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Clinical and Biological Evaluation of NAAGA Versus Azelastine Eye Drops in Patients with Allergic Conjunctivitis and Tear Film Dysfunction: A Randomized Controlled Trial
Open Access
02.06.2025
ORIGINAL RESEARCH
Erschienen in:
Verfasst von
Mario Troisi
Mario Troisi
Eye Clinic, Department of Neurosciences, Reproductive and Odontostomatological Sciences, University of Naples Federico II, 80131, Naples, Italy
Ophthalmologic Unit, University Hospital of Salerno, 84100, Salerno, Italy
Salvatore Troisi
Korrespondierender Autor
Salvatore Troisi
Ophthalmologic Unit, University Hospital of Salerno, 84100, Salerno, Italy
Allergic conjunctivitis is a common ocular condition characterized by discomfort, itching, and redness, which significantly impacts quality of life. Its frequent overlap with dry eye disease (DED) complicates diagnosis and management, as both conditions share inflammation and tear film dysfunction as underlying mechanisms. Effective treatments must address both the inflammatory and tear film aspects of these conditions. While traditional therapies include antihistamines and mast cell stabilizers, innovative approaches focus on agents with dual anti-inflammatory and antiallergic properties. N-acetyl-aspartyl-glutamate (NAAGA) has shown potential in alleviating symptoms of both allergic conjunctivitis and DED through mechanisms involving mast cell stabilization, inhibition of inflammatory mediators, and improvement of tear film stability. This study compares the efficacy of NAAGA and azelastine hydrochloride, an established antihistamine, in improving symptoms and clinical markers of tear film dysfunction in patients with allergic conjunctivitis.
Methods
This randomized, single-blind study included 134 patients with atopy and mild to moderate tear film dysfunction. Participants received either NAAGA (49 mg/ml, four times daily) or azelastine hydrochloride (0.05%, twice daily) for 4 weeks. The primary endpoint was the change in Ocular Surface Disease Index (OSDI) scores. Secondary endpoints included tear osmolarity, Schirmer test results, tear break-up time (TBUT), fluorescein staining, and matrix metalloproteinase-9 (MMP-9) levels.
Results
Both treatments improved all parameters significantly over 4 weeks. NAAGA reduced OSDI scores from 26.12 ± 4.70 to 11.84 ± 3.43, compared to azelastine’s improvement from 24.57 ± 4.70 to 15.54 ± 4.36 (p < 0.001). NAAGA showed superior reductions in tear osmolarity (from 320.99 ± 4.35 to 312.33 ± 3.25 mOsm/l) compared to azelastine (from 320.13 ± 3.46 to 318.57 ± 3.46 mOsm/l, p < 0.001), and greater enhancements in Schirmer test results (6.51 ± 1.95 mm to 10.08 ± 1.88 mm) and TBUT (4.10 ± 1.70 to 7.91 ± 1.79 s).
Conclusions
NAAGA outperformed azelastine in alleviating symptoms and improving clinical markers of tear film dysfunction in allergic conjunctivitis. Its dual action on inflammation and tear stability highlights its therapeutic potential. Further studies are warranted to confirm these findings and explore additional applications.
Trial Registration
ClinicalTrials.gov identifier, NCT12345678.
Key Summary Points
Why carry out this study?
Allergic conjunctivitis and dry eye disease (DED) frequently coexist, sharing inflammation and tear film dysfunction as underlying mechanisms, which complicate diagnosis and management.
Existing therapies often fail to address both allergic and inflammatory components simultaneously, highlighting the need for treatments with dual mechanisms of action.
This study compared the efficacy of N-acetyl-aspartyl-glutamate (NAAGA) and azelastine hydrochloride in improving symptoms and clinical markers of tear film dysfunction in allergic conjunctivitis.
What was learned from the study?
NAAGA demonstrated greater improvements in Ocular Surface Disease Index (OSDI) scores, tear osmolarity, Schirmer test results, and tear break-up time (TBUT) compared to azelastine, supporting its broader therapeutic benefits.
NAAGA’s dual antiallergic and anti-inflammatory effects make it a promising treatment for patients with coexisting allergic conjunctivitis and DED.
These findings suggest the potential for NAAGA to address unmet needs in ocular therapy, warranting further research into its broader applications.
