Early results on the use of chitosan-N-acetylcysteine (Lacrimera®) in the management of dry eye disease of varied etiology

PurposeTo evaluate the effect of once daily administration of chitosan-N-acetylcysteine (Lacrimera®) in the management of dry eye disease (DED).MethodsEighteen patients (3 male, 15 female) aged 25–86 years (mean 61.1) and suffering from moderate to severe DED with superficial punctate keratitis (SPK) were retrospectively evaluated after a trial of Lacrimera® drops (1 drop in the morning for 5 days only). All the patients were using other artificial tears before the treatment. All lubricants were stopped, and Lacrimera® was started instead. Slit-lamp examination and images were taken before and at 1 and 3 weeks follow-up after the treatment. The subjective (Ocular Surface Disease Index, OSDI) and objective (Oxford Grading System, OGS) evaluation was recorded. A paired student’s t test was performed to analyse the data.ResultsAt baseline, the SPK grade was I to IV (OGS) and the OSDI ranged from 25 to 71.4. Fifteen patients showed a statistically significant (p < 0.0001) improvement in OGS and the OSDI at 3 weeks post-treatment. Three patients showed no improvement.ConclusionsA single-dose instillation of chitosan-N-acetylcysteine for five consecutive days improved signs and symptoms in patients affected from DED from a variety of causes, who were refractory to standard treatment with lubricants. Given its posology, the absence of side effects and the results obtained Lacrimera® should be taken into consideration as a viable option in patients with moderate to severe DED

The development of a novel human corneal substitute using decellularized corneas

The development of a novel human corneal substitute using decellularized cornea

Human antimicrobial peptides in ocular surface defense

Sight depends on the passage of light through the transparent cornea and being focused on the fovea. Its exposed position renders it vulnerable to microbial infection. The cornea has developed a wide array of defense mechanisms against infection, of which endogenous antimicrobial peptides (AMPs) are key. AMPs are essentially small molecular weight cationic peptides with a wide range of activity against virus, bacteria, fungi and parasites. Some proteins such as RNases and S100As are also included in this group. Several AMPs act synergistically allowing low expression of multiple AMPs to act efficiently. AMPs also have a range of non-microbicidal functions and serve as signaling molecules, immunomodulators; show anti-tumour activity, and influence vascularization and wound healing. Different toll-like receptors (TLR) have been implicated in the preferential induction of specific AMPs. A range of bacteria, including mycobacteria tuberculosis, viruses including herpes virus, fungi and parasites including acanthamoeba, that cause ocular infections have been shown to induce specific AMPs via TLR activation. Non-TLR mediated induction of AMP expression can occur and several molecules such as L-isoleucine, sodium butyrate, vitamin D3, phenylbutyrate, vasoactive intestinal peptide, and etinostat have been identified in this regard. Given the rising microbe resistance to antibiotics, the slow rate of development of new antibiotics and the limited access to effective antibiotics by patients living in the developing world, an ideal solution would be to find AMPs that are effective singly or in combination with each other or other antimicrobial proteins to reduce, if possible eliminate reliance on antibiotics alone

Strategies in Translating the Therapeutic Potentials of Host Defense Peptides

The golden era of antibiotics, heralded by the discovery of penicillin, has long been challenged by the emergence of antimicrobial resistance (AMR). Host defense peptides (HDPs), previously known as antimicrobial peptides, are emerging as a group of promising antimicrobial candidates for combatting AMR due to their rapid and unique antimicrobial action. Decades of research have advanced our understanding of the relationship between the physicochemical properties of HDPs and their underlying antimicrobial and non-antimicrobial functions, including immunomodulatory, anti-biofilm, and wound healing properties. However, the mission of translating novel HDP-derived molecules from bench to bedside has yet to be fully accomplished, primarily attributed to their intricate structure-activity relationship, toxicity, instability in host and microbial environment, lack of correlation between in vitro and in vivo efficacies, and dwindling interest from large pharmaceutical companies. Based on our previous experience and the expanding knowledge gleaned from the literature, this review aims to summarize the novel strategies that have been employed to enhance the antimicrobial efficacy, proteolytic stability, and cell selectivity, which are all crucial factors for bench-to-bedside translation of HDP-based treatment. Strategies such as residues substitution with natural and/or unnatural amino acids, hybridization, L-to-D heterochiral isomerization, C- and N-terminal modification, cyclization, incorporation with nanoparticles, and “smart design” using artificial intelligence technology, will be discussed. We also provide an overview of HDP-based treatment that are currently in the development pipeline

