Development of a Temperature and pH Dual-Sensitive In-Situ Gel for Treating Allergic Conjunctivitis.

The purpose of this study was to improve the efficacy of olopatadine hydrochloride (OT) in treating allergic conjunctivitis (AC). To achieve this goal, we developed an eye formulation without antimicrobial agents using a temperature-pH dual-sensitive in situ gel technology combined with heat sterilization. Various types of carbomers were evaluated and their optimal doses determined. The prescription containing poloxamer 407 (P407) and poloxamer 188 (P188) was optimized using central composite design for response surface methodology (CCD-RSM). The final optimized dual-sensitive in situ gel (TP-gel) consisted of 0.1% olopatadine hydrochloride, 18.80% P407, 0.40% P188, 0.30% Pemulen™TR-1(TR-1), 4.0% mannitol, and 0.08% Tri(hydroxymethyl)aminomethane(Tris).Sterilization was performed at a temperature of 121℃ for a duration of 20 min. Experimental results showed that TP-gel had good safety profile and remained on the ocular surface for approximately (65.83 ± 8.79) minutes, which is four times longer than eye drops. The expression levels of IL-13, IL-17, and OVA-IgE in mouse ocular tissues with allergic conjunctivitis treated with TP-gel were significantly reduced. This suggests that TP-gel has the potential to be an effective treatment method for allergic conjunctivitis.

Seeing eye to eye: a modified Delphi method-based multidisciplinary expert consensus on the diagnosis and treatment of vernal keratoconjunctivitis.

Vernal keratoconjunctivitis (VKC) is a chronic, recurrent, inflammatory disease that affects both eyes, often with asymmetric severity, potentially causing major visual complications. The seasonal management of VKC can be challenging, especially when specialists with different diagnostic and therapeutic approaches need to be consulted. The aim of this expert panel was to reach a national consensus among pediatric allergologists and ophthalmologists on the diagnosis and treatment of VKC. This consensus was developed by an expert panel of 17 Italian pediatric allergologists and ophthalmologists with over a decade of experience. Ten statements on VKC diagnosis and treatment formulated after a thorough review of current literature were evaluated by the panelists. The level of agreement was quantitatively assessed using a 5-point Likert scale. Consensus was reached if ≥ 75.0% of panelists agreed to any given statement. The consensus emphasizes the importance of evaluation by multispecialty reference centers or experienced specialists for accurate diagnosis. Prompt diagnosis, especially during active phases, is crucial and should occur before corticosteroid therapy. The Bonini score from 2007 is the preferred tool for VKC assessment, although future revisions may be considered. Short cycles of topical corticosteroids should be preferred over prolonged use, even during immunomodulatory therapy. When cyclosporine fails, tacrolimus should be considered. CONCLUSION: This is the first consensus on the management of VKC that has gathered the expert opinions of both pediatricians and ophthalmologists. The outcome of this multidisciplinary effort provides a uniform approach to VKC diagnosis and treatment, thereby facilitating patient management across the country. WHAT IS KNOWN: • Vernal keratoconjunctivitis (VKC) is a chronic recurrent ocular disease particularly prevalent in the pediatric population. • Despite its relevance, there is a lack of standardized approaches shared between pediatricians and ophthalmologists, leading to notable variations in clinical practice. WHAT IS NEW: • This expert panel, comprising 17 pediatric allergologists and ophthalmologists, has reached a national consensus to provide standardized guidance for VKC management. • The consensus emphasizes the importance of a multidisciplinary approach to managing VKC, ensuring consistent and effective patient care.

Novel therapeutic receptor agonists and antagonists in allergic conjunctivitis.