Introduction
Allergic conjunctivitis, the most common form of ocular allergy, is an inflammatory condition triggered by allergens such as pollen, dust, and pet dander [1, 2]. These allergens stimulate immune responses in sensitive individuals, causing discomfort, redness, itching, tearing, inflammation of the conjunctiva and, in severe cases, involvement of the cornea. Understanding the clinical presentation and mechanisms of ocular allergies is critical for effective management [3, 4].
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The symptoms of allergic conjunctivitis often overlap with dry eye disease (DED). Both conditions are influenced by environmental factors, such as climate and pollution, and exposure to seasonal allergens can exacerbate DED symptoms, particularly in spring [5‐7]. Tear film dysfunction can be worsened by the chronic inflammation characteristic of ocular allergies, in which the increased concentration of inflammatory mediators in the tear film damages the corneo-conjunctival epithelium and nerve fibers [8]. Similarly, DED is driven by a “vicious cycle” based on epithelial and nerve damage and inflammation, in which dysregulated immune responses lead to further tear film instability and glandular dysfunction [9‐13]. Conversely, ocular surface compromise and impaired tear clearance associated with dry eye disease can exacerbate allergic manifestations by prolonging the retention of allergens and inflammatory mediators on the ocular surface [5‐7].
Given this overlap, treating patients with atopy should address both ocular allergies and DED symptoms, such as tear film instability and inflammation [14].
Therapies for ocular allergies typically include antihistamines like levocabastine, epinastine, azelastine, and emedastine, which block H1 receptors [15], and mast cell stabilizers, such as sodium cromoglycate and N-acetyl-aspartyl-glutamate (NAAGA), which prevent histamine release and degranulation [16]. NAAGA, a neuropeptide also known as spaglumic acid, also inhibits inflammatory cell activation, complement cascade, and leukotriene production [17‐19]. This anti-inflammatory potential has been highlighted by Brignole-Baudouin et al., who observed that NAAGA reduces the expression of HLA-DR, a marker of conjunctival inflammation, thereby supporting its role in alleviating inflammatory symptoms in DED [21]. More recent findings by Shin et al. suggest that NAAGA not only shows effectiveness in DED treatment but also achieves faster symptom relief with fewer adverse events compared to cyclosporine A, enhancing its therapeutic profile in managing ocular inflammation [22]. However, its dual antiallergic and anti-inflammatory role in ocular allergies requires further study. Additionally, Lazreg et al. found NAAGA effective as monotherapy in moderate allergic conjunctivitis, demonstrating its tolerability and efficacy without the need for corticosteroids in many cases [23]. Azelastine, a commonly used second-generation H1 receptor antagonist with a low affinity for cholinergic receptors, stabilizes mast cells and reduces inflammation by antagonizing chemical mediators [24, 25].
This study aimed to evaluate the effects of NAAGA and azelastine on symptoms and clinical markers of dry eye, including inflammation, in patients affected by allergic conjunctivitis.
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Methods
Study Setting and Design
This was a prospective, randomized, single-blind study conducted at Salerno Hospital University from April 21, 2023 through March 28, 2024. Participants were randomly assigned using a computer-generated sequence (http://www.sealedenvelope.com) with allocation concealment through sealed opaque envelopes. The study employed a single-blind design, in which the investigator responsible for outcome assessment (S.T.) was blinded to the treatment assignment. A second investigator (M.T.) was responsible for participant enrollment according to predefined inclusion and exclusion criteria, performing the randomization to assign participants to one of the study arms, and linking the outcomes to the corresponding treatment groups at the conclusion of the study. The study was approved by the Salerno Hospital University Ethics Committee (authorization number 31/2019) and retrospectively registered at ClinicalTrials.gov (identifier, NCT06800274). All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional research committee and with the 1964 Helsinki Declaration and its later amendments. Written informed consent was obtained from all participants prior to inclusion in the study.
Eligibility Criteria
Consecutive patients with a history of allergic disease, associated with symptoms of ocular discomfort, and mild (13–22 points of the Ocular Surface Disease Index, OSDI) to moderate (23–32 points) alteration of the precorneal tear film, were evaluated.
Other inclusion criteria were as follows: history of atopy (positive skin prick test, positivity for specific blood IgE or Prist result > 100 kU/l); positive, in each eye, for one or more of the following diagnostic criteria: TBUT (tear film break-up time) < 10 s, Schirmer I test at 5′ < 10 mm, corneal staining > 1 (CLEK system), tear osmolarity > 308 mOsm/l.
