Publications

RATIONALE

One-quarter to one-third of individuals with asthma smoke, which may affect response to therapy and contribute to poor asthma control.

OBJECTIVES

To determine if the response to an inhaled corticosteroid or a leukotriene receptor antagonist is attenuated in individuals with asthma who smoke.

METHODS

In a multicenter, placebo-controlled, double-blind, double-dummy, crossover trial, 44 nonsmokers and 39 light smokers with mild asthma were assigned randomly to treatment twice daily with inhaled beclomethasone and once daily with oral montelukast.

MEASUREMENTS AND MAIN RESULTS

Primary outcome was change in prebronchodilator FEV(1) in smokers versus nonsmokers. Secondary outcomes included peak flow, PC(20) methacholine, symptoms, quality of life, and markers of airway inflammation. Despite similar FEV(1), bronchodilator response, and sensitivity to methacholine at baseline, subjects with asthma who smoked had significantly more symptoms, worse quality of life, and lower daily peak flow than nonsmokers. Adherence to therapy did not differ significantly between smokers and nonsmokers, or between treatment arms. Beclomethasone significantly reduced sputum eosinophils and eosinophil cationic protein (ECP) in both smokers and nonsmokers, but increased FEV(1) (170 ml, p = 0.0003) only in nonsmokers. Montelukast significantly increased a.m. peak flow in smokers (12.6 L/min, p = 0.002), but not in nonsmokers.

CONCLUSIONS

In subjects with mild asthma who smoke, the response to inhaled corticosteroids is attenuated, suggesting that adjustments to standard therapy may be required to attain asthma control. The greater improvement seen in some outcomes in smokers treated with montelukast suggests that leukotrienes may be important in this setting. Larger prospective studies are required to determine whether leukotriene modifiers can be recommended for managing asthma in patients who smoke.

BACKGROUND

The rise in community-onset methicillin-resistant Staphylococcus aureus (MRSA) infections potentially complicates the empiric management of cellulitis. The threshold at which drugs active against MRSA, such as clindamycin and trimethoprim/sulfamethoxazole (TMP/SMX), should be incorporated into empiric therapy is unknown.

OBJECTIVE

To evaluate the cost-effectiveness of using cephalexin, TMP/SMX, or clindamycin for outpatient empiric therapy of cellulitis, given various likelihoods of infection due to MRSA.

METHODS

A decision analysis of the empiric treatment of cellulitis was performed from the perspective of a third-party payer. The model included initial therapy with cephalexin, clindamycin, or TMP/SMX, followed by treatment with linezolid in cases of clinical failure. Probability and cost estimates were obtained from clinical trials, epidemiologic data, and publicly available cost data and were subjected to sensitivity analysis.

RESULTS

Under the base-case scenario (37% probability of infection by S. aureus and a 27% MRSA prevalence), cephalexin was the most cost-effective option. Clindamycin became a more cost-effective therapy at MRSA probabilities from 41-80% when the probability of staphylococcal infection was greater than 40%. TMP/SMX was cost-effective only at very high likelihoods of MRSA infection. Variables with the most influence in the model were probability of S. aureus being methicillin-resistant, cost of linezolid, probability of a cure with cephalexin for a non-MRSA infection, and probability of infection due to S. aureus.

CONCLUSIONS

Cephalexin remains a cost-effective therapy for outpatient management of cellulitis at current estimated MRSA levels. Cephalexin was the most cost-effective choice over most of the modeled range of probabilities, with clindamycin becoming more cost-effective at high likelihoods of MRSA infection. TMP/SMX is unlikely to be cost-effective for treatment of simple cellulitis. Further studies of the microbiology of cellulitis, the epidemiology of MRSA, and the clinical effectiveness of clindamycin and TMP/SMX in skin and soft tissue infections are needed.

This highlight article summarizes the current published literature of ion channels and ion transport in type I cells. Twenty years ago, the general theory of ion and fluid transport in the lung was that the alveolar type II cells, known to contain ion channels, governed ion transport and that the type I cells, believed to be incapable of ion transport, only allowed passive movement of water. Unable to reconcile the extraordinarily large surface area covered by type I cells (95% of the internal surface area of the lung) with such minimal biological activity, investigators set out to demonstrate that type I cells were capable of ion transport and played a role in regulating lung fluid balance. Various methods were employed to show that type I cells contained ENaC (HSC and NSC channels), CNG and K(+) channels, and CFTR, further necessitating a revision of the current theories of ion and fluid transport in the lung.

Three functional mouse flavin-containing monooxygenases (mFMOs) (i.e., mFMO1, mFMO3, and mFMO5) have been reported to be the major FMOs present in mouse liver. To examine the biochemical features of these enzymes, recombinant enzymes were expressed as maltose-binding protein fusion proteins (i.e., MBP-mFMO1, MBP-mFMO3, and MBP-mFMO5) in Escherichia coli and isolated and purified with affinity chromatography. The substrate specificity of these three mouse hepatic FMO enzymes were examined using a variety of substrates, including mercaptoimidazole, trimethylamine, S-methyl esonarimod, and an analog thereof, and a series of 10-(N,N-dimethylaminoalkyl)-2-(trifluoromethyl)phenothiazine analogs. The kinetic parameters of the three mouse FMOs for these substrates were compared in an attempt to explore substrate structure--function relationships specific for each mFMO. Utilizing a common phenothiazine substrate for all three enzymes, we compared the pH dependence for the recombinant enzymes under similar conditions. In addition, thermal stability for mFMO1, mFMO3, and mFMO5 enzymes was examined in the presence and absence of NADPH. The results revealed unique features for mFMO5, suggesting possible impact on the functional significance of this abundantly expressed FMO5 isoform in both human and mouse liver.