One Hundred Years of Treatment and Onward
http://www.100md.com
美国呼吸和危急护理医学 2005年第6期
Pulmonary Division, Department of Medicine, Brigham and Women's Hospital
Physiology Program, Department of Environmental Health, Harvard School of Public Health, Boston, Massachusetts
ABSTRACT
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.
Key Words: adrenergic anticholinergic asthma corticosteroid
Although asthma has been described as a medical entity since the time of Aretaeus, the Cappadocian, in approximately 100 A.D. (see review by Marketos and Ballas [1]), the constellation of physical findings and signs that we currently recognize as asthma dates from the work of John Floyer (2) in 1698. Floyer defined asthma as "laborious respiration with lifting of the shoulders and wheezing." He understood that asthma was intermittent and episodic and that the treatment of asthma needs to consist of rescue and controller therapy, termed by him as treatment "both in fit and out of it."
By 1900, it was well established that certain forms of asthma could be brought on by exposure to environmental allergens. In Stedman's Twentieth Century Practice, published in 1896, Sir Thomas Granger Stewart and George Alexander Gibson (3) wrote about asthma:
The treatment of asthma involves the treatment of the patient during fits and between the fits. The general indications are:
To allay the spasm during the paroxysm;
To find out and remove the exciting cause ...
To treat complications and sequelae and to improve the general health.
Thus, more than 100 years ago, the general approach to asthma treatment was then as it is now: acute rescue treatment, controller treatment, and prevention of long-term complications. This article examines the evolution of the treatment of asthma by environmental manipulation and drug treatments over the past 100 years. Because we want to identify the most commonly used general practices until the late 20th century, we take most of our guidance from generally accepted textbooks of medicine. We also have tried to identify the key contributions that led to the evolution of asthma treatment.
IDENTIFICATION OF ENVIRONMENTAL ALLERGENS
In the 1896 textbook of Stedman, as noted previously, Stewart and Gibson (3) offer advice for the management of the patient with asthma based on removal of the offending allergens from the environment: "This may be the avoidance of certain foods, the avoidance of exposure to dust or pollen or flowers ... or other specific irritants. It may be the correction of a gastric ... disorder ... or it may be the removal of nasal polyps."
Although our methods of identifying allergens to which certain patients are hypersensitive have improved since this summary more than 100 years ago, the general approach to environmental manipulation treatment remains the same. Before the mid-1800s, relevant allergens could be identified only through careful history taking. Just more than 100 years ago, techniques were developed for skin testing to establish the diagnosis of hay fever; these were then applied to the diagnosis of allergen-driven asthma. In the last 30 years, radioallergosorbent testing and other tests designed to identify IgE specific for a given allergen became available (4).
It is still somewhat controversial as to whether allergen elimination leads to an improvement in asthmatic status. There have been recent controlled clinical trials in which selective covering of mattresses with houseeCdust-miteeCproof covers failed to show a benefit in asthma severity or lung function (5, 6). However, in these studies, only a single environmental intervention was used. Another study, in which multiple environmental interventions were used, including covering mattresses, using high-efficiency particle-filtering vacuum cleaners, removing cigarette smoke from the environment, and remediating other household allergens, such as those from cockroaches and rodents, was associated with a small improvement in the number of asthma symptom days experienced by inner-city children (7). However, in this study, objective measures of lung function were not recorded.
In summary, over the last century, we have recognized that asthma may be precipitated by certain environmental exposures and that eliminating these exposures may be of value in asthma treatment. We have become more sophisticated in our methods of identifying potentially deleterious environmental exposures, but, as many clinicians know, eliminating such exposures from the patient's environment is often not easy to do.
ASTHMA PHARMACOTHERAPY
There are four general types of pharmacologic treatment that have been used for asthma over the past 100 years. Interestingly, most of the treatments, once introduced, have remained in the pharmacopeia, although the specific entities and methods of delivery have changed. These four overlapping epochs of the pharmacologic treatment of asthma are as follows: (1) the use of anticholinergic belladonna-related alkaloids; (2) the use of noneCanti-cholinergic bronchodilator stimulation; (3) the use of corticosteroids; and (4) the use of specifically targeted asthma treatments—namely, cromones, antileukotrienes, and anti-IgE. Each of these will be considered separately.
ANTICHOLINERGIC ASTHMA TREATMENT
In Stedman's Twentieth Century Practice of Modern Medical Science, Stewart and Gibson (3) suggest that one of the primary treatments for an asthmatic paroxysm was the use of belladonna alkaloids; often these were delivered by smoking "asthma cigarettes" (Figure 1).
Smoking tobacco benefits a few, but the addition of a little stramonium to tobacco, or the smoking of cigarettes composed largely of stramonium, is of far greater service [in the treatment of an asthmatic paroxysm]. There are many forms of cigarettes sold by the druggists.
Stramonium is the dried leaf and the flowering or fruiting tops of the plant, Datura stramonium. This is also referred to as the thorn-apple plant. The active ingredients in this were alkaloids of belladonna, which we now know had the effect of inhibiting cholinergic neurotransmission and thereby reflex bronchoconstriction.
In 1914, in the eighth edition of the Principles and Practice of Medicine, Osler (8) points out that hypodermic injections of pilocarpine can be effective in the treatment of asthma. He also claims that the sedative antispasmodics, such as belladonna, "may be given in solution or used in the form of cigarettes. Nearly all the popular remedies either in this form or in pastilles contain some plant of the order Solanaceae ... Excellent cigarettes are now manufactured and asthmatics try various sorts since one form benefits one patient, another form another patient."
Thus, in 1914, anticholinergics by injection or inhalation were considered as first-line asthma therapies. Osler also made the important observation of the intraindividual differences in the response to asthma treatment. We now appreciate that these differences may reflect genetic variations in the mechanisms leading to the asthmatic response among subjects.
