Long-term treatment with oral N-acetylcysteine: affects lung function but not sputum inflammation in cystic fibrosis subjects. A phase II randomized placebo-controlled trial.

PURPOSE: To evaluate the effects of oral N-acetylcysteine (NAC), which replenishes systemic glutathione, on decreasing inflammation and improving lung function in CF airways. METHODS: A multicenter, randomized, double-blind proof of concept study in which 70 CF subjects received NAC or placebo orally thrice daily for 24 weeks. ENDPOINTS: primary, change in sputum human neutrophil elastase (HNE) activity; secondary, FEV(1) and other clinical lung function measures; and safety, the safety and tolerability of NAC and the potential of NAC to promote pulmonary hypertension in subjects with CF. RESULTS: Lung function (FEV(1) and FEF(25-75%)) remained stable or increased slightly in the NAC group but decreased in the placebo group (p=0.02 and 0.02). Log(10) HNE activity remained equal between cohorts (difference 0.21, 95% CI -0.07 to 0.48, p=0.14). CONCLUSIONS: NAC recipients maintained their lung function while placebo recipients declined (24 week FEV1 treatment effect=150 mL, p<0.02). However no effect on HNE activity and other selected biomarkers of neutrophilic inflammation were detected. Further studies on mechanism and clinical outcomes are warranted.

Phase II studies of nebulised Arikace in CF patients with Pseudomonas aeruginosa infection.

RATIONALE: Arikace is a liposomal amikacin preparation for aerosol delivery with potent Pseudomonas aeruginosa killing and prolonged lung deposition. OBJECTIVES: To examine the safety and efficacy of 28 days of once-daily Arikace in cystic fibrosis (CF) patients chronically infected with P aeruginosa. METHODS: 105 subjects were evaluated in double-blind, placebo-controlled studies. Subjects were randomised to once-daily Arikace (70, 140, 280 and 560 mg; n=7, 5, 21 and 36 subjects) or placebo (n=36) for 28 days. Primary outcomes included safety and tolerability. Secondary outcomes included lung function (forced expiratory volume at one second (FEV1)), P aeruginosa density in sputum, and the Cystic Fibrosis Quality of Life Questionnaire-Revised (CFQ-R). RESULTS: The adverse event profile was similar among Arikace and placebo subjects. The relative change in FEV1 was higher in the 560 mg dose group at day 28 (p=0.033) and at day 56 (28 days post-treatment, 0.093L±0.203 vs -0.032L±0.119; p=0.003) versus placebo. Sputum P aeruginosa density decreased >1 log in the 560 mg group versus placebo (days 14, 28 and 35; p=0.021). The Respiratory Domain of the CFQ-R increased by the Minimal Clinically Important Difference (MCID) in 67% of Arikace subjects (560 mg) versus 36% of placebo (p=0.006), and correlated with FEV1 improvements at days 14, 28 and 42 (p<0.05). An open-label extension (560 mg Arikace) for 28 days followed by 56 days off over six cycles confirmed durable improvements in lung function and sputum P aeruginosa density (n=49). CONCLUSIONS: Once-daily Arikace demonstrated acute tolerability, safety, biologic activity and efficacy in patients with CF with P aeruginosa infection.

Validation of parent self reported home safety practices.

OBJECTIVES: To evaluate the validity of parents' self reported home safety practices concerning smoke detectors, bike helmets, car seats, and water heater temperature. SETTING: Parents of children 12 years old and under whose child had made at least one visit to a study clinic in the years 2000-2003. METHODS: As part of a randomized controlled trial to improve patient provider communication and preventive practices, parents' responses to telephone interview were compared with observations of safety practices during a home visit. Home visits were completed within nine weeks of the telephone interview. Parents were not told that the visit was part of a validation study and home visit observers were unaware of the interview responses. The authors calculated sensitivities, specificities, positive and negative predictive values, and their corresponding confidence intervals. RESULTS: Sensitivity (0.78 to 0.98) and positive predictive values (0.75 to 1.00) were high for all items. Specificities and negative predictive values were more variable and the highest estimates (specificity 0.95 to 1.00, negative predictive value 0.95 to 0.97) were for car seat types. CONCLUSIONS: The results suggest that parent self report practice of certain injury prevention behaviors (owning a car seat, hot water temperatures) is reliable, whereas self reports on other practices (working smoke detectors, properly fitting bike helmets) may be overstated.

