Here are the other article abstracts in this special issue of JACI. Not sure how much actual new research there is here, but this set of researchers seems pretty convinced about Xopenex.
Peter
Clinical experience with levalbuterol
Harold S. Nelson, MD [MEDLINE LOOKUP]
Denver, Colo
Abstract TOP
Although racemic albuterol is an effective bronchodilator, regular use has been associated with some loss of bronchodilator potency, decreased protection against bronchoprovocation, increased sensitivity to allergen challenge, and increased sensitivity to some bronchoconstrictor stimuli. In experimental animals racemic albuterol has produced bronchial hyperresponsiveness, which could also be induced by administration of (S)-albuterol. These findings suggest that the pure or homochiral formulation of (R)-albuterol (levalbuterol) might be more effective as a bronchodilator than the racemic form. Single doses of levalbuterol provided more prolonged protection against methacholine challenge than the racemate, whereas (S)-albuterol significantly increased sensitivity to methacholine. In a 4-week study in adults, equivalent amounts of pure levalbuterol provided greater bronchodilation than did similar amounts of levalbuterol given as racemic mixtures. Furthermore, after 4 weeks, the baseline morning FEV1 was lower in those receiving the racemate than in those receiving placebo or levalbuterol. In a single-dose study in children, the same conclusion regarding greater bronchodilation with pure levalbuterol compared with the same amount of levalbuterol in a racemic mixture was confirmed. These studies appear to confirm the greater efficacy of pure levalbuterol over a similar amount in a racemic mixture. This implies a deleterious effect of (S)-albuterol on both the acute bronchodilator response and baseline airway caliber, the exact mechanism of which will require further investigation. (J Allergy Clin Immunol 1999;104:S77-84.)
Prospects for improved therapy in chronic obstructive pulmonary disease by the use of levalbuterol
John Costello, MD, FRCP [MEDLINE LOOKUP]
London, UK
Abstract TOP
Like asthma, chronic obstructive pulmonary disease (COPD) is a chronic disease, the most prominent symptom of which is airway obstruction. Airway inflammation may be pathogenomic in both diseases, but only in COPD does inflammation predominate as a determinant of symptoms to make obstruction largely refractory to treatment. Despite a more limited degree of reversibility than in asthma, 2-agonists are used extensively to reduce airway obstruction and to achieve symptomatic improvement, with racemic albuterol being widely favored. In asthma, bronchodilation and bronchoprotection largely account for symptomatic benefit. In COPD, the capacity of racemic albuterol to ameliorate these symptoms is more limited and suppression of edema and of infiltration and activation of leukocytes acquire greater significance. During regular use of racemic albuterol in asthma, bronchoprotection diminishes progressively as hyperresponsiveness becomes increasingly pronounced, a process that is associated with an infiltration and activation of eosinophils. These paradoxic effects of racemic albuterol may be attributed to pharmacologic actions of the distomer, (S)-albuterol. As would be expected, homochiral (R)-albuterol (levalbuterol) is more potent and effective in asthma and may have significant advantages if used in COPD. A substantial (4–8-fold) reduction in the dose of levalbuterol anticipates lesser side effects and diminished risk in patients with cardiovascular disease. Additionally, the increased potency and duration of bronchodilation observed in asthma may extend to COPD. Finally, removal of the proinflammatory actions of (S)-albuterol may eliminate the persisting obstruction and decrease elastance that are associated with enhanced inflammation and may allow levalbuterol to suppress edema and diminish leukocyte activation more effectively. (J Allergy Clin Immunol 1999;104:S61-8.)
