Inhalation Therapy for Stable COPD: 20 Years of GOLD Reports.

The Global Initiative for Chronic Obstructive Lung Disease (GOLD) was formed in the late 1990s to spread awareness of chronic obstructive pulmonary disease (COPD) as a major public health problem and facilitate its prevention and treatment. GOLD has since become internationally recognized for the development of evidence-based strategy documents, most notably the annual GOLD Reports, for COPD diagnosis, management, and prevention. The GOLD Reports incorporate the latest evidence and expert consensus to guide the management and prevention of COPD on a global level. Since the first GOLD Report in 2001, profound innovations have taken place regarding inhaler device options, available pharmaceuticals, knowledge regarding effective dosages and potential side effects, and the various combinations of drugs used to relieve symptoms. Concomitantly, an evolution of expert opinion on how best to apply these innovations to the care of patients with COPD has also taken place, an evolution that is nowhere more detailed or definitive than in the 20 years of annual GOLD Reports. We summarize key features and trends in inhalation therapy for stable COPD in these Reports.

Nitrous or nitric? Same difference. Molecular formulas in the 1840s.

The molecular formulas given by James Y. Simpson for nitrous oxide, diethyl ether, and chloroform are difficult to interpret today. The organic formulas are "incorrect" today because Jean Dumas (the influential chemist who was one of the discoverers of chloroform) used John Dalton's presumption of molecular simplicity. That is, water was long presumed to be HO. The nitrous oxide formula was incorrect owing to confusion with Dalton's nitrous gas, now termed nitric oxide. The Simpson formulas illustrate that inhaled anesthesia arrived at the time of a cusp in the history of chemistry.

Current issues with beta2-adrenoceptor agonists: historical background.

The discovery that dessicated adrenal glands had beneficial effects in asthma arose in 1900 following a vogue for studying organotherapy at the end of the 19th century. The adrenal hormone adrenaline was found to have sympathomimetic properties and was isolated and synthesized in 1901. The first nonselective beta-agonist, isoproterenol, was isolated in 1940, followed by the development of selective beta2-agonists in the 1960s and the introduction of the long-acting beta2-agonists in the 1990s. The introduction of beta2-selectivity reduced adverse effects, as did developments in inhaler technology that allowed subjects to inhale much smaller doses of drug selectively to the airways. The beta2-agonists are some of the more important drugs to have been developed in the 20th century. Excessive doses can cause problems, and attempts to maximize the benefit from beta2-agonists and to reduce adverse effects has led to considerable epidemiological, clinical, and mechanistic research over the last 50 yr.

Asthma: one hundred years of treatment and onward.

There have been four types of drug treatment of asthma that have been used over the past 100 years. Belladonna alkaloids, derived from the thorn-apple plant were used in 1905, and chemically synthesized entities in this class are still in use today. Western medicine began to use adrenergic stimulants approximately 100 years ago, but they were likely used in Asian medicine long before that. Systemic treatment with corticosteroids was introduced into the treatment of asthma in the mid-20th century; inhaled corticosteroids have been in use for over 35 years. The last 40 years have also seen the development of the first targeted asthma treatments: cromones, antileukotrienes, and anti-IgE. As we learn more of the biology of asthma, we anticipate that more effective targeted asthma treatments will be developed.

Short-acting beta-agonist research: a perspective. 1997.

Asthma mortality increased sharply in New Zealand in 1977, prompting a national investigation into circumstances of asthma deaths. Subsequent observations of improved asthma control in subjects withdrawn from regular beta(2)-agonist treatment raised the question of whether asthma severity and, therefore, mortality could relate to frequent beta-agonist use. A randomized controlled trial of regular inhaled fenoterol versus as-needed bronchodilator use showed worsened asthma control during regular treatment despite concomitant use of inhaled corticosteroids. Assessment of these findings led to delay in the publishing of the American Asthma Guidelines, which were modified to suggest caution in using beta(2)-agonist treatments. Simultaneously, case control studies in New Zealand suggested that prescription of fenoterol was a substantial risk factor for asthma mortality. The causal association was hotly debated, but increasing evidence pointed to an adverse effect of fenoterol on asthma severity and, hence, mortality. This was supported by dramatic decreases in both morbidity and mortality when fenoterol was effectively withdrawn from use in New Zealand. The link between worsening asthma morbidity and mortality, and the use of potent short-acting beta(2)-agonists fulfills the Bradford Hill criteria for attributing causality. Application of evidence from randomized, controlled trials of short-acting beta-agonist use has led to a major shift in therapy in asthma to the recommendation of as-needed use only of short-acting beta-agonists and decreased patient reliance on regular bronchodilator therapy.

Inhaled adrenergic bronchodilators: historical development and clinical application.

The adrenergic bronchodilators that have been developed for oral inhalation represent successive refinement in terms of receptor specificity and duration of action. Beta agonist bronchodilators have durations of 4-6 hours, or, in the case of salmeterol, of up to 12 hours, offering convenient dosing. Inhalation of the aerosol formulations targets the lung directly. The release of levalbuterol now provides an agent with a single isomer active on beta-2 receptors. The currently available agents offer clinicians and patients with reversible obstructive lung disease a choice of sophisticated drugs for airway smooth muscle relaxation. Although improvements in the drugs have reduced adverse effects and beta agonists are considered safe, concerns persist about the effect of beta agonists in asthma. An improved understanding of asthma pathophysiology may lead to more appropriate use of beta agonists in asthma.

The evolution of beta-agonists.

Inhaled beta-agonists have become the mainstay of bronchodilator therapy for reactive airway diseases, either alone or in conjunction with other medications. The history of the development of beta-agonists is a fascinating one that spans more than 5000 years. Scientific investigation for the past several hundred years has elucidated the physiology of bronchoconstriction and bronchodilation. In the past decade, a wealth of knowledge has come forth since the discovery of the beta-adrenoceptor which, along with advances in pharmacology, have helped answer the questions of how beta-agonists work. From these advancements, three classes of beta-agonists have been developed: catecholamines, resorcinols, and saligenins. The chemical structures of the more commonly used agents in each class, their interaction with the beta-adrenoceptor, and their beneficial and adverse effects are discussed. Review of the duration of action of these agents may suggest a new way of classifying them into ultrashort-acting, short-acting, intermediate-acting, and long-acting.