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ORIGINAL ARTICLE
Comparative evaluation of Latanoprostene Bunod, Timolol Maleate, and latanoprost Ophthalmic Solutions to assess their safety and efficacy in lowering intraocular pressure for the management of Open-Angle Glaucoma
Yulong WangI, Yue LiaoII, Xin NieI,
Corresponding author
NyasiaSantosgjs@yahoo.com

Corresponding author.
I Department of Ophthalmology, Chongqing General Hospital, Chongqing, China
II Department of Pharmacy, Chongqing General Hospital, Chongqing, China
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          "en" => "<p id="spara20" class="elsevierStyleSimplePara elsevierViewall">Intraocular pressure measurements&#46; Data are represented as mean&#177;SD&#46; One-way ANOVA following the Tukey test was performed for statistical analysis&#46; &#42;significantly lower than BL&#46; &#35;Significantly lower than LP cohort and TM cohort&#46; BL&#58; Before treatment&#59; EL&#58; At the end of 3 months of treatment&#59; SD&#58; standard deviation&#59; ANOVA&#58; analysis of variance&#59; LP&#58; those who received latanoprost eye drops&#59; LB&#58; those who received latanoprostene bunod eye drops&#59; TM&#58; those who received timolol eye drops <span class="elsevierStyleItalic">p</span>&#60;0&#46;05 and I&#62;3&#46;336 were considered significant&#46;</p>"
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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 the third leading cause of irreversible blindness worldwide&#46; Open-angle glaucoma may lead to permanent blindness &#40;<a class="elsevierStyleCrossRef" href="#bib1">1</a>&#44;<a class="elsevierStyleCrossRef" href="#bib2">2</a>&#41;&#46; Elevated intraocular pressure &#40;IOP&#41; is responsible for glaucoma&#44; and most treatments are designed to reduce IOP &#40;<a class="elsevierStyleCrossRef" href="#bib3">3</a>&#41;&#46; Worldwide&#44; approximately 80 million people have been predicted to have glaucoma by the end of 2020&#44; with 11 million being bilaterally blind&#46; While half of the population with glaucoma in high-income countries is unaware of their disease&#44; this figure is over 90&#37; in low-income countries&#44; particularly in the rural settings &#40;<a class="elsevierStyleCrossRef" href="#bib4">4</a>&#41;&#46;</p><p id="para20" class="elsevierStylePara elsevierViewall">The ultimate goal of glaucoma treatment is to slow down disease progression to a rate in which the patient will not experience a vision-related decrease in quality of life &#40;<a class="elsevierStyleCrossRef" href="#bib5">5</a>&#44;<a class="elsevierStyleCrossRef" href="#bib6">6</a>&#41;&#46; Glaucoma treatment in developing countries should consider clinical&#44; laser&#44; and surgical approaches&#46; Glaucoma medications do not improve vision&#44; may have important side effects&#44; and are relatively expensive&#46; Thus&#44; compliance can be a major issue&#44; which is related to the level of education and socio-economic status of the patient &#40;<a class="elsevierStyleCrossRef" href="#bib5">5</a>&#44;<a class="elsevierStyleCrossRef" href="#bib6">6</a>&#41;&#46;</p><p id="para30" class="elsevierStylePara elsevierViewall">Latanoprost&#44; a Prostaglandin F2 alpha &#40;PGF2&#945;&#41; analog&#44; was approved by the United States Food and Drug Administration &#40;USFDA&#41; in 1996 &#40;<a class="elsevierStyleCrossRef" href="#bib4">4</a>&#41;&#46; Latanoprost is a prostanoid selective FP receptor agonist that is believed to reduce IOP by increasing the outflow of the aqueous humor&#46; Studies have suggested that the main mechanism of action is increased uveoscleral outflow&#46; The higher the level of IOP&#44; the greater is the likelihood of the optic nerve damage and visual field loss &#40;<a class="elsevierStyleCrossRef" href="#bib4">4</a>&#41;&#46; The mechanism of action of timolol is through reduction in formation of the aqueous humor in the ciliary body in the eye&#46; It was the first beta-blocker approved for topical use in the treatment of glaucoma in the US &#40;1978&#41; &#40;<a class="elsevierStyleCrossRef" href="#bib7">7</a>&#41;&#46;</p><p id="para40" class="elsevierStylePara elsevierViewall">In November 2017&#44; the USFDA approved latanoprostene bunod ophthalmic solution&#44; a nitric oxide-donating prodrug of latanoprost&#44; for lowering IOP&#40;<a class="elsevierStyleCrossRef" href="#bib4">4</a>&#41;&#46; Latanoprostene bunod is hydrolyzed by corneal esterases to the prostanoid FP receptor agonist latanoprost acid &#40;active metabolite&#41; and butanediol mononitrate&#44; which is further metabolized to 1&#46;4-butanediol and nitric oxide &#40;NO&#41; &#40;active metabolite&#41; &#40;<a class="elsevierStyleCrossRef" href="#bib8">8</a>&#41;&#46; Latanoprost acid increases matrix metalloproteinase &#40;MMP&#41;-1&#44; MMP-3&#44; and MMP-9 expression in the ciliary muscles&#44; promoting the remodeling of the extracellular matrix and&#44; subsequently&#44; increases aqueous humor outflow through the uveoscleral pathway &#40;<a class="elsevierStyleCrossRef" href="#bib8">8</a>&#44;<a class="elsevierStyleCrossRef" href="#bib9">9</a>&#41;&#46; The efficacy of timolol ophthalmic solution in the reduction of IOP has also been reported &#40;<a class="elsevierStyleCrossRef" href="#bib10">10</a>&#44;<a class="elsevierStyleCrossRef" href="#bib11">11</a>&#41;&#46;</p><p id="para50" class="elsevierStylePara elsevierViewall">A preclinical study reported that latanoprostene bunods have an IOP-lowering effect in patients who do not respond to latanoprost &#40;<a class="elsevierStyleCrossRef" href="#bib12">12</a>&#41;&#46; However&#44; IOP-lowering treatments have safety issues&#46; Timolol has been