PURPOSE OF REVIEW: Allergic conjunctivitis is characterized by the development of pathophysiological changes to the ocular surface, which occurs when pro-allergic and pro-inflammatory mediators interact with their cognate receptors expressed on immune and nonimmune cells. Traditional treatments with antihistamines and corticosteroids provide relief, but there is a need for more efficacious and tolerable long-term therapy with a better safety profile. This article aims to provide an overview of the mode of action and clinical application of agonist therapies targeting glucocorticoid, melanocortin, and toll-like receptors, as well as antagonist therapies targeting cytokine, chemokine, integrin, and histamine receptors. RECENT FINDINGS: There has been considerable advancement in immunology and pharmacology, as well as a greater understanding of the cellular and molecular mechanisms of allergic conjunctivitis. Recent research advancing therapy for allergic conjunctivitis has focused on developing synthetic molecules and biologics that can interfere with the process of the allergic immune reaction. SUMMARY: This review discusses novel therapeutic receptors being explored agonistically or antagonistically to develop alternative treatment options for allergic conjunctivitis. These novel approaches hold promise for improving the management of allergic eye diseases, offering patients hope for more effective and safer treatment options in the future.

Allergic Conjunctivitis Management: Update on Ophthalmic Solutions.

PURPOSE OF REVIEW: The aim of this review, is to present an updated revision of topical management of SAC and PAC, based on the available scientific evidence and focused on the impact of ophthalmic solution formulations on eye surface. RECENT FINDINGS: Physicians treating ocular allergy should be aware of tear film and tear film disruption in SAC and PAC, and how eye drop composition and additives affect the physiology of the allergic eye. Seasonal and perennial allergic conjunctivitis (SAC and PAC) are the most frequent causes of ocular allergy (OA), and both conditions are underdiagnosed and undertreated. SAC and PAC are immunoglobulin E (IgE)-mediated hypersensitivity reactions. The additional tear film disruption caused by the release of inflammatory mediators increases and exacerbates the impact of signs and symptoms and may trigger damage of the ocular surface. Comorbidities are frequent, and dry eye disease in particular must be considered. Clinical guidelines for the management of SAC and PAC recommend topical therapy with antihistamines, mast cells stabilizers or dualaction agents as first-line treatment, but care should be taken, as many medications contain other compounds that may contribute to ocular surface damage.

Evaluation methods using tear volume in a conjunctivitis mice model.

Allergic conjunctival disease is an immune-mediated inflammatory disease of the conjunctiva. To develop clinically useful drugs, it is necessary to develop quantitative evaluation methods that reflect the clinical symptoms in experimental animal models. Allergic conjunctivitis model mice were systemically sensitised with ovalbumin (OVA) administered intraperitoneally and locally sensitised with OVA eye drops between day 14-28. Next, conjunctivitis induced by ocular administration of OVA solution to sensitised mice was evaluated based on tear volume. Additionally, we evaluated increase in tear volume induced by direct ocular instillation of histamine, compound 48/80, and carrageenan. An increase in antigen-induced tear volume was observed in the mice model. Additionally, direct instillation of histamine, compound 48/80, and carrageenan increased tear volume. Furthermore, levocabastine inhibited the increase in tear volume in antigen-induced allergic conjunctivitis and histamine- and compound 48/80-induced conjunctivitis models. In contrast, betamethasone suppressed carrageenan-induced tear volume but not histamine- or compound 48/80-induced tear volume. Histamine may be involved in increased tear volume in allergic conjunctivitis. Betamethasone is not directly involved in the action of histamine and is thought to suppress increase in tear volume. Evaluation of tear volume in a conjunctivitis mice model is highly quantitative; therefore, it is possible to evaluate drug efficacy. This is considered a useful index compared with conventional methods.

Predisposition to conjunctivitis and male sex reduces drug survival of dupilumab in adults and adolescents.

BACKGROUND: There are currently limited data on dupilumab drug survival (DS), especially on factors possibly associated with drug discontinuation. MATERIALS AND METHODS: The primary endpoint of this study is to evaluate the parameters that may determine drug discontinuation and the predictive factors associated with dupilumab DS. We considered as independent associated factors: childhood onset of disease, gender, age of onset of AD, age of initiation of dupilumab, previous use of cyclosporine, initial mean EASI, atopic family history, and predisposition to allergic conjunctivitis. RESULTS: On 413 patients DS was 94.5% at 1 year, 89.5% at 2 years, and 83.7% at 3 years, and after a mean follow-up of 40.5 months (±1.6) 53 patients had discontinued the drug permanently (12.8%). Univariate analysis showed that the only factor associated with a reduction in drug survival was a predisposition to allergic conjunctivitis (p 0.009). At multivariate Cox regression, male sex (HR, 2.34; 95% CI, 1.14-4.78; p 0.02) and predisposition to allergic conjunctivitis (HR, 2.61; 95% CI, 1.37-5.00; p 0.004) were associated with lower DS of dupilumab. CONCLUSION: Male gender and predisposition to allergic conjunctivitis are negative predictors for maintenance of response to treatment with dupilumab and consequently associated with lower DS rates.

