Anti-Inflammatories in the Treatment of Dry Eye Disease: A Review.

Inflammation is an important driver of dry eye disease (DED) pathogenesis. An initial insult that results in the loss of tear film homeostasis can initiate a nonspecific innate immune response that leads to a chronic and self-sustaining inflammation of the ocular surface, which results in classic symptoms of dry eye. This initial response is followed by a more prolonged adaptive immune response, which can perpetuate and aggravate inflammation and result in a vicious cycle of chronic inflammatory DED. Effective anti-inflammatory therapies can help patients exit this cycle, and effective diagnosis of inflammatory DED and selection of the most appropriate treatment are therefore key to successful DED management and treatment. This review explores the cellular and molecular mechanisms of the immune and inflammatory components of DED, and examines the evidence base for the use of currently available topical treatment options. These agents include topical steroid therapy, calcineurin inhibitors, T cell integrin antagonists, antibiotics, autologous serum/plasma therapy, and omega-3 fatty acid dietary supplements.

Developing evidence-based guidance for the treatment of dry eye disease with artificial tear supplements: A six-month multicentre, double-masked randomised controlled trial.

PURPOSE: To assess the six-month therapeutic profiles of lipid and non-lipid-based artificial tear supplements in managing dry eye disease (DED). METHODS: Ninety-nine participants fulfilling the TFOS DEWS II diagnostic criteria for DED (64% females; mean ± SD age, 44 ± 16 years) were enrolled in a prospective, multicentre, double-masked, parallel group, randomised controlled trial. Participants instilled lipid-based nanoemulsion drops or non-lipid-based aqueous drops for six months, at least four times daily. Symptomology, tear film and ocular surface characteristics were assessed at Days 0, 30, 60, 90, 120, 150 and 180. RESULTS: Sustained reductions in OSDI, DEQ-5, and SANDE symptom scores from baseline were observed from Day 30 onwards in both groups (all p < 0.05) and decreased superior lid wiper epitheliopathy grades from Day 60 onwards (all p ≤ 0.01). Improvements in non-invasive tear film breakup time, and sodium fluorescein and lissamine green staining scores followed from Day 120 onwards in both groups (all p < 0.05). Tear lipid layer grades increased from Day 90 onwards only with the lipid-based drops, and with significantly greater improvement in those with suboptimal lipid layer thickness at baseline (grade ≤3; p = 0.02). By Day 180, 19% of participants no longer fulfilled the diagnostic criteria for DED. CONCLUSIONS: Over a six-month treatment period, improvements in dry eye symptomology preceded tear film and ocular surface changes with regular use of both lipid and non-lipid-based artificial tear supplements. Both formulations addressed most mild-to-moderate forms of aqueous deficient and evaporative DED, while evaporative cases benefitted preferentially from lipid-based supplementation. This represents a first step towards mapping DED therapeutic strategies according to disease subtype and severity.

Immuno-pathogenesis of nCOVID-19 and a possible host-directed therapy including anti-inflammatory and anti-viral prostaglandin (PG J2) for effective treatment and reduction in the death toll.

Coronaviruses including severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2, also known as 2019-nCoV especially in China) replicate and divide in host cells. During this they are partly hidden from the innate immune responses although inflammatory consequences of viral replication still occur. We propose that anti-inflammatory antiviral prostaglandins may not only restrict viral replication but also prevent inflammatory responses in the lungs and other vital organs that are known to be part of the immuno-pathogenesis of coronavirus disease-19 (COVID-19). The combination of anti-inflammatory antiviral prostaglandins with interferons may lead to the clearance of viruses inside growth-restricted infected cells. However, further experimental studies and clinical trials should be conducted to evaluate the safety and efficacy of these possible therapies.

The Development of an Antimicrobial Contact Lens - From the Laboratory to the Clinic.

