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CLINICAL SCIENCE
Ocular surface evaluation in patients treated with a fixed combination of prostaglandin analogues with 0.5% timolol maleate topical monotherapy: a randomized clinical trial
Heloisa Helena RussI,II,
Corresponding author
heloisaruss@onda.com.br

Tel.: 55 41 3015-6222
, Pedro Antônio Nogueira-FilhoII,III, Jeison de Nadai BarrosIII, Nubia Vanessa Lima de FariaIII, Fabiano Montiani-FerreiraIV, José Álvaro Pereira GomesII,III, Paulo Augusto Arruda MelloV
I Graefe Institute of Ophthalmology, Glaucoma Department, Curitiba/PR, Brazil
II Federal University of São Paulo, CASO-Ocular Surface Advanced Center, São Paulo/SP, Brazil
III Brasília Base Hospital, Glaucoma Department, Brasilia/DF, Brazil
IV Federal University of Paraná, Veterinary Department, Curitiba/PR, Brazil
V Federal University of São Paulo, Ophthalmology, São Paulo/SP, Brazil
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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="cesec10" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle60">INTRODUCTION</span><p id="para10" class="elsevierStylePara elsevierViewall">Glaucoma is a chronic&#44; multifactorial&#44; progressive optic neuropathy that requires long-term treatment with topical hypotensive medications &#40;<a class="elsevierStyleCrossRef" href="#bib1">1</a>&#41;&#46; Several classes of drugs are currently available to treat this condition&#44; including prostaglandin &#40;PG&#41; analogues as well as fixed combinations &#40;FCs&#41; of prostaglandin&#47;prostamide analogues combined with 0&#46;5&#37; timolol maleate &#40;<a class="elsevierStyleCrossRef" href="#bib2">2</a>&#41;&#46;</p><p id="para20" class="elsevierStylePara elsevierViewall">Beta-blockers are often used to treat glaucoma and were considered the &#8220;gold standard&#8221; for starting glaucoma treatment until recently&#44; when they were replaced by prostaglandin analogues &#40;<a class="elsevierStyleCrossRef" href="#bib2">2</a>&#41;&#46; Beta-blockers have many systemic side effects&#44; especially bradycardia and bronchospasms&#44; as well as effects on the central nervous system&#46;</p><p id="para30" class="elsevierStylePara elsevierViewall">While the systemic side effects induced by topical PG analogues are rare&#44; iris hyperpigmentation&#44; excessive eyelash growth and conjunctival hyperemia have been reported among the local side effects caused by these drugs &#40;<a class="elsevierStyleCrossRefs" href="#bib3">3&#8211;5</a>&#41;&#46; Conditions suggestive of the stimulation or reactivation of ocular inflammatory responses&#44; such as anterior uveitis or cystoid macular edema&#44; have also been associated with the use of PG analogues &#40;<a class="elsevierStyleCrossRef" href="#bib6">6</a>&#41;&#46;</p><p id="para40" class="elsevierStylePara elsevierViewall">Ocular surface dysfunction has also been related to glaucoma treatment&#46; Beta-blockers have been known to induce conjunctival hyperemia&#44; punctate keratitis and corneal anesthesia&#44; as well as dry eye and allergic blepharoconjunctivitis &#40;<a class="elsevierStyleCrossRefs" href="#bib7">7&#8211;9</a>&#41;&#46;</p><p id="para50" class="elsevierStylePara elsevierViewall">Previous studies with patients who received long-term treatment with topical medications showed that both hypotensive drugs and their preservatives &#40;especially benzalkonium chloride &#8211; BAK&#41; could increase the number of inflammatory cells and fibroblasts in the substantia propria of the conjunctiva and reduce the number of goblet cells&#44; thereby inducing ocular surface changes manifested clinically as dry eye &#40;<a class="elsevierStyleCrossRefs" href="#bib8">8&#8211;11</a>&#41;&#46; The length of administration&#44; concentration and amount of these drugs have been related to the severity of the side effects&#46; In addition&#44; there has been strong evidence suggesting that these changes might increase the risk of trabeculectomy failure &#40;<a class="elsevierStyleCrossRef" href="#bib12">12</a>&#44;<a class="elsevierStyleCrossRef" href="#bib13">13</a>&#41;&#46; However&#44; most of the information on this subject was published prior to the introduction of PG analogues&#46;</p><p id="para60" class="elsevierStylePara elsevierViewall">The purpose of this study was to evaluate &#40;clinically&#44; histologically and via immunocytochemistry&#41; the ocular surface changes induced by glaucoma treatment with topical FCs of PG analogues and timolol&#46;</p></span><span id="cesec20" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle70">MATERIALS AND METHODS</span><span id="cesec30" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle80">Inclusion criteria</span><p id="para70" class="elsevierStylePara elsevierViewall">Eligible patients were adults &#40;&#8805;18 years of age&#41; with a clinical diagnosis of primary open-angle glaucoma &#40;POAG&#41; or ocular hypertension &#40;OH&#41; in at least one eye and with no previous topical hypotensive treatment&#46; The selected patients had a open iridocorneal angle upon gonioscopy examination&#46; POAG was diagnosed on the basis of characteristic optic disc changes and&#47;or glaucomatous visual field loss demonstrated on the Humphrey visual field analyzer &#40;HFA&#41; &#40;Humphrey Instruments&#44; Inc&#46;&#44; Zeiss Humphrey&#44; San Leandro&#44; California&#44; USA&#41;&#46; IOP&#44; measured at 8 a&#46;m&#46;&#44; had to be between 26 mm Hg and 35 mm Hg in the study eye&#40;s&#41;&#46; In addition&#44; patients were required to have a corrected distance visual acuity &#40;CDVA&#41; of 20&#47;70 or better in each eye&#44; and those with glaucoma had to have a recent &#40;within three months&#41; visual field examination showing a mean deviation greater than -15 dB and no fixation threat&#46; Finally&#44; the eligible patients were required to be able to follow instructions&#44; to be willing and able to attend all of the study visits&#44; and to provide informed consent prior to screening&#46;</p></span><span id="cesec40" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle90">Exclusion criteria</span><p id="para80" class="elsevierStylePara elsevierViewall">Patients were excluded if they met any of the following criteria&#58; previous ocular surgery&#59; active ocular inflammation&#59; or clinically diagnosed dry eye&#46; Patients with hypersensitivity or poor tolerance to any components of the study medication&#59; with bronchial asthma or history of bronchial asthma&#59; with bronchial hyperreactivity or severe chronic obstructive pulmonary disease that would preclude the safe administration of a topical beta-blocker&#59; sinus bradycardia&#44; second-degree or third-degree atrioventricular block&#44; sinoatrial block&#44; overt cardiac failure&#44; or cardiogenic shock that would preclude the safe administration of a topical beta-blocker&#59; or a severe medical or psychiatric condition were also excluded from the study&#46;</p><p id="para90" class="elsevierStylePara elsevierViewall">A prospective&#44; randomized&#44; single-blind&#44; multicenter&#44; parallel group&#44; interventional study was conducted between March 2009 and September 2010 at the Federal University of S&#227;o Paulo &#40;UNIFESP&#41; in S&#227;o Paulo&#44; Brazil&#46;</p><p id="para100" class="elsevierStylePara elsevierViewall">The participants were allocated to each treatment group following the sequence of a randomization table&#46; The randomization table was generated using software &#40;Stata&#44; version 11&#44; College Station&#44; Texas&#44; USA&#41; and