In the 1927 edition of Cecil's A Text-book of Medicine, Francis Rackemann (9) again suggests the use of the smoke of stramonium leaves, atropine, and belladonna. In the seventh edition of Cecil's A Textbook of Medicine, published in 1947, Rackemann (10) still suggests the use of asthma powders or asthma cigarettes with the active ingredient consisting of belladonna-type alkaloids. However, by 1975, when the 14th edition of the textbook was published, belladonna alkaloids were not considered a significant enough part of asthma treatment to be included by J.B.L. Howell (11).
The treatment of asthma with ipratropium bromide, a stable atropine-like compound, was introduced in the 1980s (12). Although its use in asthma rescue treatment has not been approved by the U.S. Food and Drug Administration, it was used successfully in a recent study sponsored by the National Institutes of Health Asthma Clinical Research Network (13), as an asthma rescue therapy in patients with mild intermittent asthma. This was necessary because the study identified a subset of patients with asthma who had adverse responses to adrenergic bronchodilators, and it was therefore necessary to manage these patients with a nonadrenergic bronchodilator, such as ipratropium bromide.
These data show that the use of belladonna alkaloids has been advocated in the treatment of asthma for more than 100 years. The mechanism of effect is not known with precision but is likely the inhibition of reflex bronchoconstriction mediated via cholinergic pathways.
NONeCANTI-CHOLINERGIC BRONCHODILATORS
Methyl Xanthines
Bronchodilators other than belladonna alkaloids were not mentioned in Stedman's 1896 textbook or in Osler's 1914 edition of the Principles and Practice of Medicine; although in that latter work, coffee is recommended as a treatment for asthma. There is no mention by Rackemann of the use of theophylline, or related compounds, in the fourth edition (published in 1937) of Cecil's Textbook of Medicine (14), but in the fifth edition (1940), this treatment is mentioned (15): "Aminophylline in doses of 0.25 Gm. dissolved in 10 cc. of water is often very effective when injected intravenously." From that time forward into the present, methyl xanthines have been used, most often in the form of theophylline or the water-soluble, related compound aminophylline, for the treatment of asthma. Although the mechanism of action of these agents is not established with certainty, they are bronchodilators by virtue of their ability to inhibit phosphodiesterase and thus to inhibit the breakdown of cyclic AMP. However, they have many other potential mechanisms of action in asthma, and a full review of their use in asthma is beyond the scope of this article; readers are referred to authoritative reviews by others (16).
Theophylline continues to be an inexpensive and effective asthma treatment. However, it has a low ratio of therapeutic benefit to potentially toxic side effects. Dosing needs to be carefully monitored to be sure that a given patient is receiving the benefits of treatment without its side effects. To complicate matters, theophylline metabolism varies substantially both among individuals and in a given subject. Even when an effective dose is established, it is important to continue to monitor plasma drug levels. Given these difficulties, many consider that theophylline is not a first-line asthma therapy.
Direct Adrenergic Bronchodilators
Direct adrenergic bronchodilators were introduced in Western medicine for the treatment of asthmatic attacks in the early 1900s. In an article in the Lancet in 1910, Melland (17) described dramatic responses to adrenaline injection in three patients with asthma who were unresponsive to usual asthma treatment. In 1926, Thomas (18) described the use of ephedrine in asthma, but it is highly likely that this treatment had already been used in China for centuries. When the seventh edition of Cecil's Textbook of Medicine was published, Rackemann (9) wrote,
The treatment of an attack is usually simple. Adrenalin chloride injected subcutaneously can control almost any attack from a time varying from minutes to hours. The dose of 0.25 c.c. of a 1:1000 solution often works as well as 1.0 c.c. The dose can be repeated at half-hour intervals if necessary.
In the 1947 edition, Rackemann (10) amended this statement to suggest that epinephrine could be given by inhalation of a 1:100 solution to relieve asthmatic bronchoconstriction (Figure 2). By the mid-1950s, metered-dose inhalers had been devised for the delivery of epinephrine and isoproterenol, the latter being a relatively specific -adrenergic agonist. These inhalers were widely used for asthma treatment; they are still in use today, even though there are bronchodilators available with fewer side effects.
However, there were significant adverse effects associated with this treatment. There was an epidemic of asthma deaths that occurred in Britain during the mid-20th century. Analysis of epidemiologic data suggested that this epidemic was associated with the widespread use of isoproterenol forte—a high-strength isoproterenol solution packaged in the metered-dose inhaler (19, 20). The epidemic abated when the high potency inhaler was withdrawn from the market and a physician education campaign to be sure that patients with asthma were adequately treated was launched. Because the actions were taken together, it is impossible to know with confidence which was responsible for the improved outcomes.
In the 1960s and 1970s, relatively specific 2-adrenergic agonists were developed for use by inhalation (21). Albuterol (known outside the United States as salbutamol), metaproterenol, isoetherine, terbutaline, and others were introduced into the marketplace. These agents had rapid onset of action, produced bronchodilation lasting 4 to 6 hours, and became the "bronchodilator of choice." Since the mid-1980s, bronchoconstriction that could be relieved by the inhalation of a specific 2 agonist was commonly included as a diagnostic criterion of asthma. Rossing and others (22) showed that inhalation of selective 2 agonists was equally, if not more, effective than injection of subcutaneous epinephrine for the relief of the airway obstruction associated with acute asthma attacks. Eventually this led to the widespread use of inhaled selective 2 bronchodilators as the primary treatment of acute asthmatic airway obstruction.
