New therapeutics based on emerging concepts in pulmonary fibrosis

Introduction: Fibrosis is an irreversible pathological endpoint in many chronic diseases, including pulmonary fibrosis. Idiopathic pulmonary fibrosis (IPF) is a progressive and often fatal condition characterized by (myo)fibroblast proliferation and transformation in the lung, expansion of the extracellular matrix, and extensive remodeling of the lung parenchyma. Recent evidence indicates that IPF prevalence and mortality rates are growing in the United States and elsewhere. Despite decades of research on the pathogenic mechanisms of pulmonary fibrosis, few therapeutics have succeeded in the clinic, and they have failed to improve IPF patient survival.

Areas covered: Based on a literature search and our own results, we discuss the key cellular and molecular responses that contribute to (myo)fibroblast actions and pulmonary fibrosis pathogenesis; this includes signaling pathways in various cells that aberrantly and persistently activate (myo)fibroblasts in fibrotic lesions and promote scar tissue formation in the lung.

Expert opinion: Lessons learned from recent failures and successes with new therapeutics point toward approaches that can target multiple pro-fibrotic processes in IPF. Advances in preclinical modeling and single-cell genomics will also accelerate novel discoveries for effective treatment of IPF.     

Neuroprotection in glaucoma

Neuroprotective therapies in glaucoma may play a role in preventing ischemia and oxidative damage that results in apoptosis of retinal ganglion cells and optic nerve damage. Although intraocular pressure (IOP) is the only known modifiable risk factor for glaucoma, disease progression commonly occurs despite IOP control, suggesting that factors other than IOP play a role in its pathogenesis and can potentially act as targets for neuroprotection. Factors including mediators of apoptosis, ischemic changes, poor ocular blood flow and neurotoxins have been hypothesized to play a role in glaucoma progression. Neuroprotective targets include glutamate-induced neurotoxicity, nitric oxidase synthetase, neurotropins, calcium channel receptors, free radicals, vascular insufficiency, the rho-kinase pathway, and more. Drugs related to these factors are being evaluated for their role in neuroprotection, although this area of investigation faces several challenges including limited evidence for these agents’ efficacy in clinical studies. Additionally, while IOP-lowering therapies are considered neuroprotective as they generally slow the progress of glaucoma progression, they are limited by the extent of their effect beyond IOP control. The aim of this article is to review the current treatment options available for neuroprotection and to explore the drugs in the pipeline.     

Subjective and objective measures of the patient experience before,during, and after intravitreal anti–vascular endothelial growth factor injections

Purpose:To assess patient experience of intravitreal injections using vital-signs, visual-experience, pain-rating and emotional response during intravitreal anti-VEGF injections.Methods:A prospective observational study of patient experience of intravitreal anti-VEGF injections done following metrics were collected pre-injection, during injection, and post-injection: pain assessment using visual analog score, fear-response rating, visual-experience questionnaire, and vital-signs.Results:A total of one-hundred-and-seventy-four patients undergoing intravitreal anti-VEGF injections for retinal pathologies were included in the study. Mean age was 58.8 ± 10.4 years in <5 injection group (n = 133) and 59.02 ± 9.0 years in ≥5 injection group (n = 41) (P = 0.90).During injection, 90.2% of patients in <5 injection group reported moderate or severe pain compared to 78% of patients in ≥5 injection group. In pre and post-injection phases, mild-to-moderate pain was reported in both groups (P = <0.001). Ninety-two (52.9%) patients reported having a mild frightening experience. There was no statistical significance in patients assessment of fear with respect to age, sex, or number of injections. The Systolic Blood Pressure (SBP) during and following injection ((SBP 171.7 ± 21.1,150.8 ± 16.2) procedures was significantly higher in cases with <5 injections when comparing to cases with >5 injections (SBP 159.7 ± 26.4, 143.2 ± 17.0) (P = 0.003), (P = 0.011). DBP, heart rate, pulse rate measurements were similar among patients in all phases of the study.Conclusion:We report a large sample size with comprehensive assessments of the patient experience. Higher pain ratings in the <5 injection group, the increase in the SBP in the pre-and during injection phases, and the overall rating of mild-to-moderate fear during the procedure.     