Treatment of Vernal Keratoconjunctivitis Using Upadacitinib.

This case report presents a case of improvement of vernal keratoconjunctivitis associated with initiation of an oral Janus kinase inhibitor upadacitinib.

The new preservative-free ophthalmic formulation of bilastine 0.6% preserves the ocular surface epithelial integrity in a comparative in vitro study.

Allergic conjunctivitis (AC) is the most common form of allergic eye disease and an increasingly prevalent condition. Topical eye drop treatments are the usual approach for managing AC, although their impact on the ocular surface is not frequently investigated. The aim of this study was to perform a comparative physicochemical characterization, and in vitro biological evaluations in primary conjunctival and corneal epithelial cells of the new multidose preservative-free bilastine 0.6% and main commercially available eye drops. MTT assay was used to measure cell viability; oxidative stress was analyzed with a ROS-sensitive probe; and apoptosis was evaluated monitoring caspase 3/7 activation. Differences in pH value, osmolarity, viscosity and phosphate levels were identified. Among all formulations, bilastine exhibited pH, osmolarity and viscosity values closer to tear film (7.4, 300 mOsm/l and ~ 1.5-10 mPa·s, respectively), and was the only phosphates-free solution. Single-dose ketotifen did not induce ROS production, and single-dose azelastine and bilastine only induced a mild increase. Bilastine and single-dose ketotifen and azelastine showed high survival rates attributable to the absence of preservative in its formulation, not inducing caspase-3/7-mediated apoptosis after 24 h. Our findings support the use of the new bilastine 0.6% for treating patients with AC to preserve and maintain the integrity of the ocular surface.

Applications of topical immunomodulators enhance clinical signs of vernal keratoconjunctivitis (VKC) and atopic keratoconjunctivitis (AKC): a meta-analysis.

PURPOSE: This meta-analysis aimed to review the safety and efficacy of topical cyclosporine A (CsA) and topical tacrolimus in allergic eye disease. METHODS: A systematic search identified thirteen studies and a total of 445 patients for inclusion, making this the largest meta-analysis published on the subject. The current review was performed in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). RESULTS: Thirteen randomized control trials were included in the meta-analysis. Eleven studies used CsA as the treatment, and two used Tacrolimus. In total, 445 participants were included, of whom 76.6% were male. The mean age of participants across the included studies was 14 years. All studies reported clinical signs as evaluated by an examining clinician. Signs were usually assessed by anatomical region, with the most common regions being the conjunctiva and the cornea, and the most common signs assessed were hyperemia and papillae. Three studies accounted for more than 50% of the meta-analysis's weight. Effect size (d) ranged from - 2.37 to - 0.03, negative values favoring immunomodulators. Fixed Effect Meta-Analysis returned an SMD of - 0.81 (95% CI [- 0.98, - 0.65]). However, there was significant heterogeneity (I2 = 61%, Qw = 30.76) in the outcome measure (P = 0.0021); therefore, a random-effect meta-analysis was also completed in which the pooled SMD was - 0.98 (95% CI [- 1.26, - 0.69], τ2 = 0.16). CONCLUSIONS: This study affirms the current scientific community's stance that immunomodulators effectively treat clinical signs, including blepharitis, conjunctival hyperemia, edema, papillae, and corneal damage in severe ocular allergic disease.

Reserve drug as first-line management: Topical interferon α-2b for vernal keratoconjunctivitis.

