There is an increase in vascularity in the asthmatic airway. Although inhaled corticosteroids (ICS) are an effective anti-inflammatory treatment in asthma, there are few data on any effects 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/mm2 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/mm2, p<0.05; 95% CI for the difference 48 to 286). There was no significant difference between asthmatic subjects on ICS and those not on ICS or control subjects in the number of vessels/mm2 (mean 421 (IQR 281–534)). However, patients who received ⩾800 μg/day BDP tended to have a reduced number of vessels/mm2 compared with patients not on ICS and those receiving ⩽500 μg/day BDP (mean 366 (IQR 153–608) versus 494 (IQR 391–583), p = 0.08; 95% CI for the difference –31 to 288). Similarly, there was an increase in the percentage of lamina propria occupied by vessels in asthmatic patients not on ICS compared with controls (mean 15.6% (IQR 13.1–18.0) versus 10.1% (IQR 8.4–13.3), p<0.01; 95% CI for the difference 2.4 to 9.3) but a significant decrease in the percentage of lamina propria occupied by vessels was detected in asthmatic patients on ICS (mean 11.4% (IQR 9.1–14.9), p<0.01; 95% CI for the difference 0.7 to 7.7) compared with those not on ICS. The density of vessels correlated significantly with both airway hyperresponsiveness and percentage change in forced expiratory volume in one second (FEV1) after bronchodilator (r = –0.38 for PD20 methacholine and r = 0.49 for change in percentage FEV1 after bronchodilator versus number of vessels/mm2, p<0.05).
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.
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.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.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%).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].
Introduction: Plecanatide is an orally administered 16 amino acid analog of the human GI peptide uroguanylin (UG). UG binds to and activates the guanylate cyclase-C (GC-C) receptor in the proximal small intestine in a pH-dependent manner, contributing to fluid secretion and normal bowel function. Plecanatide similarly binds to GC-C in a pH-dependent manner and is being developed for the treatment of CIC. Results are presented from the recently completed long-term, open-label study of plecanatide in CIC patients. Methods: The primary objective of this multicenter study was to assess the long term safety and tolerability of once daily plecanatide for the treatment of CIC. Patients who completed a previous double-blind study (Phase 2b or either of the two Phase 3 studies), select patients who had screen failed for either of the Phase 3 studies, or select patients who had not previously been treated with plecanatide may have been eligible for this study. Enrolled patients received 52 weeks (3mg) or up to 72 weeks (6mg) of plecanatide. Dose adjustments were not permitted. In addition to spontaneous adverse event (AE) reporting, patients completed Patient Global Assessment (PGA) questionnaires which included measures of patient satisfaction and desire to continue treatment on a scale of 1 to 5 (higher scores are better). Results: There were 2370 patient exposures in this study with the majority (90.5%) receiving treatment with the 6 mg dose; 1932 (81.5%) completed or were receiving study drug at the time the study met its enrollment goal and was ended. Treatment emergent adverse events (TEAEs) were qualitatively and quantitatively similar to those observed in prior double blindstudies. The most common AEs were diarrhea (7.1%) and urinary tract infection (2.2%). The remainder of the AEs occurred in < 2% of the patients. AEs leading to discontinuation occurred in 5.3% of patients; diarrhea leading to discontinuation occurred in 3.1%. The majority of TEAEs were mild or moderate in intensity and were generally considered not related to plecanatide treatment. The median score for treatment satisfaction was 4.0 (4=quite satisfied) and for continuation of treatment was 4.0 (4=quite likely). Conclusion: In this long term trial of CIC patients, plecanatide was well tolerated with low AE rates and low discontinuation rates. PGA assessments indicate that the patients were both satisfied with their treatment and likely to continue with plecanatide therapy.
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.Patients in group A received tobramycin eight hourly using a dose aimed at generating a peak concentration of 10 mg/l with trough concentrations below 2 mg/l, 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.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) mg/l) than in group A (7.9 (1.9) mg/l), whilst the average trough level was higher in group A (0.8 (0.3) mg/l) than in group B (0.5 (0.2) mg/l). There was a difference in the number of ototoxic events between patients in group A (seven of 18, 38.9%) and group B (none of eight), but no difference was found in other outcome measures assessed.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.
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