Editorial
Hypotensive eyedrops: The neverending story. Should we consider more than active principles?
Colirios hipotensores: la historia interminable. ¿Hay que considerar algo más que los principios activos?
M.D. Pinazo-Durána,b,c,
, V. Zanón-Morenoa,b,c, R. Herrero Vanrellc,d, S.M. Sanz-Gonzáleza,b,c, J.J. García-Medinac,e,f, J. Benitez del Castillo Sánchezg
Corresponding author
a Unidad de Investigación Oftalmológica «Santiago Grisolía»-Fundación FISABIO, Hospital Universitario Doctor Peset, Valencia, Spain
b Unidad de Oftalmobiología Celular y Molecular (UOCEM), Universidad de Valencia, Valencia, Spain
c Red Temática de Investigación Cooperativa en Patología Ocular (OFTARED), Spain
d Departamento de Farmacia y Tecnología Farmacéutica, Facultad de Farmacia, Universidad Complutense de Madrid, Madrid, Spain
e Servicio de Oftalmología, Hospital General Universitario Reina Sofía, Murcia, Spain
f Departamento de Oftalmología, Facultad de Medicina, Universidad de Murcia, Murcia, Spain
g Departamento de Oftalmología, Hospital de Jerez, Jerez de la Frontera, Cádiz, Spain
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To date, the only effective medical treatment is diminishing intraocular pressure (IOP). To this end, in addition to laser and anti-glaucomatous surgery, ophthalmic preparations are applied having “active principles” aimed at diminishing IOP. However, extended treatments with hypotensor eyedrops produce alterations on the ocular surface and the functional lacrimal unit (FLU) as well as the appearance of dry eye (DE) expressions that have a direct impact on the eyesight and quality of life of patients.<a class="elsevierStyleCrossRefs" href="#bib0065"><span class="elsevierStyleSup">1,2</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">According to Act 29 of July 26, 2006, on Guarantees and Rational Use of Medicaments and Health Products, a medicament for human use is “any substance or combination thereof presented as having properties for treating or preventing diseases in humans or that may be used or administered in order to restore, correct or modify physiological functions by executing pharmacologic, immunologic or metabolic action or establishing a medical diagnostic”. In said text, the active principle is attributed properties having adequate activity to constitute a medicament.</p><p id="par0015" class="elsevierStylePara elsevierViewall">Medicaments comprise the active principle (one or in association) and excipients (one or more). Excipients are included in pharmaceutical forms as a vehicle for carrying active principles. In addition, excipients can be utilized for facilitating the preparation and stability of a medicament or as an agent capable of modifying smell and taste or the physical and chemical properties of a medicament and its bioavailability. Accordingly, excipients must be chemically and biologically inert, in addition to being compatible and not irritating.</p><p id="par0020" class="elsevierStylePara elsevierViewall">As stated in the 5<span class="elsevierStyleSup">th</span> edition of the Royal Pharmacopoeia of Spain,<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">3</span></a> excipients and eyedrops can be utilized for various purposes such as adjusting the viscosity or pH of the pharmaceutical preparation, increasing the solubility of the active principle, regulating viscosity or stabilizing the entire formulation. Excipients, at the applied concentrations, should not negatively affect the desired curative action or produce local irritations.</p><p id="par0025" class="elsevierStylePara elsevierViewall">In addition, if the preparations are utilized in multidose dispensers, they must include an antimicrobial preservative at a concentration sufficient to ensure germicidal effect and to remain active during the period of use of the eyedrops. Benzalconium chloride</p><p id="par0030" class="elsevierStylePara elsevierViewall">(BAC) at a concentration between 0.004-0.02% has been one of the most utilized preservatives in hypotensor eyedrops.</p><p id="par0035" class="elsevierStylePara elsevierViewall">On the basis of numerous publications that have appeared in recent years, BAC is pointed out as the cause of the adverse effects of anti-glaucomatous medications on the ocular surface.<a class="elsevierStyleCrossRefs" href="#bib0080"><span class="elsevierStyleSup">4,5</span></a> For this reason, attempts have been made to utilize less aggressive preservatives in said eyedrops or eliminating them altogether. Trzeciecka et al.