Exclusion criteria were: age < 18 years, severe ocular surface affections, unilateral dry eye syndrome, refractive surgery performed in the last 6 months, eye surgery in the last 3 months, previous herpetic keratitis, signs of infection of ocular surface, systemic or topic therapies with steroids or antihistamines in the last 3 months, administration of local therapies in the last 14 days.
Interventions
Patients were randomly assigned to either 4.9% NAAGA in a single dose (Naaxia®, Laboratoires Thea, France) four times daily or 0.05% azelastine hydrochloride colloid in a single dose (Tebarat®, FB Vision S.p.A., Italy) twice daily, for 4 weeks.
Specific diagnostic tests and procedures for dry eye disease were performed at week 0 (baseline), week 2 and week 4, in the following order to ensure independent results between tests: OSDI symptom questionnaire; measurement of tear osmolarity (TearLab®, TearLab Corporation, Southlake, TX, USA); Schirmer I test without anesthesia; measurement of TBUT; test for MMP-9 (InflammaDry®; performed only at week 0 and 4); vital staining with fluorescein and evaluation of the cornea under the biomicroscope with CLEK scheme (only at week 0 and 4).
Each patient was also administered a self-assessment questionnaire of the main symptoms of ocular discomfort, to be completed at time 0 (inclusion in the study) and every week for the 4 weeks of therapy.
Data Analysis
The primary endpoint was the OSDI score. Secondary endpoints were: tear osmolarity; Schirmer type I test; TBUT; MMP-9 analysis; vital staining with fluorescein and biomicroscopic evaluation; patient-reported assessment.
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A post-hoc power analysis was conducted to assess the adequacy of the sample size. With 80 participants in group A and 54 in group B, at a significance level of 0.05 and an effect size of 2.13 for the ΔOSDI comparison between groups, the achieved power exceeded 0.99. Additionally, power analysis for each pairwise within-group comparison of OSDI variation across week 0, week 2, and week 4 revealed a minimum power of 0.98, confirming that our sample size was more than sufficient to detect significant effects.
Data were analyzed by descriptive statistics. Normality was assessed using the Shapiro–Wilk test. For intra-group changes, parametric (paired t test) and non-parametric (Wilcoxon signed-rank test) tests were applied depending on data distribution. For inter-group comparisons, Student’s t test was used for normally distributed data, while the Mann–Whitney U test was employed for skewed data. Categorical variables were analyzed using the chi-square test. A p value < 0.05 was considered statistically significant. All analyses were performed by SPSS (IBM Corp. Released 2023. IBM SPSS Statistics for Windows, Version 29.0.2.0, IBM Corp., Armonk, NY, USA).
Results
Baseline Characteristics
At the start of the study, 216 subjects were assessed for eligibility. Of these, 52 were excluded for not meeting the inclusion or exclusion criteria, and four declined to participate. A total of 160 participants were subsequently enrolled and randomly assigned in a 1:1 ratio to receive either NAAGA or azelastine, with 80 individuals allocated to each group. However, due to differences in several key baseline variables, a propensity score matching (PSM) process was applied to balance the groups. After matching, the sample size was reduced to 134 participants, with 80 (59.7%) remaining in the NAAGA group (aged 51.6 ± 11.4 years; 57.5% females) and 54 (40.3%) in the azelastine group (aged 50.7 ± 12.1 years; 59.3% females). All participants were of Caucasian race. Figure 1 reports study participant flow diagram.
Fig. 1
Study participant flow diagram: randomized controlled trial (RCT) comparing N-acetyl-aspartyl-glutamate (NAAGA) and azelastine in the treatment of allergic conjunctivitis with dry eye, including randomization, propensity score matching, and final analysis
Table 1 depicts the baseline characteristics of the two groups. No statistical differences were reported in any variable assessed. This ensured that both groups started the study with comparable characteristics.