Contact lens wear is generally safe and provides excellent vision. However, contact lens wear is often associated with the risk of developing ocular surface infection and inflammation, and in severe cases, the infection can result in loss of vision. Antimicrobial peptide-coated contact lenses have been made to help reduce the incidence of infection and inflammation. This paper reviews the research progress from conception, through the laboratory and preclinical tests to the latest information on clinical testing of an antimicrobial contact lens. We provide insights into the pathways followed and pitfalls that have been encountered. The journey has not always been linear or smooth, but has resulted in some of the first published clinical testing of antimicrobial peptide-coated contact lenses in humans. We hope this may help lead to the development and commercialisation of antimicrobial contact lenses in the future.

Lipid Supplements and Clinical Aspects of Tear Film in Habitual Lens Wearers.

PURPOSE: To establish the effect of lipid supplements on the tear lipid layer and their influence on lens wear comfort in habitual lens wearers. METHODS: Forty habitual soft contact lens wearers were recruited to a double-masked, randomized crossover trial. An emulsion drop containing phosphatidylglycerine (Systane Balance; Alcon) and a saline drop as a placebo or a liposomal spray containing phosphatidylcholine (Tears again; BioRevive) and a saline spray as a placebo were used three times a day for 2 weeks with 48 hours washout between each intervention. Ocular comfort, lipid layer grade, and stability of the tear film using a Tearscope and tear evaporation rate using a modified VapoMeter were assessed after 6 hours of lens wear with lenses in situ. RESULTS: Neither of the lipid supplements improved lens wear comfort compared to baseline. The noninvasive surface drying time significantly reduced with the placebo spray at day 1 (P = .002) and day 14 (P = .01) whereas the lipid spray had no effect. With the lipid drop and placebo, noninvasive surface drying time was unchanged compared to baseline (P > .05) on day 1, but by day 14, noninvasive surface drying time was reduced with the lipid drop (P = .02) and placebo (P < .001). Symptomatic wearers showed shorter noninvasive surface drying time compared to asymptomatic wearers with the spray treatment on both days (P = .03) but not with the lipid drop (P = .64). The placebo drop significantly changed the lipid layer distribution (P = .03) with a higher percentage of thinner patterns compared to the baseline distribution at day 14. A weak but significant correlation was shown between ocular comfort and noninvasive surface drying time (r = -0.21, P = .003) and tear evaporation rate (r = 0.19, P = .008). Ocular comfort was not associated with lipid layer patterns (r = 0.13, P = .06). CONCLUSIONS: Ocular comfort during contact lens wear improved with increased tear film stability and a reduced tear evaporation rate. However, the lipid supplements did not improve ocular comfort from baseline.

In vitro effects of docosahexaenoic and eicosapentaenoic acid on human meibomian gland epithelial cells.

To investigate the effect of ω-3 fatty acids on human meibomian gland epithelial cells (HMGECs, cell line) in vitro. HMGECs were stimulated with docosahexaenoic acid (DHA) or combinations with eicosapentaenoic acid (EPA) and acetyl sialic acid (ASA). Sudan III fat staining, viability and proliferation assays, electric cell-substrate impedance sensing, real-time PCR for gene expression of cyclooxygenase-2 and 15-lipoxygenase and ELISAs for resolvin D1 (RvD1), IFNγ, TNFα and IL-6 were applied. Lipid droplet accumulation and viability was increased by 100 µM DHA in the presence or absence of EPA in serum cultured HMGECs. In contrast, HMGECs cultured with DHA and EPA under serum-free conditions showed minimal lipid accumulation, decreased proliferation and viability. Normalized impedance was significantly reduced in serum-free cultured HMGECs when stimulated with DHA and EPA. HMGECs cultured in serum containing medium showed increased normalized impedance under DHA and EPA stimulation compared to DHA or EPA alone or controls. IL-6 and IFNγ were downregulated in HMGECs treated for 72 h with DHA and EPA. In general, TNFα, IFNγ and IL-6 levels were decreased after 72 h compared to 24 h in serum containing medium with or without DHA or EPA. The concentration of RvD1 was elevated 2-fold after DHA treatment. Cyclooxygenase-2 gene expression decreased compared to controls during DHA stimulation after 72 h. Treatment with DHA and ASA revealed a decreased 15-lipoxygenase gene expression which was reduced after three days of DHA incubation. DHA and EPA supplementation affected HMGECs in vitro and supported anti-inflammatory effects by influencing cytokine levels, decreasing COX-2 expression and increasing the production of RvD1.

