Michael P. Habib

High-dose, short-course levofloxacin for community-acquired pneumonia: a new treatment paradigm.

Levofloxacin demonstrates concentration-dependent bactericidal activity most closely related to the pharmacodynamic parameters of the ratio of area under the concentration-time curve (AUC) to minimum inhibitory concentration (MIC) and the ratio of peak plasma concentration (C(max)) to MIC. Increasing the dose of levofloxacin to 750 mg exploits these parameters by increasing peak drug concentrations, allowing for a shorter course of treatment without diminishing therapeutic benefit. This was demonstrated in a multicenter, randomized, double-blind investigation that compared levofloxacin dosages of 750 mg per day for 5 days with 500 mg per day for 10 days for the treatment of mild to severe community-acquired pneumonia (CAP). In the clinically evaluable population, the clinical success rates were 92.4% (183 of 198 persons) for the 750-mg group and 91.1% (175 of 192 persons) for the 500-mg group (95% confidence interval, -7.0 to 4.4). Microbiologic eradication rates were 93.2% and 92.4% in the 750-mg and 500-mg groups, respectively. These data demonstrate that 750 mg of levofloxacin per day for 5 days is at least as effective as 500 mg per day for 10 days for treatment of mild-to-severe CAP.

Cigarette smoke decreases inducible nitric oxide synthase in lung epithelial cells.

Cigarette smoking has been associated with decreased exhaled nitric oxide (NO). To investigate the mechanism of this decrease, the effects of a cigarette smoke extract were evaluated a murine lung epithelial cell line (LA-4), a human lung epithelial cell line (A549), and primary cultures of human lung epithelial cells induced to produce NO by cytokines. NO production was evaluated by measuring nitrite, a stable end product of NO, in cell culture supernatant fluids. Cigarette smoke extract caused a reduction in the cytokine-induced nitrite concentrations in the culture supernatant fluids from all 3 cell types (P<.01, all comparisons). To further investigate these observations, immunohistochemistry demonstrated a decrease in cytokine-induced inducible NO synthase (iNOS) protein expression and iNOS mRNA after cigarette smoke extract exposure in LA-4 cells. However, iNOS mRNA half-life was not altered by the smoke extract, suggesting that the smoke extract decreased NO by decreasing iNOS mRNA transcription. These findings demonstrate that cigarette smoke extract decreases iNOS expression and NO production from lung epithelial cells.

Effect of diabetes, insulin, and glucose load on lipid peroxidation in the rat

Lipid peroxidative activity in rats made diabetic with streptozocin and rats made acutely hyperglycemic by intraperitoneal dextrose administration was determined by measurement of exhaled ethane during exposure in vivo to ethane-free air (EFA). Diabetic rats demonstrated increased ethane in the expired breath while breathing EFA (5.82 +/- 0.56 pmol/min/100 g) compared with control rats (4.02 +/- 0.23 pmol/min/100 g). Insulin treatment of diabetic rats attenuated the ethane produced (4.88 +/- 0.23 pmol/min/100 g). Acute hyperglycemia increased exhaled ethane to levels higher than those seen in diabetic rats (9.87 +/- 0.98 pmol/min/100 g). Saline injected intraperitoneally to control rats produced ethane levels similar to those of untreated nondiabetic controls (4.11 +/- 0.52 pmol/min/100 g). Chronic uncontrolled hyperglycemia and acute hyperglycemia are associated with increased in vivo ethane production.

Insomnia in patients with COPD.

STUDY OBJECTIVES Chronic obstructive pulmonary disease (COPD) is a leading cause of morbidity and mortality and may frequently be associated with sleep disturbances. However, the correlates of insomnia in COPD patients have not been well characterized. The aim of the current study was to describe the prevalence of insomnia disorder in COPD and to elucidate the demographic and clinical characteristics of COPD patients that are associated with insomnia. DESIGN Cross-sectional study. SETTING Clinic-based sample from an academic hospital. PARTICIPANTS Patients with stable COPD. MEASUREMENTS An interviewer-conducted survey was administered to 183 participants with COPD. Seventy-two of these participants (30 with and 42 without insomnia) maintained a sleep diary and underwent actigraphy for 7 days. RESULTS Insomnia (chronic sleep disturbance associated with impaired daytime functioning) was present in 27.3% of participants. Current tobacco users (odds ratio (OR), 2.13) and those with frequent sadness/anxiety (OR, 3.57) had higher odds, but oxygen use was associated with lower odds (OR, 0.35) of insomnia. Patients with insomnia had worse quality of life and a higher prevalence of daytime sleepiness. Actigraphy revealed shorter sleep duration and lower sleep efficiency, and a sleep diary revealed worse self-reported sleep quality in participants with insomnia. CONCLUSION Insomnia disorder is highly prevalent in patients with COPD; current tobacco use and sadness/anxiety are associated with a higher prevalence, and oxygen use with a lower prevalence of insomnia; patients with insomnia have poorer quality of life and increased daytime sleepiness; and insomnia is associated with worse objective sleep quality.

