No abstract is provided for this article.
The optimal treatment for mild asthma is uncertain. We assessed the effects of adding a long-acting inhaled beta-agonist, formoterol, to low doses of an inhaled corticosteroid, budesonide, for 1 yr in subjects with mild asthma, receiving no or only a small dose of inhaled corticosteroid. The 698 corticosteroid free patients (Group A) were assigned to twice daily treatment with 100 μ g budesonide, 100 μ g budesonide plus 4.5 μ g formoterol, or placebo. The 1,272 corticosteroid-treated patients (Group B) were assigned to twice daily treatment with 100 μ g budesonide, 100 μ g budesonide plus 4.5 μ g formoterol, 200 μ g budesonide, or 200 μ g budesonide plus 4.5 μ g formoterol. The main outcome variables were time to the first severe asthma exacerbation and poorly controlled asthma days. In Group A, budesonide alone reduced the risk for severe exacerbations by 60% and poorly controlled days by 48%; adding formoterol increased lung function with no change in other end points. By contrast, in Group B, adding formoterol reduced the risk for the first severe exacerbation and for poorly controlled days by 43 and 30%, respectively. Thus, in corticosteroid-free patients, low dose inhaled budesonide alone reduced severe exacerbations and improved asthma control, and in patients already receiving inhaled corticosteroid, adding formoterol was more effective than doubling the corticosteroid dose.
Nitrates and beta-blockers have been the mainstay in the therapy of chronic stable angina pectoris for many years. Since an important number of patients remains symptomatic, new potent anti-ischemic agents like the calcium antagonists fulfil a great clinical need. Combined therapy with beta-blockers and calcium antagonists is attractive, since both classes of drugs have differing and eventually complementary modes of action. On the other hand, both have direct negative inotropic and chronotropic effects. We reviewed the anti-anginal, electrophysiologic and hemodynamic effects of combined treatment with a beta-blocker and verapamil or nifedipine. Combined therapy provides greater symptomatic relief than monotherapy with beta-blockers or slow channel blockers alone. While incidental adverse negative inotropic and chronotropic interactions have been reported, particularly when verapamil is involved, their hemodynamic interplay appears beneficial rather than detrimental in the majority of patients. Indeed, combined therapy is effective and safe, at least when a preserved or only moderately impaired left ventricular function is present. However, caution must be exercised in patients with more impaired left ventricular function, and combined therapy with verapamil must be avoided when conduction disturbances are likely to occur.
Asthma is successfully treated in most patients through the use of conventional corticosteroid therapy. The majority (90 to 95%) of patients respond effectively to moderate doses of inhaled corticosteroids with minimal side effects. Nevertheless, there is a small population of asthmatic patients, including present and ex-cigarette smokers, who fail to respond adequately to corticosteroid treatment even at high doses or with the addition of supplementary therapy. These patients account for a disproportionate amount of healthcare costs because they exacerbate more frequently and are more likely to be admitted to hospital due to their asthma. Cigarette smoking is an important factor associated with corticosteroid resistance in asthmatics, and there is scope for the development of novel therapies to target this subgroup of asthmatics. This review summarizes the various hypotheses underlying corticosteroid insensitivity in smoking asthmatics and discusses the development of potential novel therapies based on these concepts.
1. To determine whether circadian variations in adrenergic responsiveness might underlie nocturnal wheezing in asthma, we measured cardiovascular, airway and plasma adenosine 3':5'-cyclic monophosphate (cyclic AMP) responses to stepwise infusions of L-adrenaline (0.01, 0.03 and 0.075 microgram min-1 kg-1) at 4 h intervals over 24 h in five extrinsic asthmatic men. 2. Peak expiratory flow, blood pressure, heart rate and plasma cyclic AMP showed a significant circadian variation with peak values at 16.00 hours and trough values at 04.00 hours. 3. The beta 2-adrenoceptor-mediated increases in peak flow and cyclic AMP were similar at all times, but adrenergic responsiveness (measured by response/log dose of infused adrenaline) was greater at 04.00 hours than at 16.00 hours because of the lower baseline values at night. 4. Blood pressure and heart rate responses to adrenaline infusions did not significantly differ over 24 h. 5. Airway responses to inhaled adrenaline were studied on the second day; the mean peak flow after adrenaline was similar at 16.00 hours to that at 04.00 hours and since the pretreatment values were lower at 04.00 hours, the magnitude of response to inhaled adrenaline was greater at night. 6. We conclude that there is no significant circadian change in adrenergic responses in asthma and that adrenoreceptor dysfunction is not important in the pathogenesis of nocturnal asthma.