Randomized,double-blinded,placebo-controlled trial evaluating simethicone pretreatment with bowel preparation during colonoscopy

BACKGROUND The presence of small air bubbles and foam are an impediment to a successful colonoscopy. They impair an endoscopist's view and diminish the diagnostic accuracy of the study. This has been particularly noted to be of concern with the switch to lower volume polyethylene glycol(PEG) and bisacodyl combination preparation.AIM To evaluate the effect of oral simethicone addition to bowel preparation on intraluminal bubbles reduction during colonoscopy.METHODS Described is a prospective, randomized, multi-center, double-blinded, placebocontrolled study to evaluate the use of premixed simethicone formulation with split-regimen, low-volume PEG-bisacodyl combination bowel preparation for 168 outpatients undergoing screening, surveillance, and diagnostic colonoscopies.Primary outcome includes evaluation of bubbles during colonoscopy graded using the Intraluminal Bubbles Scale. Secondary outcomes include evaluation ofthe Boston Bowel Preparation Scale(BBPS), total number of polyps, polyp size differentiation, polyp laterality, adenoma detection, mass detection, cecal insertion time, withdrawal time, and patient-reported adverse events.RESULTS Higher Intraluminal Bubbles grades III and IV(less than 75% of the mucosa cleared of bubbles/foam requiring intervention with simethicone infused wash)were detected in the placebo group [Simethicone n = 4/84 vs Placebo n = 20/84(P= 0.007)]. BBPS total score was 7.42 [standard deviation(SD) = ± 1.51] in the simethicone group and 7.28(SD = ± 1.44) in the placebo group(P = 0.542) from a total of 9. Significantly higher number of adenomas were detected in the simethicone group(P = 0.001).CONCLUSION The addition of simethicone to bowel preparation is well advised for its antifoaming properties. The results of this study suggest that addition of oral simethicone can improve bowel wall visibility.     

Visual acuity outcomes in ranibizumab-treated neovascular age-related macular degeneration; stratified by baseline vision

Background: Ranibizumab (Lucentis, Novartis, Basel, Switzerland) is currently indicated for use in neovascular age‐related macular degeneration (NVAMD). This study assessed the real‐life outcomes based on baseline visual acuity when treated with intravitreal ranibizumab on a three + pro re nata (PRN) dosing schedule for NVAMD. Design: This retrospective chart‐review was conducted at King's College Hospital. The patients were stratified into three groups based on baseline Early treatment diabetic retinopathy study (ETDRS) letters: 27 with poor visual acuity (24–34 letters), 33 with intermediate visual acuity (35–54 letters) and 27 with good visual acuity (≥=55 letters). Methods: All patients received a three + PRN dosing schedule of ranibizumab injections (0.5 mg per 0.05 mL) based on changes in visual acuity and macular thickness on optical coherence tomography (OCT) and all patients completed 12‐month follow up. Main Outcome Measures: The mean change in visual acuity at 12 months in the three groups. Results: Mean gain in ETDRS letters at 12 months was +14.00 (P < 0.0001), +7.10 (P = 0.012) and +2.85 (P = 0.19), and mean number of injections was 5.30, 6.12 and 5.70 in the poor, intermediate and good baseline vision group, respectively, over the 12‐ month follow‐up period. Conclusions: Poor baseline visual acuity (24–34 ETDRS letters) is a predictor of maximum gain in visual acuity. However, eyes with better baseline visual acuity (55 letters) had a better final visual acuity.     

Qualitative and quantitative OCT response of diffuse diabetic macular oedema to macular laser photocoagulation

Purpose

To assess the quantitative and morphological changes of the macula in response to macular grid laser for diabetic macular oedema (DMO) using optical coherence tomography (OCT).

Patients and Methods

Cirrus OCT macular cube scans of 30 eyes of 25 patients were retrospectively analysed before and 4 months after macular grid laser for diffuse DMO. The oedema was quantified and response evaluated in the nine early-treatment diabetic retinopathy study (ETDRS) zones of the macula. Post-laser OCT changes were compared with the baseline features, including morphology patterns, changes in both logarithmic transformed (logOCT) and standardised average macular thickness (AMT), total macular volume, number of parafoveal quadrants involved, and the presence of intact 3rd hyper-reflective band (HRB).

Results

The rate of change of retinal thickness in response to laser was maximum in the central (8.17%) and perifoveal inferior quadrants (0.04%). Diffuse retinal thickening on OCT responded best to treatment. The AMT of 300–350 μm had the worst response (+0.94%). Eyes with less than four quadrants of oedema showed good response. Disrupted HRB was associated with poor visual gain (−0.33 ETDRS letters).

Conclusion

The topographic location of oedema on the retinal map and the morphological patterns of the oedema on OCT are useful predictors of treatment response in diffuse DMO.