(R)-Albuterol for Asthma: Pro [a.k.a. (S)-Albuterol for Asthma: Con]

PREFACE

The Question

Is there scientific evidence to support the replacement of the ß-agonist racemic albuterol with levalbuterol-that is, (R)-albuterol? The argument presented below further refines the question as "Do we wish to continue to treat asthma with a mixture of albuterol, of which half is an agent with no known benefit-that is, (S)-albuterol-and which may exacerbate the disease?"

Racemic Albuterol: An Unresolved Mixture as a Medical Advance

Over the past 35 years, racemic albuterol, as an equal mixture composed of 50% active isoform and 50% "inactive" or "inert" isoform, has been used as a ß-receptor agonist in the treatment of asthma (1). The active isoform, or eutomer, designated as (R)-albuterol (where "R" stands for rectus), has molecular constituents arranged in a clockwise, or right-hand-turning, order of mass number priority, bound to the chiral carbon (i.e., catechol ring, amino-containing aliphatic chain, and hydroxyl group). (R)-albuterol has a 100-fold greater affinity for the ß^sub 2^-adrenoreceptor than the "inactive" mirror-image customer (S)-albuterol (2) (where S stands for sinistre), which has the same constituents as (R)-albuterol, but bound to the chiral carbon in the reverse, counterclockwise, or left-hand-turning, order (3, 4). Chiral molecules may also be named for their rotation of the plane of polarized light (e.g., D-, named for dextrorotatory, or right-handed optical rotation of polarized light; and L-, levorotatory, or left-handed rotation of polarized light). These two [(R)-/(S)-, and D-/L-] nomenclatures are distinct. However, in the context of ß-agonists, (R)- is equivalent to L-, and (S)- is equivalent to D-. Hence, (R)-albuterol is also known as levalbuterol.

The effectiveness of (R)-albuterol is dependent on its similarity of molecular structure to (-)epinephrine, naturally synthesized by the adrenal medulla. Accordingly, therapeutic effects of racemic albuterol derive from the presence of (R)-albuterol, mediated through selective binding to the ß^sub 2^-adrenoreceptors within the airway (1, 4), promoting relaxation of airway smooth muscle, attendant dilation of the airway, and decreased airflow resistance. Likely due, in part, to the 100-fold binding affinity difference between (R)-albuterol and (S)-albuterol, conventional understanding has held that (S)-albuterol is inert in the presence of, and compared with, its (R)-albuterol counterpart. Manufacture of the racemic mixture of albuterol has been relatively inexpensive, and its direct delivery to the airway is simple, through inhalation with a metered-dose inhaler or nebulizer.

(R)- and (S)-Albuterol Separated: Advancements of Technology

The original technology for the resolution of albuterol enantiomers from the racemate used liquid column chromatography, yielding high (98-99%), but incomplete, purities of (R)-albuterol (5). Newer resolution technology allows isolation of the diastereomeric salt through chiral-acid treatment of the racemate, obtaining an (R)-albuterol purity of nearly 100% (6); therefore, (S)-albuterol is functionally absent.

The efficient, modern synthesis of albuterol enantiomers also has resulted in a nearly pure (> 99%) version of the "inactive" or "inert" enantiomer, (S)-albuterol (6). Furthermore, techniques have been developed to measure levels of (S)-albuterol accurately within blood and other samples (5, 7-10), allowing assessment of metabolism. The pharmacokinetic profile of circulating (S)-albuterol, after a single inhalation of racemic albuterol, indicates that (S)-albuterol is metabolized up to 10 times more slowly than (R)-albuterol, persisting in the circulation up to 12 hours (9).