reported to be safer than latanoprost &#40;<a class="elsevierStyleCrossRef" href="#bib13">13</a>&#41;&#46; Therefore&#44; this study retrospectively compared the efficacy and safety of latanoprost&#44; latanoprostene bunod&#44; and timolol in patients with ocular hypertension or primary open-angle glaucoma&#46;</p></span><span id="cesec20" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle70">MATERIAL AND METHODS</span><span id="cesec30" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle80">Ethics approval and consent to participate</span><p id="para60" class="elsevierStylePara elsevierViewall">The study protocol was approved by the Medical Council of China and local institutional review board &#40;PHU&#47;CL&#47;15&#47;19 dated October 5&#44; 2019&#41;&#46; Informed consent was obtained from each participant before the trial&#46; Data regarding treatment and follow-up of patients were collected from the hospitals for analysis after obtaining approval&#46;</p></span><span id="cesec40" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle90">Study population</span><p id="para70" class="elsevierStylePara elsevierViewall">From February 15&#44; 2018 to July 12&#44; 2019&#44; 345 patients were seen in the outpatient setting of the parent hospital and referring hospitals with an IOP of &#8805;21 mmHg&#46; Among them&#44; 104 patients were prescribed latanoprost&#44; 94 patients with latanoprostene bunod&#44; and 115 patients were prescribed timolol maleate for lowering IOP&#46; The data on treatment and follow-up of these 313 patients were included in the analysis &#40;<a class="elsevierStyleCrossRef" href="#fig1">Fig&#46; 1</a>&#41;&#46;</p><elsevierMultimedia ident="fig1"></elsevierMultimedia></span><span id="cesec50" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle100">Cohorts</span><p id="para80" class="elsevierStylePara elsevierViewall">Patients who received 0&#46;005&#37; w&#47;v latanoprost eye drops once daily in the evening in the affected eye&#40;s&#41; for 3 months were included in the LP cohort &#40;n&#61;104&#41;&#46; Those who received 0&#46;0024&#37; w&#47;v latanoprostene bunod eye drops once daily in the evening in the affected eye&#40;s&#41; for 3 months were included in the LB cohort &#40;n&#61;94&#41;&#46; Those who received 0&#46;5&#37; w&#47;v timolol maleate eye drops twice daily &#40;morning and evening&#41; in the affected eye&#40;s&#41; for 3 months were included in the TM cohort &#40;n&#61;115&#41;&#46;</p><span id="cesec60" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle110">Exclusion criteria</span><p id="para90" class="elsevierStylePara elsevierViewall"><ul class="elsevierStyleList" id="celist10"><li class="elsevierStyleListItem" id="celistitem10"><span class="elsevierStyleLabel">1&#46;</span><p id="para100" class="elsevierStylePara elsevierViewall">History of hypersensitivity or contraindications to latanoprost&#44; NO-donating medications&#44; timolol maleate&#44; other &#946;-adrenergic receptor antagonists&#44; or any ingredients in the study drugs</p></li><li class="elsevierStyleListItem" id="celistitem20"><span class="elsevierStyleLabel">2&#46;</span><p id="para110" class="elsevierStylePara elsevierViewall">Significant corneal surface abnormalities in either eye or other significant ophthalmic disease</p></li><li class="elsevierStyleListItem" id="celistitem30"><span class="elsevierStyleLabel">3&#46;</span><p id="para120" class="elsevierStylePara elsevierViewall">Patients requiring treatment with ocular or systemic corticosteroids or had an anticipated need to initiate or modify medication that was known to affect IOP</p></li><li class="elsevierStyleListItem" id="celistitem40"><span class="elsevierStyleLabel">4&#46;</span><p id="para130" class="elsevierStylePara elsevierViewall">Patients who did not want to fill the informed consent and could not be followed-up</p></li></ul></p></span></span><span id="cesec70" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle120">IOP measurements</span><p id="para140" class="elsevierStylePara elsevierViewall">IOP was measured in the morning or evening&#44; and the average of three readings was considered for analysis&#46;</p></span><span id="cesec80" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle130">Safety measurements</span><p id="para150" class="elsevierStylePara elsevierViewall">Safety measurements included slip-lamp examinations&#44; ophthalmoscopy&#44; and treatment-emergent unwanted issues during the 3 months of treatment&#46;</p><span id="cesec90" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle140">Standardization regarding sleep and medication&#58;</span><p id="para160" class="elsevierStylePara elsevierViewall">Before the 24-h laboratory recording&#44; the patients were instructed to maintain 8 h of regular sleep every day&#44; for a minimum of 7 days&#46; Sleep patterns were verified using a wrist monitor for light exposure&#44; arm movements&#44; and a wake&#47;sleep log&#46; Patients were asked to abstain from alcohol for a minimum of 7 days and regular coffee for a minimum of 2 days before reporting to the laboratory&#46; The 8-h sleep time for each patient in the laboratory was adjusted close to the recorded bedtime in the previous week&#44; and this period was referred to as the nocturnal&#47;sleep period&#46;</p></span><span id="cesec100" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle150">Measurement of IOP and blood pressure&#58;</span><p id="para170" class="elsevierStylePara elsevierViewall">Measurements of IOP and blood pressure&#47;heart rate were assessed by experienced physicians&#46; IOP was measured using a calibrated pneumatonometer&#46; Topical proparacaine 0&#46;5&#37; was used as the local