In vitro and in vivo evaluation of novel ciprofloxacin-releasing silicone hydrogel contact lenses.

PURPOSE: The purpose of this study was to evaluate ciprofloxacin-releasing silicone hydrogel contact lens materials in vitro and in vivo for the treatment of microbial keratitis. METHODS: Model silicone hydrogel contact lens materials were manufactured using a molecular imprinting technique to modify ciprofloxacin release kinetics. Various contact lens properties, including light transmission and surface wettability, were determined, and the in vitro ciprofloxacin release kinetics elucidated using fluorescence spectrophotometry. The materials then were evaluated for their ability to inhibit Pseudomonas aeruginosa growth in vitro and in an in vivo rabbit model of microbial keratitis. RESULTS: Synthesized lenses had similar material properties to commercial contact lens materials. There was a decrease in light transmission in the shorter wavelengths due to incorporation of the antibiotic, but over 80% light transmission between 400 and 700 nm. Modified materials released for more than 8 hours, significantly longer than unmodified controls (P < 0.05). In vivo, there was no statistically significant difference between the number of colony-forming units (CFU) recovered from corneas treated with eye drops and those treated with one of two modified contact lenses (P > 0.05), which is significantly less than corneas treated with unmodified control lenses or those that received no treatment at all (P < 0.05). CONCLUSIONS: These novel contact lenses designed for the extended release of ciprofloxacin may be beneficial to supplement or augment future treatments of sight-threatening microbial keratitis.

Effect of antibiotic drops on adverse events during extended lens wear.

PURPOSE: Overnight lens wear is associated with increased lens contamination and risk of developing a corneal infiltrate or infectious event. Antibacterial lenses have been proposed as a potential strategy for reducing lens contamination. A proof-of-principle study was conducted to investigate what effect control of potential pathogens, through the use of antibiotic eye drops, would have on the incidence of corneal infiltrative events (CIEs) and on the ocular microbiota and lens contamination. METHODS: This is a prospective, open-label, controlled, parallel-group, 1-month clinical study in which 241 subjects were dispensed with lotrafilcon A silicone hydrogel lenses for 30 days of continuous wear. Subjects were randomized into either test (moxifloxacin 0.5%) or control (rewetting solution) group. One drop was instilled into each eye on waking and before sleeping, while lenses were on-eye. Follow-ups were conducted after one night and 1 month. Lid margin swabs were taken at baseline and at 1 month and worn lenses were aseptically collected at 1 month. RESULTS: The incidence of CIEs was not significantly different between the test (2.6%) and control (3.9%) groups (p = 0.72). Microorganism levels from the test group swabs were significantly lower than those from the control group (p = 0.001). Gram-positive bacteria were less frequently recovered from lower lid swabs from the test group (39.6% vs. 66.0% [p < 0.001], test vs. control, respectively) or from contact lens samples (1.9% vs. 10.5% [p = 0.015], test vs. control, respectively), but there was no difference in gram-negative bacteria (GNB). Corneal infiltrative events were associated with higher levels of lens contamination (p = 0.014) and contamination of lenses with GNB (CIE: 7.3% vs. 0.6% [p = 0.029], GNB contamination vs. no GNB contamination, respectively). DISCUSSION: Twice-daily antibiotic instillation during continuous wear of lenses did not significantly influence the rate of inflammatory events. Corneal infiltrative events were associated with higher levels of lens contamination in general and with contamination by GNB specifically.

Review of resistance of ocular isolates of Pseudomonas aeruginosa and staphylococci from keratitis to ciprofloxacin, gentamicin and cephalosporins.