THE PRO POSITION

Racemic Albuterol as a Problematic Drug

One characteristic of the concern regarding racemic albuterol is induction of unexpected bronchospasm, bronchoconstriction, and airway hyperresponsiveness, identified in numerous reports since 1973 (11-21), and sometimes termed "ß-agonist paradox." A potentially related finding by the NHLBI Asthma Clinical Research Network (20) was that long-term regular use of racemic albuterol, in patients with mild asthma homozygous for the Arg/ Arg polymorphism at the 16th amino acid position of the ß^sub 2^-adrenoreceptor (about one-sixth of the asthmatic population in the United States [21] and 25% of African-Americans [22]), is associated with both an impaired bronchodilator response to racemic albuterol and a rapid deterioration of morning peak flow on its cessation, eventually mitigated by ipratopium. Similarly, a clinical trial in New Zealand revealed a fivefold increase in asthma exacerbations in patients with homozygous Arg-16 mild to moderate asthma with chronic racemic albuterol dosing (23). Although the exact cause of these unexpected paradoxical phenomena remains unclear, there is evidence that the use of racemic albuterol contributes to their development (24), which should be of some concern, given that nearly two-thirds of patients with asthma are routinely managed with racemic ß^sub 2^-adrenoreceptor agonists (25, 26).

In contrast, several clinical studies have indicated that regular racemic albuterol use for mild, stable asthma is not associated with deterioration of control (27, 28), with the Cochrane Database study going so far as to suggest that the reduced lung function and increased airway hyperresponsiveness with shortacting ß-agonist use is not a problem of major clinical importance (29). However, patients with unstable and more severe asthma, who would be most likely to use racemic albuterol more often, were excluded from those studies (30), and may represent a proportion of the asthmatic population as high as 25 to 30% (31); therefore, this scenario cannot be considered uncommon. Thus, the use of racemic albuterol may be problematic for desired long-term control, and in fact, may precipitate "paradoxical worsening" with continued use, and in some instances, death (14, 17, 32-36).

(R)-Albuterol: Measurable Efficacy in Cellular and Animal Models

Animal studies show that (R)-albuterol is effective at promoting ß^sub 2^-adrenoreceptor-mediated effects (e.g., decreased smooth muscle contractility, bronchodilation, and diminished airway hyperresponsiveness [37-41]); a study in bovine airway smooth muscle demonstrated decrements in intracellular calcium levels, which would promote relaxation (40). Suppression of airway inflammation (decreased eosinophils and goblet cell hyperplasia), proinflammatory mediators (interleukin [IL]-4 and superoxides), and circulating IgE also have been reported in mice and rats (41-43). A perceived weakness of some of those studies is that several effects of (R)-albuterol were not different from those of the racemate (38, 44); however, they evaluated periods of 1 to 48 hours, and do not address long-term exposure. Studies of longer term administration of racemic albuterol (= 48 hours) in mice and guinea-pigs have demonstrated the following: (7) progressive susceptibility to spasmogens (especially cholinergics) and airway hyperresponsiveness, (2) airway epithelial cell proliferation, (3) increased airway mucosal thickening and obstruction, (4) enhanced sensitivity to inhaled allergen, and (5) death with subsequent allergen exposure (37, 44-47). These findings are consistent with a possible effect of (S)-albuterol, within the racemate, to enhance cholinergic receptor activation (45), and an eventual loss of a protective effect of (R)-albuterol, which may not be attributable to the simple explanation of ß^sub 2^-adrenoreceptor desensitization (48).

(R)-Albuterol: Indications of Advantage in Human Studies

Studies in human tissues, cells, and subjects have indicated that (R)-albuterol is effective at inducing ß^sub 2^-adrenoreceptor-mediated effects promoting bronchodilation and suppression of inflammation. (R)-albuterol reduces methacholine sensitivity in human bronchial rings (49). In addition, (R)-albuterol (1) suppresses proinflammatory mediators (e.g., peroxidase, superoxide, IL-2, IL-5, IL-13, IFN-?, and granulocyte-macrophage colony-stimulating factor [GM-CSF]) in human eosinophils, T cells, and airway smooth muscle cells (50-53); (2) increases intracellular cAMP levels and inhibits cell proliferation by activation of the cAMP/protein kinase A pathway with simultaneous inhibition of phosphatidylinositol 3'-OH (PI-3) kinase and nuclear factor (NF)-?B expression in human airway smooth muscle cells (HASMCs) (54, 55); (3) increases inducible nitric oxide synthase (iNOS) mRNA and decreases GM-CSF mRNA and protein release in human airway epithelial cells (56); and (4) amplifies the antiinflammatory effect of glucocorticoids on suppression of GM-CSF in HASMCs (52). Importantly, as compared with (R)-albuterol, the racemate increased GM-CSF release, and activities of intracellular PI-3 kinase, NF-?B, and inhibitory G-protein (G^sub i^), in HASMCs (52, 54). However, as noted above, some effects of (R)-albuterol and the racemate were statistically indistinct (49, 50, 53, 54); however, this cannot be said of the individual enantiomer comparisons of (R)-albuterol and (S)-albuterol outlined further below.

