Hugh Greville

Inhaled, dual release liposomal ciprofloxacin in non-cystic fibrosis bronchiectasis (ORBIT-2): a randomised, double-blind, placebo-controlled trial

Background The delivery of antipseudomonal antibiotics by inhalation to Pseudomonas aeruginosa-infected subjects with non-cystic fibrosis (CF) bronchiectasis is a logical extension of treatment strategies successfully developed in CF bronchiectasis. Dual release ciprofloxacin for inhalation (DRCFI) contains liposomal ciprofloxacin, formulated to optimise airway antibiotic delivery. Methods Phase II, 24-week Australian/New Zealand multicentre, randomised, double-blind, placebo-controlled trial in 42 adult bronchiectasis subjects with ≥2 pulmonary exacerbations in the prior 12 months and ciprofloxacin-sensitive P aeruginosa at screening. Subjects received DRCFI or placebo in three treatment cycles of 28 days on/28 days off. The primary outcome was change in sputum P aeruginosa bacterial density to the end of treatment cycle 1 (day 28), analysed by modified intention to treat (mITT). Key secondary outcomes included safety and time to first pulmonary exacerbation—after reaching the pulmonary exacerbation endpoint subjects discontinued study drug although remained in the study. Results DRCFI resulted in a mean (SD) 4.2 (3.7) log10 CFU/g reduction in P aeruginosa bacterial density at day 28 (vs −0.08 (3.8) with placebo, p=0.002). DRCFI treatment delayed time to first pulmonary exacerbation (median 134 vs 58 days, p=0.057 mITT, p=0.046 per protocol). DRCFI was well tolerated with a similar incidence of systemic adverse events to the placebo group, but fewer pulmonary adverse events. Conclusions Once-daily inhaled DRCFI demonstrated potent antipseudomonal microbiological efficacy in adults with non-CF bronchiectasis and ciprofloxacin-sensitive P aeruginosa. In this modest-sized phase II study, DRCFI was also well tolerated and delayed time to first pulmonary exacerbation in the per protocol population.

Ciprofloxacin dry powder for inhalation in non-cystic fibrosis bronchiectasis: a phase II randomised study

This phase II, randomised, double-blind, multicentre study (NCT00930982) investigated the safety and efficacy of ciprofloxacin dry powder for inhalation (DPI) in patients with non-cystic fibrosis bronchiectasis. Adults who were culture positive for pre-defined potential respiratory pathogens (including Pseudomonas aeruginosa and Haemophilus influenzae) were randomised to ciprofloxacin DPI 32.5 mg or placebo administered twice daily for 28 days (with 56 days of follow-up). Bacterial density in sputum (primary end-point), pulmonary function tests, health-related quality of life and safety were monitored throughout the study. 60 subjects received ciprofloxacin DPI 32.5 mg and 64 received placebo. Subjects on ciprofloxacin DPI had a significant reduction (p<0.001) in total sputum bacterial load at the end of treatment (-3.62 log10 CFU·g−1 (range -9.78–5.02 log10 CFU·g−1)) compared with placebo (-0.27 log10 CFU·g−1 (range -7.96–5.25 log10 CFU·g−1)); the counts increased thereafter. In the ciprofloxacin DPI group, 14 (35%) out of 40 subjects reported pathogen eradication at end of treatment versus four (8%) out of 49 in the placebo group (p=0.001). No abnormal safety results were reported and rates of bronchospasm were low. Ciprofloxacin DPI 32.5 mg twice daily for 28 days was well tolerated and achieved significant reductions in total bacterial load compared with placebo in subjects with non-cystic fibrosis bronchiectasis.