PURPOSE: To elucidate the efficacy and safety profile of interferon α-2b in vernal keratoconjunctivitis (VKC). METHODS: In this prospective interventional study, VKC patients fulfilling the inclusion and exclusion criteria were included and their signs and symptoms were scored based on the Clinical Scoring System. Patients were treated with topical interferon α-2b eye drop (1 MIU/ml) QID dosing for 6 weeks. Changes in symptoms and signs were evaluated at 2, 4, 8 weeks and 6 months after initiating treatment. A higher score meant severe disease, and a decline in score meant improvement in clinical signs and symptoms. Categorical variables were presented in number and percentage (%) and continuous variables as mean ± standard deviation (SD). Post-medication total subjective symptom score (TSSS) and total objective sign score (TOSS) were compared with baseline, and a P- value of <0.05 was considered significant. Possible ocular and systemic complications were evaluated. RESULTS: The study included 40 patients (32 male and eight female) with a mean age of 8.05 ± 2.33 years. Mean baseline TSSS and TOSS were 6.71 ± 0.564 and 6.59 ± 0.262, respectively, which reduced to 2.71 ± 0.011 ( P = 0.040) and 2.96 ± 0.210 ( P = 0.032), respectively, at 4 weeks and further reduced to 0.42 ± 0.552 and 0.47 ± 0.434, respectively, at 8 weeks. After 6 months of stopping the drug, mean TSSS and TOSS did increase to 2.80 ± 0.820 ( P = 0.044) and 2.50 ± 0.520 ( P = 0.030), respectively, but was still statistically significant improvement compared to the baseline. Also, no ocular or systemic side effects were observed anytime during the study period. CONCLUSION: Eye drop interferon α-2b (1 million IU/ml) is a safe and effective option as first-line monotherapy for VKC. No side effects and recurrence were observed for 6 months.

[New and future treatment approaches for allergic conjunctivitis]. / Neue und zukünftige Therapieansätze in der Behandlung der allergischen Konjunktivitis.

BACKGROUND: In severe and recurrent ocular allergies conventional ophthalmic drugs can reach their limits, especially in chronic forms. The first novel immunomodulators and biologicals are already in clinical use and could provide relief. OBJECTIVE: Based on the immunopathophysiological mechanisms of ocular allergies, possible targets for innovative treatment approaches are presented. An overview of promising new and future immunomodulators and biologicals and their modes of action is also given. MATERIAL AND METHODS: Current reviews on ocular allergies and the treatment of systemic allergic diseases were screened. Case reports on the treatment of ocular allergy using immunomodulators and biologicals were analyzed. The clinical relevance and possible applications are presented. RESULTS: In chronic forms of ocular allergies, complex ocular surface inflammatory responses mediated via immunoglobulin E (IgE), mast cells, CD4-positive type 2 T­helper cells and eosinophilic granulocytes are predominant. Cyclosporine A 0.1% eyedrops have been approved in Europe since 2018 for children aged 4 years and older with severe vernal keratoconjunctivitis (VKC). In addition, case reports present promising data on the systemic off-label use of biologicals, such as dupilumab or omalizumab, in refractory VKC or atopic keratoconjunctivitis (AKC). CONCLUSION: A profound understanding of the immunopathophysiology of ocular allergies is necessary to detect further targets for future immunomodulators and biologicals. Currently, immunomodulatory therapy remains limited to cyclosporine A eyedrops. Other immunomodulatory agents, such as tacrolimus and biologicals can only be used off-label. Further studies on the controlled clinical use of these substances in the treatment of VKC or AKC are underway.

Formulation of hesperidin-loaded in situ gel for ocular drug delivery: a comprehensive study.

BACKGROUND: Allergic conjunctivitis is one of the most common eye disorders. Different drugs are used for its treatment. Hesperidin is an active substance isolated from Citrus sinensis L. (Rutaceae) fruit peels, with known anti-inflammatory activity but low solubility. It was complexed with cyclodextrin and encapsulated in situ gel to extend its duration in the eye. RESULTS: The optimized formulation comprised 1% hesperidin, 1.5% hydroxyethyl cellulose, and 16% poloxamer 407. The viscosity at 25 °C was 492 ± 82 cP, and at 35 °C it was 8875 ± 248 cP, the pH was 7.01 ± 0.03, gelation temperature was 34 ± 1.3 °C, and gelation time was 33 ± 1.2 s. There was a 66% in vitro release in the initial 2 h, with a burst effect. A lipoxygenase (LOX) inhibition test determined that hesperidin was active at high doses on leukotyrens seen in the body in allergic diseases. In cell-culture studies, the hesperidin cyclodextrin complex loaded in situ gel, BRN9-CD (poloxamer 16%, hydroxy ethyl cellulose (HEC) 1.5%), enhanced cell viability in comparison with the hesperidin solution. It was determined that BRN9-CD did not cause any irritation in the ocular tissues in the Draize test. CONCLUSION: The findings of this study demonstrate the potential of the in situ gel formulation of hesperidin in terms of ease of application and residence time on the ocular surface. Due to its notable LOX inhibition activity and positive outcomes in the in vivo Draize test, it appears promising for incorporation into pharmaceutical formulations. © 2024 The Authors. Journal of The Science of Food and Agriculture published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.