August 1999, part 2 • Volume 104 • Number 2
The asthma-like pharmacology and toxicology of (S)-isomers of agonists
Dean Handley, PhD [MEDLINE LOOKUP]
Marlborough, Mass
Abstract TOP
2 agonists were designed to emulate the bronchodilation and mast cell suppression effects of human adrenaline, an endogenous neuromediator. Endogenous adrenaline is produced exclusively as the single enantiomer or isomer, (R)-adrenaline, although all selective 2 agonists are marketed as racemic drugs, composed of a precise 50:50 mixture of R and S isomers. Isomers are compounds that are nonsuperimposable mirror images. The R isomers of agonists, essentially all congeners of (R)-adrenaline, exhibit the observed bronchodilation and clinical benefit of the racemate. The S isomers of the racemic agonists are devoid of clinical benefit, are assumed to be benign, and have not been studied until recently. In contradistinction to their assumed benign status, extensive studies with (S)-albuterol have shown that it opposes the bronchodilation effects of (R)-albuterol (levalbuterol), may be proinflammatory, and exhibits the potential to exacerbate airway reactivity to a variety of spasmogens by enhancing contractile responses. Clinically, (S)-albuterol can increase airway reactivity and, because of its slow metabolism, exists in higher and prolonged plasma concentrations than levalbuterol. The sustained presence of (S)-albuterol may help to explain why racemic agonists have not demonstrated a significant clinical anti-inflammatory potential. Furthermore, the adverse effects (S)-albuterol may contribute to paradoxic bronchospasm and the occurrence of severe reagenic-like reactions seen with racemic albuterol. These adverse effects of (S)-albuterol are completely avoided with single isomer version of (R)-albuterol (levalbuterol). The removal of (S)-albuterol increased the clinical potency of levalbuterol, such that bronchodilator efficacy is achieved at one-fourth the dose of racemic albuterol, but with marked reduction in side effects. Levalbuterol, a third generation agonist, retains the clinical benefit of racemic albuterol without the proinflammatory and potentially detrimental effects of (S)-albuterol. (J Allergy Cli
Contrasting properties of albuterol stereoisomers
Clive P. Page, PhDa [MEDLINE LOOKUP]
John Morley, PhDb [MEDLINE LOOKUP]
London, UK
Abstract TOP
Racemic albuterol is composed of an equimolar mixture of stereoisomers. For asthma therapy, (R)-albuterol is the eutomer and (S)-albuterol is the distomer. By interacting with 2-adrenoceptors, (R)-albuterol has bronchodilator, bronchoprotective, anti-edematous properties and inhibits activation of mast cells and eosinophils. (S)-albuterol does not activate 2-adrenoceptors and does not modify activation of 2-adrenoceptors by (R)-albuterol so that for many years it was presumed to be biologically inert. Recently, it has been established that regular and excessive use of racemic albuterol induces paradoxical reactions in some subjects with asthma. Because such effects cannot be accounted for by activation of 2-adrenoceptors, the pharmacologic profile of (S)-albuterol has been more carefully defined. (S)-albuterol has distinctive pharmacologic properties that are unrelated to activation of 2-adrenoceptors. Thus, (S)-albuterol intensifies bronchoconstrictor responses of sensitized guinea pigs and induces hypersensitivity of asthmatic airways; it also promotes the activation of human eosinophils in vitro. These actions of (S)-albuterol may explain why racemic albuterol can intensify allergic bronchospasm and promote eosinophil activation in asthmatic airways. The capacity of (S)-albuterol to elevate intracellular Ca2+ would account for the paradox because this action will oppose, or even nullify, the consequences of adenylyl cyclase activation by (R)-albuterol. Because (S)-albuterol is metabolized more slowly than (R)-albuterol and is retained preferentially within the airways, paradoxical effects become more prominent during regular and excessive use of racemic albuterol. Because (S)-albuterol has detrimental effects in asthmatic airways, levalbuterol [homochiral (R)-albuterol] should have advantages over racemic albuterol in therapy for asthma. (J Allergy Clin Immunol 1999;104:S31-41.)
agonists: What is the evidence that their use increases the risk of asthma morbidity and mortality?
Richard Beasley, DM [MEDLINE LOOKUP]
Neil Pearce, PhD [MEDLINE LOOKUP]
Julian Crane, FRACP [MEDLINE LOOKUP]
Carl Burgess, MD [MEDLINE LOOKUP]
Wellington, New Zealand
Abstract TOP
In this article, studies that have examined the effects on morbidity and mortality of -agonist drugs are reviewed. With regard to morbidity, there is considerable evidence that the regular use of -agonist drugs as a class could potentially lead to worsening asthma control because of the effects on bronchial hyperresponsiveness, the development of tolerance and reduced protection against provoking stimuli, an increased allergen load, and masking of the symptoms of deteriorating asthma. Despite these effects, the short-acting -agonist drugs albuterol and terbutaline and the long-acting -agonist drugs salmeterol and formoterol have, in general, not been associated with a significant worsening of asthma control or an increased frequency of severe attacks. In contrast, there is evidence that the regular use of isoproterenol and fenoterol may lead to worsening asthma control. With regard to deaths, available evidence indicates that the high-dose preparations of isoproterenol and fenoterol are associated with increased mortality and were the major causes of the epidemics of asthma mortality observed in some countries. The increased risk of death associated with isoproterenol and fenoterol is probably the result of both long-term effects with their regular use leading to worsening asthma control and acute effects resulting from their overuse in the situation of a life-threatening attack of asthma. In contrast, the use of the short-acting -agonists albuterol and terbutaline is not associated with an increased risk of mortality. Although this lack of risk may also apply to formoterol and salmeterol, in the absence of sufficient studies specifically addressing the risk of death, this remains uncertain. (J Allergy Clin Immunol 1999;103:S18-30.)