Table 1
Baseline characteristics of the two groups
Characteristic
NAAGA (n = 80)
Azelastine (n = 54)
p valuea
Mean age (years)
51.6 ± 11.4
50.7 ± 12.1
0.682
Sex (female, %)
57.5%
59.3%
0.812
Race (Caucasian, %)
100%
100%
–
OSDI (mean ± SD)
26.12 ± 4.70
24.57 ± 4.70
0.144
Tear osmolarity (mOsm/l)
320.99 ± 4.35
320.13 ± 3.46
0.493
Schirmer test (mm)
6.51 ± 1.95
7.06 ± 1.86
0.134
TBUT (s)
4.10 ± 1.70
4.80 ± 2.38
0.121
InflammaDry (MMP-9 positive, %)
26.3%
27.8%
0.845
CLEK score (mean ± SD)
1.75 ± 1.37
1.30 ± 1.24
0.062
Patient diary (mean ± SD)
6.75 ± 1.85
7.07 ± 1.37
0.102
Statistical tests used: Independent t test for continuous variables (age, OSDI, tear osmolarity, Schirmer test, TBUT, CLEK score, patient diary). Chi-square test for categorical variables (sex, race, InflammaDry)
NAAGAN-acetyl-aspartyl-glutamate, SD standard deviation, OSDI Ocular Surface Disease Index, TBUT tear break-up time, CLEK Collaborative Longitudinal Evaluation of Keratoconus
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OSDI Score
The OSDI scores decreased significantly over time in both treatment groups (Fig. 2). In the NAAGA group, the mean OSDI score dropped from 26.12 ± 4.70 at baseline to 17.61 ± 3.42 at week 2, and further to 11.84 ± 3.43 by week 4. Similarly, the azelastine group showed a reduction in OSDI scores, from 24.57 ± 4.70 at baseline to 19.89 ± 4.43 at week 2, and 15.54 ± 4.36 by week 4. While both groups experienced a significant improvement in symptoms over the course of the study, the NAAGA group exhibited a greater overall reduction in OSDI scores compared to the azelastine group, with the difference between the two groups becoming statistically significant by week 4 (p < 0.001).
Fig. 2
Mean Ocular Surface Disease Index (OSDI) scores over time for the N-acetyl-aspartyl-glutamate (NAAGA) and azelastine groups. Bars represent SDs (standard deviations)
Tear osmolarity showed a significant reduction over time in both treatment groups (Fig. 3). In the NAAGA group, the mean tear osmolarity decreased from 320.99 ± 4.35 mOsm/l at baseline to 312.33 ± 3.25 mOsm/l by week 4. Similarly, in the azelastine group, tear osmolarity dropped from 320.13 ± 3.46 mOsm/l at baseline to 318.57 ± 3.46 mOsm/l by week 4. Although both groups experienced improvements in tear film stability, the NAAGA group demonstrated a greater reduction in tear osmolarity compared to the azelastine group. This difference was statistically significant by the end of the study (p < 0.001).
Fig. 3
Mean tear osmolarity over time for the N-acetyl-aspartyl-glutamate (NAAGA) and azelastine groups. Bars represent SDs (standard deviations)
Tear production, as measured by the Schirmer test I, showed the same trend as the OSDI and tear osmolarity (Fig. 4). In the NAAGA group, the mean Schirmer test result increased from 6.51 ± 1.95 mm at baseline to 10.08 ± 1.88 mm by week 4. In comparison, the azelastine group showed a more modest improvement, with the mean score rising from 7.06 ± 1.86 mm at baseline to 7.44 ± 1.99 mm at week 4. While both groups experienced increases in tear production, the improvement was greater in the NAAGA group. This difference became statistically significant by week 4 (p < 0.001).
Fig. 4
Results of the Schirmer test over time for the N-acetyl-aspartyl-glutamate (NAAGA) and azelastine groups. Bars represent SDs (standard deviations)
TBUT was measured using fluorescein staining with cobalt blue filter. Three consecutive measurements were taken, and the mean value was recorded to ensure accuracy. In the NAAGA group, the mean TBUT increased from 4.10 ± 1.70 s at baseline to 7.91 ± 1.79 s by week 4 (Fig. 5). In the azelastine group, the TBUT also improved, rising from 4.80 ± 2.38 s at baseline to 5.87 ± 1.60 s by week 4. Although both groups experienced enhancements in tear film stability, the improvement was more pronounced in the NAAGA group. By week 4, the difference in TBUT between the two groups was statistically significant (p < 0.001).