The adrenergic bronchodilator armamentarium has advanced with the development of selective 2 agonists that were engineered to provide a long duration of bronchodilator activity. Long-acting bronchodilators, such as fenoterol, formoterol, and salmeterol, were introduced into the marketplace worldwide for use in the control of asthma symptoms (23). These agents are effective bronchodilators, but a number of studies have shown that they should not be used as the sole agents for the treatment of asthma, but rather should be used in a coordinated program of asthma medications, which includes agents such as inhaled corticosteroids or leukotriene antagonists (24, 25).
In the past 4 years, there have been data available to suggest that a proportion of patients who regularly use selective 2-adrenergic agonists, such as albuterol, may develop residual bronchoconstriction many hours after the acute bronchodilator effect of the medication has worn off. Findings from retrospective analyses (26, 27) and a double-blind, randomized, placebo-controlled, genotype-stratified crossover trial indicate that patients possessing the Arg-Arg genotype, at position 16 of the 2-adrenergic receptor, are at risk for developing this residual bronchoconstriction (13). Not only is this manifested by lower flow rates but patients with this genotype had increased asthma symptoms and increased asthma medication use during the period of regular treatment with albuterol, compared with placebo in patients harboring the Arg-Arg genotype as well as compared with patients with the GLY-GLY genotype at position 16 of the 2-adrenergic receptor. Although these data need to be replicated in a larger trial powered on asthma exacerbations, it makes sense to consider alternative asthma action plans for patients who appear to develop adverse effects when treated with 2-adrenergic agonists on a regular basis.
CORTICOSTEROIDS
Corticosteroids were not generally available for medicinal use until the late 1940s. In the early 1950s, anecdotal case reports showed that treatment with adrenal corticotropic hormone or corticosteroids resulted in an improvement in asthma. For example, McCombs (28) described five cases of asthma refractory to treatment with standard therapy that had a significant response to systemic treatment with corticosteroids or adrenal corticotropic hormone (Figure 3). He wrote, "There is no doubt that in the five cases herein reported corticotropin and cortisone brought about changes that could not have been produced so regularly by any other known method of treatment." By the 1970s, systemic corticosteroids had been accepted as the standard therapy to both treat and prevent asthma exacerbations. For patients with severe asthma, either the use of daily or every-other-day oral corticosteroids was considered state-of-the-art therapy. The major issues were how to treat asthma in patients with disease of moderate severity without encumbering the severe side effects associated with daily corticosteroid therapy.
The solution to this problem came in the form of inhaled corticosteroids. Brown and colleagues (29) reported that patients who were dependent on oral corticosteroids could be switched to inhaled corticosteroids (Figure 4). Later, a large trial organized by the British Thoracic Society showed that steroid-naive patients with moderate to severe asthma could be controlled with this treatment (30). Although these studies were widely confirmed (31, 32), physicians and patients were slow to adopt their use, perhaps because their effects on the airways were delayed compared with those achieved with bronchodilators. However, over time, it became clear that they were effective asthma treatments and safe relative to the use of systemic corticosteroids.
The study that had the biggest impact on the use of inhaled corticosteroids was that of Haahtela and coworkers (33). In this trial, patients with newly diagnosed asthma were randomly assigned to receive inhaled corticosteroids or an inhaled 2 agonist as their primary asthma treatment for 2 years. Over the period of the trial, there was less bronchial responsiveness among the patients treated with inhaled corticosteroids than there was among the patients treated with terbutaline. In a follow-up study, patients who had been assigned to terbutaline were assigned to corticosteroids and experienced a smaller degree of improvement than those who had started on corticosteroids, suggesting that treatment early on was more effective than treatment later into the course of asthma (34).
However, this study was not designed to directly test the critical question: Would the regular use of inhaled corticosteroids modify the long-term effects of asthma There have been two large long-term studies that have been designed to do so. In the Childhood Asthma Management Program (CAMP) study, children, aged 7 to 12 years at onset, were assigned to treatment with inhaled corticosteroids, nedocromil, or placebo on a daily basis (35). There were no differences over the 5 years of study with respect to the rate of loss of lung function between the groups, whereas there were differences, in favor of inhaled budesonide, in the time to first asthma exacerbation. These data indicated that corticosteroids were effective at preventing asthma paroxysms but did not modify the underlying loss of lung function associated with chronic asthma. In a double-blind, randomized, placebo-controlled trial, adults and children with newly diagnosed asthma were assigned to treatment with inhaled budesonide or placebo (36). As in the CAMP trial, there were fewer asthma exacerbations in the group assigned to budesonide. There was an overall 0.88% improvement, in lung function expressed as a percentage of predicted value, over time in favor of budesonide, but the effects were not consistent over age groups, raising questions as to the robustness of the findings.
Inhaled corticosteroids have side effects. When used on a regular basis for long periods of time, there are documented adverse effects, such as loss of stature (35, 36), decreased bone mineralization, glaucoma, and cataracts (37eC39). Inhaled corticosteroids have been recommended and used in the treatment of asthma for just over 30 years; they are very effective as "asthma-controller" therapies, but there are no convincing data that they are disease-modifying treatments.
SPECIFICALLY TARGETED ASTHMA TREATMENTS
After 1960, substantial research efforts were put into understanding the pathobiology of asthma. Three specifically targeted asthma treatments have emerged from this research effort. The first was disodium cromoglycate; the story of its discovery is of interest in light of the current environment for clinical research. The drug's discoverer was a physician named Roger Altounyan (1922eC1987), who had a very clear asthmatic response to inhaled guinea pig dander. Altounyan was convinced of the antiasthmatic properties of certain folk remedies. As a researcher and employee of a small drug company, he worked with chemists to extract potentially active ingredients from natural products and tested these by administering them to himself before exposing himself by inhalation to extracts of guinea pig dander. Using this process as his "discovery model," he identified disodium cromoglycate, which was eventually marketed as an antiasthmatic drug. Both it and another drug in the same family, nedocromil sodium, are available as asthma treatments (40, 41) but are used most frequently in children.