Effect of agonists on inflammatory cells
Peter J. Barnes, DM, DSc, FRCP [MEDLINE LOOKUP]
London, UK
Abstract TOP
Although the major action of racemic 2-agonists on the airways is relaxation of airway smooth muscle, these drugs have several other effects mediated through 2-adrenergic receptors expressed on other cell types. These additional actions of 2-agonists may contribute to the efficacy of 2-agonists in relieving asthma symptoms. 2-agonists inhibit plasma exudation in the airways by acting on 2-receptors on postcapillary venule cells. They inhibit the secretion of bronchoconstrictor mediators from airway mast cells and inhibit effects on release of mediators from eosinophils, macrophages, T-lymphocytes, and neutrophils. In addition, 2-agonists may have an inhibitory effect on the release of neuropeptides from sensory nerves. The effect of 2-agonists on mediator release from structural cells in the airways such as epithelial cells is uncertain. Despite all of these inhibitory effects on inflammatory cells in vitro, 2-agonists do not appear to reduce the chronic inflammation of asthma. Desensitization is more readily seen in inflammatory cells than in airway smooth muscle cells and may account for this discrepancy. Corticosteroids may increase expression of 2-receptors in inflammatory cells to overcome the desensitization in response to chronic 2-agonist exposure. (J Allergy Clin Immunol 1999;104:S10-17.)
August 1999, part 2 • Volume 104 • Number 2
Observations on emerging patterns of asthma in our society
Evalyn N. Grant, MDa [MEDLINE LOOKUP]
Robin Wagner, MHSAb [MEDLINE LOOKUP]
Kevin B. Weiss, MDc [MEDLINE LOOKUP]
Chicago, Ill
Abstract TOP
Epidemiologic studies of temporal and geographic variation in asthma morbidity have identified asthma as an important public health concern. Knowledge gained from these studies has resulted in intense focus on this condition by agencies such as the National Institutes of Health and the World Health Organization. In this report, studies of recent asthma trends and patterns are explored. These studies show increases in US prevalence through 1994. Data on measures of morbidity show complex longitudinal patterns but are notable for large differences in emergency department services and hospitalizations by age and race. Very recent trends for US asthma mortality suggest widening of an existing racial gap. Limited comparisons are possible between these US trends and international trends but do suggest that US increases in prevalence and mortality rates may reflect world-wide patterns. Also, within the US, it is clear that geographic variation exists in asthma prevalence, morbidity, and mortality rates. Changes in certain environmental risk factors and exposures may contribute to recent trends, but little information is available relating specific risk factors to either longitudinal asthma trends, geographic variability, or high-risk populations. (J Allergy Clin Immunol 1999;104:S1-9.)
Molecular and genetic basis of 2-adrenergic receptor function
Stephen B. Liggett [MEDLINE LOOKUP]
Cincinnati, Ohio
Abstract TOP
The 2-adrenergic receptor has been cloned, mutated, and recombinantly expressed such that many structural features involved in receptor function have been defined. Agonists bind in a pocket formed by transmembrane spanning domains 3, 5, and 6, where key contact points initiate receptor activation. An interaction with the -hydroxyl group of -agonists and Asn293 of the latter transmembrane domain is the basis of the stereoselectivity of R- vs S-isomers of catecholamine-like agonists. Sites within the receptor that serve to dampen the signal with continuous agonist exposure have also been identified and include sites for phosphorylation by protein kinase A and G-protein–coupled receptor kinases and structural features that direct the receptor toward degradation (downregulation). Several regions of the 2-adrenergic receptor show genetic diversity within the human population, such that expression, coupling, and agonist regulation may be different in individuals with these polymorphisms. (J Allergy Clin Immunol 1999;103:S42-6.) |