anesthetic&#46; Each plot of IOP measurement by the pneumatonometer was evaluated according to commonly accepted standards&#46; Blood pressure and heart rate were measured immediately before IOP measurements using an automated arm monitor&#46;</p></span><span id="cesec110" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle160">Evaluation of adverse effects&#58;</span><p id="para180" class="elsevierStylePara elsevierViewall">Ocular adverse effects were recorded by asking questions&#44; visual inspections&#44; and using the appropriate instruments as applicable&#46; Systematic adverse effects were evaluated by measuring systolic and diastolic blood pressures and heart rate&#46; Normal systolic and diastolic blood pressure values were 160 and 90 mmHg&#44; respectively&#46; The normal heart rate was considered as 80 beats per min &#40;bpm&#41;&#46;</p></span></span><span id="cesec120" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle170">Statistical analyses</span><p id="para190" class="elsevierStylePara elsevierViewall">SPSS version 25 &#40;IBM Corporation&#44; Armonk&#44; NY&#44; USA&#41; was used for statistical analysis&#46; Fischer&#39;s exact test was performed for ordinal data&#44; and one-way analysis of variance &#40;ANOVA&#41; was performed for numerical data&#46; The Tukey&#39;s test was performed for post hoc analysis&#46; The results were considered significant at the 95&#37; confidence level&#46;</p></span></span><span id="cesec130" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle180">RESULTS</span><span id="cesec140" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle190">Enrollment</span><p id="para200" class="elsevierStylePara elsevierViewall">The study patients&#39; ages ranged from 45 to 65 years&#44; and the male&#58; female ratio was 1&#58;1&#46; Other demographic parameters and clinical conditions are reported in <a class="elsevierStyleCrossRef" href="#tbl1">Table 1</a>&#46; There were no significant differences among the cohorts at the time of initial diagnosis &#40;<span class="elsevierStyleItalic">p</span>&#62;0&#46;05&#41;&#46;</p><elsevierMultimedia ident="tbl1"></elsevierMultimedia></span><span id="cesec150" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle200">Efficacy</span><p id="para210" class="elsevierStylePara elsevierViewall">At the end of 3 months of treatment&#44; all the enrolled drugs showed a significant decrease in IOP&#46; After 3 months of treatment&#44; latanoprost &#40;24&#46;13&#177;1&#46;12 mmHg <span class="elsevierStyleItalic">vs</span>&#46; 19&#46;45&#177;1&#46;01 mmHg&#44; <span class="elsevierStyleItalic">p</span>&#60;0&#46;0001&#44; q&#61;42&#46;749&#41;&#44; latanoprostene bunod &#40;23&#46;98&#177;1&#46;22 mmHg <span class="elsevierStyleItalic">vs</span>&#46; 17&#46;45&#177;1&#46;89 mmHg&#44; <span class="elsevierStyleItalic">p</span>&#60;0&#46;0001&#44; q&#61;43&#46;945&#41;&#44; and timolol &#40;24&#46;39&#177;1&#46;65 mmHg <span class="elsevierStyleItalic">vs</span>&#46; 19&#46;68&#177;1&#46;08 mmHg&#44; <span class="elsevierStyleItalic">p</span>&#60;0&#46;0001&#44; q&#61;38&#46;404&#41; were all successful in the reduction of IOP&#46; The LB cohort had the highest reduction in IOP compared to the LP &#40;<span class="elsevierStyleItalic">p</span>&#60;0&#46;0001&#44; q&#61;14&#46;654&#41; and TM cohorts &#40;<span class="elsevierStyleItalic">p</span>&#60;0&#46;0001&#44; q&#61;16&#46;723&#44; <a class="elsevierStyleCrossRef" href="#fig2">Fig&#46; 2</a>&#41;&#46;</p><elsevierMultimedia ident="fig2"></elsevierMultimedia></span><span id="cesec160" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle210">Safety</span><p id="para220" class="elsevierStylePara elsevierViewall">All treatments had some common adverse ocular effects&#46; The total ocular adverse effects reported in the TM cohort were less than those in the LP and LB cohorts <span class="elsevierStyleItalic">&#40;p</span>&#61;0&#46;031&#44; <a class="elsevierStyleCrossRef" href="#tbl2">Table 2</a>&#41;&#46;</p><elsevierMultimedia ident="tbl2"></elsevierMultimedia><p id="para230" class="elsevierStylePara elsevierViewall">At the end of 3 months of treatment&#44; timolol showed a decline in heart rate&#59; however&#44; latanoprostene bunod and latanoprost did not affect the heart rate &#40;<a class="elsevierStyleCrossRef" href="#tbl3">Table 3</a>&#41;&#46; After 3 months of treatment&#44; latanoprost &#40;77&#177;2 bpm <span class="elsevierStyleItalic">vs</span>&#46; 76&#177;5 bpm&#44; <span class="elsevierStyleItalic">p</span>&#61;0&#46;059&#41; and latanoprostene bunod &#40;76&#177;3 bpm <span class="elsevierStyleItalic">vs</span>&#46; 75&#177;5&#44; <span class="elsevierStyleItalic">p</span>&#61;0&#46;0002&#44; q&#61;2&#46;789&#41; did not decrease heart rate&#59; however&#44; timolol &#40;77&#177;5 bpm <span class="elsevierStyleItalic">vs</span>&#46; 75&#177;1 bpm&#44; <span class="elsevierStyleItalic">p</span>&#60;0&#46;0001&#44; q&#61;6&#46;776&#41; reduced heart rate &#40;<a class="elsevierStyleCrossRef" href="#fig3">Fig&#46; 3</a>&#41;&#46;</p><elsevierMultimedia ident="tbl3"></elsevierMultimedia><elsevierMultimedia ident="fig3"></elsevierMultimedia><p id="para240" class="elsevierStylePara elsevierViewall">The mean percentage changes from baseline were similar in all three treatment groups for corneal thickness &#40;1&#46;15&#177;0&#46;03&#44; 1&#46;16&#177;0&#46;11&#44; and 1&#46;14&#177;0&#46;08&#44; <span class="elsevierStyleItalic">p</span>&#61;0&#46;193&#41;&#46;</p></span></span><span id="cesec170" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle220">DISCUSSION</span><p id="para250" class="elsevierStylePara elsevierViewall">Latanoprost&#44; latanoprostene bunod&#44; and timolol were all