a block size of three&#46; The participants were enrolled and assigned to each group by the study coordinator&#46;</p><p id="para110" class="elsevierStylePara elsevierViewall">After the sample size was calculated&#44; 33 patients were selected &#40;11 patients were randomly distributed into three different groups according to medication regimen&#41; by two examiners &#40;HR and NL&#41; and were allocated using permuted-block randomization &#40;block size&#8202;&#61;&#8202;3&#59; allocation rate 1&#58;1&#58;1&#41; into the following three groups&#44; independently of age&#44; sex or residence&#58; latanoprost&#43;timolol &#40;LT&#41;&#59; bimatoprost&#43;timolol &#40;BT&#41;&#59; or travoprost&#43;timolol &#40;TT&#41; &#40;<a class="elsevierStyleCrossRef" href="#fig1-cln_68p1318">Figure 1</a>&#41;&#46;</p><elsevierMultimedia ident="fig1-cln_68p1318"></elsevierMultimedia><p id="para120" class="elsevierStylePara elsevierViewall">The medications were administered once daily in the evening for 12 weeks in selected patients in all of the groups&#46;</p><p id="para130" class="elsevierStylePara elsevierViewall">The clinical data collected included the patients&#39; demographic data &#40;age&#44; sex and ethnicity&#41;&#46; All of the patients underwent routine ophthalmological examinations prior to and after three months of treatment&#46; The ocular surface evaluation included biomicroscopic examination of the lids&#44; conjunctiva&#44; cornea and tear film&#46; The diagnostic tests included Schirmer&#39;s test with anesthesia&#44; Lissamine green vital staining&#44; tear film break-up time &#40;TBUT&#41; and impression cytology&#46; The OSDI questionnaire was also applied&#46; After the ocular surface evaluation&#44; intraocular pressure &#40;IOP&#41; was measured with the Goldmann applanation tonometer&#46;</p><p id="para140" class="elsevierStylePara elsevierViewall">The patients were examined at two centers &#40;Graefe Institute of Ophthalmology and Brasilia Base Hospital&#41;&#44; following instructions provided by the Cornea and External Disease Service in the Department of Ophthalmology&#44; UNIFESP&#46; All of the IOP measurements were obtained at the same time &#40;8 a&#46;m&#46;&#41;&#46; The rooms where the examinations were performed had neither air conditioning nor windows&#44; and the air humidity and temperature were controlled with specific equipment&#46; Prior to the examination&#44; the patients rested for 20 minutes with the door to the room closed&#46; The tests were performed by two researchers &#40;HR and NL&#41; and were analyzed at the Ocular Surface Advanced Center &#40;CASO&#41; by two blinded investigators &#40;JB and PANF&#41;&#46;</p><p id="para150" class="elsevierStylePara elsevierViewall">Those investigators who assessed the primary outcomes of the study were blinded to the allocation status of the participants&#46; The statistician who performed the data analysis was blinded to all information&#46;</p><p id="para160" class="elsevierStylePara elsevierViewall">Dry eye was defined as a TBUT score of &#60;5 seconds &#40;2&#37; fluorescein&#44; Ophthalmos&#44; S&#227;o Paulo&#44; SP&#44; Brazil&#41;&#44; &#60;5 mm wetting in the Schirmer&#39;s test &#40;Schirmer strips&#44; Ophthalmos&#44; S&#227;o Paulo&#44; SP&#44; Brazil&#41; with topical anesthesia &#40;0&#46;5&#37; proxymetacaine chlorohydrate&#44; Anestalcon&#174;&#44; Alcon Laborat&#243;rios do Brasil&#44; S&#227;o Paulo&#44; SP&#44; Brazil&#41; and corneal and conjunctival staining with 1&#37; Lissamine green &#40;Ophthalmos&#44; S&#227;o Paulo&#44; SP&#44; Brazil&#41; &#8805;3 on the van Bijsterveld scale &#40;0 to 9&#41;&#46;</p></span><span id="cesec50" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle100">Impression cytology</span><p id="para170" class="elsevierStylePara elsevierViewall">After the ocular surface evaluation&#44; all of the patients were subjected to impression cytology &#40;IC&#41; sampling by two researchers &#40;HR and NL&#41;&#46; Following topical anesthesia&#44; IC specimens were collected &#40;HAWP 304&#44; Millipore&#44; Bedford&#44; Massachusetts&#44; USA&#41; from an exposed area of the bulbar conjunctiva &#40;temporal region&#41; and an unexposed area of the conjunctiva &#40;superior region&#41; adjacent to the corneal limbus&#46; All of the strips were processed for periodic acid Schiff and Gill&#39;s hematoxylin staining&#46; Glass slides mounted with Entellan &#40;Merck&#44; Darmstadt&#44; Germany&#41; were examined with a blinded procedure under light microscopy by an experienced professional &#40;JNB&#41;&#46; For quality control&#44; only IC specimens were included with at least one third of the filter surface covered by visible epithelial cells&#46; The conjunctiva samples were evaluated according to established techniques for the following parameters&#58; cellularity&#59; cell-to-cell contact&#59; nuclear-to-cytoplasmic &#40;N&#47;C&#41; ratio&#59; nuclear chromatin&#59; goblet cell density&#59; keratinization&#59; and distribution of inflammatory cells&#46; A score of 0 to 3 was assigned to each of these features&#58; 0 - normal findings&#59; 1 - borderline features&#59; and 2 and 3 - abnormal features &#40;29&#44;30&#41;&#46; The total score for each sample was classified as A &#40;normal&#59; total score 0-3&#41;&#44; B &#40;borderline&#59; total score 4-6&#41; or C &#40;abnormal&#59; total score &#62;6&#41;&#46; The goblet cell densities were considered normal when the cells were abundant&#44; borderline when there was a slightly or moderately reduced number of cells and abnormal when there was a distinct reduction in the number of cells &#40;the presence of one or no goblet cells&#41;&#46;</p></span><span id="cesec60" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle110">Immunocytochemistry</span><p id="para180" class="elsevierStylePara elsevierViewall">Other conjunctival impression cytology samples were obtained from the same areas as the first samples&#44; using Biopore membranes &#40;Millicell-CM 0&#46;4 &#956;m PICM 012550&#44; Millipore Corp&#44; Bedford&#44; Massachusetts&#44; USA&#41;&#44; and were immunostained with monoclonal antibodies to HLA-DR and IL-6&#46; The samples with cells covering more than 80&#37; of the membrane area or samples covering between 40&#37; and 80&#37; &#40;where the cells were confluent and present in a discrete area&#41; were considered suitable for immunocytological analysis&#46; Samples with cellularity of less than 40&#37; were considered unsuitable&#46; The number of cells positive for HLA-DR and IL-6 and the total number of cells in five adjacent microscopic high-power fields &#40;40X&#41; were counted by the two masked observers &#40;JNB and PANF&#41;&#46; The results for each phenotype were expressed as a percentage of the total number of cells and were compared pre- and post-treatment&#46;</p></span><span id="cesec70" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle120">Statistical analysis</span><p id="para190" class="elsevierStylePara elsevierViewall">The sample size calculation was based on a pilot study performed at one of the study sites&#46; Two principal outcomes&#44; the Schirmer&#39;s test and impression cytology&#44; were selected for this purpose&#46; To detect a difference of 3 mm &#40;SD 2 mm&#41; with the Schirmer&#39;s test at two points in time &#40;pre- and post-treatment&#41;&#44; a sample size of 10 was necessary to obtain a power of 80&#37; at the 5&#37; significance level&#46; This sample size &#40;N&#8202;&#61;&#8202;10&#41; would provide a power of 94&#37; to detect a difference of 0&#46;4 