An initial bronchoprovocation study in humans suggested superiority of (R)-albuterol over the racemate (57); however, some subsequent human studies have not had the same finding (58-65). In particular, recent small pediatric clinical trials in the emergency department (ED; 70-140 subjects) have suggested no differences between (R)-albuterol and the racemate; however, the ability to observe functional differences were likely affected by the following factors: (1) added administration of ipratropium and oral steroids to both albuterol study groups (63, 64); (2) administration of racemate that was four times that of (R)-albuterol (5.0 vs. 1.25 mg) (65); (3) addition of ipratropium to the racemate-only study group (65); and (4) and exclusion of subjects having taken (R)-albuterol, but not racemic albuterol, 24 hours before presentation to the ED (64). Another common characteristic of the negative studies is a focus on acute treatment (< 1 week) and single administrations, of limited use in determination of true difference between the (R)-albuterol and racemic albuterol in a more chronic usage setting, in patients with more severe asthma (30, 33, 34, 36). For example, similar to the animal studies, racemic albuterol in humans has been reported to enhance sensitivity to allergen (including late-phase responses) and increase airway hyperreactivity (28, 34, 66-68), through effects potentially not attributable to ß^sub 2^-adrenoreceptor desensitization (32).

Some clinical trials of (R)-albuterol have indicated adequate safety, efficacy, and equivalence (69-71), and others have shown modest to moderate increments in FEV^sub 1^ (5-20%), as compared with the racemate (24, 72-75); however, those studies were not designed to assess superiority. A retrospective analysis has demonstrated further differences in FEV^sub 1^ over time due to (R)-albuterol (76), whereas a recent large (922 patients) retrospective chart review of two geographically distinct EDs indicated that administration of (R)-albuterol was associated with one-half to two-thirds fewer admissions, and therefore greater total cost savings ($400,000 savings from a $5,000 cost, with an 80:1 risk-benefit ratio favoring (R)-albuterol), in comparison to racemic albuterol (77). Even so, some have concluded that the differences do not warrant replacement of the racemic albuterol with (R)-albuterol, given the seemingly modest physiologic advantage, and the significant initial cost differential (78-82). Despite those disagreements, consensus is beginning to emerge that more comprehensive clinical trials of (R)-albuterol, (S)-albuterol, and racemic albuterol are needed to fully resolve this question (77-79, 81-87), particularly based on the compelling basic preclinical findings. In this regard, one recent ED clinical trial reported lung function improvements and reduced hospitalization in asthma patients treated with (R)-albuterol versus racemic albuterol that were beyond modest (> 35%, 120- to 300-ml increase in FEV^sub 1^). The greatest responses were observed in patients not treated with steroids and who had high circulating levels of the supposedly "inactive" (S)-albuterol (88), a surrogate marker for chronic racemic albuterol overuse, which is commonly observed in patients with poorly controlled asthma (30).

(S)-Albuterol: The Sinister Face of Janus

Repeated inhalations of racemic albuterol produce plasma (S)-albuterol levels four times higher than (R)-albuterol in patients without asthma (89). It is believed that this difference is due to the preferential sulfation of (R)-albuterol by hepatic and lung cell sulphonotransferases specific for the (R)-albuterol, but suboptimal for (S)-albuterol (9, 90-92), and, importantly, which may be further reduced in patients with asthma (84, 93). These differences in circulating levels may reflect bioavailability secondary to selective intestinal absorption and renal clearance of the swallowed portion of the inhaled racemate (94). Even so, with evidence indicating that (S)-albuterol is preferentially retained within the lung (95), it stands to reason that circulation, delivery, and binding of (S)-albuterol would persist beyond (R)-albuterol.

