ECTOINE IN THE TREATMENT OF IRRITATION AND INFLAMMATION OF THE SURFACE OF THE EYE

ECTOINE IN THE TREATMENT OF IRRITATION AND INFLAMMATION OF THE SURFACE OF THE EYE

Andreas Bilstein , Anya Heinrich , Anna Rybachuk , and Ralph Mesges 

Translated and shortened.

The surface of the eye is exposed to various non-specific stress factors, which leads to irritation and inflammation of the epithelium, which causes discomfort in patients. Ectoin is a bacterial extremolite that is able to protect proteins and biological membranes from damage caused by extreme environmental conditions, such as heat, UV light, high osmolality , or dryness. Data from preclinical and clinical studies confirm its effectiveness in the treatment of several inflammatory diseases associated with the epithelium, including the surface of the eye. In this review, we analyzed 16 recent clinical trials of ectoine eye drops in patients with allergic conjunctivitis or other nonspecific eye inflammation caused, for example, by ophthalmic surgery. The results of these studies were considered in the context of other published works on ectoine . Thus, patients with irritations and non-specific inflammations of the eye surface have been successfully treated with eye drops containing ectoine . In these patients, there was a significant improvement in the ocular symptoms of allergic rhinoconjunctivitis , postoperative secondary dry eye syndrome, or reepithelialization of the eye after surgery. The use of ectoine as an adjunct to antihistamines in allergic patients hastened symptom relief by several days, and its use as an adjunct to antibiotics resulted in faster wound closure. Ectoine is a natural substance with an excellent tolerability and safety profile, and is therefore a useful alternative for patients with inflammatory ocular surface irritation who wish to avoid the local reactions and side effects associated with pharmacological therapy, or who wish to improve the effectiveness of a standard treatment regimen.

Ectoin , an extremolite , is a natural defense molecule found in bacteria that survive extreme conditions of salinity, drought, radiation, pH , and temperature [ 1 , 2 ]. Ectoin forms a protective hydration shield around proteins and other biomolecules [ 3 ], which is based on its strong ability to bind water molecules [ 4 ]. This method of action is known as "preferential exclusion" [ 5 , 6 , 7 ]. This effect protects proteins from damage and irreversible denaturation and stabilizes biological membranes [ 4 , 8-10 ] . In preclinical studies, ectoine has been shown to protect lung and skin cells from damage caused by toxic pollution particles and prevent further activation of inflammatory cascades [11-16 ] . A similar effect was observed in model systems for inflammatory bowel diseases [ 17 ]. It is interesting that ectoine can stabilize lipid layers in pulmonary surfactants, as well as the tear film of the eyes against physical stress [ 18-22 ] .

Encouraging results from clinical trials were reviewed by Casale and colleagues [ 23 ], who attributed the efficacy of topical ectoine in upper respiratory tract inflammations such as acute pharyngitis/laryngitis [ 24 , 25 ], rhinosinusitis , dry rhinitis, and acute bronchitis [ 26 ]. In addition, several trials have shown the effectiveness of ectoine in various diseases with impaired barrier functions, such as dry rhinitis [ 27 ], mucosal mucositis caused by chemotherapy [ 28 ], lung inflammation caused by environmental pollutants [ 29 ], prevention of upper respiratory infections pathways [ 30 ] and atopic dermatitis [ 31 ]. In addition, studies have been published on allergic rhinoconjunctivitis [ 27 , 32 , 33 ] and dry eye syndrome [ 34 , 35 ] . Among these published studies, the use of ectoine for ophthalmic indications prompted us to perform a detailed analysis of the use of ectoine in this field. The surface of the eye (cornea, conjunctiva and tear film) is a sensitive part of the human body that is exposed to various environmental factors, such as heat, dry air, pollutants or allergens.

Allergic diseases, including allergic rhinoconjunctivitis , are a global health burden. The global prevalence of all allergic diseases is reported to be 20-30% [ 36 ], resulting in high pressure on socio-economic systems. A report by the Global European Network on Allergy and Asthma indicated that cost savings of more than €100 billion could realistically be expected from better treatment of allergic diseases [ 37 ]. The 2008 and 2016 Allergic Rhinitis and its Effects on Asthma (ARIA) guidelines assist physicians in developing a treatment algorithm for allergic rhinitis and conjunctivitis based on the severity and duration of symptoms [ 38 , 39 ]. Pharmacological therapy using oral/local antihistamines , intranasal glucocorticosteroids , oral glucocorticosteroids , decongestants and chromones , is considered a key point in the treatment of allergic rhinitis and conjunctivitis. Nevertheless, a relevant proportion of symptomatic patients is still undertreated [ 40–44 ]. A study found that about 60% of allergic rhinitis patients in the US are "very interested" in trying new drugs [ 45 ]. Moreover, many patients are reluctant to use pharmacologic therapy due to fear of local irritation and side effects associated with sedating antihistamines , which in turn may lead to poor compliance [ 46 , 47 ]. Thus, non-pharmacological therapy with the best tolerability and safety profile is of interest to many patients with allergic rhinoconjunctivitis .

