Paula J. Anderson

Effect of Systemic Glucocorticoids on Exacerbations of Chronic Obstructive Pulmonary Disease

BACKGROUND AND METHODS Although their clinical efficacy is unclear and they may cause serious adverse effects, systemic glucocorticoids are a standard treatment for patients hospitalized with exacerbations of chronic obstructive pulmonary disease (COPD). We conducted a double-blind, randomized trial of systemic glucocorticoids (given for two or eight weeks) or placebo in addition to other therapies, for exacerbations of COPD. Most other care was standardized over the six-month period of follow-up. The primary end point was treatment failure, defined as death from any cause or the need for intubation and mechanical ventilation, readmission to the hospital for COPD, or intensification of drug therapy. RESULTS Of 1840 potential study participants at 25 Veterans Affairs medical centers, 271 were eligible for participation and were enrolled; 80 received an eight-week course of glucocorticoid therapy, 80 received a two-week course, and 111 received placebo. About half the potential participants were ineligible because they had received systemic glucocorticoids in the previous 30 days. Rates of treatment failure were significantly higher in the placebo group than in the two glucocorticoid groups combined at 30 days (33 percent vs. 23 percent, P=0.04) and at 90 days (48 percent vs. 37 percent, P=0.04). Systemic glucocorticoids (in both groups combined) were associated with a shorter initial hospital stay (8.5 days, vs. 9.7 days for placebo, P=0.03) and with a forced expiratory volume in one second that was about 0.10 liter higher than that in the placebo group by the first day after enrollment. Significant treatment benefits were no longer evident at six months. The eight-week regimen of therapy was not superior to the two-week regimen. The patients who received glucocorticoid therapy were more likely to have hyperglycemia requiring therapy than those who received placebo (15 percent vs. 4 percent, P=0.002). CONCLUSIONS Treatment with systemic glucocorticoids results in moderate improvement in clinical outcomes among patients hospitalized for exacerbations of COPD. The maximal benefit is obtained during the first two weeks of therapy. Hyperglycemia of sufficient severity to warrant treatment is the most frequent complication.

Consensus statement: aerosols and delivery devices.

MYRNA B. DOLOVICH, P.Eng., NEIL R. MacINTYRE, F.A.A.R.C, PAULA J. ANDERSON, M.D., CARLOS A. CAMARGO, JR., M.D., Dr.P.H, NANCY CHEW, M.S., R.A.C., CYNTHIA H. COLE, M.D., M.P.H., RAJIV DHAND, M.D., JAMES B. FINK, M.S., R.R.T., F.A.A.R.C., NICHOLAS J. GROSS, M.D., Ph.D., DEAN R. HESS, Ph.D., R.R.T., F.A.A.R.C, ANTHONY J. HICKEY, Ph.D., CHONG S. KIM, Ph.D., TED B. MARTONEN, Ph.D., DAVID J. PIERSON, M.D., F.A.A.R.C, BRUCE K. RUBIN, M.D., and GERALD C. SMALDONE, M.D., Ph.D.

Barriers to adherence to cystic fibrosis infection control guidelines

In 2003, the American Cystic Fibrosis (CF) Foundation published revised, evidence‐based guidelines for infection control. We sought to assess potential barriers to adherence to these guidelines experienced by health care professionals (HCPs) caring for CF patients.

Hydrolyzed casein and whey protein meals comparably stimulate net whole-body protein synthesis in COPD patients with nutritional depletion without an additional effect of leucine co-ingestion

BACKGROUND & AIMS Muscle wasting commonly occurs in COPD, negatively affecting outcome. The aim was to examine the net whole-body protein synthesis response to two milk protein meals with comparable absorption rates (hydrolyzed casein (hCAS) vs. hydrolyzed whey (hWHEY)) and the effects of co-ingesting leucine. METHODS Twelve COPD patients (GOLD stage II-IV) with nutritional depletion, were studied following intake of a 15 g hCAS or hWHEY protein meal with or without leucine-co-ingestion, according to a double-blind randomized cross-over design. The isotopic tracers L-[ring-(2)H5]-Phenylalanine, L-[ring-(2)H2]-Tyrosine, L-[(2)H3]-3-Methylhistidine (given via continuous intravenous infusion), and L-[(15)N]-Phenylalanine (added to the protein meals) were used to measure endogenous whole-body protein breakdown (WbPB), whole-body protein synthesis (WbPS), net protein synthesis (NetPS), splanchnic extraction and myofibrillar protein breakdown (MPB). Analyses were done in arterialized-venous plasma by LC/MS/MS. RESULTS WbPS was greater after intake of the hCAS protein meal (P < 0.05) whereas the hWHEY protein meal reduced WbPB more (P < 0.01). NetPS was stimulated comparably, with a protein conversion rate greater than 70%. Addition of leucine did not modify the insulin, WbPB, WbPS or MPB response. CONCLUSIONS Hydrolyzed casein and whey protein meals comparably and efficiently stimulate whole-body protein anabolism in COPD patients with nutritional depletion without an additional effect of leucine co-ingestion. This trial was registered at clinicaltrials.gov as NCT01154400.