Efficacy of a Cationic Emulsion of Cyclosporine in Moderate Vernal Keratoconjunctivitis.

PURPOSE: The aim of this study was to demonstrate the efficacy of cyclosporine A 0.1% cationic emulsion (CsA CE) eye drops 4 times a day in pediatric patients affected by a moderate form of vernal keratoconjunctivitis (VKC). METHODS: This was a prospective study of pediatric patients, aged 5-16 years, with an active moderate form of VKC who were poor responders to topical antihistamines treatment and were treated 4 times a day with CsA CE. The clinical signs were graded for analysis as follows: hyperemia, tarsal papillae, and limbal papillae. RESULTS: Twenty-eight patients (22 males and 6 females) with a minimum follow-up period of 3 months were included in the analysis. Statistical analysis excluded tarsal papillae because of the very low baseline value. The clinical score of hyperemia and limbal papillae improved from the first evaluation and was maintained over the follow-up. No side effects were noted. CONCLUSION: CsA CE has been proposed as a treatment for severe forms of VKC. This study has shown that administration 4 times a day is also effective in the treatment of moderate forms of VKC in children.

Exploration of efficacy and mechanism of 0.05% cyclosporine eye drops (II) monotherapy in allergic conjunctivitis-associated dry eye.

PURPOSE: To explore the efficacy and relevant mechanism of 0.05% cyclosporine A (CsA) eye drops (II) monotherapy in patients with allergic conjunctivitis-associated dry eye (ACDE). METHODS: Prospective, randomized, controlled study. Fifty-three patients with mild-to-moderate ACDE were randomly assigned to two groups. The CsA group received 0.05% CsA eye drops (II) monotherapy four times daily. The control group received 0.1% olopatadine twice daily combined with 0.1% preservative-free artificial tears four times daily. Clinical symptoms and signs, tear total IgE, and lymphotoxin-α (LT-α) concentrations were assessed at pre- and post-treatment days 7, 30, and 60. And we further measured six tear cytokines levels using a microsphere-based immunoassay. RESULTS: The CsA group showed significant improvement in symptoms (Ocular Surface Disease Index and itching scores) and signs (conjunctival hyperaemia, conjunctival oedema, conjunctival papillae, tear break-up time (TBUT), corneal fluorescein staining, and goblet cell density) at each follow-up period compared to pre-treatment (all P < 0.050). And its improvement in itching scores (P7th < 0.001, P30th = 0.039, and P60th = 0.031) and TBUT (P7th = 0.009, P30th = 0.003, and P60th = 0.005) was more significant than the control group at all follow-up periods. The tear total IgE, interleukin (IL)-5, IL-6, periostin, eotaxin-3, and MMP-9 levels significantly decreased in the CsA group at day 60 after treatment (all P < 0.050). And the changed values in tear total IgE were positively correlated with the change in itching scores. CONCLUSIONS: 0.05% CsA eye drops (II) monotherapy can rapidly improve the symptoms and signs, especially in ocular itching and TBUT, in patients with ACDE. And its efficacy is superior to 0.1% olopatadine combined with artificial tears. Moreover, CsA downregulates the expression levels of tear inflammatory cytokines, including tear total IgE, IL-5, IL-6, periostin, eotaxin-3, and MMP-9. Among that, the reduction in tear total IgE levels may reflect the improvement of ocular itching.

Management of vernal keratoconjunctivitis: Navigating a changing treatment landscape.