successful in reducing IOP after 3 months&#46; Latanoprostene bunod produced a greater reduction in IOP than latanoprost and timolol&#46; Therefore&#44; this study showed that the efficacy of latanoprostene bunod was comparatively higher than latanoprost and timolol&#44; with latanoprostene bunod reaching the target of &#8804;17&#46;5 mmHg &#40;<a class="elsevierStyleCrossRef" href="#bib14">14</a>&#41;&#46; The results of the study were consistent with previous randomized&#44; double-blinded studies &#40;<a class="elsevierStyleCrossRef" href="#bib1">1</a>&#44;<a class="elsevierStyleCrossRef" href="#bib6">6</a>&#41; and a preclinical study &#40;<a class="elsevierStyleCrossRef" href="#bib12">12</a>&#41;&#46; Pharmacological therapies in open-angle glaucoma include PG analogs or <span class="elsevierStyleItalic">&#946;</span>-blockers &#40;<a class="elsevierStyleCrossRef" href="#bib15">15</a>&#41;&#46; Latanoprostene bunod is a PG F2a analog with NO-donating moiety and reduces IOP through the trabecular meshwork &#40;<a class="elsevierStyleCrossRef" href="#bib16">16</a>&#41; and uveoscleral outflow pathway&#46; Latanoprostene bunod is more effective in the treatment of open-angle glaucoma than latanoprost and timolol&#46;</p><p id="para260" class="elsevierStylePara elsevierViewall">This study reported higher ocular adverse events for latanoprostene bunods than for timolol&#46; The ocular adverse events were comparable to those of the randomized&#44; double-blinded studies &#40;<a class="elsevierStyleCrossRef" href="#bib1">1</a>&#44;<a class="elsevierStyleCrossRef" href="#bib6">6</a>&#41; and randomized crossover clinical trial &#40;<a class="elsevierStyleCrossRef" href="#bib17">17</a>&#41;&#46; Further research is required to decrease ocular adverse effects related to latanoprostene bunod treatment in open-angle glaucoma&#46;</p><p id="para270" class="elsevierStylePara elsevierViewall">Unlike latanoprost and latanoprostene bunods&#44; timolol eye drops decreased heart rate and systolic and diastolic blood pressure at the end of 3 months of treatment&#46; The results of these non-ocular adverse events were not comparable with the randomized&#44; double-blinded studies &#40;<a class="elsevierStyleCrossRef" href="#bib1">1</a>&#44;<a class="elsevierStyleCrossRef" href="#bib6">6</a>&#41;&#59; however&#44; they were comparable with a prospective study &#40;<a class="elsevierStyleCrossRef" href="#bib18">18</a>&#41; and randomized crossover clinical trial &#40;<a class="elsevierStyleCrossRef" href="#bib17">17</a>&#41;&#46; Timolol is a <span class="elsevierStyleItalic">&#946;</span>-blocker and administration for 3 months led to a systemic effect and decrease in heart rate and blood pressure &#40;<a class="elsevierStyleCrossRef" href="#bib18">18</a>&#41;&#46;</p><p id="para280" class="elsevierStylePara elsevierViewall">In 2016&#44; Weinreb et al&#46; reported that latanoprostene bunod 0&#46;024&#37; demonstrated a significantly greater lowering of IOP than timolol 0&#46;5&#37; administered twice daily over 3 months of treatment &#40;<a class="elsevierStyleCrossRef" href="#bib19">19</a>&#41;&#46;</p><p id="para290" class="elsevierStylePara elsevierViewall">Medeiros et al&#46; concluded in 2016 that the administration of latanoprostene bunod 0&#46;024&#37; daily in the evening was noninferior to timolol 0&#46;5&#37; twice daily over 3 months of treatment&#44; with significantly greater IOP-lowering in patients with open-angle glaucoma or ocular hypertension at all but the earliest time point evaluated&#44; and demonstrated a good safety profile &#40;<a class="elsevierStyleCrossRef" href="#bib20">20</a>&#41;&#46;</p><p id="para300" class="elsevierStylePara elsevierViewall">This study has some limitations&#46; As a retrospective study&#44; there were chances of bias in the selection of patients&#46; A large double-blind placebo-controlled randomized trial is required to explore this hypothesis unambiguously&#46; Patients&#39; demographic and clinical conditions can also affect the adverse events during the treatment period&#59; however&#44; the study did not evaluate the effects of such parameters on clinical outcomes&#46;</p></span><span id="cesec180" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle230">CONCLUSIONS</span><p id="para310" class="elsevierStylePara elsevierViewall">Because of its novel mechanism of action&#44; latanoprostene bunod was more successful in reducing IOP in patients with open-angle glaucoma than latanoprost and timolol&#44; with manageable adverse events&#46; Latanoprostene bunod is superior to latanoprost and timolol in the treatment of open-angle glaucoma&#46;</p><p id="para320" class="elsevierStylePara elsevierViewall">Future Implication&#58; Large ample size prospective studies are needed to validate that latanoprostene bunod 0&#46;024&#37; medication has the potential to be used as a first-line therapy for patients to reduce IOP&#44; decrease the risk of glaucoma progression&#44; and preserve vision while maintaining their quality of life&#46;</p></span><span id="cesec190" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle240">AUTHOR CONTRIBUTIONS</span><p id="para330" class="elsevierStylePara elsevierViewall">Wang Y contributed in Conceptualization &#40;Equal&#41;&#44; Data curation &#40;Equal&#41;&#44; Investigation &#40;Lead&#41; Methodology &#40;Equal&#41;&#44; Project administration &#40;Lead&#41;&#44; Supervision &#40;Lead&#41;&#44; Writing-review &#38; editing &#40;Lead&#41;&#46; Liao Y contributed in Conceptualization &#40;Equal&#41;&#44; Data curation &#40;Equal&#41;&#44; Formal analysis &#40;Lead&#41;&#44; Investigation &#40;Equal&#41;&#44; Methodology &#40;Lead&#41;&#44; Resources &#40;Lead&#41;&#44; Validation &#40;Equal&#41;&#46; Xin Nie X contributed in Conceptualization &#40;Lead&#41;&#44; Investigation &#40;Equal&#41;&#44; Software &#40;Equal&#41;&#44; Writing-original draft &#40;Lead&#41;&#46;</p></span></span>"