Although these agents were discovered by searching for drugs with antiasthmatic effects, and in that sense are targeted treatments, their exact mechanism of "antiallergic" action is not known with certainty. In contrast, antileukotriene and anti-IgE treatments for asthma were developed to target specific known pathobiologies of asthma. The antileukotrienes were developed to block the potent biological bronchoconstrictor, previously known as slow-reacting substance of anaphylaxis, or SRS-A, and now appreciated to be a mixture of the acidic lipids, leukotrienes, C4, D4, and E4 (42). The role of these substances in asthma seemed reasonable because they are released by mast cells during anaphylactic reactions and because of their potent bronchoconstrictor properties. Inhibitors of the synthesis of leukotrienes—namely, zileuton—or of action of the leukotrienes at the Cys LT1 receptor—namely, pranlukast, zafirlukast, and montelukast—ameliorated laboratory-induced asthma; clinical trials were then performed demonstrating the effectiveness of this treatment compared with placebo. In these trials, antileukotrienes resulted in fewer asthma exacerbations and better lung function in patients with mild to moderate asthma than in patients treated with placebo. It is important to note, however, that, in a number of "head-to-head" comparisons, antileukotrienes, which have only been available for prescription for less than a decade, have not been as effective as inhaled corticosteroids for asthma control. However, the benefits of oral dosing and the lack of any theoretic or known long-term toxicity make them part of the current asthma pharmacopeia.
The third targeted asthma treatment is anti-IgE treatment (43). The work of multiple groups demonstrated that much of the acute asthmatic response could be attributed to activation of mast cells through cross-linking of IgE. A humanized monoclonal antibody was developed that reduced the amount of circulating free IgE, and subsequently the magnitude of clinical response elicited when patients with known specific allergies were exposed to these allergens.
In the clinical trials that have led to the availability of this form of treatment, anti-IgE was shown to result in a reduction of the amount of corticosteroids required to control asthma in patients with disease severe enough to require chronic systemic steroid treatment (44). They are currently approved for use in patients with moderate to severe asthma, and their overall place in the management of asthma is still being worked out.
CHANGING THE TREATMENT PARADIGMS
Among our current asthma treatments, bronchodilators derive their effect from diminished smooth muscle constriction. It has been assumed that corticosteroids are effective in preventing asthmatic exacerbations by diminishing the inflammatory component of asthma, but the precise nature of this inflammatory component and how the corticosteroids affect this response is not yet known. As we move into the future, it would be worthwhile to consider the role of inflammation and bronchoconstriction in asthmatic events. This is especially important in light of the so-called Dutch hypothesis, which suggests that patients with recurrent airway constriction are those who may go on to develop chronic airway obstruction.
THE FUTURE
The benefits of corticosteroids in asthma have been extensively studied; however, as noted previously, the results from the CAMP study highlight the inability of corticosteroids to affect long-term airway function in asthma. Studies demonstrating the remarkable benefit of adding long-acting agonists to inhaled corticosteroids suggest that bronchoconstriction itself may contribute to airway remodeling in asthma (45, 46). The effects of bronchoconstriction on the airway indicate that the mechanical forces impinging on airway epithelial cells are not insignificant; they are likely up to 10-fold greater than seen during normal breathing. Such forces have been shown to activate the epidermal growth factor receptor (47), a key receptor in pulmonary biology, which is upregulated in the epithelium of asthmatic airways (48) and mediates cell proliferation, migration, and differentiation.
In in vitro models of bronchoconstriction, mechanical stimulation of human airway epithelial cells elicits activation of important profibrotic mediators, such as endothelin and transforming growth factor (49), and can stimulate cocultured fibroblasts to take on a "remodeling" phenotype producing collagen. Thus, recurrent mechanical stress from bronchoconstriction may contribute to the pathogenesis of airway remodeling. Such a mechanism could explain the basis for the Dutch hypothesis and is consistent with the findings that corticosteroids do not alter the chronic progression of asthma.
Dissecting the specific pathways that lead to injury in asthma will be the key to a better understanding and control of the acute and chronic manifestations of asthma. New technologies, such as gene expression profiling with DNA microarrays, hold the promise to elucidation of these pathways (50). By examining the gene expression of the entire genome under different conditions, we can now investigate multiple signaling pathways in an unbiased manner. Such studies have identified novel components to asthma pathogenesis (51), such as the arginase system. The application of microarray technology to models of bronchoconstriction has identified a wide panel of mechanoresponsive genes that may contribute to alteration of the airway (52). These include a group of plasminogen activator/plasmin system genes that have well-recognized roles in extracellular matrix remodeling (53). Remarkably, plasminogen activator inhibitor-1 was also identified as an upregulated gene in a number of asthmatic models (54eC56). It is at the intersection of these various studies, comparing overlapping and complementary genes, that future key mediators of the asthma phenotype will likely be identified.
The ultimate goal of understanding these multiple mechanistic pathways in asthma is to develop better and more effective targeted therapies. Because asthma is a syndrome, rather than a biochemical or immunologic disease, with multiple environmental and genetic determinants, it will likely require multiple types of therapy. Interrupting molecular pathways in asthma pathogenesis using new approaches, such as drugs specifically targeting the epidermal growth factor receptor, arginase or plasminogen activator systems, or yet unidentified disease pathogenesis pathways, may lead to better disease control, and perhaps the reduction and elimination of the need for corticosteroids. As archaic as "asthma cigarettes" appear to us today, the next 100 years should bring specific asthma therapies that will make the state-of-the-art treatments we use today seem like obsolete, blunt tools from the remote past.