Fig. 5
Tear break-up time (TBUT) over time for the NAAGA and azelastine groups. Bars represent SDs (standard deviations)
Inflammation, as assessed by the InflammaDry® test for MMP-9, showed notable improvements in both treatment groups throughout the study (Table 2). In the NAAGA group, 26.3% of participants tested positive for MMP-9 at baseline, which decreased to 8.8% by week 4. Similarly, in the azelastine group, the percentage of MMP-9 positive participants declined from 27.8% at baseline to 11.1% by week 4. The difference between the two groups by week 4 did not reach statistical significance (p = 0.651) (Table 3).
Table 2
Comparison of intra-group changes from baseline to week 4 for InflammaDry (MMP-9 positivity), CLEK score, and patient’s diary outcomes in the NAAGA and azelastine groups
Outcome measure
Timepoint
NAAGA (n = 80)
p value
Azelastine (n = 54)
p value
InflammaDry (MMP-9 positive, %)
Baseline
26.3%
–
27.8%
–
Week 4
8.8%
< 0.001
11.1%
0.002
CLEK score (mean ± SD)
Baseline
1.75 ± 1.37
–
1.30 ± 1.24
–
Week 4
0.32 ± 0.57
< 0.001
0.63 ± 0.78
0.001
Patient’s diary (mean ± SD)
Baseline
6.75 ± 1.85
–
7.07 ± 1.37
–
Week 4
1.54 ± 0.93
< 0.001
2.85 ± 1.04
< 0.001
P values in bold are statistically significant
Statistical tests used for intra-group comparisons: Wilcoxon signed-rank test (for non-normally distributed variables). Paired t test (for normally distributed variables). Statistical tests used for inter-group differences: Mann–Whitney U test (for non-normally distributed variables). Independent t test (for normally distributed variables)
NAAGAN-acetyl-aspartyl-glutamate, SD standard deviation, MMP-9 matrix metalloproteinase-9, CLEK Collaborative Longitudinal Evaluation of Keratoconus, CI confidence interval
Table 3
Intra-group changes along with inter-group differences (mean ± SD and 95% CI) to compare treatment effects between NAAGA and azelastine. Bold represents statistical significance
Outcome measure
NAAGA change (mean ± SD)
Azelastine change (mean ± SD)
Difference (mean ± 95% CI)
p value
InflammaDry (MMP-9 positive, %)
− 17.5%
− 16.7%
–
0.651
CLEK score
− 1.43 ± 0.62
− 0.67 ± 0.59
− 0.76 (− 1.01, − 0.51)
< 0.001
Patient’s diary
− 5.21 ± 1.12
− 4.22 ± 1.07
− 0.99 (− 1.41, − 0.57)
< 0.001
Statistical tests used for intra-group comparisons: Wilcoxon signed-rank test (for non-normally distributed variables). Paired t test (for normally distributed variables). Statistical tests used for inter-group differences: Mann–Whitney U test (for non-normally distributed variables). Independent t test (for normally distributed variables)
NAAGAN-acetyl-aspartyl-glutamate, SD standard deviation, MMP-9 matrix metalloproteinase-9, CLEK Collaborative Longitudinal Evaluation of Keratoconus, CI confidence interval
Vital Staining
Vital staining, as measured by the CLEK score, improved significantly in both treatment groups during the study (Table 2). In the NAAGA group, the mean CLEK score decreased from 1.75 ± 1.37 at baseline to 0.32 ± 0.57 by week 4. The azelastine group also showed a reduction, with the mean CLEK score dropping from 1.30 ± 1.24 at baseline to 0.63 ± 0.78 by week 4. By the end of the study, the difference between the groups reached statistical significance (p < 0.001) (Table 3).
Patient-Reported Assessment
The patient’s diary, which recorded eye discomfort, showed significant improvements in both treatment groups throughout the study (Table 2). In the NAAGA group, the mean diary score decreased from 6.75 ± 1.85 at baseline to 1.54 ± 0.93 by week 4. Similarly, the azelastine group showed a reduction in mean scores, dropping from 7.07 ± 1.37 at baseline to 2.85 ± 1.04 by week 4. While both groups experienced marked reductions in reported eye discomfort, the NAAGA group demonstrated a more pronounced decrease. By week 4, the difference between the groups was statistically significant (p < 0.001), indicating that NAAGA led to greater overall improvements in patient-reported symptoms (Table 3).