Vernal keratoconjunctivitis (VKC) is a chronic, progressive, and potentially sight-threatening form of ocular inflammatory disease that primarily affects children and young adults. Prevalence varies by region, ranging from <2 per 10,000 in the United States to as high as 1,100 per 10,000 in parts of Africa. The rarity of VKC in developed countries can make differential diagnosis challenging, and treatment is often delayed until the disease is advanced, and symptoms are significantly impacting patients' quality of life. Although once viewed primarily as an immunoglobulin E-mediated condition, approximately 50% of patients with VKC do not exhibit allergic sensitization. It is now recognized that the immunopathology of VKC involves multiple inflammatory pathways that lead to the signs, symptoms, and conjunctival eosinophilic and fibroproliferative lesions that are a hallmark of the disease. We examine the evolution of our understanding of the immunopathology of VKC, the expanding VKC treatment armamentarium, the clinical implications of emerging treatment approaches, and future directions for VKC research and practice.

Epinastine Cream: A Novel Once-Daily Therapeutic Agent for Allergic Conjunctivitis.

Purpose: To investigate the in vivo efficacy of epinastine cream in type I allergic models. Methods: The dose, timing, and antiallergic effect of epinastine cream on the conjunctiva were evaluated postapplication to the eyelid skin of guinea pigs with histamine- or ovalbumin-induced allergic conjunctivitis. Additionally, we assessed its antiallergic effects on the skin postapplication to the dorsal skin of guinea pigs with ovalbumin-induced passive cutaneous anaphylaxis. Efficacy was estimated by determining the amount of dye that leaked from conjunctival or dorsal skin tissue vessels as a measure of vascular permeability, scoring the severity of allergic symptoms, and observing the scratching behaviors using clinical parameters. Results: In the histamine-induced conjunctivitis model, epinastine cream strongly inhibited conjunctival vascular permeability in a dose-dependent manner. The inhibitory effect of 0.5% epinastine cream 24 h postapplication was significantly higher than that of 0.1% epinastine hydrochloride ophthalmic solution 8 h postadministration. Additionally, the 0.5% epinastine cream inhibited conjunctival vascular permeability 15 min postapplication, and the effect was sustained over 24 h. Furthermore, the 0.5% epinastine cream effectively suppressed clinical symptom scores and exhibited ameliorated scratching bouts in conjunctival allergic reactions in the experimental allergic conjunctivitis model. Additionally, it significantly inhibited vascular permeability in skin allergic reactions in the passive cutaneous anaphylaxis model. Conclusions: The results suggest that epinastine cream is a strong, long-lasting, and skin-penetrating inhibitor of type I allergic reactions. The 0.5% epinastine cream applied once daily could be a promising, potent, and long-acting therapeutic agent for allergic conjunctivitis.

Fundamental Aspects and Relevance of Components in Antihistamine Eye Drops.

Ocular allergy covers a series of immune-allergic inflammatory diseases of the ocular surface, with different degrees of involvement and severity. These pathologies are caused by a variety of IgE- and non-IgE-mediated immune mechanisms and may involve all parts of the external eye, including the conjunctiva, cornea, eyelids, tear film, and commensal flora. The most frequent is allergic conjunctivitis, a condition with different clinical forms that are classified according to the degree of involvement and the presence or absence of proliferative changes in the palpebral conjunctiva, associated atopic dermatitis, and mechanical stimuli by foreign bodies, including contact lenses. Treatment guidelines for allergic conjunctivitis propose a stepwise approach that includes medications for both ophthalmic and oral administration depending on symptom severity, allergic comorbidities, and degree of control. In the case of antihistamines, eye drops are the most prescribed ophthalmic formulations. To avoid disrupting the delicate balance of the ocular surface, topical ophthalmic medications must be well tolerated. The primary aim of this article is to review the physicochemical characteristics and other features of excipients (preservative agents, buffers, pH adjusters, viscosity enhancers, wetting agents or cosolvents, antioxidants, tonicity adjusters, and osmo-protectants) and active compounds (ocular antihistamines) that must be considered when developing formulations for ophthalmic administration of antihistamines. We also provide a brief overview of antihistamine eye drops that could be of interest to professionals treating ocular allergy and encourage the use of preservative-free formulations when possible.