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Physiology Program, Department of Environmental Health, Harvard School of Public Health, Boston, Massachusetts
ABSTRACT
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.
Key Words: adrenergic anticholinergic asthma corticosteroid
Although asthma has been described as a medical entity since the time of Aretaeus, the Cappadocian, in approximately 100 A.D. (see review by Marketos and Ballas [1]), the constellation of physical findings and signs that we currently recognize as asthma dates from the work of John Floyer (2) in 1698. Floyer defined asthma as "laborious respiration with lifting of the shoulders and wheezing." He understood that asthma was intermittent and episodic and that the treatment of asthma needs to consist of rescue and controller therapy, termed by him as treatment "both in fit and out of it."
By 1900, it was well established that certain forms of asthma could be brought on by exposure to environmental allergens. In Stedman's Twentieth Century Practice, published in 1896, Sir Thomas Granger Stewart and George Alexander Gibson (3) wrote about asthma:
The treatment of asthma involves the treatment of the patient during fits and between the fits. The general indications are:
To allay the spasm during the paroxysm;
To find out and remove the exciting cause ...
To treat complications and sequelae and to improve the general health.
Thus, more than 100 years ago, the general approach to asthma treatment was then as it is now: acute rescue treatment, controller treatment, and prevention of long-term complications. This article examines the evolution of the treatment of asthma by environmental manipulation and drug treatments over the past 100 years. Because we want to identify the most commonly used general practices until the late 20th century, we take most of our guidance from generally accepted textbooks of medicine. We also have tried to identify the key contributions that led to the evolution of asthma treatment.
IDENTIFICATION OF ENVIRONMENTAL ALLERGENS
In the 1896 textbook of Stedman, as noted previously, Stewart and Gibson (3) offer advice for the management of the patient with asthma based on removal of the offending allergens from the environment: "This may be the avoidance of certain foods, the avoidance of exposure to dust or pollen or flowers ... or other specific irritants. It may be the correction of a gastric ... disorder ... or it may be the removal of nasal polyps."
Although our methods of identifying allergens to which certain patients are hypersensitive have improved since this summary more than 100 years ago, the general approach to environmental manipulation treatment remains the same. Before the mid-1800s, relevant allergens could be identified only through careful history taking. Just more than 100 years ago, techniques were developed for skin testing to establish the diagnosis of hay fever; these were then applied to the diagnosis of allergen-driven asthma. In the last 30 years, radioallergosorbent testing and other tests designed to identify IgE specific for a given allergen became available (4).
It is still somewhat controversial as to whether allergen elimination leads to an improvement in asthmatic status. There have been recent controlled clinical trials in which selective covering of mattresses with houseeCdust-miteeCproof covers failed to show a benefit in asthma severity or lung function (5, 6). However, in these studies, only a single environmental intervention was used. Another study, in which multiple environmental interventions were used, including covering mattresses, using high-efficiency particle-filtering vacuum cleaners, removing cigarette smoke from the environment, and remediating other household allergens, such as those from cockroaches and rodents, was associated with a small improvement in the number of asthma symptom days experienced by inner-city children (7). However, in this study, objective measures of lung function were not recorded.
In summary, over the last century, we have recognized that asthma may be precipitated by certain environmental exposures and that eliminating these exposures may be of value in asthma treatment. We have become more sophisticated in our methods of identifying potentially deleterious environmental exposures, but, as many clinicians know, eliminating such exposures from the patient's environment is often not easy to do.
ASTHMA PHARMACOTHERAPY
There are four general types of pharmacologic treatment that have been used for asthma over the past 100 years. Interestingly, most of the treatments, once introduced, have remained in the pharmacopeia, although the specific entities and methods of delivery have changed. These four overlapping epochs of the pharmacologic treatment of asthma are as follows: (1) the use of anticholinergic belladonna-related alkaloids; (2) the use of noneCanti-cholinergic bronchodilator stimulation; (3) the use of corticosteroids; and (4) the use of specifically targeted asthma treatments—namely, cromones, antileukotrienes, and anti-IgE. Each of these will be considered separately.
ANTICHOLINERGIC ASTHMA TREATMENT
In Stedman's Twentieth Century Practice of Modern Medical Science, Stewart and Gibson (3) suggest that one of the primary treatments for an asthmatic paroxysm was the use of belladonna alkaloids; often these were delivered by smoking "asthma cigarettes" (Figure 1).
Smoking tobacco benefits a few, but the addition of a little stramonium to tobacco, or the smoking of cigarettes composed largely of stramonium, is of far greater service [in the treatment of an asthmatic paroxysm]. There are many forms of cigarettes sold by the druggists.
Stramonium is the dried leaf and the flowering or fruiting tops of the plant, Datura stramonium. This is also referred to as the thorn-apple plant. The active ingredients in this were alkaloids of belladonna, which we now know had the effect of inhibiting cholinergic neurotransmission and thereby reflex bronchoconstriction.
In 1914, in the eighth edition of the Principles and Practice of Medicine, Osler (8) points out that hypodermic injections of pilocarpine can be effective in the treatment of asthma. He also claims that the sedative antispasmodics, such as belladonna, "may be given in solution or used in the form of cigarettes. Nearly all the popular remedies either in this form or in pastilles contain some plant of the order Solanaceae ... Excellent cigarettes are now manufactured and asthmatics try various sorts since one form benefits one patient, another form another patient."
Thus, in 1914, anticholinergics by injection or inhalation were considered as first-line asthma therapies. Osler also made the important observation of the intraindividual differences in the response to asthma treatment. We now appreciate that these differences may reflect genetic variations in the mechanisms leading to the asthmatic response among subjects.