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          "titulo" => "KEYWORDS"
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          "titulo" => "INTRODUCTION"
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        2 => array:3 [
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          "titulo" => "MATERIAL AND METHODS"
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              "titulo" => "Ethics approval and consent to participate"
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              "titulo" => "Study population"
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              "titulo" => "Cohorts"
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              "titulo" => "IOP measurements"
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              "titulo" => "Safety measurements"
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                  "titulo" => "Standardization regarding sleep and medication&#58;"
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                  "titulo" => "Measurement of IOP and blood pressure&#58;"
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                  "titulo" => "Evaluation of adverse effects&#58;"
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              "titulo" => "Efficacy"
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          "titulo" => "DISCUSSION"
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          "titulo" => "REFERENCES"
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    "pdfFichero" => "main.pdf"
    "tienePdf" => true
    "fechaRecibido" => "2020-04-01"
    "fechaAceptado" => "2020-07-24"
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          "palabras" => array:5 [
            0 => "Intraocular Pressure"
            1 => "Latanoprost"
            2 => "Latanoprostene Bunod"
            3 => "Open-Angle Glaucoma"
            4 => "Timolol"
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        "resumen" => "<span id="ceabs10" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle10">OBJECTIVES&#58;</span><p id="spara70" class="elsevierStyleSimplePara elsevierViewall">Timolol maleate has been reported to be a safer intraocular pressure &#40;IOP&#41; lowering treatment than latanoprost&#46; The United States Food and Drug Administration approved latanoprostene bunod&#44; a nitric oxide-donating prodrug of latanoprost&#44; for lowering IOP&#46; This study compared the safety and efficacy of latanoprost&#44; latanoprostene bunod&#44; and timolol maleate in patients with open-angle glaucoma&#46;</p></span> <span id="ceabs20" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle20">METHODS&#58;</span><p id="spara80" class="elsevierStyleSimplePara elsevierViewall">Patients who received latanoprost eye drops once daily in the evening were included in the latanoprost Ophthalmic Solutions &#40;LP&#41; cohort &#40;n&#61;104&#41;&#46; Those who received latanoprostene bunod eye drops once daily in the evening were included in the Latanoprostene Bunod &#40;LB&#41; cohort &#40;n&#61;94&#41;&#46; Those who received timolol eye drops twice daily were included in the Timolol Maleate &#40;TM&#41; cohort &#40;n&#61;115&#41;&#46; All treatments were administered to the affected eye&#40;s&#41; for 3 months&#46; Informed Consent has been taken from each participant before the trial&#46;</p></span> <span id="ceabs30" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle30">RESULTS&#58;</span><p id="spara90" class="elsevierStyleSimplePara elsevierViewall">At the end of 3 months of treatment&#44; latanoprost&#44; latanoprostene bunod&#44; and timolol were all successful in reducing IOP&#46; The LB cohort had the highest reduction in IOP&#44; compared to the LP and TM cohorts&#46; All treatments had some common adverse ocular effects&#46;</p></span> <span id="ceabs40" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle40">CONCLUSION&#58;</span><p id="spara100" class="elsevierStyleSimplePara elsevierViewall">Latanoprostene bunod was superior to latanoprost and timolol for the treatment of open-angle glaucoma&#46;</p></span>"
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            "titulo" => "RESULTS&#58;"
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        "nota" => "<p class="elsevierStyleNotepara" id="cenpara40">No potential conflict of interest was reported&#46;</p>"
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          "en" => "<p id="spara10" class="elsevierStyleSimplePara elsevierViewall">Flow chart of the study&#46;</p>"
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          "en" => "<p id="spara20" class="elsevierStyleSimplePara elsevierViewall">Intraocular pressure measurements&#46; Data are represented as mean&#177;SD&#46; One-way ANOVA following the Tukey test was performed for statistical analysis&#46; &#42;significantly lower than BL&#46; &#35;Significantly lower than LP cohort and TM cohort&#46; BL&#58; Before treatment&#59; EL&#58; At the end of 3 months of treatment&#59; SD&#58; standard deviation&#59; ANOVA&#58; analysis of variance&#59; LP&#58; those who received latanoprost eye drops&#59; LB&#58; those who received latanoprostene bunod eye drops&#59; TM&#58; those who received timolol eye drops <span class="elsevierStyleItalic">p</span>&#60;0&#46;05 and I&#62;3&#46;336 were considered significant&#46;</p>"
