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.     

An Improvement of the Efficacy of Moxifloxacin HCl for the Treatment of Bacterial Keratitis by the Formulation of Ocular Mucoadhesive Microspheres

The aim of this study was to prepare novel ocular mucoadhesive microspheres of Moxifloxacin HCl to increase its residence time on the ocular surface and to enhance its therapeutic efficacy in ocular bacterial keratitis. Microspheres were fabricated with different grades of Methocel and Sodium CMC as polymers. Microspheres were evaluated for their particle size, morphology, encapsulation efficiency, mucoadhesion, antimicrobial efficacy, and in vitro drug release studies. In vivo studies were carried out for the promising formulation on eyes of albino rabbits by inducing bacterial keratitis. A sterile microspheres suspension in light mineral oil was applied to infected eyes twice a day. A marketed conventional eye drop was used as a positive control. Eyes were examined daily for improvement of clinical signs of bacterial keratitis by an ophthalmologist. The average particle size of microspheres was found to be less than 80 μm. Methocel microspheres were found to have a smoother surface than Sodium CMC. Entrapment efficiency was enhanced with an increased polymer concentration and viscosity. The formulation containing Methocel K100M with a drug: polymer ratio of 1:2 exerted longer corneal and conjunctival mucoadhesion time of 8.45±0.15 h and 9.40±0.53 h respectively. In vitro release of Moxifloxacin HCl from microspheres was retarded with increased viscosity and concentration of polymers, and was controlled by diffusion as well as polymer relaxation. All formulations showed comparable antimicrobial activity in comparison with conventional marketed eye drops. The formulation containing Methocel K100M with a drug: polymer ratio of 1:2 was found to be a promising formulation and was used for the in vivo studies. The in vivo studies revealed that microspheres demonstrated significantly lower clinical scores and reduced the total duration of therapy than the marketed Moxifloxacin HCl eye drops. In vitro and in vivo studies showed that ocular mucoadhesive microspheres of Moxifloxacin HCl were found to have an improved efficacy in the treatment of ocular bacterial keratitis in comparison with the marketed formulation.     

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.