In the 1927 edition of Cecil's A Text-book of Medicine, Francis Rackemann (9) again suggests the use of the smoke of stramonium leaves, atropine, and belladonna. In the seventh edition of Cecil's A Textbook of Medicine, published in 1947, Rackemann (10) still suggests the use of asthma powders or asthma cigarettes with the active ingredient consisting of belladonna-type alkaloids. However, by 1975, when the 14th edition of the textbook was published, belladonna alkaloids were not considered a significant enough part of asthma treatment to be included by J.B.L. Howell (11).
The treatment of asthma with ipratropium bromide, a stable atropine-like compound, was introduced in the 1980s (12). Although its use in asthma rescue treatment has not been approved by the U.S. Food and Drug Administration, it was used successfully in a recent study sponsored by the National Institutes of Health Asthma Clinical Research Network (13), as an asthma rescue therapy in patients with mild intermittent asthma. This was necessary because the study identified a subset of patients with asthma who had adverse responses to adrenergic bronchodilators, and it was therefore necessary to manage these patients with a nonadrenergic bronchodilator, such as ipratropium bromide.
These data show that the use of belladonna alkaloids has been advocated in the treatment of asthma for more than 100 years. The mechanism of effect is not known with precision but is likely the inhibition of reflex bronchoconstriction mediated via cholinergic pathways.
NONeCANTI-CHOLINERGIC BRONCHODILATORS
Methyl Xanthines
Bronchodilators other than belladonna alkaloids were not mentioned in Stedman's 1896 textbook or in Osler's 1914 edition of the Principles and Practice of Medicine; although in that latter work, coffee is recommended as a treatment for asthma. There is no mention by Rackemann of the use of theophylline, or related compounds, in the fourth edition (published in 1937) of Cecil's Textbook of Medicine (14), but in the fifth edition (1940), this treatment is mentioned (15): "Aminophylline in doses of 0.25 Gm. dissolved in 10 cc. of water is often very effective when injected intravenously." From that time forward into the present, methyl xanthines have been used, most often in the form of theophylline or the water-soluble, related compound aminophylline, for the treatment of asthma. Although the mechanism of action of these agents is not established with certainty, they are bronchodilators by virtue of their ability to inhibit phosphodiesterase and thus to inhibit the breakdown of cyclic AMP. However, they have many other potential mechanisms of action in asthma, and a full review of their use in asthma is beyond the scope of this article; readers are referred to authoritative reviews by others (16).
Theophylline continues to be an inexpensive and effective asthma treatment. However, it has a low ratio of therapeutic benefit to potentially toxic side effects. Dosing needs to be carefully monitored to be sure that a given patient is receiving the benefits of treatment without its side effects. To complicate matters, theophylline metabolism varies substantially both among individuals and in a given subject. Even when an effective dose is established, it is important to continue to monitor plasma drug levels. Given these difficulties, many consider that theophylline is not a first-line asthma therapy.
Direct Adrenergic Bronchodilators
Direct adrenergic bronchodilators were introduced in Western medicine for the treatment of asthmatic attacks in the early 1900s. In an article in the Lancet in 1910, Melland (17) described dramatic responses to adrenaline injection in three patients with asthma who were unresponsive to usual asthma treatment. In 1926, Thomas (18) described the use of ephedrine in asthma, but it is highly likely that this treatment had already been used in China for centuries. When the seventh edition of Cecil's Textbook of Medicine was published, Rackemann (9) wrote,
The treatment of an attack is usually simple. Adrenalin chloride injected subcutaneously can control almost any attack from a time varying from minutes to hours. The dose of 0.25 c.c. of a 1:1000 solution often works as well as 1.0 c.c. The dose can be repeated at half-hour intervals if necessary.
In the 1947 edition, Rackemann (10) amended this statement to suggest that epinephrine could be given by inhalation of a 1:100 solution to relieve asthmatic bronchoconstriction (Figure 2). By the mid-1950s, metered-dose inhalers had been devised for the delivery of epinephrine and isoproterenol, the latter being a relatively specific -adrenergic agonist. These inhalers were widely used for asthma treatment; they are still in use today, even though there are bronchodilators available with fewer side effects.
However, there were significant adverse effects associated with this treatment. There was an epidemic of asthma deaths that occurred in Britain during the mid-20th century. Analysis of epidemiologic data suggested that this epidemic was associated with the widespread use of isoproterenol forte—a high-strength isoproterenol solution packaged in the metered-dose inhaler (19, 20). The epidemic abated when the high potency inhaler was withdrawn from the market and a physician education campaign to be sure that patients with asthma were adequately treated was launched. Because the actions were taken together, it is impossible to know with confidence which was responsible for the improved outcomes.
In the 1960s and 1970s, relatively specific 2-adrenergic agonists were developed for use by inhalation (21). Albuterol (known outside the United States as salbutamol), metaproterenol, isoetherine, terbutaline, and others were introduced into the marketplace. These agents had rapid onset of action, produced bronchodilation lasting 4 to 6 hours, and became the "bronchodilator of choice." Since the mid-1980s, bronchoconstriction that could be relieved by the inhalation of a specific 2 agonist was commonly included as a diagnostic criterion of asthma. Rossing and others (22) showed that inhalation of selective 2 agonists was equally, if not more, effective than injection of subcutaneous epinephrine for the relief of the airway obstruction associated with acute asthma attacks. Eventually this led to the widespread use of inhaled selective 2 bronchodilators as the primary treatment of acute asthmatic airway obstruction.