<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">6</span></a> study the effects of prolonged administration of a number of prostaglandin analogs (PGA), tafluprost, latanoprost and bimatoprost in rabbit eyes and after 8 weeks observed that latanoprost produced less tolerance, induced conjunctival hyperemia and increased blinking. In addition, histological studies demonstrated the infiltration of macrophages in the eyelids and alteration of goblet cells, although they did not identify increases in inflammation biomarkers in tears or aqueous humor. However, utilizing tears of patients with slight-moderate primary open angle glaucoma (POAG) without DE diagnostic against controls of the same age and sex, our research group has determined a significant increase of pro-inflammatory cytokins (interleukin [IL]-6) in tears of patients with POAG in treatment with eyedrops against controls.<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">7</span></a> In addition, our most recent study that included 30 glaucomatous patients treated with different APG presentations with preservatives (APG<span class="elsevierStyleHsp" style=""></span>+<span class="elsevierStyleHsp" style=""></span>Ps) and 11 patients that instilled a formulation without preservatives (APG-Ps) in single dosis (tafluprost 0,0015%) demonstrated the presence of significantly higher IL-1β levels in the APG<span class="elsevierStyleHsp" style=""></span>+<span class="elsevierStyleHsp" style=""></span>Ps group that reflected the inflammatory activity in ocular surface structures related to the toxic effects of Ps vis-à-vis products without Ps.<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">8</span></a> This was also demonstrated by Jee et al.<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">9</span></a> when comparing the cytokin expression in tears after treatment with and without preservatives in postoperative cataract surgery of patients with DE, while Sánchez et al.<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">10</span></a> determined increases in CD3, CD11b and HLA-DR pro-inflammatory molecules by means of flow cytometry.</p><p id="par0040" class="elsevierStylePara elsevierViewall">However, some authors demonstrated that the formulation of preservative-free anti-hypotensive agents could also contain other substances that could have negative effects on the integrity of FLU and contributes to DE expressions in glaucomatous patients. On the basis of the above studies and according to the recent findings of Smedowski et al.<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">11</span></a> and Esaki et al.<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">12</span></a> who analyzed the effects of hypotensor eyedrops without Ps (tafluprost and monoprost) and found that different solubility excipients included in said eyedrops (polysorbate 80 -a non-ionic surfactant- in the former and macrogol glycerol hydroxystereate 40 [MGHS40] in the latter, respectively) have very different actions on the ocular surface. MGHS40 produces an inflammatory response regulated by IL-6 and cytotoxicity increase in cellular lines of human corneal epithelium, while the other excipient is better tolerated. Therefore, it can be deduced that excipients can cause toxicity on ocular surface structures through 3 main mechanisms: inflammatory response increase (with expression of cytokins and chemokins), oxidative stress increase and mitochondrial dysfunction (formation of oxygen reactive species and diminished antioxidant capacity), and death due to apoptosis of epithelial cells (with hypo-expression of caspase-3 inducing enzyme).</p><p id="par0045" class="elsevierStylePara elsevierViewall">The authors conclude that excipients of hypotensor eyedrops should be researched in greater depth because they could produce side effects on the ocular surface that are similar or more severe than formerly known.</p><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0005">Conflict of interests</span><p id="par0050" class="elsevierStylePara elsevierViewall">The authors wish to state that there is no conflict of interest in the utilized procedures or the results of this study. Anti-glaucomatous treatments with hypotensor eyedrops were selected randomly and the study was carried out independently, without receiving funding from any company that could be involved in any way in said study.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:2 [ 0 => array:2 [ "identificador" => "sec0005" "titulo" => "Conflict of interests" ] 1 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as: Pinazo-Durán MD, Zanón-Moreno V, Herrero Vanrell R, Sanz-González SM, García-Medina JJ, Benitez del Castillo Sánchez J. Colirios hipotensores: la historia interminable. ¿Hay que considerar algo más que los principios activos? 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| Year/Month | Html | Total | |
|---|---|---|---|
| 2020 September | 0 | 1 | 1 |
| 2018 February | 3 | 1 | 4 |
| 2018 January | 11 | 0 | 11 |
| 2017 December | 4 | 0 | 4 |
| 2017 November | 15 | 1 | 16 |
| 2017 May | 1 | 0 | 1 |