Risk factors for adverse health effects following hazardous materials incidents.

To identify risk factors for persistent morbidity, we conducted a prospective study of individuals involved in hazardous materials incidents reported to the Washington Poison Center. Between December 1997 and October 1999, 202 subjects in 87 incidents were surveyed by telephone. Medical symptoms persisting for a minimum of 8 days after the incident were reported in 51 (25%) subjects, and 18 (9%) left work or school for more than 2 days because of the exposure. Medical intervention was reported in 46 (58%) of 79 subjects for whom medical records were available, and objective abnormalities were found in 57 (72%). Multiple logistic regression analysis indicated that subjects with dermal exposures, three or more alcoholic drinks per week, and previous use of psychiatric medications were more likely to report persistent symptoms. Divorced, widowed, or separated subjects, asthmatic subjects, and those having initial dermal symptoms were more likely to miss work or school for more than 2 days. Of patients evaluated at a health care facility, subjects with preexisting hypertension were more likely to receive medical treatment or have objective medical findings, whereas those with inhalation exposures and those decontaminated at the scene were less likely to be treated or have abnormalities. In our study, both incident and individual factors were predictive of adverse health effects, and these findings should be considered in planning the care of patients involved in hazardous materials incidents.

Hazardous materials events: evaluation of transport to health care facility and evacuation decisions.

The study objective was to analyze hazardous materials event and victim factors associated with transportation of victims to a health care facility, and evacuation or shelter-in-place of nearby populations. A retrospective review was conducted on hazardous materials events in Washington State from 1993 to 1997. Bivariate and multiple logistic regression were used to identify risk factors for transportation, evacuation, and shelter-in-place. Over five years, 2,654 victims from 457 events were reported, with 1,859 (70%) transported to a health care facility. Evacuation occurred in 279 (61%) events and shelter-in-place in 14 (3%) events. After excluding 14 deaths, regression analysis indicated that victims with trauma (OR 5.87, 95% CI 1.41-24.5), thermal burns (6.90, 1.15-41.3), dizziness/other CNS symptoms (1.59, 1.00-2.54), and headache (1.54, 1.01-2.35) were most likely to be transported. Chemical releases inside buildings (2.09, 1.06-4.10, compared with transportation events), and involving 3-5 victims (2.86, 1.54-5.31, compared to 1 victim) or > or =6 victims (8.74, 4.01-19.0), were most likely to involve evacuation or shelter-in-place. Events involving sulfuric acid (0.15, 0.05-0.49) and sodium hydroxide (0.19, 0.04-0.94) were least likely to involve evacuation or shelter-in-place. Prehospital decisions to transport victims to a health care facility and evacuate or shelter-in-place nearby populations are associated with event and victim factors. Further research is needed to determine if these factors also predict need for medical care or removal from exposure, and to develop evidence-based prehospital care protocols for hazardous materials exposure victims.

Reduction in apolipoprotein-mediated removal of cellular lipids by immortalization of human fibroblasts and its reversion by cAMP: lack of effect with Tangier disease cells.

High density lipoprotein (HDL) phospholipids and apolipoproteins remove cellular lipids by two distinct mechanisms, but their relative contribution to reverse cholesterol transport is unknown. Whereas phospholipid-mediated cholesterol efflux from cultured cells reflects the activity of the HDL receptor SR-BI, apolipoprotein-mediated lipid removal is regulated in response to changes in cellular cholesterol content (positive) and cell proliferation rates (negative). Here we show that immortalization of human skin fibroblast lines with the papillomavirus E6/E7 oncogenes increased their proliferation rates and selectively reduced the activity of the apolipoprotein-mediated lipid removal pathway. This reduction was accompanied by a decrease in cellular cAMP levels and was reversed by treatment with a cAMP analog. The stimulatory effect of cAMP was independent of changes in cellular phenotype or activities of cholesteryl ester cycle enzymes. The severely impaired apolipoprotein-mediated lipid removal pathway in Tangier disease fibroblasts, which persisted after immortalization, was not improved by treatment with a cAMP analog, implying that the cellular defect in Tangier disease is upstream from this cAMP-dependent signaling pathway.These results indicate that papillomavirus-induced immortalization of fibroblasts selectively reduces the activity of the apolipoprotein-mediated lipid removal pathway by a cAMP-dependent process, perhaps to prevent loss of cellular lipids needed for continual membrane synthesis.