Background-There is an increase in vascularity in the asthmatic airway. Although inhaled corticosteroids (ICS) are an eVective anti-inflammatory treatment in asthma, there are few data on any eVects on structural changes. Methods-Endobronchial biopsy specimens from seven asthmatic subjects not receiving ICS and 15 receiving 200-1500 µg/ day beclomethasone dipropionate (BDP) were immunohistochemically stained with an anti-collagen type IV antibody to outline the endothelial basement membrane of the vessels. These were compared with biopsy tissue from 11 non-asthmatic controls (four atopic and seven non-atopic).Results-There was a significant increase in the density of vessels (number of vessels/mm 2 of lamina propria) in the asthmatic subjects not on ICS compared with non-asthmatic controls (mean 485 (interquartile range (IQR) 390-597) versus 329 (IQR 248-376) vessels/mm 2 , p<0.05; 95% CI for the diVerence 48 to 286). There was no significant diVerence between asthmatic subjects on ICS and those not on ICS or control subjects in the number of vessels/mm 2 (mean 421 (IQR 281-534)). However, patients who received >800 µg/ day BDP tended to have a reduced number of vessels/mm 2 compared with patients not on ICS and those receiving <500 Conclusion-These findings suggest that ICS, especially at higher doses, may reduce airway wall vascularity in asthmatic subjects but further longitudinal intervention studies are required to confirm this suggestion.

Background:Plecanatide, with the exception of a single amino acid replacement, is identical to human uroguanylin and is approved in the United States for adults with chronic idiopathic constipation (CIC). This double-blind, placebo-controlled, phase III study evaluated the efficacy and safety of plecanatide versus placebo in CIC.Methods:Adults meeting modified Rome III CIC criteria were randomized to plecanatide 3 mg (n = 443), 6 mg (n = 449), or placebo (n = 445). Patients recorded bowel movement (BM) characteristics [including spontaneous BMs (SBMs) and complete SBMs (CSBMs)] and rated CIC symptoms in daily electronic diaries. The primary endpoint was the percentage of durable overall CSBM responders (weekly responders for ⩾9 of 12 treatment weeks, including ⩾3 of the last 4 weeks). Weekly responders had ⩾3 CSBMs/week and an increase of ⩾1 CSBM from baseline for the same week.Results:A significantly greater percentage of durable overall CSBM responders resulted with each plecanatide dose compared with placebo (3 mg = 20.1%; 6 mg = 20.0%; placebo = 12.8%; p = 0.004 each dose). Over the 12 weeks, plecanatide significantly improved stool consistency and stool frequency. Significant increases in mean weekly SBMs and CSBMs began in week 1 and were maintained through week 12 in plecanatide-treated patients. Adverse events were mostly mild/moderate, with diarrhea being the most common (3 mg = 3.2%; 6 mg = 4.5%; placebo = 1.3%).Conclusions:Plecanatide resulted in a significantly greater percentage of durable overall CSBM responders and improved stool frequency and secondary endpoints. Plecanatide was well tolerated; the most common AE, diarrhea, occurred in a small number of patients.[ClinicalTrials.gov identifier: NCT02122471]

Background -There is evidence that administration of higher doses of aminoglycosides given less frequently improves the bactericidal effect and reduces the potential to cause side effects. To investigate this, a prospectively randomised open label therapeutic trial was undertaken in stratified groups of patients with cystic fibrosis to examine the efficacy and toxic potential of an aminoglycoside dosing regimen designed to generate high peak drug concentrations at 12 hourly intervals compared with conventional dosing at eight hourly intervals. Methods -Patients in group A received tobramycin eight hourly using a dose aimed at generating a peak concentration of 10 mgIl with trough concentrations below 2 mglI, and those in group B received the total daily dose required to achieve eight hourly target concentrations administered as two equal 12 hourly doses. Clinical outcomes measured and assessed included vestibular symptoms, hearing and renal function, length of hospital stay, readmission rate, and mortality. Results -Twenty nine patients were recruited during a six month period, 20 to group A and nine to group B. The average peak tobramycin level was higher in group B (12.5 (2.2) mgIl) than in group A (7.9 (1.9) mgIl), whilst the average trough level was higher in group A (0-8 (0.3) mgIl) than in group B (0-5 (0.2) mg/l). There was a difference in the number ofototoxic events between patients in group A (seven of 18, 38c9%) and group B (none of eight), but no difference was found in other outcome measures assessed. Conclusions -These results suggest that 12 hourly high peak aminoglycoside dosing may be less toxic than equivalent eight hourly dosing, without any apparent difference in efficacy. (Thorax 1996;51:369-373) Keywords: aminoglycosides, cystic fibrosis, ototoxicity.Aminoglycoside antibiotics provide an effective and inexpensive treatment for Gram negative infections, yet their usefulness as antibiotics has been limited by their potential to cause ototoxicity and nephrotoxicity. }6ere is evidence from both human and animal models that larger doses of aminoglycosides given less frequently reduce their potential to cause such side effects.4"'7 The efficacy of larger less frequent aminoglycoside dosing regimens becomes a concern in patient groups whose clearance of the drug makes the interdose interval more critical, and these patient groups must be included in any rational analysis of this issue. Patients with cystic fibrosis represent such a group.The primary pathogens implicated in the chronic lung infection associated with cystic fibrosis are Staphylococcus aureus, Streptococcus pneumoniae, Haemophilus influenzae, and Pseudomonas aeruginosa, the latter being responsible for chronic infection in 70-90% of all these patients.""24 P aeruginosa undergoes phenotypic adaptation within the lungs of patients with cystic fibrosis, the most important being the emergence of mucoid strains. The aim of this study was to examine the efficacy and toxic potential of a dosing regimen oftobramycin which generate...

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