BIIL 284 reduces neutrophil numbers but increases P. aeruginosa bacteremia and inflammation in mouse lungs

Background: A clinical study to investigate the leukotriene B4 (LTB4)-receptor antagonist BIIL 284 in cystic fibrosis (CF) patients was prematurely terminated due to a significantly increased risk of adverse pulmonary events. We aimed to establish the effect of BIIL284 in models of Pseudomonas aeruginosa lung infection, thereby contributing to a better understanding of what could have led to adverse pulmonary events in CF patients. Methods: P. aeruginosa DNA in the blood of CF patients during and after acute pulmonary exacerbations and in stable patients with non-CF bronchiectasis (NCFB) and healthy individuals was assessed by PCR. The effect of BIIL 284 treatment was tested in an agar bead murine model of P. aeruginosa lung infection. Bacterial count and inflammation were evaluated in lung and other organs. Results: Most CF patients (98%) and all patients with NCFB and healthy individuals had negative P. aeruginosa DNA in their blood. Similarly, the P. aeruginosa-infected mice showed bacterial counts in the lung but not in the blood or spleen. BIIL 284 treatment decreased pulmonary neutrophils and increased P. aeruginosa numbers in mouse lungs leading to significantly higher bacteremia rates and lung inflammation compared to placebo treated animals. Conclusions: Decreased airway neutrophils induced lung proliferation and severe bacteremia in a murine model of P. aeruginosa lung infection. These data suggest that caution should be taken when administering anti-inflammatory compounds to patients with bacterial infections

Protective effect of urodilatin (URO) or ANP against an acetylcholine(ACH)-induced bronchoconstriction in the rat in vivo: Abstract

Inhaled ANP inhibits histamine induced bronchoconstriction in man. We compared the protective effect of equimolar doses of intravenous ANP and URO against a bronchoconstriction induced by ACH-inhalation in 46 anaesthetized intubated spontaneously breathing Wistar-rats. The animals received an intravenous infusion of 0.5 ml ANP, URO or vehicle (NaCl) for 10 min. During the infusion period an ACH-challenge test was started after 5 min. Using whole-bodyplethysmography typical spontaneous respiratory function parameters were recorded under steady state conditions before the infusion and before and at the of the ACH-challenge. Forced parameters (volume-time and flow-volume relation) were measured in hyperventilation-induced apnoe after the ACH-challenge and included e.g. FVC, FEV0.1, FEV0.2, PEF, MMEF, FEF75, FEF50 and FEF25. ACH induced a significant bronchoconstriction without any significant difference between the treatment groups regarding the spontaneous breathing and forced volume-time relation parameters. The more sensitive flow-volume curve, however, showed a significant protective effect of 11.4 and 22.8 pmol/kg/min (40 and 80 ng/kg/min) URO compared to the control group while the infusion of ANP was without any significant influence in all three dose groups. Heart rate was controlled by ECG and did not change significantly during the infusion period before and at the end of the ACH-challenge. It is concluded that intravenous URO but not ANP shows a significant protective effect against ACH-induced bronchoconstriction in rats in vivo

Report of the European Respiratory Society/European Cystic Fibrosis Society task force on the care of adults with cystic fibrosis

The improved survival in people with cystic fibrosis has led to an increasing number of patients reaching adulthood. This trend is likely to be maintained over the next decades, suggesting a need to increase the number of centres with expertise in the management of adult patients with cystic fibrosis. These centres should be capable of delivering multidisciplinary care addressing the complexity of the disease, in addition to addressing the psychological burden on patients and their families. Further issues that require attention are organ transplantation and end of life management.Lung disease in adults with cystic fibrosis drives most of the clinical care requirements, and major life-threatening complications, such as respiratory infection, respiratory failure, pneumothorax and haemoptysis, and the management of lung transplantation require expertise from trained respiratory physicians. The taskforce therefore strongly reccommends that medical leadership in multidisciplinary adult teams should be attributed to a respiratory physician adequately trained in cystic fibrosis management.The task force suggests the implementation of a core curriculum for trainees in adult respiratory medicine and the selection and accreditation of training centres that deliver postgraduate training to the standards of the HERMES programme