A RQUIVOS B RASILEIROS DE ORIGINAL ARTICLE Ophthalmic adverse effects of nasal decongestants on an experimental rat model Efeitos oftálmicos adversos de descongestionantes nasais em modelo experimental com ratos Ayse Ipek Akyuz Unsal1, Yesim Basal2, Serap Birincioglu3, Tolga Kocaturk1, Harun Cakmak1, Alparslan Unsal4, Gizem Cakiroz5, Nüket Eliyatkın6, Ozden Yukselen7, Buket Demirci5 1. Department of Ophthalmology, Medical Faculty, Adnan Menderes University, Aydin, Turkey. 2. Department of Otorhinolaringology, Medical Faculty, Adnan Menderes University, Aydin, Turkey. 3. Department of Pathology, Veterinary Faculty, Adnan Menderes University, Aydin, Turkey. 4. Department of Radiology, Medical Faculty, Adnan Menderes University, Aydin, Turkey. 5. Department of Medical Pharmacology, Medical Faculty, Adnan Menderes University, Aydin, Turkey. 6. Department of Medical Pathology, Medical Faculty, Adnan Menderes University, Aydin, Turkey. 7. Department of Pathology, Aydin State Hospital, Aydin, Turkey. ABSTRACT | Purpose: To investigate the potential effects of cause ophthalmic problems such as dry eyes, corneal edema, chronic exposure to a nasal decongestant and its excipients cataracts, retinal nerve fiber layer, and vascular damage in on ocular tissues using an experimental rat model. Methods: rats. Although these results were obtained from experimental Sixty adult male Wistar rats were randomized into six groups. animals, ophthalmologists should keep in mind the potential The first two groups were control (serum physiologic) and ophthalmic adverse effects of this medicine and/or its excipients Otrivine® groups. The remaining four groups received the and exercise caution with drugs containing xylometazoline, Otrivine excipients xylometazoline, benzalkonium chloride, ethylene diamine tetra acetic acid, benzalkonium chloride and sorbitol, and ethylene diamine tetra acetic acid. Medications sorbitol for patients with underlying ocular problems. were applied into both nostrils twice a day for 8 weeks. Before Keywords: Nasal decongestants/adverse effects; Animal, model; the rats were sacrificed, epithelial staining, the Schirmer test, and intraocular pressure measurements were performed under Tissues/drug effects; Eye/drug effects; Rats ketamine/xylasine anesthesia (50 and 5 mg/kg, respectively). RESUMO | Objetivo: Investigar os possíveis efeitos da exposi­ Results: Epithelial defects and dry eye were common findings ção crônica de descongestionante nasal e seus excipientes em in all study groups. Cataracts developed in two cases clini­ tecidos oculares, utilizando um modelo experimental com ratos. cally. Histopathological evaluation revealed many different Métodos: Sessenta ratos Wistar adultos machos foram divididos pathological alterations in all parts of the ocular tissues such aleatoriamente em seis grupos. Os primeiros dois grupos foram as corneal edema, polypoid proliferation and hyalinization controle (soro fisiológico) e Otrivina®. Os quatro grupos restantes of the vessel wall, cystic formation of the lens, retinal nerve receberam os excipientes de Otrivina, tais como Xilometazolina, fiber layer degeneration, and corpora amylacea formation Benzalcônio, Sorbitol e Ácido Etilenodiamino Tetracético (EDTA). of the lacrimal gland. Conclusions: Prolonged usage of the Os medicamentos foram aplicados em ambas as narinas dos nasal decongestant xylometazoline and its excipients may ratos, duas vezes ao dia, durante 8 semanas. Antes que os ratos fossem sacrificados, a coloração epitelial, o teste de Schirmer e a medida da pressão intraocular foram realizados sob anestesia com Ketamina/Xilasina (50 e 5 mg/kg, respectivamente). Resul- tados: Defeitos epiteliais e olho seco foram achados comuns Submitted for publication: March 2, 2017 nos grupos de estudo. A catarata desenvolveu­se clinicamente Accepted for publication: September 3, 2017 Funding: This study was supported by research fund from Adnan Menderes em dois casos. A avaliação histopatológica revelou a existência University (TPF-14016). de alterações em todas as partes dos tecidos oculares, tais Disclosure of potential conflicts of interest: None of the authors have any potential conflicts of interest to disclose. como edema de córnea, proliferação polipoide e hialinização Corresponding author: Ayse Ipek Akyuz Unsal. da parede vascular, formação cística da lente, degeneração Adnan Menderes University. Faculty of Medicine - Department of Ophthalmology - da camada de fibra nervosa da retina (RNFL) e formação de 09100 - Aydin - Turkiye - E-mail: [email protected] corpos amiláceos da glândula lacrimal. Conclusões: O uso Approved by the following research ethics committee: Adnan Menderes University for Animal Experiments (HADYEK # 2013/095). prolongado do descongestionante nasal Xilometazolina e seus ■ http://dx.doi.org/10.5935/0004-2749.20180012 Arq Bras Oftalmol. 