In addition to allergic irritation of the ocular surface, other harmful exposures, such as trauma, burns, or physical trauma, also lead to inflammation and irritation of the epithelium exposed to air, the conjunctiva, and the cornea. After the initial damage, the inflammatory stimulus leads to symptoms similar to those described for dry eye syndrome (DSS). In most cases, SCO symptoms develop as a result of a wide range of different causes and are not limited to previous surgical intervention (cataract, strabismus correction, and LASIK [ 48-52 ]), but SCO can also occur as a result of environmental exposure, past inflammatory diseases (chronic blepharitis, traumatic erosion of the cornea, keratitis of various etiologies, etc.), wearing contact lenses, taking certain medications ( cholinergic and antihistamine drugs, alpha- and beta-blockers, etc. [ 53 ]). In all the mentioned cases, the initial violation of the eye surface is accompanied by a period of irritation and discomfort on the eye surface, which contributes to a decrease in the quality of life. Along with the use of necessary medications, such as antibiotics (in case of surgery), steroids (in case of inflammation) or lubricants and wound healing agents, it is necessary to treat discomfort on the surface of the eye and promote a faster recovery period.

After initial controlled trials of the treatment of allergic rhinoconjunctivitis ectoine , reviewed by Eichel [ 54 ], and the first documented ectoine CSO treatments [ 35 ], several real-world, interventional or non-interventional trials of ectoine- based eye drops have been conducted . In this article, we analyzed the literature on the treatment of ocular surface irritations for various indications. We focused on ectoine treatment of allergic rhinoconjunctivitis and postoperative treatment of eye irritation and discomfort. The systematic review presented here aims to investigate the evidence for the use of this interesting substance for the topical treatment of ocular surface irritations.

16 clinical studies were included [33 , 56-70 ] , which studied the potential role of ectoine in allergic conjunctivitis, vernal conjunctivitis, functional epiphora , and ocular surface irritation after external damage in a total of 1795 patients.

With the exception of one study [ 65 ], all studies were real-world studies of the use of 2% ectoine eye drops in a variety of situations over a period of up to 6 months, either as monotherapy or in combination with other interventions .

The comparators used were systemic or topical antihistamines [ 33 , 68 ], standard of care (variety of drugs according to national guidelines), placebo [ 65 , 72 , 73 ] and fluorometholone [ 61 ].

A total of 1,795 subjects were studied in 16 different studies, of which 1,225 used ectoine eye drops during the corresponding observation period. Four clinical trials specifically studied the effect of ectoine in children and adolescents (a total of 524 subjects, of which 492 used ectoine eye drops ); the youngest child was 2 years old. Two other trials included children and adults but did not publish the ages of the participants. Fourteen of the 16 studies included both men and women. Two studies included only male patients. Most of the research was conducted in Ukraine, as well as in Germany, Poland, Canada, Spain and Italy.

Details of the study design and included studies can be found in the original article.

ectoine eye drops . This is particularly interesting because some studies have examined very sensitive patient groups, such as children aged 2 years and older and patients who have recently undergone eye surgery . In particular, 4 studies specifically treated children and adolescents with ectoine eye drops , and 2 studies evaluated eye drops in children, adolescents, and adults. None of the studies reported serious side effects .

4.1. Study design and available information

We have identified two major areas of ocular irritation and inflammation where ectoine eye drops (EODs) have been studied: (1) allergic conjunctivitis and (2) nonspecific ocular irritation and inflammation caused by physical injury to the eye (eg, surgery or burn ).

Within allergic conjunctivitis, 5 studies studied the effect of EOC on seasonal allergic rhinitis [ 33 , 59 , 62 , 65 , 68 ], and 2 studies included patients with spring conjunctivitis [ 56 , 57 ]. The primary endpoints of all studies were patient-reported symptoms, along with study-specific measures associated with the relevant study endpoints. Studies differed in study populations (children, adults), period of EOC use (1 week to 6 months) and design (comparative, cross-over, add-on, non-comparative, with concurrent eye and nose treatment, retrospective case ), only one trial was placebo-controlled . The total number of participants in 7 allergic conjunctivitis studies was 444, including 254 children. Interestingly, one study included 192 patients, while the other 6 included an average of 42 patients.