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          "en" => "<p id="spara30" class="elsevierStyleSimplePara elsevierViewall">Heart rate evaluation&#46; Data are represented as mean&#177;SD&#46; One-way ANOVA following the Tukey test was performed for statistical analysis&#46; &#42;significantly lower than BL&#46; BL&#58; Before treatment&#59; EL&#58; At the end of the 3 months of treatment&#59; SD&#58; standard deviation&#59; ANOVA&#58; Analysis of variance&#59; LP&#58; those who received latanoprost eye drops&#59; LB&#58; those who received latanoprostene bunod eye drops&#59; TM&#58; those who received timolol eye drops <span class="elsevierStyleItalic">p</span>&#60;0&#46;05 and q&#62;3&#46;336 were considered significant&#46;</p>"
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          "leyenda" => "<p id="TFN01t01" class="elsevierStyleSimplePara elsevierViewall">Ordinal data are presented as number &#40;percentage&#41;&#44; and numerical data are presented as mean&#177;SD&#46;</p><p id="TFN02t01" class="elsevierStyleSimplePara elsevierViewall">Fischer&#39;s exact test was performed for ordinal data&#44; and one-way ANOVA was performed for numerical data&#46; <span class="elsevierStyleItalic">p</span>&#60;0&#46;05 was considered significant&#46;</p><p id="TFN03t01" class="elsevierStyleSimplePara elsevierViewall">SD&#58; Standard deviation&#59; LP&#58; those who received latanoprost eye drops&#59; LB&#58; those who received latanoprostene bunod eye drops&#59; TM&#58; those who received timolol eye drops&#46;</p>"
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                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " colspan="2" align="left" valign="\n
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                  \t\t\t\t" scope="col">Cohort</th><th class="td" title="\n
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                  \t\t\t\t" scope="col">LP&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="center" valign="\n
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                  \t\t\t\t" scope="col">LB&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col">TM&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " rowspan="2" align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col">Comparison between cohorts</th></tr><tr title="table-row"><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " colspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col">Eye drop</th><th class="td" title="\n
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                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col">0&#46;005&#37; latanoprost&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col">0&#46;0024&#37; latanoprostene bunod&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col">0&#46;5&#37; timolol&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th></tr><tr title="table-row"><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " colspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col">Patients</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col">104&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col">94&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col">115&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col"><span class="elsevierStyleItalic">p</span>-value&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " rowspan="3" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Age &#40;years&#41;</td><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">Minimum&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">45&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">45&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">46&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  " rowspan="3" align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;684</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">Maximum&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">65&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">64&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">65&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">Mean&#177;SD&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">58&#46;42&#177;6&#46;12&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">57&#46;65&#177;6&#46;01&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">57&#46;99&#177;6&#46;44&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  " rowspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Sex</td><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">Male&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">55 &#40;53&#41;&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">49 &#40;52&#41;&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">53 &#40;46&#41;&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  " rowspan="2" align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;544</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">Female&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">49 &#40;47&#41;&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">45 &#40;48&#41;&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">62 &#40;54&#41;&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  " colspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Family history</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">9 &#40;9&#41;&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">7 &#40;7&#41;&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">8 &#40;7&#41;&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">0&#46;891&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  " rowspan="3" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Ethnicity</td><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">Han