cells &#40;SD 0&#46;2 cells&#41; in the mean number of cells in the impression cytology test&#46; Therefore&#44; a sample size of 11 per treatment group was used in this study&#46;</p><p id="para200" class="elsevierStylePara elsevierViewall">The Kolmogorov-Smirnov &#40;K-S&#41; test was used to determine whether the continuous variables had a normal distribution&#46; One-way ANOVA with a significance level of 5&#37; was used to compare the continuous variables&#44; and the Kruskal-Wallis test was used to compare the continuous variables with a non-Gaussian distribution&#46; When statistically significant differences were found&#44; the data were further analyzed using post hoc comparisons with Fisher&#39;s exact test &#40;for comparisons of up to three groups&#41; or the Tukey-Kramer test &#40;comparisons of more than three groups&#41; for <span class="elsevierStyleItalic">p</span>-value correction&#46; The calculations were performed with StatView statistical software &#40;SAS Institute Inc&#46;&#44; Cary&#44; North Carolina&#44; USA&#41;&#46; The level of statistical significance was set at <span class="elsevierStyleItalic">p</span>&#8202;&#61;&#8202;0&#46;05&#46;</p></span><span id="cesec80" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle130">Ethics</span><p id="para210" class="elsevierStylePara elsevierViewall">The study was approved by the UNIFESP Medical Ethics Committee &#40;reference no&#46; 0954&#47;06&#41; and was registered with an internationally accredited site &#40;UTN U1111-1129-2872&#59; RBR-7mmp6k- <a href="http://www.ensaiosclinicos.gov.br">www&#46;ensaiosclinicos&#46;gov&#46;br</a>&#41; in accordance with the guidelines set forth in the Declaration of Helsinki&#46; All of the patients provided informed consent&#46; The research was funded by the Federal University of S&#227;o Paulo&#47;FAPESP&#46;</p></span></span><span id="cesec90" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle140">RESULTS</span><p id="para220" class="elsevierStylePara elsevierViewall">The results of the statistical analysis were unaffected by the demographic data &#40;age&#44; sex and ethnicity&#41; &#40;<a class="elsevierStyleCrossRef" href="#t1-cln_68p1318">Table 1</a>&#41;&#46;</p><elsevierMultimedia ident="t1-cln_68p1318"></elsevierMultimedia><p id="para230" class="elsevierStylePara elsevierViewall">All three combinations &#40;LT&#44; BT and TT&#41; produced a statistically significant reduction in IOP &#40;<span class="elsevierStyleItalic">p</span>&#8202;&#61;&#8202;0&#46;0001&#41;&#46; The mean IOP for the TT group was 24&#46;72&#177;1&#46;03 mm Hg &#40;95&#37; CI 22&#46;66-26&#46;78&#41; prior to treatment and 14&#46;00&#177;0&#46;44 mm Hg &#40;95&#37; CI 13&#46;12-14&#46;88 mm Hg&#41; after treatment&#59; the corresponding figures for the BT group were 22&#46;32&#177;5&#46;58 mm Hg &#40;95&#37; CI 11&#46;16-33&#46;48&#41; and 12&#46;10&#177;2&#46;96 mm Hg &#40;95&#37; CI 6&#46;18-18&#46;02&#41;&#44; respectively&#44; and for the LT group&#44; they were 20&#46;32&#177;4&#46;99 mm Hg &#40;95&#37; CI 10&#46;34-30&#46;3&#41; and 11&#46;59&#177;3&#46;11 mm Hg&#44; respectively &#40;95&#37; CI 5&#46;37-17&#46;81&#41;&#46;</p><p id="para240" class="elsevierStylePara elsevierViewall">The ocular surface evaluations revealed a significant decrease in the Schirmer&#39;s test values for the patients treated with all of the drugs&#58; the mean value for the TT group was 8&#46;95&#177;0&#46;21 mm &#40;95&#37; CI 8&#46;53-9&#46;37&#41; prior to treatment and 7&#46;18&#177;0&#46;73 mm &#40;95&#37; CI 5&#46;72-8&#46;64&#41; after treatment &#40;<span class="elsevierStyleItalic">p</span>&#8202;&#61;&#8202;0&#46;0001&#41;&#59; the corresponding figures for the LT group were 13&#46;77&#177;4&#46;72 mm &#40;95&#37; CI 4&#46;33-23&#46;21&#41; and 9&#46;09&#177;3&#46;65 mm &#40;95&#37; CI 1&#46;79-16&#46;39&#41; &#40;<span class="elsevierStyleItalic">p</span>&#8202;&#61;&#8202;0&#46;0007&#41;&#44; respectively&#44; and they were 12&#46;45&#177;3&#46;85 mm &#40;95&#37; CI 4&#46;75-20&#46;15&#41; and 9&#46;95&#177;3&#46;68 mm &#40;95&#37; CI 2&#46;59-17&#46;31&#41; &#40;<span class="elsevierStyleItalic">p</span>&#8202;&#61;&#8202;0&#46;0333&#41;&#44; respectively&#44; for the BT group&#46;</p><p id="para250" class="elsevierStylePara elsevierViewall">The TBUT decreased significantly in the TT and LT groups&#46; The mean values for the former were 11&#46;95&#177;1&#46;49 seconds &#40;95&#37; CI 8&#46;97-14&#46;93&#41; prior to treatment and 9&#46;54&#177;0&#46;85 seconds &#40;95&#37; CI 7&#46;84-11&#46;24&#41; after treatment &#40;<span class="elsevierStyleItalic">p</span>&#60;0&#46;0001&#41;&#44; and for the latter&#44; the values were 13&#46;86&#177;3&#46;18 seconds &#40;95&#37; CI 7&#46;5-20&#46;22&#41; and 11&#46;68&#177;3&#46;38 seconds &#40;95&#37; CI 4&#46;92-18&#46;44&#41;&#44; respectively &#40;<span class="elsevierStyleItalic">p</span>&#8202;&#61;&#8202;0&#46;0025&#41;&#46; For the BT group&#44; the difference was not statistically significant &#40;<span class="elsevierStyleItalic">p</span>&#8202;&#61;&#8202;0&#46;45&#41;&#46;</p><p id="para260" class="elsevierStylePara elsevierViewall">Scores for Lissamine green staining increased significantly in patients treated with TT &#40;mean score of 2&#46;36&#177;0&#46;65 &#91;95&#37; CI 1&#46;06-3&#46;66&#93; prior to treatment and 6&#177;0&#46;01 &#91;95&#37; CI 5&#46;98-6&#46;02&#93; after treatment &#91;<span class="elsevierStyleItalic">p</span>&#60;0&#46;0001&#93;&#41; and with BT &#40;mean score of 2&#177;1&#46;48 &#91;95&#37; CI 0&#46;94-4&#46;96&#93; prior to treatment and 3&#46;27&#177;1&#46;45 &#91;95&#37; CI 0&#46;37-6&#46;17&#93; after treatment &#91;<span class="elsevierStyleItalic">p</span>&#8202;&#61;&#8202;0&#46;0007&#93;&#41;&#46; For the LT group&#44; this difference was not statistically significant &#40;<span class="elsevierStyleItalic">p</span>&#8202;&#61;&#8202;0&#46;22&#41;&#46;</p><p id="para270" class="elsevierStylePara elsevierViewall">The OSDI scores increased in all of the groups&#44; but the difference was only significantly different in the TT group &#40;mean score 33&#46;74&#177;6&#46;88 &#91;95&#37; CI 19&#46;98-47&#46;5&#93; prior to treatment and 39&#46;94&#177;3&#46;92 &#91;95&#37; CI 32&#46;1-47&#46;78&#93; after treatment &#91;<span class="elsevierStyleItalic">p</span>&#8202;&#61;&#8202;0&#46;02&#93;&#41;&#46; All of the groups could be classified as having mild to moderate dry eye on the OSDI scale&#46;</p><p id="para280" class="elsevierStylePara elsevierViewall"><a class="elsevierStyleCrossRef" href="#t2-cln_68p1318">Table 2</a> summarizes the clinical ocular surface data for the three groups&#46;</p><elsevierMultimedia ident="t2-cln_68p1318"></elsevierMultimedia><span id="cesec100" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle150">Impression cytology</span><p id="para290" class="elsevierStylePara elsevierViewall">Although the total score &#40;histological classification&#41; was worse for all of the groups after treatment&#44; this change was not statistically significant&#46; However&#44; when specific IC parameters were considered&#44; an increase in cellularity could be observed in all of the groups&#58; TT - 0&#46;04&#177;0&#46;30 cells &#40;95&#37; CI -0&#46;56-0&#46;64&#41; prior to treatment and 0&#46;386&#177;0&#46;58 cells &#40;95&#37; CI -0&#46;774-1&#46;546&#41; after treatment &#40;<span class="elsevierStyleItalic">p</span>&#8202;&#61;&#8202;0&#46;0008&#41;&#59; BT - 0&#46;27&#177;0&#46;66 &#40;95&#37; CI -1&#46;05-1&#46;59&#41; and 0&#46;70&#177;0&#46;82 cells &#40;95&#37; CI -0&#46;94-2&#46;34&#41; prior