All studies of allergic conjunctivitis showed a significant improvement in patient-reported outcomes after EOC use, which was significantly better than placebo [ 65 ] and at least comparable to standard pharmacological treatments such as ketotifen or azelastine [ 33 , 68 ]. Use in combination with standard therapy resulted in more rapid reduction in symptoms than standard therapy alone [ 68 ]. Interestingly, one long-term use in patients with vernal conjunctivitis delayed the use of corticosteroids in 75% of patients [ 56 ]. All 7 studies reported very good tolerability and safety of EOC in both children and adults , which was even significantly better than established over-the-counter drugs such as ketotifen or azelastine [ 33 , 57 ].

As shown above, the general picture described in the reviewed studies is good efficacy of EOC in the treatment of allergic conjunctivitis symptoms, both as monotherapy and in combination with other interventions , as well as very good tolerability and an excellent safety profile . The results of the additional effect of ectoine when used together with pharmacotherapy are particularly interesting , since various allergic rhinitis studies suggest combined therapy.

The remaining 9 studies examined non-specific eye irritation and inflammation of the ocular surface after a harmful exposure such as surgery, eye burn or an unclassified disorder. In 7 studies, treatment with EOC was performed in the postoperative phase for various reasons (strabismus, traumatic injuries, and progressive keratoconus ) [ 58 , 60 , 63 , 64 , 67 ]. One study examined the effect on functional epiphora of unknown origin [ 61 ], another on healing after ocular burn [ 66 ], and one study on the effect during aseptic uveitis after penetrating injury [ 67 ]. Subgroup analysis of irritation due to long-term contact lens wear was also performed in one study [ 70 ]. Again, with a total of 268 children and adolescents in 2 studies conducted exclusively in this population [ 64 , 67 ], EOC was applied to a very sensitive patient population.

One of the characteristic results of all studies was the positive effect of EOC on wound healing and re-epithelialization in relevant studies: Pastukh et al . [ 63 ], Gorokhovska et al. [ 60 ], and Sarzhevska and Tabakova [ 66 ] reported faster healing when EOC was used simultaneously with the usual regimen after eye damage, and Rykov et al. reported a positive effect on the reduction of postoperative scars [ 64 ]. All 8 studies performed during, after injury, or in the postoperative phase reported positive effects of EOC compared to standard treatment or even sodium hyaluronate instillation [ 66 ]. Such symptoms of irritation/inflammation of the ocular epithelium, such as conjunctival hyperemia or foreign body sensation, are often referred to as secondary dry eye syndrome. These results are supported by a study by Martinez et al., which demonstrated the comparative effectiveness of EOC with fluorometholone in the treatment of functional symptoms of epiphora without the typical negative side effects, such as intraocular pressure, that are associated with corticosteroid treatment [61 ] .

 

In this review, we provide evidence based on a review of 16 independent studies in 6 countries that ocular surface irritation and inflammation can be treated with ectoine- based eye drops , alone or in combination with other (pharmacological) treatments. Although many studies have shown limitations in study design or reporting, the following can be confirmed: ectoine is a natural substance with a unique mechanism of action on the ocular surface and an excellent tolerability and safety profile. This conclusion is confirmed by the works of other colleagues who considered the effectiveness of ectoine in inflammation of the upper respiratory tract or allergic rhinitis and other indications. In particular, studies of dry eye syndrome, which were not the subject of this review, should be analyzed in detail to further strengthen the evidence base for the use of ectoine in the eye.

This systematic literature review extends previously existing knowledge about the substance in two ways.

On the one hand, some of the articles cited in the review report on patients with allergic conjunctivitis or rhinoconjunctivitis treated in real-world scenarios. This means that many patients had comorbidities and were taking concomitant medications for the underlying pathology or other comorbidities. From this real-world evidence, we can conclude that the effects demonstrated in these situations are generally the same as those previously observed in more selected populations of controlled trials.

On the other hand, these recently published articles expand our knowledge in the field of new indications beyond allergic conjunctivitis. There are reports of the use of ectoine in traumatic uveitis after penetrating eye injuries and similar traumatic situations. Also, the substance was studied in the case of a vulnerable postoperative state of the eye after surgical interventions on the cornea or during operations to correct strabismus, as well as post-burn treatment. From these observations, we learn that in the surgical field of ophthalmology, traumatology, non-surgical injuries or irritations of the eye surface, the special properties of ectoine regarding the restoration of barrier functions may open a new perspective for this method of treatment.

Thus, ectoine- based eye drops are a viable alternative or additional option for the treatment of non-specific eye irritation and eye inflammation, acting through stabilization of the organ's epithelial barrier .

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