BACKGROUND: Microbial keratitis is a rare disease but most commonly caused by bacterial infection. Two of the most common bacteria to cause microbial keratitis are Pseudomonas aeruginosa and Staphylococcus aureus. Antibiotic therapy to treat keratitis caused by these bacteria is either monotherapy with a fluoroquinolone or combination therapy with fortified gentamicin. METHODS: Literature searches were made in Medline and Pubmed using the search terms [Pseudomonas] or [Staphylococcus] and [fluoroquinolone] or [cephalosporin] or [gentamicin] and [keratitis] or [cornea]. Rates of resistance to ciprofloxacin, gentamicin or cephalosporins were then compared for isolates from different geographic regions. RESULTS: There are low resistance rates of P. aeruginosa and S. aureus to ciprofloxacin in isolates from Australia. Isolates from the Indian subcontinent are more commonly resistant to ciprofloxacin, with resistance rates of greater than 20 per cent being reported. Data from USA and Europe indicate that if the S. aureus is a methicillin resistant strain, then resistance to ciprofloxacin increases, often to greater than 80 per cent of isolates. Resistance to gentamicin and cephalosporins is also generally low in isolates from Australia. Again resistance is increased in isolates from the Indian subcontinent, as well as from South America. CONCLUSION: In Australia, the major ocular pathogens are generally sensitive to the most commonly used antibiotics to treat microbial keratitis. The prescription of fluoroquinolones, aminoglycosides and cephalosporins is generally reserved for treatment of significant or sight-threatening conditions such as microbial keratitis. This approach is not likely to contribute to an increase in resistance rates.

Role of carnitine in disease.

Carnitine is a conditionally essential nutrient that plays a vital role in energy production and fatty acid metabolism. Vegetarians possess a greater bioavailability than meat eaters. Distinct deficiencies arise either from genetic mutation of carnitine transporters or in association with other disorders such as liver or kidney disease. Carnitine deficiency occurs in aberrations of carnitine regulation in disorders such as diabetes, sepsis, cardiomyopathy, malnutrition, cirrhosis, endocrine disorders and with aging. Nutritional supplementation of L-carnitine, the biologically active form of carnitine, is ameliorative for uremic patients, and can improve nerve conduction, neuropathic pain and immune function in diabetes patients while it is life-saving for patients suffering primary carnitine deficiency. Clinical application of carnitine holds much promise in a range of neural disorders such as Alzheimer's disease, hepatic encephalopathy and other painful neuropathies. Topical application in dry eye offers osmoprotection and modulates immune and inflammatory responses. Carnitine has been recognized as a nutritional supplement in cardiovascular disease and there is increasing evidence that carnitine supplementation may be beneficial in treating obesity, improving glucose intolerance and total energy expenditure.

Broad spectrum of antibacterial activity of a new multipurpose disinfecting solution.

PURPOSE: Contact lens-related corneal infection and inflammation have been associated with microbial contamination of the contact lens or contact lens storage case. Antimicrobial performance of contact lens disinfection systems is an important factor in reducing contamination. The purpose of this study was to evaluate the antimicrobial efficacy of a new multipurpose disinfecting solution (MPDS), preserved with 0.001% polyquaternium-1 and 0.0005% myristamidopropyl dimethylamine, against a range of bacteria and fungi. METHODS: The MPDS was challenged with a broad range of clinical and environmental isolates, including 10 gram-positive and eight gram-negative bacterial strains and three strains of fungi. The panel of reference microorganisms recommended by the International Organization for Standardization standards was also included. Samples were removed for analysis after 4 hours, 6 hours, or 24 hours of exposure to the MPDS. The number of survivors was determined by plate counts. RESULTS: The new MPDS showed antimicrobial activity against the five reference microorganisms in excess of that recommended by International Organization for Standardization standards. The solution showed a broad spectrum of antibacterial activity, showing more than a 3 log reduction (mean, 4.2 +/- 1.4) in 8 of 10 gram-positive bacteria and more than a 4 log reduction (mean, 5.3 +/- 0.5) in all eight gram-negative bacteria at the 6-hour disinfection time. The efficacy of the solution was increased with longer exposure times (P<0.01). Some differences in activity between clinical and the reference bacterial strains were observed. The solution exceeded the 1 log unit reduction for all fungal species tested. CONCLUSIONS: The new MPDS produced a significant reduction in the growth of various clinical and environmental bacteria and fungi.