Safety and Compliance
During the study, no relevant adverse events (AEs) occurred in either group. The only adverse events (AEs) experienced by patients were mild and transient. Specifically, mild transient burning after instillation occurred in three patients (3.8%) in the NAAGA group and four patients (7.4%) in the azelastine group. Additionally, itching was reported by one patient (1.9%) and mild eye redness by another patient (1.9%) in the azelastine group. None of these adverse events interfered with the continuation of therapy (Table 4). We recorded a good treatment compliance (> or = 80%) by both groups. All enrolled patients successfully completed the study, with no instances of loss to follow-up.
Table 4
Summary of any adverse events (AEs) experienced by subjects in the NAAGA and azelastine treatment groups
Any adverse events (AEs)
NAAGA (n = 80)
Azelastine (n = 54)
Burning
3 (3.8%)
4 (7.4%)
Itching
0 (0.0%)
1 (1.9%)
Eye redness
0 (0.0%)
1 (1.9%)
NAAGAN-acetyl-aspartyl-glutamate
Discussion
This study shows that both NAAGA and azelastine significantly improve symptoms of dry eye and ocular allergies in patients with atopic background. While both treatments were effective, our data suggest that NAAGA may offer some advantages, particularly in improving OSDI score, tear osmolarity, and TBUT.
The overlap between allergic conjunctivitis and DED is notable, as both conditions are influenced by environmental triggers like allergens and climate factors, especially in springs [5‐10]. Patel et al. reported that seasonal allergens, temperature, and humidity are associated with an increase in DED flares [3]. Allergens can provoke immune responses that disrupt tear film stability, leading to further ocular surface damage. This connection underscores the role of inflammation as a shared mechanism in both DED and allergic conjunctivitis, creating a "vicious circle" where inflammatory cytokines and chemotactic factors perpetuate ocular surface damage and increase tear film instability. Suarez-Cortés et al. highlighted shared biomarkers across DED and ocular allergy, including interleukins IL-1α, IL-1β, and IL-17, as well as TNFα and IFNγ, which reflect parallel inflammatory pathways in these conditions [14]. Currently available anti-inflammatory treatment options include topical steroid therapy, calcineurin inhibitors, T cell integrin antagonists, antibiotics such as azithromycin and tetracyclines, autologous serum/plasma therapy, and omega-3 fatty acid dietary supplements [26]. Azithromycin ophthalmic solution, in particular, offers not only antibacterial and anti-inflammatory, but also lipid-regulating effects, making it a valid option for the treatment of dry eye disease associated with meibomian gland dysfunction [27]. However, its utility in dry eye associated with allergic conjunctivitis is limited, as allergic conjunctivitis is driven by an immune response that azithromycin does not specifically target.
Azelastine, a phthalazinone derivative, is a selective histamine (H1) receptor antagonist with a low affinity for muscarinic receptors compared to other antihistamines, that acts through multiple mechanisms to alleviate allergic conjunctivitis symptoms. It not only blocks the H1 receptors, reducing symptoms like itching and redness, but also acts secondarily as a dual-function anti-inflammatory agent by stabilizing mast cells and inhibiting the release of other mediators involved in allergic responses—such as leukotrienes, prostaglandins, and cytokines. This mechanism provides rapid relief from allergic symptoms reducing undesirable anticholinergic side effects, such as dry eye [28]. Additionally, azelastine has been shown to counteract the effects of other inflammatory mediators, including leukotrienes and platelet-activating factor (PAF), further reducing inflammation and ocular irritation [24]. This combination of antihistaminic and anti-inflammatory effects allows azelastine to be effective in managing both early and late-phase allergic responses, making it a valuable option for treating allergic conjunctivitis.
On the other hand, NAAGA functions as a mast cell stabilizer and possesses several anti-inflammatory properties. In addition to preventing mast cell degranulation—which triggers the release of histamine and other inflammatory mediators—NAAGA acts at multiple levels of the allergic inflammatory cascade. In a previous study, Leonardi et al. showed that NAAGA reduces the release of eosinophil cationic protein (ECP), a key mediator in ocular surface inflammation, particularly in conditions like vernal keratoconjunctivitis (VKC) [29]. The reduction of ECP in tears could be a contributing factor to the improvements observed in our study, as ECP is known to damage the corneal epithelium and exacerbate inflammation.