Lubiprostone for Constipation in Adults with Cystic Fibrosis: A Pilot Study

Background Constipation is prevalent in the cystic fibrosis (CF) population and yet there are few data demonstrating the effectiveness of currently used treatments. Lubiprostone is a laxative that works by activating the type 2 chloride channel in the gastrointestinal tract and thus has the potential to be especially effective for constipation associated with CR Objective: To evaluate the effectiveness of lubiprostone for the treatment of constipation in adults with CF. Methods: In this pilot study, participants acted as their own controls and comparisons were made between run-in and treatment periods. During the 2-week run-in period, participants continued their usual treatment for constipation; during the 4-week treatment period, participants received lubiprostone 24 μg twice daily. Efficacy outcomes Included spontaneous bowel movement frequency, Bristol Stool Scale scores, and Patient Assessment of Constipation Symptoms (PAC-SYM) survey scores. Outcomes were assessed during both the run-in and treatment periods (0, 2, and 4 weeks of treatment). Safety outcomes included spirometry, body weight, and serum chemistry. Results: Seven participants completed the study. Mean (SD) baseline forced expiratory volume in 1 second was 83.0% (9.4) of predicted and body mass index was 24.0 (2.8) kg/m2, indicating an overall healthy, well-nourished group of adults with CR Lubiprostone improved overall symptoms of constipation as measured by PAC-SYM survey scores (1.18 [0.56], 0,54 (0.27], and 0.44 [0.36] at 0, 2, and 4 weeks, respectively; p < 0.001). Spontaneous bowel movement frequency and Bristol Stool Scale scores were not statistically significantly different between periods. There were no differences in safety measures. Transient chest tightness and shortness of breath were reported by 2 separate participants, although neither participant withdrew due to these adverse effects. Conclusions: Lubiprostone may be an effective option for the treatment of constipation in adults with CF

Differences in physicians’ self-reported knowledge of, attitudes toward, and responses to the black box warning on long-acting β-agonists

BACKGROUND Inhaled corticosteroids and long-acting beta-agonists (LABAs) are recommended for treating moderate to severe persistent asthma. The Food and Drug Administration has issued a black box warning (BBW) for LABAs. OBJECTIVE To investigate physician knowledge of the BBW and its effect on the practice of specialists (pulmonologists and allergists) and primary care physicians (PCPs) (internists and family physicians). METHODS A total of 1,107 physicians responded to a questionnaire to determine their awareness of the BBW and whether it changed their practice. RESULTS The group comprised 429 pulmonologists (38.8%), 395 allergists (35.7%), 141 internists (12.7%), 132 family physicians (11.9%), and 10 pediatricians (0.9%). Comparing specialists with PCPs, there was approximately a 10% difference in the rate of knowledge concerning the BBW (99.0% vs 90.8%, P < .001). Approximately a quarter of specialists agreed with the BBW compared with 52.9% of family physicians and 40.3% of internists. Twice as many PCPs vs specialists agreed with the warning (45.6% vs 24.2%, P < .001). The PCPs were more likely to alter their prescribing habits than were specialists (40.1% vs 34.6%, P < .005). Specialists were more likely to discuss the warning with patients than were PCPs (87.4% vs 64.8%, P < .001). For mild persistent asthma, most respondents chose inhaled corticosteroids as the preferred first-line therapy, but 11.4% of PCPs and 2.1% of specialists identified LABA monotherapy as their first choice. For moderate to severe asthma, the pattern of response was similar. CONCLUSION Although most physicians were aware of the BBW for LABAs, there was a difference in how specialists and PCPs approached it and altered their prescribing habits.

