating stimulus for exercise induced asthma,5 the effects of diltiazem and placebo were compared under carefully controlled experimental conditions designed to standardise the inhalation thermal challenge during exercise. MethodsPatients We investigated 10 patients with bronchial asthma (five men and five women with a mean age of 27*9 years, range 19-41). Nine patients were judged atopic on the basis of positive skin test reactions to common allergens. All patients gave a history suggesting exercise induced asthma. All were non-smokers and did not require regular medication. Sympathomimetic agents, which were taken occasionally, were withheld for 12 hours before the study sessions. The patients were instructed about the aim of the study and gave their consent.
To investigate the mechanisms contributing to refractoriness in exercise induced asthma a methacholine challenge test was performed 30 minutes before and 30 minutes after two exercise tests 45 minutes apart. Exercise was performed by 12 asthmatic patients while they were breathing cold air. There was a smaller airway response to the second exercise test than to the first, though there was wide variation between subjects. The response to the second methacholine challenge was reduced in some patients but showed no significant change overall. Refractoriness to exercise induced asthma positively correlated with a reduced response to methacholine. These data suggest that mediator depletion does not fully explain refractoriness.Recently Hahn and coworkers showed that refractoriness to exercise induced asthma was not associated with a diminished airway response to histamine.'Since an increase in catecholamine activity with exercise should attenuate the airway response2 to both exercise and histamine, these authors favoured mediator depletion as the cause of refractoriness to exercise induced asthma.Patients with asthma show large variation in their refractoriness in repeated exercise tests.3 We therefore carried out a study to determine whether the response to a methacholine challenge performed 30 minutes after two exercise tests 45 minutes apart was related to the degree of refractoriness to exercise induced asthma. Methacholine was chosen because it stimulates airway smooth muscle directly via muscarinic receptors, whereas histamine induced bronchoconstriction is mediated by both direct and indirect pathways.4 Methods PATIENTSWe studied,12 patients with bronchial asthma, six men and six women with a mean age of 24 years (range
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