Moreover, NAAGA inhibits the production of leukotriene B4 (LTB4), a potent chemotactic factor that promotes leukocyte recruitment and increases vascular permeability [29]. By limiting LTB4 synthesis, NAAGA may help reduce the severity of allergic reactions, such as conjunctival hyperemia and chemosis. In addition, NAAGA has been reported to inhibit complement activation through both the classical and alternative pathways, thereby reducing mast cell and eosinophil degranulation [28].
This broader upstream activity may account for the more pronounced anti-inflammatory effects observed with NAAGA compared to azelastine, which acts mainly downstream at the H1 receptor level.
The findings from Shin et al. provide additional support for NAAGA’s effectiveness in treating dry eye symptoms and inflammation, specifically in comparison to cyclosporine A (CsA) [22]. In their study, NAAGA demonstrated a more rapid improvement in dry eye and meibomian gland dysfunction (MGD) parameters, with significant reductions in OSDI scores from baseline. At 1 month, the OSDI score for patients treated with NAAGA decreased from 30.41 ± 20.08 to a mean of 12.26 ± 13.74, versus from 25.30 ± 19.04 to 22.24 ± 17.60 in the CsA group. By 3 months, the NAAGA group showed an even more pronounced improvement, with a mean OSDI of 7.74 ± 7.19, while the CsA group reported an OSDI of 13.63 ± 14.94 (p < 0.05). Shin et al. also noted a faster increase in TBUT in the NAAGA group, which rose from 3.28 ± 1.49 s at baseline to 5.92 ± 2.31 s at 3 months, compared to a more modest improvement in the CsA group, which reached 3.83 ± 2.04 s over the same period. Additionally, patients using NAAGA reported significantly lower discomfort scores than those on CsA, underscoring NAAGA’s greater tolerability.
Brignole-Baudouin et al. further demonstrated the efficacy of NAAGA in reducing inflammation in patients affected by DED by showing a significant reduction in the expression of HLA-DR, a marker of conjunctival inflammation, following NAAGA treatment [21]. Their findings are particularly relevant in highlighting NAAGA’s role in modulating immune responses at the ocular surface, which is critical in inflammatory dry eye and allergy-driven tear film dysfunction. This anti-inflammatory effect, distinct from the symptomatic relief provided by antihistamines like azelastine, underscores NAAGA’s therapeutic potential in addressing the underlying inflammation associated with DED and allergic conjunctivitis.
Recently, a new artificial tear formulation containing NAAGA, along with hyaluronic acid (HA) and trehalose, has been introduced, aiming to capitalize on NAAGA’s anti-inflammatory properties. El Fekih et al. showed that this preservative-free combination significantly improved dry eye symptoms, with an average OSDI reduction of 44.6 ± 15.9 points over 42 days of treatment [30]. Furthermore, the formulation was highly effective in reducing conjunctival hyperemia (96.8% of patients showed improvement), highlighting its potential as a comprehensive treatment for moderate-to-severe DED with an added anti-inflammatory benefit. This addition of NAAGA to an artificial tear solution represents a promising option for patients with DED who require both symptomatic relief and inflammation control.
Finally, several studies have shown that antihistamines can exert anticholinergic effects at various levels. Although second-generation antihistamines, such as azelastine, have been developed as relatively selective H1 receptor antagonists with the primary aim of minimizing centrally mediated effects like sedation, their potential impact on tear production cannot be ruled out [31, 32]. In turn, the anticholinergic effects of systemic and topical antihistamines likely contribute to the exacerbation of dry eye symptoms, a role that is often underestimated [33, 34].
Although NAAGA yielded the greater improvements in tear film stability and tolerability in our cohort, drug selection must remain patient-specific. Azelastine—a rapid-acting second-generation H1 antagonist—blocks histamine receptors within minutes, provides twice-daily dosing, and is widely available as low-cost generics; it therefore remains the first-line option when immediate symptom relief and dosing simplicity are paramount [35]. Its Summary of Product Characteristics limits unsupervised treatment to no more than 6 weeks, after which alternative therapy or specialist review is advised.