A novel antimicrobial peptide on the ocular surface shows decreased expression in inflammation and infection

PURPOSE: Antimicrobial peptides (AMPs) are cationic host defense peptides with microbicidal and cell-signaling properties. They show promise as potential therapeutic agents. In the present study, a beta-defensin AMP gene was isolated from the ocular surface for the first time, and its expression was characterized in the presence of ocular inflammation and/or infection.METHODS: Total RNA was obtained from impression cytology samples of the conjunctiva and cornea of normal patients and of those with bacterial, viral, acanthamoeba, or dry eye disease. The expression of the beta-defensin AMP DEFB-109 was determined by using reverse transcription-polymerase chain reaction (RT-PCR). Relative quantification of the gene in the various groups was performed by means of real-time PCR.RESULTS:DEFB-109 was constitutively expressed in all samples. The gene showed significantly decreased expression in the presence of all types of inflammation/infection. Reduced expression featured most prominently in acanthamoeba infection; the least change from normal was in dry eye.CONCLUSIONS:The discovery of DEFB-109 on the ocular surface enhances our knowledge of the profile of AMPs at this important mucosal surface. The fact that its expression is significantly reduced in both inflammatory and infective ocular surface disease reflects not only an intimate balance between this host defense gene and microbes but indicates a role other than purely microbicidal. This discovery will enable the mechanisms behind the intriguing phenomenon of reduced gene expression of an AMP in disease states to be uncovered

Corneal nerves in health and disease

The cornea is the most sensitive structure in the human body. Corneal nerves adapt to maintain transparency and contribute to corneal health by mediating tear secretion and protective reflexes and provide trophic support to epithelial and stromal cells. The nerves destined for the cornea travel from the trigeminal ganglion in a complex and coordinated manner to terminate between and within corneal epithelial cells with which they are intricately integrated in a relationship of mutual support involving neurotrophins and neuromediators. The nerve terminals/receptors carry sensory impulses generated by mechanical, pain, cold and chemical stimuli. Modern imaging modalities have revealed a range of structural abnormalities such as attrition of nerves in neurotrophic keratopathy and post-penetrating keratoplasty; hyper-regeneration in keratoconus; decrease of sub-basal plexus with increased stromal nerves in bullous keratopathy and changes such as thickening, tortuosity, coiling and looping in a host of conditions including post corneal surgery. Functionally, symptoms of hyperaesthesia, pain, hypoaesthesia and anaesthesia dominate. Morphology and function do not always correlate. Symptoms can dominate in the absence of any visible nerve pathology and vice-versa. Sensory and trophic functions too can be dissociated with pre-ganglionic lesions causing sensory loss despite preservation of the sub-basal nerve plexus and minimal neurotrophic keratopathy. Structural and/or functional nerve anomalies can be induced by corneal pathology and conversely, nerve pathology can drive inflammation and corneal pathology. Improvements in accuracy of assessing sensory function and imaging nerves in vivo will reveal more information on the cause and effect relationship between corneal nerves and corneal diseases

Host Defence Peptides: A Potent Alternative to Combat Antimicrobial Resistance in the Era of the COVID-19 Pandemic

One of the greatest challenges facing the medical community today is the ever-increasing trajectory of antimicrobial resistance (AMR), which is being compounded by the decrease in our antimicrobial armamentarium. From their initial discovery to the current day, antibiotics have seen an exponential increase in their usage, from medical to agricultural use. Benefits aside, this has led to an exponential increase in AMR, with the fear that over 10 million lives are predicted to be lost by 2050, according to the World Health Organisation (WHO). As such, medical researchers are turning their focus to discovering novel alternatives to antimicrobials, one being Host Defence Peptides (HDPs). These small cationic peptides have shown great efficacy in being used as an antimicrobial therapy for currently resistant microbial variants. With the sudden emergence of the SARS-CoV-2 variant and the subsequent global pandemic, the great versatility and potential use of HDPs as an alternative to conventional antibiotics in treating as well as preventing the spread of COVID-19 has been reviewed. Thus, to allow the reader to have a full understanding of the multifaceted therapeutic use of HDPs, this literature review shall cover the association between COVID-19 and AMR whilst discussing and evaluating the use of HDPs as an answer to antimicrobial resistance (AMR)

Host defense peptides at the ocular surface: roles in health and major diseases, and therapeutic potentials.