Use of the Chloride Channel Activator Lubiprostone for Constipation in Adults with Cystic Fibrosis: A Case Series

Objective: To describe the use of lubiprostone for constipation in 3 adults with cystic fibrosis (CF). Case Summary: This case series describes the use of lubiprostone for the treatment of constipation in 3 adutts with CF (mean ± SD length of therapy 17.3 ± 1.5 mo). All 3 patients were prescribed lubiprostone 24 μg twice daily after hospitalization for treatment of intestinal obstruction. Patient 1 continues on chronic polyethylene glycol (PEG) 3350 and lubiprostone and has not had a recurrence of obstruction. Patient 2 requires aggressive chronic therapy with PEG 3350, lubiprostone, and methylnaltrexone. She has had 1 recurrence of obstruction. Patient 3 continues with lubiprostone taken several times per week with good control of constipation and no recurrence of obstruction to date. The adverse effect profile has been tolerable in all 3 patients. Discussion: CF is caused by a genetic mutation resulting in a dysfunctional or absent CF transmembrane conductance regulator that normally functions as a chloride channel. This results in viscous secretions in multiple organ systems including the lungs and intestinal tract. Accumulation of viscous intestinal contents contributes to constipation, which is common among adults with CF and can sometimes lead to intestinal obstruction. Lubiprostone is indicated for chronic constipation and works by activating type 2 chloride channels (CIC-2) in the intestinal tract. Because it utilizes an alternate chloride channel, lubiprostone may be especially effective for constipation in patients with CF. Conclusions: Lubiprostone provides an additional option for the treatment of constipation in adults with CF. Its use in the CF population deserves further study.

Effect of propellant on the pharmacokinetics and pharmacodynamics of inhaled albuterol in asthmatic subjects

Hydrofluoroalkane (HFA) propellants have largely replaced chlorofluorocarbon (CFC) propellants in metered dose inhalers (MDI). It is important to document the pharmacokinetics (PK) and pharmacodynamics (PD) of medications delivered using HFA propellants compared to CFC propellants. Six adult asthmatics with mild to moderate asthma were selected for the study. Each subject inhaled 180 microg of albuterol from an MDI with holding chamber. Venous blood was collected for measuring albuterol levels at intervals over 12 h, and spirometric measurements of airflow were measured over the same time period. Plasma samples were analyzed using a GC/MS assay developed in our laboratory. PK and PD parameters were calculated by nonlinear regression using WinNonlin. There were no statistically significant differences between PD parameters for HFA versus CFC propellants. The area under the plasma albuterol concentration versus time curve (AUC) was 72% greater for the HFA formulation, indicating a greater lung bioavailability (p = 0.015). This difference in bioavailability did not result in a statistically significant difference in FEV(1) values between the two propellants.

Deposition of sidestream cigarette smoke in the human respiratory tract II. Deposition of ultrafine smoke particles

Sidestream cigarette smoke was generated into an inhalation chamber from which five normal male volunteers inhaled the smoke. Size distribution of the smoke aerosol was: count median diameter, 0.11 micron, mass median diameter 0.43 micron. Deposition fraction measured as concentration difference for each size fraction between inhaled and exhaled aerosol for each size interval was: 0.075 micron, 0.24 +/- 0.04; 0.13 micron, 0.15 +/- 0.04; 0.24 micron, 0.10 +/- 0.04; and 0.42 micron, 0.07 +/- 0.02. The declining deposition fraction as size approaches 0.5 micron is consistent with previous theoretical and experimental data.

Determination of albuterol in plasma after aerosol inhalation by gas chromatography-mass spectrometry with selected-ion monitoring

Albuterol is a beta2-adrenergic agonist commonly used as a bronchodilator for the treatment of patients with asthma. We have developed an assay to determine plasma levels as low as 50 pg/ml of albuterol by gas chromatography-mass spectrometry (GC-MS). This assay utilizes isotopically labeled albuterol ([13C]albuterol) as an internal standard. In this assay albuterol and the internal standard are recovered from 1 ml of plasma using solid-phase extraction. The samples are then derivatized to trimethylsilyl ethers using N,O-bis(trimethylsilyl)trifluoro-acetamide with 1% trimethylchlorosilane. The samples are then analyzed by GC-MS with selected-ion monitoring (SIM) for the ions m/z 369.15 and 370.15. The method has been validated for a concentration range of 50-10000 pg/ml in plasma.