The adrenergic bronchodilator armamentarium has advanced with the development of selective 2 agonists that were engineered to provide a long duration of bronchodilator activity. Long-acting bronchodilators, such as fenoterol, formoterol, and salmeterol, were introduced into the marketplace worldwide for use in the control of asthma symptoms (23). These agents are effective bronchodilators, but a number of studies have shown that they should not be used as the sole agents for the treatment of asthma, but rather should be used in a coordinated program of asthma medications, which includes agents such as inhaled corticosteroids or leukotriene antagonists (24, 25).
In the past 4 years, there have been data available to suggest that a proportion of patients who regularly use selective 2-adrenergic agonists, such as albuterol, may develop residual bronchoconstriction many hours after the acute bronchodilator effect of the medication has worn off. Findings from retrospective analyses (26, 27) and a double-blind, randomized, placebo-controlled, genotype-stratified crossover trial indicate that patients possessing the Arg-Arg genotype, at position 16 of the 2-adrenergic receptor, are at risk for developing this residual bronchoconstriction (13). Not only is this manifested by lower flow rates but patients with this genotype had increased asthma symptoms and increased asthma medication use during the period of regular treatment with albuterol, compared with placebo in patients harboring the Arg-Arg genotype as well as compared with patients with the GLY-GLY genotype at position 16 of the 2-adrenergic receptor. Although these data need to be replicated in a larger trial powered on asthma exacerbations, it makes sense to consider alternative asthma action plans for patients who appear to develop adverse effects when treated with 2-adrenergic agonists on a regular basis.
CORTICOSTEROIDS
Corticosteroids were not generally available for medicinal use until the late 1940s. In the early 1950s, anecdotal case reports showed that treatment with adrenal corticotropic hormone or corticosteroids resulted in an improvement in asthma. For example, McCombs (28) described five cases of asthma refractory to treatment with standard therapy that had a significant response to systemic treatment with corticosteroids or adrenal corticotropic hormone (Figure 3). He wrote, "There is no doubt that in the five cases herein reported corticotropin and cortisone brought about changes that could not have been produced so regularly by any other known method of treatment." By the 1970s, systemic corticosteroids had been accepted as the standard therapy to both treat and prevent asthma exacerbations. For patients with severe asthma, either the use of daily or every-other-day oral corticosteroids was considered state-of-the-art therapy. The major issues were how to treat asthma in patients with disease of moderate severity without encumbering the severe side effects associated with daily corticosteroid therapy.
The solution to this problem came in the form of inhaled corticosteroids. Brown and colleagues (29) reported that patients who were dependent on oral corticosteroids could be switched to inhaled corticosteroids (Figure 4). Later, a large trial organized by the British Thoracic Society showed that steroid-naive patients with moderate to severe asthma could be controlled with this treatment (30). Although these studies were widely confirmed (31, 32), physicians and patients were slow to adopt their use, perhaps because their effects on the airways were delayed compared with those achieved with bronchodilators. However, over time, it became clear that they were effective asthma treatments and safe relative to the use of systemic corticosteroids.
The study that had the biggest impact on the use of inhaled corticosteroids was that of Haahtela and coworkers (33). In this trial, patients with newly diagnosed asthma were randomly assigned to receive inhaled corticosteroids or an inhaled 2 agonist as their primary asthma treatment for 2 years. Over the period of the trial, there was less bronchial responsiveness among the patients treated with inhaled corticosteroids than there was among the patients treated with terbutaline. In a follow-up study, patients who had been assigned to terbutaline were assigned to corticosteroids and experienced a smaller degree of improvement than those who had started on corticosteroids, suggesting that treatment early on was more effective than treatment later into the course of asthma (34).
However, this study was not designed to directly test the critical question: Would the regular use of inhaled corticosteroids modify the long-term effects of asthma There have been two large long-term studies that have been designed to do so. In the Childhood Asthma Management Program (CAMP) study, children, aged 7 to 12 years at onset, were assigned to treatment with inhaled corticosteroids, nedocromil, or placebo on a daily basis (35). There were no differences over the 5 years of study with respect to the rate of loss of lung function between the groups, whereas there were differences, in favor of inhaled budesonide, in the time to first asthma exacerbation. These data indicated that corticosteroids were effective at preventing asthma paroxysms but did not modify the underlying loss of lung function associated with chronic asthma. In a double-blind, randomized, placebo-controlled trial, adults and children with newly diagnosed asthma were assigned to treatment with inhaled budesonide or placebo (36). As in the CAMP trial, there were fewer asthma exacerbations in the group assigned to budesonide. There was an overall 0.88% improvement, in lung function expressed as a percentage of predicted value, over time in favor of budesonide, but the effects were not consistent over age groups, raising questions as to the robustness of the findings.
Inhaled corticosteroids have side effects. When used on a regular basis for long periods of time, there are documented adverse effects, such as loss of stature (35, 36), decreased bone mineralization, glaucoma, and cataracts (37eC39). Inhaled corticosteroids have been recommended and used in the treatment of asthma for just over 30 years; they are very effective as "asthma-controller" therapies, but there are no convincing data that they are disease-modifying treatments.
SPECIFICALLY TARGETED ASTHMA TREATMENTS
After 1960, substantial research efforts were put into understanding the pathobiology of asthma. Three specifically targeted asthma treatments have emerged from this research effort. The first was disodium cromoglycate; the story of its discovery is of interest in light of the current environment for clinical research. The drug's discoverer was a physician named Roger Altounyan (1922eC1987), who had a very clear asthmatic response to inhaled guinea pig dander. Altounyan was convinced of the antiasthmatic properties of certain folk remedies. As a researcher and employee of a small drug company, he worked with chemists to extract potentially active ingredients from natural products and tested these by administering them to himself before exposing himself by inhalation to extracts of guinea pig dander. Using this process as his "discovery model," he identified disodium cromoglycate, which was eventually marketed as an antiasthmatic drug. Both it and another drug in the same family, nedocromil sodium, are available as asthma treatments (40, 41) but are used most frequently in children.
