These results provide the first evidence that levels of beta-adrenergic agonists that are physiologically efficacious in experimental models can be achieved with conventional delivery systems in ventilated, critically ill patients with acute respiratory failure from pulmonary edema.

Stimulation of active fluid transport with beta-adrenergic receptor (betaAR) agonists can accelerate the resolution of alveolar edema. However, chronic betaAR-agonist administration may cause betaAR desensitization and downregulation that may impair physiological responsiveness to betaAR-agonist stimulation. Therefore, we measured baseline and terbutaline- (10(-3) M) stimulated alveolar fluid clearance in mice that received subcutaneously (miniosmotic pumps) either saline or albuterol (2 mg. kg(-1). day(-1)) for 1, 3, or 6 days. Continuous albuterol administration increased plasma albuterol levels (10(-5) M), an effect that was associated with 1) a significant decrease in betaAR density and 2) attenuation, but not ablation, of maximal terbutaline-induced cAMP production. Forskolin-mediated cAMP-release was unaffected. Continuous albuterol infusion stimulated alveolar fluid clearance on day 1 but did not increase alveolar fluid clearance on days 3 and 6. However, terbutaline-stimulated alveolar fluid clearance in albuterol-treated mice was not reduced compared with saline-treated mice. Despite significant reductions in betaAR density and agonist-mediated cAMP production by long-term betaAR-agonist exposure, maximal betaAR-agonist-mediated increase in alveolar fluid clearance is not diminished in mice.

Racemic beta2 agonists are composed of a 50:50 mixture of R and S isomers. The R isomer exhibits virtually all the bronchodilation, whereas the S isomers are generally considered inert. However, (S)-albuterol was shown to enhance bronchial reactivity to methacholine, eosinophil activation, and histamine-induced influx of fluid, proteins, and neutrophils into the airspaces. Actions such as these may compress the potency and foreshorten the duration of (R)-albuterol. Accordingly, pure (R)-albuterol provides bronchodilation at lower doses than racemate, allowing for fewer beta-adrenergic-mediated side effects. In addition, differential metabolism may allow for the progressive accumulation of (S)-albuterol. This logic is applicable to long-acting beta2 agonists: the therapeutically active (R,R)-formoterol is currently being developed in the United States, and preliminary results suggest rapid improvements in FEV1 with up to 24-hour duration of action. These combined observations with the R isomers of beta2 agonists suggest that potential improvements in therapeutic indices can be achieved with isomerically pure versions of existing racemic drugs.

Albuterol, in all marketed forms, is sold as a racemate, composed of a 50:50 mixture of (R)- and (S)-isomers. Racemic albuterol and the single isomer version (R)-albuterol (levalbuterol) were compared in a randomized, double-blind, dose-ranging five-way crossover study in patients (n = 20) with mild persistent to moderate persistent asthma. Placebo, racemic albuterol (2.50 mg), or levalbuterol (0.31, 0.63, or 1.25 mg) were delivered as single, nebulized doses to 5 male and 15 female nonsmoking patients with asthma aged 18-50 years. Serial pulmonary function was assessed at 15-min intervals and mean time to onset of activity and duration of improvement of forced expiratory volume in 1 sec (FEV1) were measured. In addition, blood chemistries, electrocardiogram (ECG) readings, and patient subjective assessment of adverse symptoms were recorded. Levalbuterol was found to provide significant bronchodilatory activity and was well tolerated. Levalbuterol 1.25 mg provided the greatest increase and duration in FEV1 improvement, whereas racemic albuterol (2.50 mg) and levalbuterol 0.63 mg provided comparable effects. The lower doses of levalbuterol were associated with a less marked effect on heart rate and potassium than racemic albuterol or high-dose levalbuterol. These data suggest that 0.63 mg levalbuterol provides bronchodilation equivalent to 2.50 mg racemic albuterol with less beta-mediated side effects.

The once widely held notion that acute allograft rejection is mediated by cytolytic T lymphocytes (CTL) (1, 2) 1 recently has been called into question (3). In the mouse, Loveland and colleagues (4, 5) demonstrated by adoptive transfer that T lymphocyte subsets enriched for Lyt-l+,2 -cells, and therefore thought to lack CTL precursors, were as effective in restoring allograft immunity as were unseparated T lymphocytes. In the rat, Dallman et al. (6) demonstrated that subsets enriched for T helper lymphocytes (OX8-, W3/25 ÷) could restore allograft immunity, but subsets enriched for CTL (OX8 +, W3/25-) could not. The simplest interpretation of these observations is that CTL are neither necessary nor sufficient for allograft rejection. However, several considerations suggest that such an interpretation may be invalid. First, Dallman et al. (6) found significant numbers of OX8 + cells in rejecting allografts of recipients reconstituted only with OX8-lymphocytes. As noted by the investigators, the presence of the OX8 + must be adequately explained before ruling out CTL as important effector cells in allograft rejection. Second, it is questionable whether adoptive transfer of the CTL subset, which is also likely to include T suppressor lymphocytes, is a fair evaluation of CTL function in allograft rejection since regulatory forces may be strongly shifted in favor of nonreactivity. Finally, but perhaps most importantly, the prediction of T lymphocyte function on the basis of cell surface differentiation antigens appears to be more complex than previously supposed (7-9). For example, unlike "typical" Lyt-l-,2 + CTL, some mouse CTL reactive with class II'histocompatibility antigens express the Lyt-l+,2 -phenotype (8). This could be particularly important in allograft rejection where a CTL response to class II antigens of donor vascular-endothelial cells may represent a critical determinant of the rejection process (10-12). Hence, it seems doubtful that any rigid conclusions concerning the relevance of CTL to allograft rejection can be deduced from the study of adoptively transferred lymphocytes that have 234J. ExP. MED.