Sight is arguably the most important sense in human. Being constantly exposed to the environmental stress, irritants and pathogens, the ocular surface - a specialized functional and anatomical unit composed of tear film, conjunctival and corneal epithelium, lacrimal glands, meibomian glands, and nasolacrimal drainage apparatus - serves as a crucial front-line defense of the eye. Host defense peptides (HDPs), also known as antimicrobial peptides, are evolutionarily conserved molecular components of innate immunity that are found in all classes of life. Since the first discovery of lysozyme in 1922, a wide range of HDPs have been identified at the ocular surface. In addition to their antimicrobial activity, HDPs are increasingly recognized for their wide array of biological functions, including anti-biofilm, immunomodulation, wound healing, and anti-cancer properties. In this review, we provide an updated review on: (1) spectrum and expression of HDPs at the ocular surface; (2) participation of HDPs in ocular surface diseases/conditions such as infectious keratitis, conjunctivitis, dry eye disease, keratoconus, allergic eye disease, rosacea keratitis, and post-ocular surgery; (3) HDPs that are currently in the development pipeline for treatment of ocular diseases and infections; and (4) future potential of HDP-based clinical pharmacotherapy for ocular diseases

Amniotic Membrane Transplantation for Infectious Keratitis: A Systematic Review and Meta-Analysis

Infectious keratitis (IK) is the 5th leading cause of blindness globally. Broad-spectrum topical antimicrobial treatment is the current mainstay of treatment for IK, though adjuvant treatment or surgeries are often required in refractory cases of IK. This systematic review aimed to examine the effectiveness and safety of adjuvant amniotic membrane transplantation (AMT) for treating IK. Electronic databases, including MEDLINE, EMBASE and Cochrane Central, were searched for relevant articles. All clinical studies, including randomized controlled trials (RCTs), non-randomized controlled studies and case series (n>5), were included. Primary outcome measure was time to complete corneal healing and secondary outcome measures included corrected-distance-visual-acuity (CDVA), uncorrected-distance-visual-acuity (UDVA), corneal vascularization and adverse events. A total of twenty-eight studies (including four RCTs) with 861 eyes were included. When compared to standard antimicrobial treatment (SAT) alone, adjuvant AMT resulted in shorter mean time to complete corneal healing (-4.08 days; 95% CI, -6.27 to -1.88;

Cathelicidin-Derived Synthetic Peptide Improves Therapeutic Potential of Vancomycin Against Pseudomonas aeruginosa

© Copyright © 2019 Mohammed, Said, Nubile, Mastropasqua and Dua. Pseudomonas aeruginosa (PA) is the leading cause of corneal blindness worldwide. A constant increase in multi-drug resistant PA strains have heightened the challenge of effectively managing corneal infections with conventional antibiotics. Antimicrobial peptides are promising antibiotic analogs with a unique mode of action. Cathelicidin-derived shorter peptides (FK13 and FK16) have previously been shown to kill a range of pathogens in both in vitro and in vivo systems. Here, our aim was to exploit the potential of FK13 or FK16 to enhance the anti-Pseudomonas activity of vancomycin, which normally has low clinical efficacy against PA. Our results have demonstrated that FK16 is more potent than FK13 against different PA strains including a clinical isolate from a patient’s ocular surface. FK16 was shown to enhance the membrane permeability of PAO1 at sub-inhibitory concentrations. Moreover, FK16 at lower concentrations was shown to increase the antibacterial susceptibility of vancomycin against PA strains up to eightfold. The bactericidal synergism between FK16 and vancomycin was shown to be stable in the presence of physiological tear salt concentration and did not cause toxic effects on the human corneal epithelial cells and human red blood cells. Our results have revealed that sub-inhibitory concentration of FK16 could augment the antimicrobial effects of vancomycin against PA. It is anticipated that the future exploitation of the peptide design approach may enhance the effectiveness of FK16 and its application as an adjuvant to antibiotic therapy for the treatment of multi-drug resistant infections