to and after treatment&#44; respectively &#40;<span class="elsevierStyleItalic">p</span>&#8202;&#61;&#8202;0&#46;008&#41;&#59; and LT - 0&#46;182&#177;0&#46;54 &#40;95&#37; CI -1&#46;498-1&#46;862&#41; and 0&#46;545&#177;0&#46;85 cells &#40;95&#37; CI -1&#46;155-2&#46;245&#41; prior to and after treatment&#44; respectively &#40;<span class="elsevierStyleItalic">p</span>&#8202;&#61;&#8202;0&#46;0022&#41;&#46;</p><p id="para300" class="elsevierStylePara elsevierViewall">The TT group had 0&#46;29&#177;0&#46;63 goblet cells &#40;95&#37; CI -0&#46;97-1&#46;55&#41; prior to treatment and 0&#46;86&#177;0&#46;93 cells &#40;95&#37; CI -1&#46;0-2&#46;72&#41; after treatment &#40;<span class="elsevierStyleItalic">p</span>&#8202;&#61;&#8202;0&#46;012&#41;&#46; For the BT group&#44; the corresponding figures were 0&#46;57&#177;0&#46;873 &#40;95&#37; CI -1&#46;176-2&#46;316&#41; and 0&#46;93&#177;0&#46;873 &#40;95&#37; CI -0&#46;816-2&#46;676&#41; &#40;<span class="elsevierStyleItalic">p</span>&#8202;&#61;&#8202;0&#46;054&#41; and 0&#46;182&#177;0&#46;54 &#40;95&#37; CI -0&#46;898-1&#46;262&#41; and 0&#46;545&#177;0&#46;85 &#40;95&#37; CI -1&#46;155-2&#46;245&#41; &#40;<span class="elsevierStyleItalic">p</span>&#8202;&#61;&#8202;0&#46;0186&#41; for the LT group&#44; respectively&#46;</p><p id="para310" class="elsevierStylePara elsevierViewall">The mean cell-to-cell contact was 0&#46;136&#177;0&#46;40 &#40;95&#37; CI -0&#46;664-0&#46;936&#41; in the TT group prior to treatment and 0&#46;59&#177;0&#46;73 &#40;95&#37; CI -0&#46;87-2&#46;05&#41; after treatment &#40;<span class="elsevierStyleItalic">p</span>&#8202;&#61;&#8202;0&#46;0005&#41;&#46; For the BT group&#44; the mean values were 0&#46;27&#177;0&#46;54 &#40;95&#37; CI -0&#46;81-1&#46;35&#41; and 0&#46;41&#177;0&#46;58 &#40;95&#37; CI -0&#46;75-1&#46;57&#41; prior to and after treatment &#40;<span class="elsevierStyleItalic">p</span>&#8202;&#61;&#8202;0&#46;26&#41;&#44; respectively&#44; and for the LT group&#44; the corresponding values were 0&#46;16&#177;0&#46;43 &#40;95&#37; CI -0&#46;7-1&#46;02&#41; and 0&#46;38&#177;0&#46;66 &#40;95&#37; CI -0&#46;94-1&#46;7&#41;&#44; respectively &#40;<span class="elsevierStyleItalic">p</span>&#8202;&#61;&#8202;0&#46;07&#41;&#46;</p><p id="para320" class="elsevierStylePara elsevierViewall">There were no changes in inflammatory cells&#44; keratinization or N&#47;C ratio &#40;<a class="elsevierStyleCrossRef" href="#t3-cln_68p1318">Table 3</a>&#41;&#46;</p><elsevierMultimedia ident="t3-cln_68p1318"></elsevierMultimedia></span><span id="cesec110" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle160">Immunocytochemistry</span><p id="para330" class="elsevierStylePara elsevierViewall">While TT induced a statistically significant increase in HLA-DR expression &#40;the mean count of cells positive for HLA-DR in the TT group was 39&#46;5&#177;70&#46;56 &#91;95&#37; CI -101&#46;62-180&#46;62&#93; prior to treatment and 88&#46;77&#177;116&#46;28 &#91;95&#37; CI -143&#46;79-321&#46;33&#93; after treatment &#40;<span class="elsevierStyleItalic">p</span>&#8202;&#61;&#8202;0&#46;0184&#41; &#91;<a class="elsevierStyleCrossRef" href="#fig2-cln_68p1318">Figure 2</a>&#93;&#41;&#44; BT and LT showed a decrease in HLA-DR expression that was not statistically significant for either group &#40;BT&#44; <span class="elsevierStyleItalic">p</span>&#8202;&#61;&#8202;0&#46;26&#59; LT&#44; <span class="elsevierStyleItalic">p</span>&#8202;&#61;&#8202;0&#46;92&#41;&#46;</p><elsevierMultimedia ident="fig2-cln_68p1318"></elsevierMultimedia><p id="para340" class="elsevierStylePara elsevierViewall">Similarly&#44; TT induced a significant increase in IL-6-positive cells &#40;<a class="elsevierStyleCrossRef" href="#fig3-cln_68p1318">Figure 3</a>&#41;&#58; the mean count was 58&#46;48&#177;91&#46;70 &#40;95&#37; CI -124&#46;92-241&#46;88&#41; prior to treatment and 150&#46;52&#177;171&#46;31 &#40;95&#37; CI -192&#46;1-493&#46;14&#41; after treatment &#40;<span class="elsevierStyleItalic">p</span>&#8202;&#61;&#8202;0&#46;0023&#41;&#46; BT and LT also showed an increase in HLA-DR expression&#44; but this increase was not statistically significant for either group &#40;BT&#44; <span class="elsevierStyleItalic">p</span>&#8202;&#61;&#8202;0&#46;33&#59; LT&#44; <span class="elsevierStyleItalic">p</span>&#8202;&#61;&#8202;0&#46;33&#41;&#46;</p><elsevierMultimedia ident="fig3-cln_68p1318"></elsevierMultimedia></span></span><span id="cesec120" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle170">DISCUSSION</span><p id="para350" class="elsevierStylePara elsevierViewall">All three medications produced a statistically significant reduction in IOP&#44; with no difference among them&#46; Our results were similar to those described by Centofanti et al&#46; regarding fixed combinations &#40;<a class="elsevierStyleCrossRef" href="#bib14">14</a>&#41;&#46;</p><p id="para360" class="elsevierStylePara elsevierViewall">Impaired tear film production associated with glaucoma treatment has been described in many articles &#40;<a class="elsevierStyleCrossRef" href="#bib8">8</a>&#44;<a class="elsevierStyleCrossRef" href="#bib10">10</a>&#41;&#46;</p><p id="para370" class="elsevierStylePara elsevierViewall">Strong evidence provided by previous clinical and experimental studies has indicated that the chronic use of antiglaucoma drugs might induce ocular surface changes&#44; causing discomfort at instillation&#44; conjunctival inflammation&#44; tear film instability&#44; subconjunctival fibrosis&#44; apoptosis of conjunctival epithelial cells and corneal surface changes &#40;<a class="elsevierStyleCrossRefs" href="#bib15">15&#8211;17</a>&#41;&#46;</p><p id="para380" class="elsevierStylePara elsevierViewall">These changes could result in a greater risk of failure when patients undergo antiglaucoma surgery&#44; particularly trabeculectomy&#44; as a result of postoperative fibrosis &#40;<a class="elsevierStyleCrossRef" href="#bib9">9</a>&#44;<a class="elsevierStyleCrossRef" href="#bib12">12</a>&#44;<a class="elsevierStyleCrossRef" href="#bib13">13</a>&#41;&#46;</p><p id="para390" class="elsevierStylePara elsevierViewall">In the present study&#44; we observed that all three drugs induced a subclinical inflammatory reaction&#46; This reaction was only detected via immunocytochemistry&#44; which revealed cells positive for inflammatory markers&#44; such as IL-6 and HLA-DR&#46; No increase in inflammatory cells was detected via IC&#46;</p><p id="para400" class="elsevierStylePara elsevierViewall">Subclinical inflammation associated with the use of latanoprost has been reported by other authors who&#44; using histopathology and immunohistochemical markers &#40;HLA-DR&#44; IL-6 and IL-8&#41;&#44; have described a strong correlation between dry eye and inflammatory cells in the conjunctival epithelium and substantia propria &#40;<a class="elsevierStyleCrossRef" href="#bib15">15</a>&#44;<a class="elsevierStyleCrossRef" href="#bib17">17</a>&#44;<a class="elsevierStyleCrossRef" href="#bib18">18</a>&#41;&#46;</p><p id="para410" class="elsevierStylePara elsevierViewall">Immunocytochemistry after three months of treatment did not reveal any changes in total score&#46; However&#44; we observed changes in other related parameters&#44; such as cellularity&#44; number of goblet cells and cell-to-cell contact&#46; The increase in cellularity without an inflammatory reaction was likely related to reactive hyperplasia of the conjunctival epithelial cells in response to the toxic effects of the drugs&#46;</p><p id="para420" class="elsevierStylePara elsevierViewall">Authors such as Guenoun et