2018;81(1):53-8 53 Ophthalmic adverse effects of nasal decongestants on an experimental rat model excipientes pode causar vários problemas oftalmológicos, como with oxymetazoline nasal spray(4). It is clear that sympa­ olho seco, edema de córnea, catarata, RNFL e dano vascular thomimetic decongestants may have a systemic adverse em ratos. Embora esses resultados tenham sido obtidos a effect after absorption from the nasal mucosa. In spite partir de animais experimentais, os oftalmologistas devem ter of the numerous case reports describing the systemic em mente os potenciais efeitos oftalmológicos adversos desse side effects, studies establishing the ophthalmic effect medicamento e/ou de seus excipientes. of nasal decongestants are limited. The first case report Descritores: Descongestionantes nasais/efeitos adversos; Modelo is most likely that of a branch retinal artery occlusion animal; Tecidos/efeito de drogas; Olho/efeito de drogas; Ratos in an otherwise healthy young man after excessive use of oxymetazoline, causing a drug­induced platelet fibrin INTRODUCTION embolus(5). Another case report described a 43­year­old In daily ophthalmology practice, clinicians encounter man who developed blurred vision, metamorphopsia, young individuals with ophthalmic problems such as and paracentral scotoma with xylometazoline(6). cataracts, dry eyes, and vascular and retinal diseases Buysschaert et al. described a 34­year­old male who with no explainable etiology. A familiar scenario to most used xylometazoline every 3 h in the last 2 years and ophthalmologists, two young male patients admitted to presented with blurred vision due to papilloedema and our clinic at different times complaining of cataracts hypertensive retinopathy(7). with an unusual etiology served as the inspiration for As preservatives and excipients are combined with this study. The only suspected cause was prolonged nasal the active drug for many reasons, including increasing decongestant usage by both patients. absorption, prolonging the shelf life, and preventing Cataract formation is a common ophthalmologic pro­ bacterial contamination of the pharmaceutical prepa­ blem. It is especially important to investigate the cause ration, these additives may also be responsible for the especially in young patients because cataracts can be aforementioned side effects. The effects of these ex­ the first sign of an important disease such as diabetes cipients were therefore investigated separately in this mellitus and patients are generally unaware of systemic study. Benzalkonium chloride (BAC), ethylene diamine problems. Although cataract etiology is well known and tetra acetic acid (EDTA), and sorbitol can typically be well understood, it is difficult to evaluate young patients found in these medications. The safety of these additives with cataracts without any known cause. For these pa­ is as important as that of the active drug. For example, tients, the use of drugs applied locally such as aerosols BAC is known to have corneal toxicity and is used to as well as nasal and eye drops should be investigated as produce animal models of dry eye. EDTA can be toxic patients often do not consider these drugs worth men­ for corneal and conjunctival cells and sorbitol leads to tioning to their doctors. Although nasal decongestants cataract formation in diabetic patients(8­12). are associated with the troublesome complication of This study was designed to investigate the potential rhinitis medicamentosa, they are often prescribed to effects of nasal decongestant agents and their excipients patients and may also be available from pharmacies on ocular tissues following chronic exposure. without a prescription. One of the most popular nasal decongestants is METHODS xylometazoline. It has been proven to be a fast and highly effective drug for the relief of nasal congestion for up Animals and experimental design to 10 h(1). Xylometazoline use is suggested for several Male Wistar rats aged between 4 and 5 months were days only to relieve common cold symptoms, but abuse obtained from the Experimental Animal Center of Adnan of the drug is commonly encountered in daily practice. Menderes University (ADU), and all experiments were One of the earliest case reports was about a 1­month­old performed according to the principles and guidelines boy who was accidentally exposed to xylometazoline approved by the ADU Animal Ethical Committee (HADYEK sprayed three times in each nostril and subsequently be­ 2013/095). This study was designed as a randomized case came intoxicated(2). Another case report was published control experimental animal study. about ischemic stroke in a young adult following the