Chinese&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">93 &#40;89&#41;&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">85 &#40;90&#41;&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">102 &#40;89&#41;&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  " rowspan="3" align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;994</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">Mongolian&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">10 &#40;10&#41;&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">8 &#40;9&#41;&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">12 &#40;10&#41;&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">Tibetan&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">1 &#40;1&#41;&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">1 &#40;1&#41;&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">1 &#40;1&#41;&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  " colspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Intraocular pressure &#40;mmHg&#41;</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">24&#46;13&#177;1&#46;12&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">23&#46;98&#177;1&#46;22&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">24&#46;39&#177;1&#46;65&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">0&#46;089&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  " colspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Heart rate &#40;bpm&#41;</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">77&#177;2&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">76&#177;3&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">77&#177;5&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">0&#46;085&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
            ]
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spara40" class="elsevierStyleSimplePara elsevierViewall">Other demographic parameters and clinical conditions of the stratified patients&#46;</p>"
        ]
      ]
      4 => array:7 [
        "identificador" => "tbl2"
        "etiqueta" => "Table 2"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "tabla" => array:3 [
          "leyenda" => "<p id="TFN01t02" class="elsevierStyleSimplePara elsevierViewall">Data are presented as number &#40;percentage&#41;&#46;</p><p id="TFN02t02" class="elsevierStyleSimplePara elsevierViewall">The Fischer&#39;s exact test was performed for statistical analysis&#46;</p><p id="TFN03t02" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleItalic">p</span>&#60;0&#46;05 was considered significant&#46;</p><p id="TFN05t02" class="elsevierStyleSimplePara elsevierViewall">LP&#58; those who received latanoprost eye drops&#59; LB&#58; those who received latanoprostene bunod eye drops&#59; TM&#58; those who received timolol eye drops&#46;</p>"
          "tablatextoimagen" => array:1 [
            0 => array:1 [
              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col">Cohort&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col">LP&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col">LB&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col">TM&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " rowspan="2" align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col">Comparison between cohorts</th></tr><tr title="table-row"><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col">Eye drop&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col">0&#46;005&#37; latanoprost&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col">0&#46;0024&#37; latanoprostene bunod&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col">0&#46;5&#37; timolol&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th></tr><tr title="table-row"><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col">Patients&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col">104&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col">94&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col">115&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col"><span class="elsevierStyleItalic">p</span>-value&nbsp;\t\t\t\t\t\t\n
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                  \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">Eye irritation&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">4 &#40;4&#41;&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">4 &#40;4&#41;&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">2 &#40;2&#41;&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">0&#46;529&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">Dry eye&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">2 &#40;2&#41;&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">2 &#40;2&#41;&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">1 &#40;1&#41;&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">0&#46;731&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">Eye pain&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">3 &#40;3&#41;&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">3 &#40;3&#41;&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">1 &#40;1&#41;&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">0&#46;445&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">Conjunctival hyperemia&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">4 &#40;4&#41;&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">3 &#40;3&#41;&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">1 &#40;1&#41;&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">0&#46;340&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">Foreign body sensation in eye &#40;s&#41;&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">3 &#40;3&#41;&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">2 &#40;2&#41;&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">1 &#40;1&#41;&nbsp;\t\t\t\t\t\t\n