al&#46; have correlated the increase in goblet cells induced by PG analogues with a possible protective effect against BAK-induced toxicity to the ocular surface &#40;<a class="elsevierStyleCrossRef" href="#bib19">19</a>&#41;&#46; In a previous study&#44; we also observed an increase in the number of goblet cells in groups treated with PG analogues &#40;latanoprost&#44; travoprost and bimatoprost&#41;&#44; but this increase was not sustained over six months &#40;<a class="elsevierStyleCrossRef" href="#bib15">15</a>&#44;<a class="elsevierStyleCrossRef" href="#bib18">18</a>&#44;<a class="elsevierStyleCrossRef" href="#bib20">20</a>&#41;&#46; This effect has been controversial&#59; hyperplasia in goblet cells seems to represent a protective mechanism in the initial phase of chronic aggression to the ocular surface&#44; as observed in allergies or responses to pollution&#44; but it is followed by a decrease in the number of these cells if the aggressive factor becomes chronic &#40;<a class="elsevierStyleCrossRef" href="#bib21">21</a>&#44;<a class="elsevierStyleCrossRef" href="#bib22">22</a>&#41;&#46;</p><p id="para430" class="elsevierStylePara elsevierViewall">Changes in cell-to-cell contact result in a loss of &#8220;gap junctions&#8221; and in edema&#44; which are reflected in the epithelial architecture and which lead to keratopathy&#46; These pathological changes in the ocular surface could partly explain the occurrence of dry eye symptoms in patients using hypotensive drugs&#46;</p><p id="para440" class="elsevierStylePara elsevierViewall">Herrera et al&#46; reported that prolonged use &#40;longer than six months&#41; of 0&#46;5&#37; timolol maleate might lead to a higher incidence of dry eye&#44; with lower TBUT values and Schirmer&#39;s test scores &#40;<a class="elsevierStyleCrossRef" href="#bib7">7</a>&#41;&#46; Several reports have also demonstrated that timolol could cause a decrease in the number of goblet cells and keratoconjunctivitis sicca &#40;<a class="elsevierStyleCrossRef" href="#bib7">7</a>&#44;<a class="elsevierStyleCrossRef" href="#bib8">8</a>&#44;<a class="elsevierStyleCrossRef" href="#bib13">13</a>&#41;&#46; Reductions in TBUT values and Schirmer&#39;s test scores have been described in many studies investigating the effects of the length of glaucoma treatment&#44; the number of medications used and preservative concentrations &#40;<a class="elsevierStyleCrossRef" href="#bib16">16</a>&#44;<a class="elsevierStyleCrossRef" href="#bib23">23</a>&#44;<a class="elsevierStyleCrossRef" href="#bib24">24</a>&#41;&#46;</p><p id="para450" class="elsevierStylePara elsevierViewall">In the present study&#44; conjunctival function and tear film stability were worse after treatment&#44; indicating deterioration of the ocular surface&#46;</p><p id="para460" class="elsevierStylePara elsevierViewall">More recently&#44; some authors have used the OSDI &#40;Ocular Surface Disease Index&#41; questionnaire&#44; a useful tool for analyzing symptoms of dry eye&#44; to measure symptoms in glaucoma patients&#59; the lower the OSDI score is&#44; the less toxic the medication is &#40;<a class="elsevierStyleCrossRef" href="#bib24">24</a>&#44;<a class="elsevierStyleCrossRef" href="#bib26">26</a>&#41;&#46; In our study&#44; OSDI scores also showed an increase&#44; with most patients having mild or moderate dry eye&#44; confirming the involvement of the lacrimal functional unit and the ocular surface&#46; Preservative-free medications have been associated with lower scores&#44; and improvements in scores have been reported for patients who switched to this type of medication &#40;<a class="elsevierStyleCrossRef" href="#bib25">25</a>&#44;<a class="elsevierStyleCrossRef" href="#bib26">26</a>&#41;&#46;</p><p id="para470" class="elsevierStylePara elsevierViewall">One of the limitations in our study was related to ethnicity&#46; The numbers of Asian and African American individuals distributed among the groups were considerably fewer than those of Caucasian and Hispanic individuals&#59; this could have been a source of bias&#46; Additionally&#44; it should be noted that&#44; in our study&#44; a large variation was observed in patients treated with travoprost&#43;timolol&#46; Although the results were considered &#8220;normal&#44;&#8221; this regimen group began with somewhat worse ocular surface conditions&#44; compared with the other groups&#46; There was a trend that was not statistically significant toward a poorer ocular surface&#44; irrespective of sex or age&#44; at the beginning of the study&#46; This finding occurred by chance and was likely related to the randomization method &#40;permuted-block&#41; used to ensure sample balance&#44; but it could lead to selection bias in a non-masked study&#46; This trend was only noticed after the investigation was completed&#46; For this reason and because of the short study period&#44; we excluded comparisons among the three drugs&#46;</p><p id="para480" class="elsevierStylePara elsevierViewall">The number of patients remaining after all of the exclusion criteria were applied was somewhat modest &#40;n&#8202;&#61;&#8202;11 per group&#41; for a multicentric study&#44; but it was substantial for a two-center investigation&#46; Thus&#44; we assert that our results can be extrapolated and are applicable for general ophthalmic clinics&#44; particularly for glaucoma and cornea specialists&#44; as well as for large multicenter studies&#46;</p><p id="para490" class="elsevierStylePara elsevierViewall">In summary&#44; this study demonstrated that there were significant changes in the ocular surface after exposure to FCs for a short period &#40;three months&#41;&#44; despite the ease of administration &#40;once daily&#41;&#44; and reduced exposure to preservatives &#40;one drop versus three if the medications were administered individually&#41;&#46; However&#44; it cannot be concluded from the present study whether any particular drug induced greater changes in the ocular surface&#46;</p></span><span id="cesec130" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle180">AUTHOR CONTRIBUTIONS</span><p id="para500" class="elsevierStylePara elsevierViewall">Russ HH&#44; Montiani-Ferreira F&#44; Gomes JA and Mello PA conceived the study and participated in its design&#46; Russ HH and Faria NL performed the data acquisition&#46; Russ HH&#44; Faria NL&#44; Nogueira-Filho PA&#44; Barros JN&#44; Montiani-Ferreira F&#44; Gomes JA and Mello PA participated in the analysis and interpretation of the data&#46; Russ HH&#44; Faria NL and Montiani-Ferreira F drafted the manuscript&#46; Russ HH&#44; Gomes JA and Mello PA revised the manuscript and approved its final version&#46;</p></span></span>"
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          "titulo" => "INTRODUCTION"
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          "titulo" => "RESULTS"
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              "titulo" => "Impression cytology"
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              "titulo" => "Immunocytochemistry"
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          "titulo" => "DISCUSSION"
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          "titulo" => "ACKNOWLEDGMENT"
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          "titulo" => "REFERENCES"
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    "pdfFichero" => "main.pdf"
    "tienePdf" => true
    "fechaRecibido" => "2013-04-03"
    "fechaAceptado" => "2013-05-13"
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          "clase" => "keyword"