With the more rapid metabolism and disappearance of (R)-albuterol, it is possible that the remaining (S)-albuterol may act through a cholinergic-like pathway (39, 40), suggesting that clinical studies using cholinergic antagonists for rescue (e.g., ipratropium) may mask these deleterious effects of (S)-albuterol when subjects are given racemic albuterol. (S)-albuterol also may influence activation of the ß^sub 2^-adrenoreceptor, perhaps acting as an antagonist or inverse agonist (96), resulting in effects that are opposite in direction and magnitude to (R)-albuterol.

Evidence for antagonist and/or inverse agonist-like actions of (S)-albuterol has accumulated in both human and animal tissue and cell preparations (43, 51-54), and in some animal models of inflammation (41, 42), suggesting that (S)-albuterol can promote release of factors that favor inflammation (e.g., superoxides, IL-4, IL-13, and GM-CSF) and smooth muscle contraction, as well as produce changes consistent with airway remodeling, such as airway smooth muscle cell proliferation (55). Importantly, it has also been reported that (S)-albuterol can amplify contraction of both human and animal airway smooth muscle (37, 41, 49), possibly by increasing intracellular calcium levels (40, 54). Recent studies in HASMCs indicate that (S)-albuterol may also amplify contraction and suppress relaxation through simultaneous down-regulation of stimulatory G-protein (G^sub s^) activation and up-regulation of G^sub i^ activation, both of which reduce cAMP (54). Again, these basic findings are consistent with findings in a recent clinical trial, in which (R)-albuterol increased FEV^sub 1^ nearly 40% more than the racemate, which also corresponded to a 40% reduction in required hospitalization, in patients with severe asthma with the highest levels of plasma (S)-albuterol (> 1,095 mg/ml) (88).

Although additional research is necessary to determine the mechanisms, these data fit with the concept of (S)-albuterol as a distomer that (1) is the mirror-image molecular structure of (R)-albuterol; (2) has a slower profile of metabolism; (3) results in contraction of airway smooth muscle, instead of relaxation; (4) increases proinflammatory cytokine release, as opposed to reducing it; (5) promotes increased intracellular calcium and release of agents that favor smooth muscle contraction; and (6) can counteract the antiinflammatory effects of steroids (4, 37, 41, 43, 51, 52, 54). Most important, these concepts are consistent with the paradoxical effects associated with chronic, repetitive racemic albuterol use in patients with uncontrolled asthma of higher severities, and may underlie inflammation and/or hyperresponsiveness that may be masked in the presence of steroids (20, 30, 31, 47, 52, 88) or cholinergic receptor antagonists, such as ipratropium (63-65).

CONCLUSIONS

There is evidence that chronic use of racemic albuterol may be problematic, possibly exacerbating disease. Compelling basic data suggest that (S)-albuterol has different effects than (R)-albuterol, including actions as an inverse agonist. Collectively, these data may explain the paradoxical behavior of the airways with the repeated, chronic use of racemic albuterol. Therefore, the notion that (S)-albuterol is "inert" under all conditions is no longer tenable, and it is highly relevant that the U.S. Food and Drug Administration no longer allows synthesis of new therapeutic compounds in a racemic form, unless it can be demonstrated that the distomer has no deleterious effects (97). Thus, racemic albuterol would not be allowed into production as a new drug today. It makes sense, based on first principles, accumulating data, and the oath to do no harm, that (R)-albuterol should replace racemic albuterol, particularly for patients with unstable moderate to severe asthma for whom ß^sub 2^-adrenoreceptor agonists form an important and ongoing portion of their therapy.

Conflict of Interest Statement: B.T.A. has received consultancy fees ($8,500), advisory fees ($4,500), and speaking fees ($7,500) from Sepracor, Inc., over the past 3 years. W.J.C. has received consultancy fees ($7,500) and speaking fees ($10,000) from Sepracor, Inc., in the past 3 years, and $18,000 in remuneration from Genetech.