Exercise-induced hypoxaemia in highly trained cyclists at 40% peak oxygen uptake

Abstract A group of 15 competitive male cyclists [mean peak oxygen uptake, V˙O2peak 68.5 (SEM 1.5 ml · kg−1 · min−1)] exercised on a cycle ergometer in a protocol which began at an intensity of 150 W and was increased by 25 W every 2 min until the subject was exhausted. Blood samples were taken from the radial artery at the end of each exercise intensity to determine the partial pressures of blood gases and oxyhaemoglobin saturation (SaO2), with all values corrected for rectal temperature. The SaO2 was also monitored continuously by ear oximetry. A significant decrease in the partial pressure of oxygen in arterial blood (PaO2) was seen at the first exercise intensity (150 W, about 40% V˙O2peak). A further significant decrease in PaO2 occurred at 200 W, whereafter it remained stable but still significantly below the values at rest, with the lowest value being measured at 350 W [87.0 (SEM 1.9) mmHg]. The partial pressure of carbon dioxide in arterial blood (PaCO2) was unchanged up to an exercise intensity of 250 W whereafter it exhibited a significant downward trend to reach its lowest value at an exercise intensity of 375 W [34.5 (SEM 0.5) mmHg]. During both the first (150 W) and final exercise intensities (V˙O2peak) PaO2 was correlated significantly with both partial pressure of oxygen in alveolar gas (PAO2, r = 0.81 and r = 0.70, respectively) and alveolar-arterial difference in oxygen partial pressure (PA−aO2, r = 0.63 and r = 0.86, respectively) but not with PaCO2. At V˙O2peakPaO2 was significantly correlated with the ventilatory equivalents for both oxygen uptake and carbon dioxide output (r = 0.58 and r = 0.53, respectively). When both PAO2 and PA−aO2 were combined in a multiple linear regression model, at least 95% of the variance in PaO2 could be explained at both 150 W and V˙O2peak. A significant downward trend in SaO2 was seen with increasing exercise intensity with the lowest value at 375 W [94.6 (SEM 0.3)%]. Oximetry estimates of SaO2 were significantly higher than blood measurements at all times throughout exercise and no significant decrease from rest was seen until 350 W. The significant correlations between PaO2 and PAO2 with the first exercise intensity and at V˙O2peak led to the conclusion that inadequatehyperventilation is a major contributor to exercise-induced hypoxaemia.

Gastric emptying, incretin hormone secretion, and postprandial glycemia in cystic fibrosis - Effects of pancreatic enzyme supplementation

CONTEXT Postprandial hyperglycemia is an important clinical problem in cystic fibrosis (CF), but the contribution of fat malabsorption, rapid gastric emptying, and the incretin axis has not been widely considered. OBJECTIVE The aim of this study was to evaluate these aspects of gut function in nondiabetic CF patients. DESIGN AND SETTING We conducted a randomized, double-blind, placebo-controlled crossover study at a clinical research laboratory. PATIENTS Five nondiabetic CF patients (three males; age, 25.8 ± 1.0 yr; body mass index, 20.2 ± 1.1 kg/m(2)) with exocrine pancreatic insufficiency and six healthy subjects of similar age and body mass index participated in the study. INTERVENTIONS CF patients consumed a radiolabeled mashed potato meal on 2 separate days, together with four capsules of Creon Forte (100,000 IU lipase) or placebo. Healthy subjects consumed the meal once, without pancreatic enzymes. MAIN OUTCOME MEASURES Gastric emptying was measured using scintigraphy, and blood was sampled frequently for blood glucose and plasma glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), and glucagon concentrations. RESULTS CF patients had more rapid gastric emptying (P < 0.001), impaired secretion of GLP-1 (P < 0.01) and GIP (P < 0.001), and greater postprandial glycemic excursions (P < 0.001) than healthy subjects. Pancreatic enzyme supplementation normalized gastric emptying and GLP-1 secretion and tended to increase glucagon (P = 0.08), but did not completely restore GIP secretion or normalize postprandial blood glucose. There was an excellent correlation between gastric emptying and blood glucose concentration at 60 min (R = 0.75; P = 0.01). CONCLUSIONS Pancreatic enzyme supplementation plays an important role in incretin secretion, gastric emptying, and postprandial hyperglycemia in CF.

Nonvolumetric Echocardiographic Indices of Right Ventricular Systolic Function: Validation with Cardiovascular Magnetic Resonance and Relationship with Functional Capacity