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          "palabras" => array:5 [
            0 => "Glaucoma"
            1 => "Conjunctiva"
            2 => "Immunohistochemistry"
            3 => "Inflammation"
            4 => "Treatment"
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        "resumen" => "<span id="ceabs10" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle10">OBJECTIVES&#58;</span><p id="spara80" class="elsevierStyleSimplePara elsevierViewall">To compare ocular surface changes induced via glaucoma treatment in patients using fixed combinations of prostaglandin analogues &#40;travoprost&#44; latanoprost and bimatoprost&#41; with 0&#46;5&#37; timolol maleate</p></span> <span id="ceabs20" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle20">METHODS&#58;</span><p id="spara90" class="elsevierStyleSimplePara elsevierViewall">A prospective&#44; multicenter&#44; randomized&#44; parallel group&#44; single-blind clinical trial was performed in 33 patients with ocular hypertension or open angle glaucoma who had not been previously treated&#46; The ocular surface was evaluated prior to and three months after treatment&#44; with a daily drop instillation of one of the three medications&#46; The main outcome measurements included the tear film break-up time&#44; Schirmer&#39;s test&#44; Lissamine green staining&#44; the Ocular Surface Disease Index questionnaire&#44; impression cytology using HE and PAS and immunocytochemistry for interleukin-6 and HLA-DR&#46; Ensaiosclinicos&#46;gov&#46;br&#58; UTN - U1111-1129-2872</p></span> <span id="ceabs30" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle30">RESULTS&#58;</span><p id="spara100" class="elsevierStyleSimplePara elsevierViewall">All of the drugs induced a significant reduction in intraocular pressure&#46; Decreases in the Schirmer&#39;s test results were observed with all of the drugs&#46; Decreases in tear-film break-up time were noted with travoprost&#47;timolol and latanoprost&#47;timolol&#46; An increase in the Lissamine green score was noted with travoprost&#47;timolol and bimatoprost&#47;timolol&#46; The Ocular Surface Disease Index score increased after treatment in the travoprost&#47;timolol group&#46; Impression cytology revealed a significant difference in cell-to-cell contact in the same group&#44; an increase in cellularity in all of the groups and an increase in the number of goblet cells in all of the groups&#46; The fixed combinations induced an increase in IL-6 expression in the travoprost&#47;timolol group&#44; in which there was also an increase in HLA-DR expression&#46;</p></span> <span id="ceabs40" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle40">CONCLUSIONS&#58;</span><p id="spara110" class="elsevierStyleSimplePara elsevierViewall">All of the fixed combinations induced a significant reduction in intraocular pressure&#44; and the travoprost&#47;timolol group showed increased expression of the inflammatory markers HLA-DR and interleukin-6&#46; All three tested medications resulted in some degree of deterioration in the ocular surface after three months of glaucoma treatment&#46;</p></span>"
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          "en" => "<p id="spara10" class="elsevierStyleSimplePara elsevierViewall">Flow diagram of the progress through the phases of this parallel&#44; randomized trial of three groups&#46;</p>"
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        "etiqueta" => "Figure 2"
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          "en" => "<p id="spara20" class="elsevierStyleSimplePara elsevierViewall">HLA-DR expression&#46; On the left&#58; images of the travatan&#43;timolol group pre-treatment&#44; with cells negative for HLA&#46; On the right&#58; the same group after treatment&#44; at 100&#215; &#40;on the top&#41; and 400&#215; &#40;on the bottom&#41; magnification&#44; respectively&#46;</p>"
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          "en" => "<p id="spara30" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleBold">IL-6 expression&#46;</span> Top images&#58; on the left&#44; the bimatoprost&#43;timolol group pre-treatment&#44; with cells negative for IL-6&#46; On the right&#58; the same group after treatment&#44; with 200&#215; magnification&#46; The figures on the bottom show the same images as above&#44; with 400&#215; magnification&#46; Note the increase in positive cells after treatment &#40;images on the right&#41;&#46;</p>"
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          "leyenda" => "<p id="spara50" class="elsevierStyleSimplePara elsevierViewall">&#42; There were significant differences between African American and Asian patients&#44; compared with Caucasians and Hispanics&#44; but not between the African American and Asian groups or between the Caucasian and Hispanic groups&#44; respectively&#46;</p>"
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                  """
              ]
            ]
          ]
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        "descripcion" => array:1 [
          "en" => "<p id="spara60" class="elsevierStyleSimplePara elsevierViewall">Clinical data prior to and three months after treatment with a fixed combination of travoprost 0&#46;004&#37;&#47;timolol 0&#46;5&#37;&#44; bimatoprost 0&#46;03&#37;&#47;timolol 0&#46;5&#37; or latanoprost 0&#46;005&#37;&#47;timolol 0&#46;5&#37; in na&#239;ve patients&#59; n&#8202;&#61;&#8202;33&#46;</p>"
        ]
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      5 => array:7 [
        "identificador" => "t3-cln_68p1318"
        "etiqueta" => "Table 3"
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        "mostrarFloat" => true
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                  \t\t\t\t\ttop\n
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                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Inflammatory cells&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t\ttop\n
                  \t\t\t\t">NC&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">NC&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">NC&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">NC&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">NC&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
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                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Cellularity <span class="elsevierStyleSup">&#40;b&#41;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;045&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;386&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;0008&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;273&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;705&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;008&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;114&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;545&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t">0&#46;0022&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Goblet cells <span class="elsevierStyleSup">&#40;C&#41;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t">0&#46;295&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t">0&#46;864&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;0012&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;568&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;932&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t">0&#46;0541&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;182&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;545&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t">0&#46;0186&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">N&#47;C ratio&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">NC&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">NC&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">NC&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">NC&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="" valign="\n