Although these agents were discovered by searching for drugs with antiasthmatic effects, and in that sense are targeted treatments, their exact mechanism of "antiallergic" action is not known with certainty. In contrast, antileukotriene and anti-IgE treatments for asthma were developed to target specific known pathobiologies of asthma. The antileukotrienes were developed to block the potent biological bronchoconstrictor, previously known as slow-reacting substance of anaphylaxis, or SRS-A, and now appreciated to be a mixture of the acidic lipids, leukotrienes, C4, D4, and E4 (42). The role of these substances in asthma seemed reasonable because they are released by mast cells during anaphylactic reactions and because of their potent bronchoconstrictor properties. Inhibitors of the synthesis of leukotrienes—namely, zileuton—or of action of the leukotrienes at the Cys LT1 receptor—namely, pranlukast, zafirlukast, and montelukast—ameliorated laboratory-induced asthma; clinical trials were then performed demonstrating the effectiveness of this treatment compared with placebo. In these trials, antileukotrienes resulted in fewer asthma exacerbations and better lung function in patients with mild to moderate asthma than in patients treated with placebo. It is important to note, however, that, in a number of "head-to-head" comparisons, antileukotrienes, which have only been available for prescription for less than a decade, have not been as effective as inhaled corticosteroids for asthma control. However, the benefits of oral dosing and the lack of any theoretic or known long-term toxicity make them part of the current asthma pharmacopeia.
The third targeted asthma treatment is anti-IgE treatment (43). The work of multiple groups demonstrated that much of the acute asthmatic response could be attributed to activation of mast cells through cross-linking of IgE. A humanized monoclonal antibody was developed that reduced the amount of circulating free IgE, and subsequently the magnitude of clinical response elicited when patients with known specific allergies were exposed to these allergens.
In the clinical trials that have led to the availability of this form of treatment, anti-IgE was shown to result in a reduction of the amount of corticosteroids required to control asthma in patients with disease severe enough to require chronic systemic steroid treatment (44). They are currently approved for use in patients with moderate to severe asthma, and their overall place in the management of asthma is still being worked out.
CHANGING THE TREATMENT PARADIGMS
Among our current asthma treatments, bronchodilators derive their effect from diminished smooth muscle constriction. It has been assumed that corticosteroids are effective in preventing asthmatic exacerbations by diminishing the inflammatory component of asthma, but the precise nature of this inflammatory component and how the corticosteroids affect this response is not yet known. As we move into the future, it would be worthwhile to consider the role of inflammation and bronchoconstriction in asthmatic events. This is especially important in light of the so-called Dutch hypothesis, which suggests that patients with recurrent airway constriction are those who may go on to develop chronic airway obstruction.
THE FUTURE
The benefits of corticosteroids in asthma have been extensively studied; however, as noted previously, the results from the CAMP study highlight the inability of corticosteroids to affect long-term airway function in asthma. Studies demonstrating the remarkable benefit of adding long-acting agonists to inhaled corticosteroids suggest that bronchoconstriction itself may contribute to airway remodeling in asthma (45, 46). The effects of bronchoconstriction on the airway indicate that the mechanical forces impinging on airway epithelial cells are not insignificant; they are likely up to 10-fold greater than seen during normal breathing. Such forces have been shown to activate the epidermal growth factor receptor (47), a key receptor in pulmonary biology, which is upregulated in the epithelium of asthmatic airways (48) and mediates cell proliferation, migration, and differentiation.
In in vitro models of bronchoconstriction, mechanical stimulation of human airway epithelial cells elicits activation of important profibrotic mediators, such as endothelin and transforming growth factor (49), and can stimulate cocultured fibroblasts to take on a "remodeling" phenotype producing collagen. Thus, recurrent mechanical stress from bronchoconstriction may contribute to the pathogenesis of airway remodeling. Such a mechanism could explain the basis for the Dutch hypothesis and is consistent with the findings that corticosteroids do not alter the chronic progression of asthma.
Dissecting the specific pathways that lead to injury in asthma will be the key to a better understanding and control of the acute and chronic manifestations of asthma. New technologies, such as gene expression profiling with DNA microarrays, hold the promise to elucidation of these pathways (50). By examining the gene expression of the entire genome under different conditions, we can now investigate multiple signaling pathways in an unbiased manner. Such studies have identified novel components to asthma pathogenesis (51), such as the arginase system. The application of microarray technology to models of bronchoconstriction has identified a wide panel of mechanoresponsive genes that may contribute to alteration of the airway (52). These include a group of plasminogen activator/plasmin system genes that have well-recognized roles in extracellular matrix remodeling (53). Remarkably, plasminogen activator inhibitor-1 was also identified as an upregulated gene in a number of asthmatic models (54eC56). It is at the intersection of these various studies, comparing overlapping and complementary genes, that future key mediators of the asthma phenotype will likely be identified.
The ultimate goal of understanding these multiple mechanistic pathways in asthma is to develop better and more effective targeted therapies. Because asthma is a syndrome, rather than a biochemical or immunologic disease, with multiple environmental and genetic determinants, it will likely require multiple types of therapy. Interrupting molecular pathways in asthma pathogenesis using new approaches, such as drugs specifically targeting the epidermal growth factor receptor, arginase or plasminogen activator systems, or yet unidentified disease pathogenesis pathways, may lead to better disease control, and perhaps the reduction and elimination of the need for corticosteroids. As archaic as "asthma cigarettes" appear to us today, the next 100 years should bring specific asthma therapies that will make the state-of-the-art treatments we use today seem like obsolete, blunt tools from the remote past.
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