Premature discontinuation of patients: A potential bias in COPD clinical trials

Premature discontinuation from clinical trials may bias results against effective therapies. In the present study mortality rates were retrospectively reviewed in a 6-month, randomised, placebo-controlled trial in which tiotropium 18 μg daily was shown to decrease chronic obstructive pulmonary disease exacerbations. Patients participated for 6 months even if trial medication was prematurely discontinued. Exposure-adjusted incidence rates (IRs) were calculated for randomisation–end trial, randomisation–end trial drug (0–ED) and end trial drug–end trial (ED–ET). Of 1,829 patients (forced expiratory volume in one second 1.04 L (36% predicted), mean age 68 yrs, 99% male), 16% tiotropium and 27% placebo patients prematurely stopped trial medication. The number of fatal events for the entire cohort was: 62 all cause, including 16 cardiac and 16 lower respiratory. IRs for fatal events per 100 patient-yrs were higher in the discontinued period: 1.9 (0–ED) versus 23.0 (ED–ET) in the tiotropium group and 1.8 versus 19.0 in the placebo group. Respective IRs for fatal cardiac events were 0.7 versus 2.8 (tiotropium) and 0.5 versus 6.2 (placebo); for fatal lower respiratory events were 0.7 versus 2.8 (tiotropium) and 0.8 versus 5.4 (placebo). Rate ratios (tiotropium/placebo) for fatal events were lower in the discontinued period: 1.4 versus 0.5 for cardiac and 0.9 versus 0.5 for lower respiratory. Higher incidence rates of fatal events occurred following premature discontinuation of study medication. Incomplete information from rate ratios occurs as a result of failure to consider outcomes of patients who discontinue early from clinical trials.

Effects of Low-Dose Hydrogen Peroxide in the Isolated Perfused Rat Lung

Isolated perfused rat lungs (IPRL) were used to determine if treatment with hydrogen peroxide would result in measurable changes in exhaled ethane during the early stages of capillary leak. Pulmonary capillary filtration coefficient, pulmonary vascular resistance, and dynamic pulmonary compliance were measured at two time points in an IPRL. Additionally, exhaled ethane was determined before and after the addition of 0.25 mM H2O2 to the perfusate in a second group of lungs. Lung wet/dry weight ratios were measured at the termination of the experiments. The ethane in the exhaled alveolar gas from IPRLs ventilated with 5%CO2/20%O2/balance N2 was quantitated using gas chromatography before and after the addition of 0.25 mM H2O2 to Krebs Ringers 5% albumin perfusate. H2O2 (0.25 mM) caused a small but significant increase in capillary filtration coefficient from 0.0122 (+/- 0.0008) to 0.0173 (+/- 0.0013) mL/min/cm H2O/g dry lung weight (p < .05). Wet/dry lung weight ratios were increased in the H2O2-treated lungs (6.0654 +/- 0.1024 versus 5.4149 +/- 0.1143; p < .05). Exhaled ethane did not increase over the period of time hydrogen peroxide was present in the perfusate. In other experiments in closed-chested rats, 0.25 mM peroxide did not cause increased exhaled ethane, whereas 1 mM H2O2 did. This latter increase in ethane was not noted in similarly perfused open-chested rats. These data indicate that small amounts of H2O2 may increase pulmonary capillary permeability without affecting exhaled ethane measurements.

Enhanced Activity of Human IL-10 After Nitration in Reducing Human IL-1 Production by Stimulated Peripheral Blood Mononuclear Cells

Nitric oxide and superoxide form the unstable compound, peroxynitrite, which can nitrate proteins and compromise function of proinflammatory cytokines at sites of inflammation. Reduced function of proinflammatory proteins such as IL-8, macrophage inflammatory protein-1α, and eotaxin suggest an anti-inflammatory effect of nitration. The effects of nitration on anti-inflammatory cytokines such as IL-10 are unknown. We hypothesized that peroxynitrite would modify the function of anti-inflammatory cytokines like IL-10. To test this hypothesis, the capacity of recombinant human IL-10 to inhibit production of human IL-1β (IL-1) from LPS-stimulated human PBMC was evaluated. Human IL-10 was nitrated by incubation with peroxynitrite or by incubation with 3-morpholinosydnonimine, a peroxynitrite generator, for 2 h and then incubated with LPS-stimulated PBMC for 6 h, and IL-1 was measured in the culture supernatant fluids. Human IL-1 production was significantly lower in the peroxynitrite- or 3-morpholinosydnonimine-nitrated IL-10 group than in the IL-10 controls (p < 0.05, all comparisons). This finding demonstrates that although peroxynitrite inhibits proinflammatory cytokines, it may augment anti-inflammatory cytokines and further point to an important role for peroxynitrite in the regulation of inflammation.