Purpose: Right ventricular (RV) systolic function as measured by right ventricular ejection fraction (RVEF) has long been recognized as an important predictor of outcome in heart failure patients. The echocardiographic measurement of RV volumes and RVEF is challenging, however, owing to the unique geometry of the right ventricle. Several nonvolumetric echocardiographic indices of RV function have demonstrated prognostic value in heart failure. Comparison studies of these techniques with each other using RVEF as a benchmark are limited, however. Furthermore, the contribution of these various elements of RV function to patient functional status is uncertain. We therefore aimed to: (1) Determine which nonvolumetric echocardiographic index correlates best with RVEF as determined by cardiac magnetic resonance (CMR) imaging (the accepted gold standard measure of RV systolic function) and (2) Ascertain which echocardiographic index best predicts functional capacity. Methods: Eighty‐three subjects (66 with systolic heart failure and 17 healthy controls) underwent CMR, 2D echocardiography, and cardiopulmonary exercise testing for comparison of echocardiographic indices of RV function with CMR RVEF, 6‐minute walk distance and VO2 PEAK. Results: Speckle tracking strain RV strain exhibited the closest association with CMR RV ejection fraction. Indices of RV function demonstrated weak correlation with 6‐minute walk distance, but basal RV strain rate by tissue velocity imaging had good correlation with VO2 PEAK. Conclusion: Strain by speckle tracking echocardiography and strain rate by tissue velocity imaging may offer complementary information in the evaluation of RV contractility and its functional effects. (Echocardiography 2012;29:455‐463)

Arterial hypoxaemia in endurance athletes is greater during running than cycling.

The effect of both training discipline and exercise modality on exercise-induced hypoxaemia (EIH) was examined in seven runners and six cyclists during 5 min high intensity treadmill and cycle exercise. There were no significant interactions between training discipline, exercise modality and arterial P(O(2)) (Pa(O(2))) when subject groups were considered separately but when pooled there were significant differences between exercise modalities. After min 2 of exercise arterial hydrogen ion concentration, minute ventilation, alveolar P(O(2)) (PA(O(2))) and Pa(O(2)) were all lower with treadmill running with the largest differential for the latter occurring at min 5 (treadmill, 80.8+/-1.8; cycle, 90.2+/-2.5, mmHg, N=13, P< or = 0.05). At every min of exercise, the differences in Pa(O(2)) between the ergometers were strongly associated with similar differences in PA(O(2)) and alveolar to arterial P(O(2)) (PA(O(2))-Pa(O(2))). It is concluded that the greater EIH with treadmill running is a consequence of the combined effect of a reduced lactic acidosis-induced hyperventilation and greater ventilation-perfusion inequality with this exercise mode.

Evaluation of the 13C‐triolein breath test for fat malabsorption in adult patients with cystic fibrosis

Background and Aims: A simple non‐invasive test not requiring the use of radioactive isotopes is required to assess fat malabsorption in adult cystic fibrosis (CF) patients. Breath tests using substrates labeled with 13C meet these conditions. The 14C‐triolein breath test is sensitive and specific for measuring fat malabsorption, but involves radiation exposure. The aim of this study was to examine the utility of a test using a 13C label and to determine whether pancreatic replacement therapy would return the test to the values of a normal control group.

Rituximab use in systemic lupus erythematosus pneumonitis and a review of current reports

Rituximab is a chimeric monoclonal antibody specific for human CD20 that causes selective transient depletion of the CD20+ B‐cell subpopulation. We report the first case of systemic lupus erythematosus (SLE) pneumonitis resistant to conventional treatments that responded well to rituximab and review current reports on the use of rituximab in SLE.

Intravenous zoledronate improves bone density in adults with cystic fibrosis (CF).

Objective  Reduced bone mineral density (BMD) and increased rates of atraumatic fracture are observed in cystic fibrosis (CF) patients, causing increasing morbidity as this population ages. The study aimed to assess the safety, tolerability and effect on BMD of intravenous zoledronate in adults with CF and osteopaenia.

Renal dysfunction in cystic fibrosis: is there cause for concern?

Most people associate cystic fibrosis (CF) with lung disease. Although this is the major cause of morbidity and mortality, CF is in fact a multi‐organ disease. Patients with CF are living longer. Accompanying their increased life expectancy are complications not previously encountered. One of the less obvious concerns is that of renal dysfunction associated with long‐term exposure to aminoglycosides as well as renally toxic immunosuppressants in lung transplant recipients. This article reviews what is known about the extent of the problem, summarizes what the current practices of measuring and monitoring renal function in patients with CF, and makes suggestions for alternative approaches. In particular, the potential role of cystatin C will be discussed. Pediatr Pulmonol. 2009; 44:947–953. ©2009 Wiley‐Liss, Inc.