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                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
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                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="center" valign="\n
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                  \t\t\t\t">NC&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="" valign="\n
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                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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        "descripcion" => array:1 [
          "en" => "<p id="spara70" class="elsevierStyleSimplePara elsevierViewall">Impression cytology scores&#46; Several parameters were analyzed&#44; but significant differences after three months of treatment were only found in&#58; &#40;a&#41; cell-to-cell contact in the TT group&#59; &#40;b&#41; cellularity in all of the groups&#59; and &#40;c&#41; number of goblet cells in the TT and LT groups&#46; NC&#58; not counted&#46;</p>"
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      "titulo" => "REFERENCES"
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        0 => array:2 [
          "identificador" => "cebibsec10"
          "bibliografiaReferencia" => array:26 [
            0 => array:3 [
              "identificador" => "bib1"
              "etiqueta" => "1"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "The ocular hypertension treatment study&#58; baseline factors that predict the onset of primary open-angle glaucoma"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [
                            0 => """
                              MO Gordon \n
                              \t\t\t\t\t\t\t\t
                              """
                            1 => """
                              JA Beiser \n
                              \t\t\t\t\t\t\t\t
                              """
                            2 => """
                              JD Brandt \n
                              \t\t\t\t\t\t\t\t
                              """
                          ]
                        ]
                      ]
                    ]
                  ]
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                    0 => array:2 [
                      "doi" => "10.1001/archopht.120.6.714"
                      "Revista" => array:7 [
                        "tituloSerie" => "Arch Ophthalmol"
                        "fecha" => "2002 Jun"
                        "volumen" => "120"
                        "numero" => "6"
                        "paginaInicial" => "714"
                        "paginaFinal" => "720"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/12049575"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
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            1 => array:3 [
              "identificador" => "bib2"
              "etiqueta" => "2"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Pharmacology"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [
                            0 => """
                              R Ritch \n
                              \t\t\t\t\t\t\t\t
                              """
                            1 => """
                              B Shields \n
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                              """
                            2 => """
                              T Krupin \n
                              \t\t\t\t\t\t\t\t
                              """
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "LibroEditado" => array:6 [
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                        "paginaInicial" => "1375"
                        "paginaFinal" => "1489"
                        "edicion" => "Second Edition"
                        "serieVolumen" => "3"
                        "serieFecha" => "1996"
                      ]
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                  ]
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              ]
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                      "titulo" => "Conjunctival hyperemia in healthy subjects after short-term dosing with latanoprost&#44; bimatoprost&#44; and travoprost"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:5 [
                            0 => """
                              WC Stewart \n
                              \t\t\t\t\t\t\t\t
                              """
                            1 => """
                              AE Kolker \n
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                              """
                            2 => """
                              JA Stewart \n
                              \t\t\t\t\t\t\t\t
                              """
                            3 => """
                              J Leech \n
                              \t\t\t\t\t\t\t\t
                              """
                            4 => """
                              AL Jackson \n
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                              """
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/s0002-9394(02)01980-3"
                      "Revista" => array:7 [
                        "tituloSerie" => "Am J Ophthalmol"
                        "fecha" => "2003"
                        "volumen" => "135"
                        "numero" => "3"
                        "paginaInicial" => "314"
                        "paginaFinal" => "320"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/12614748"
                            "web" => "Medline"
                          ]
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Hypertrichosis and increased pigmentation of eyelashes and adjacent hair in the region of the ipsilateral eyelids of patients treated with unilateral topical latanoprost"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:1 [
                            0 => """
                              MA Johnstone \n
                              \t\t\t\t\t\t\t\t
                              """
                          ]
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                    0 => array:2 [
                      "doi" => "10.1016/s0002-9394(14)70870-0"
                      "Revista" => array:7 [
                        "tituloSerie" => "Am J Ophthalmol"
                        "fecha" => "1997"
                        "volumen" => "124"
                        "numero" => "4"
                        "paginaInicial" => "544"
                        "paginaFinal" => "547"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/9323945"
                            "web" => "Medline"
                          ]
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                      "titulo" => "Increased eyelid pigmentation associated with use of latanoprost"
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                          "etal" => false
                          "autores" => array:2 [
                            0 => """