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                  \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">0&#46;546&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Total&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="center" valign="\n
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                  \t\t\t\t">16 &#40;16&#41;&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">14 &#40;14&#41;&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
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                  \t\t\t\t">6 &#40;6&#41;<a class="elsevierStyleCrossRef" href="#TFN04t02">&#42;</a>&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">0&#46;031&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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          "leyenda" => "<p id="TFN01t03" class="elsevierStyleSimplePara elsevierViewall">Data are presented as mean&#177;SD&#46;</p><p id="TFN02t03" class="elsevierStyleSimplePara elsevierViewall">One-way ANOVA following the Tukey test was performed for statistical analysis&#46;</p><p id="TFN05t03" class="elsevierStyleSimplePara elsevierViewall">BL&#58; Before treatment&#59; EL&#58; At the end of the 3 months of treatment&#59; SD&#58; Standard deviation&#59; ANOVA&#58; Analysis of variance&#59; LP&#58; those who received latanoprost eye drops&#59; LB&#58; those who received latanoprostene bunod eye drops&#59; TM&#58; those who received timolol eye drops&#46;</p><p id="TFN06t03" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleItalic">p</span>&#60;0&#46;05 and q&#62;3&#46;336 were considered significant&#46;</p>"
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                  \t\t\t\t" scope="col">Cohort&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col">Eye drop&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " colspan="3" align="center" valign="\n
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                  \t\t\t\t" scope="col">0&#46;005&#37; latanoprost</th><th class="td" title="\n
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                  \t\t\t\t  " colspan="3" align="center" valign="\n
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                  \t\t\t\t" scope="col">0&#46;0024&#37; latanoprostene bunod</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " colspan="4" align="center" valign="\n
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                  \t\t\t\t" scope="col">0&#46;5&#37; timolol</th></tr><tr title="table-row"><th 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" scope="col">Level&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="center" valign="\n
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                  \t\t\t\t" scope="col">BL&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="center" valign="\n
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                  \t\t\t\t" scope="col">EL&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" scope="col">BL&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="center" valign="\n
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                  \t\t\t\t" scope="col">EL&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t" scope="col">BL&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="center" valign="\n
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                  \t\t\t\t  " align="" valign="\n
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                  \t\t\t\t" scope="col">Patients&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t" scope="col">104&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-head\n
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                  \t\t\t\t" scope="col">94&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="center" valign="\n
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                  \t\t\t\t" scope="col">94&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
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                  \t\t\t\t" scope="col"><a class="elsevierStyleCrossRef" href="#TFN03t03">&#35;</a><span class="elsevierStyleItalic">p</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
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                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col">115&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col">115&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="center" valign="\n
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                  \t\t\t\t" scope="col"><a class="elsevierStyleCrossRef" href="#TFN03t03">&#35;</a><span class="elsevierStyleItalic">p</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col"><a class="elsevierStyleCrossRef" href="#TFN03t03">&#35;</a>q&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><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">Diastolic blood pressure &#40;mmHg&#41;&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
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                  \t\t\t\t">83&#177;4&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">82&#177;4&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
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                  \t\t\t\t">0&#46;073&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="center" valign="\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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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