NAAGA, in contrast, requires four instillations per day and is currently marketed as a branded formulation with generally higher costs for patients. Nonetheless, it is approved for unrestricted, long-term use from 4 years of age, is packaged in preservative-free single-dose units compatible with contact-lens wear, and—beyond mast-cell stabilization—acts upstream by inhibiting the complement cascade, addressing chronic ocular-surface inflammation without anticholinergic effects [30].
These pharmacodynamic, regulatory, economic, and practical distinctions should guide therapy in patients who need either rapid relief or sustained ocular-surface protection when frequent dosing is feasible for those with demanding daily schedules.
While the results of our study suggest a potential advantage for NAAGA in terms of reducing inflammation and improving tear film stability, it is important to acknowledge that more research is needed to confirm these findings. The current study did not include quantitative measures of inflammatory markers such as cytokine levels, and the improvements observed were primarily based on clinical parameters. Additionally, the small sample size and lack of a placebo control group limit the generalizability of our findings. Future studies should focus on larger, controlled trials and explore the combination of NAAGA with other therapeutic agents, such as artificial tears, to offer a more comprehensive approach to treating these conditions. Furthermore, studies measuring inflammatory mediators are necessary to better elucidate NAAGA’s mechanisms of action.
Conclusions
Overall, NAAGA demonstrated superior efficacy compared to azelastine in alleviating symptoms and improving clinical parameters of tear film dysfunction in patients with allergic conjunctivitis. Specifically, NAAGA achieved statistically significant improvements in OSDI scores, tear osmolarity, Schirmer test results, and TBUT. These findings suggest that NAAGA’s broader anti-inflammatory action and lack of anticholinergic effects may provide enhanced therapeutic benefits for managing allergic conjunctivitis, particularly in patients with concomitant mild to moderate DED.
Acknowledgements
The authors thank all study participants for their involvement and contribution to this research.
Medical Writing/Editorial Assistance
Medical writing assistance was provided by Luca Giacomelli, PhD, as a freelance medical writer. This assistance was supported by TheaPharma.
Author Contribution
Mario Troisi and Salvatore Troisi contributed to the conception of the study. Mario Troisi and Salvatore Troisi contributed to the study design. Salvatore Troisi contributed to the acquisition of the data. Mario Troisi and Maria Vittoria Turco contributed to the analysis, interpretation of the data, figures, and tables. Mario Troisi accessed and verified each dataset during the study. The research planning and execution were supervised by Mario Troisi, Salvatore Troisi, Diego Strianese, Michele Rinaldi, and Ciro Costagliola. Mario Troisi drafted the manuscript. Salvatore Troisi and Mario Troisi revised the manuscript. All authors read and approved the final version of the manuscript.
Funding
No funding or sponsorship was received to conduct this research study. The journal’s Rapid Service Fee was covered by TheaPharma.
Data Availability
The datasets generated and analyzed during the current study are available from the corresponding author upon reasonable request.
Declarations
Conflict of Interest
Mario Troisi, Salvatore Troisi, Diego Strianese, Michele Rinaldi, Maria Vittoria Turco, and Ciro Costagliola declare that they have no competing interests. Patients were not involved in the design of the study or the dissemination of the results.
Ethical Approval
The study was approved by the Salerno Hospital University Ethics Committee (authorization number 31/2019) and retrospectively registered at ClinicalTrials.gov (identifier NCT06800274). All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional research committee and with the 1964 Helsinki Declaration and its later amendments. Written informed consent was obtained from all participants prior to inclusion in the study.
Open Access This article is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License, which permits any non-commercial use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc/4.0/.
Clinical and Biological Evaluation of NAAGA Versus Azelastine Eye Drops in Patients with Allergic Conjunctivitis and Tear Film Dysfunction: A Randomized Controlled Trial
Verfasst von
Mario Troisi
Salvatore Troisi
Diego Strianese
Michele Rinaldi
Maria Vittoria Turco
Ciro Costagliola
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Deutschland ist ein Koloskopieland. Doch ist das eine gute Idee? Oder würde der Stuhltest ausreichen, um Darmkrebs im frühen Stadium zu erkennen? Prof. Markus M. Lerch und Prof. Ulrike Denzer diskutieren die Vor- und Nachteile der Screening-Verfahren. Außerdem gibt die Endoskopie-Expertin Prof. Denzer Tipps, wie suspekte Darmpolypen effektiv erkannt und abgetragen werden können.
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