                              MS Kook \n
                              \t\t\t\t\t\t\t\t
                              """
                            1 => """
                              K Lee \n
                              \t\t\t\t\t\t\t\t
                              """
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                        ]
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                    ]
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                        "tituloSerie" => "Am J Ophhtalmol"
                        "fecha" => "2000"
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                        "numero" => "6"
                        "paginaInicial" => "804"
                        "paginaFinal" => "806"
                      ]
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            5 => array:3 [
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Blood-aqueous barrier changes after the use of prostaglandin analogues in patients with pseudophakia and aphakia&#58; a 6-month randomized trial"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
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                            0 => """
                              ES Arcieri \n
                              \t\t\t\t\t\t\t\t
                              """
                            1 => """
                              A Santana \n
                              \t\t\t\t\t\t\t\t
                              """
                            2 => """
                              FN Rocha \n
                              \t\t\t\t\t\t\t\t
                              """
                            3 => """
                              GL Guapo \n
                              \t\t\t\t\t\t\t\t
                              """
                            4 => """
                              VP Costa \n
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                              """
                          ]
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                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1001/archopht.123.2.186"
                      "Revista" => array:7 [
                        "tituloSerie" => "Arch Ophthalmol"
                        "fecha" => "2005"
                        "volumen" => "123"
                        "numero" => "2"
                        "paginaInicial" => "186"
                        "paginaFinal" => "192"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/15710814"
                            "web" => "Medline"
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                        ]
                      ]
                    ]
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              ]
            ]
            6 => array:3 [
              "identificador" => "bib7"
              "etiqueta" => "7"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Ocular surface alteration after long-term treatment with antiglaucomatous drug"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:4 [
                            0 => """
                              JM Herreras \n
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                              """
                            1 => """
                              JC Pastor \n
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                              """
                            2 => """
                              M Calonge \n
                              \t\t\t\t\t\t\t\t
                              """
                            3 => """
                              VM Asensio \n
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                              """
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                    0 => array:2 [
                      "doi" => "10.1016/s0161-6420(92)31847-0"
                      "Revista" => array:7 [
                        "tituloSerie" => "Ophthalmology"
                        "fecha" => "1992"
                        "volumen" => "99"
                        "numero" => "7"
                        "paginaInicial" => "1082"
                        "paginaFinal" => "1088"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/1495787"
                            "web" => "Medline"
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                        ]
                      ]
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                ]
              ]
            ]
            7 => array:3 [
              "identificador" => "bib8"
              "etiqueta" => "8"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Adverse effects of topical antiglaucomatous medications on the conjunctiva and the lacrymal"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [
                            0 => """
                              R Nuzzi \n
                              \t\t\t\t\t\t\t\t
                              """
                            1 => """
                              C Finazzo \n
                              \t\t\t\t\t\t\t\t
                              """
                            2 => """
                              A Cerruti \n
                              \t\t\t\t\t\t\t\t
                              """
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1023/a:1006051725115"
                      "Revista" => array:7 [
                        "tituloSerie" => "Int Ophthalmol"
                        "fecha" => "1998"
                        "volumen" => "22"
                        "numero" => "1"
                        "paginaInicial" => "31"
                        "paginaFinal" => "35"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/10090446"
                            "web" => "Medline"
                          ]
                        ]
                      ]
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                ]
              ]
            ]
            8 => array:3 [
              "identificador" => "bib9"
              "etiqueta" => "9"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Adverse effects of topical antiglaucoma medication"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:4 [
                            0 => """
                              DC Broadway \n
                              \t\t\t\t\t\t\t\t
                              """
                            1 => """
                              I Grierson \n
                              \t\t\t\t\t\t\t\t
                              """
                            2 => """
                              C &#210;Brien \n
                              \t\t\t\t\t\t\t\t
                              """
                            3 => """
                              RA Hitchings \n
                              \t\t\t\t\t\t\t\t
                              """
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        "texto" => "<p id="para510" class="elsevierStylePara elsevierViewall">This study was supported by the Federal University of S&#227;o Paulo and Funda&#231;&#227;o de Amparo &#224; Pesquisa do Estado de S&#227;o Paulo &#40;FAPESP&#41;&#46;</p>"
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Article information
ISSN: 18075932
Original language: English
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es en pt

¿Es usted profesional sanitario apto para prescribir o dispensar medicamentos?

Are you a health professional able to prescribe or dispense drugs?

Você é um profissional de saúde habilitado a prescrever ou dispensar medicamentos