Pharmacological treatments for the correction of presbyopia | Archivos de la Sociedad Española de Oftalmología (English Edition)

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Fernández Jiménez-Ortiz, N. Toledano Fernández" "autores" => array:2 [ 0 => array:4 [ "nombre" => "H." "apellidos" => "Fernández Jiménez-Ortiz" "email" => array:1 [ 0 => "hector_fernan@hotmail.com" ] "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "*" "identificador" => "cor0005" ] ] ] 1 => array:2 [ "nombre" => "N." "apellidos" => "Toledano Fernández" ] ] "afiliaciones" => array:1 [ 0 => array:2 [ "entidad" => "Servicio de Oftalmología, Hospital Universitario de Fuenlabrada, Fuenlabrada, Madrid, Spain" "identificador" => "aff0005" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Estrategias farmacológicas para la corrección de la presbicia" ] ] "textoCompleto" => "IntroductionPresbyopia, from the Greek presbys, meaning “old,” and ops, meaning “to see as,” is the inability to focus on near objects due to aging. The most widely accepted definition of presbyopia is: “A refractive condition in which the accommodative ability of the eye is insufficient for near vision work due to aging”.<a class="elsevierStyleCrossRef" href="#bib0005">1</a>It affects every individual from the fifth or sixth decade of life onwards (1.7 and 2.1 billion people worldwide) and its incidence is increasing due to the aging of the population.<a class="elsevierStyleCrossRefs" href="#bib0010">2,3</a> Dependence on glasses is one of the main causes of loss of quality of life in people over 45 years of age.<a class="elsevierStyleCrossRef" href="#bib0015">3</a> Forty-five percent of said population do not have access to effective treatment, especially in rural areas of developing countries.<a class="elsevierStyleCrossRef" href="#bib0010">2</a> Presbyopia significantly impacts productivity and quality of life in both developed and developing countries,<a class="elsevierStyleCrossRef" href="#bib0020">4</a> although the impact is greater in the latter.<a class="elsevierStyleCrossRef" href="#bib0010">2</a>During accommodation, the eye changes its optical power by altering the shape of the lens, but the exact mechanism of this phenomenon has not been fully explained.<a class="elsevierStyleCrossRefs" href="#bib0025">5,6</a>There are several conflicting theories that attempt to explain this process. For accommodation to occur effectively, 3 phenomena must occur: change in lens shape, decrease in pupillary diameter and convergence.<a class="elsevierStyleCrossRef" href="#bib0035">7</a> In 1864, Donders proposed that this is due to a decrease in the contracting force of the ciliary muscle with age, and Helmholtz in 1855 suggested that the cause was “sclerosis” of the lens, which causes it to become less malleable with age.<a class="elsevierStyleCrossRef" href="#bib0040">8</a> According to this theory, accommodation occurs as a result of the elasticity of the lens (possibly also of the vitreous), which allows the lens to expand and thus increase its optical dioptric power when the zonular tension decreases. As the lens changes with age, the ability to expand and increase its refractive power is progressively lost. Possibly, a combination of these 2 mechanisms determines the natural evolution and course of presbyopia.However, both Helmholtz and Donders' theories were challenged by Schachar,<a class="elsevierStyleCrossRef" href="#bib0045">9</a> who showed that the longitudinal muscle fibers of the ciliary muscle produce more tension in the equatorial zonula, relaxing the anterior and posterior fibers thereof. This distribution of forces causes an increase in the equatorial diameter of the lens, decreasing the peripheral volume and increasing the central volume. This latter increase creates an increase in the anterior and posterior curvature of the lens which increases its optical dioptric power. According to Schachar, accommodation occurs as a result of an asymmetry in the force exerted by the ciliary muscle on the lens, with more central and less peripheral traction, increasing the curvature and, therefore, the optical dioptric power of the lens.<a class="elsevierStyleCrossRef" href="#bib0045">9</a> In turn, according to this theory, presbyopia is the result of age-related reduction of the circumlental space (the distance between the inner apex of the ciliary muscle and the lens equator), due to the increase in the equatorial diameter of the lens, which shortens the length of the muscle fibers and, therefore, does not allow this asymmetry in the traction that would cause accommodation.<a class="elsevierStyleCrossRef" href="#bib0050">10</a> This theory also failed to be unanimously accepted and illustrates the difficulty of defining the ultimate causes of presbyopia.Experimental MRI studies have observed an anterior displacement of the ciliary body during accommodation.<a class="elsevierStyleCrossRefs" href="#bib0055">11,12</a> This continuous displacement would push the pupillary margin and iris root forward, reducing the zonular tension at rest and allowing the lens to adopt a thicker and more curved shape, thereby reducing the accommodative response of the lens.<a class="elsevierStyleCrossRef" href="#bib0055">11</a> In fact, relocation of the anterior uveal tract to a more posterior position after cataract surgery appears to support this hypothesis.<a class="elsevierStyleCrossRef" href="#bib0065">13</a>The elasticity of the lens is critical for accommodation, which depends on the displacement of cytosol in the fibers to increase the refractive index of the lens.<a class="elsevierStyleCrossRef" href="#bib0030">6</a> As the latter continues to grow with age, there are not enough reducing enzymes to maintain the flow of cytosol.<a class="elsevierStyleCrossRef" href="#bib0070">14</a> This leads to a loss of lens elasticity and dynamic refractive power during accommodation.<a class="elsevierStyleCrossRef" href="#bib0070">14</a>The decrease in the amplitude of accommodation is progressive from infancy and its degree can be determined as a function of age (amplitude of accommodation = 26.45–13.82 log of age).<a class="elsevierStyleCrossRef" href="#bib0045">9</a> However, ciliary muscle contraction does not decrease with age or implantation of an intraocular lens.<a class="elsevierStyleCrossRef" href="#bib0040">8</a> In addition, the diameter of the ciliary muscle decreases with advancing age and this also does not appear to be altered by the implantation of an intraocular lens.<a class="elsevierStyleCrossRef" href="#bib0050">10</a>The origin of the lens is ectodermal and, like all ectodermal structures, it continues to grow throughout life. However, the sclera, which is of mesodermal origin, does not increase after the age of 13. The lens continues to grow throughout life due to the addition of new epithelial cells.<a class="elsevierStyleCrossRefs" href="#bib0075">15–17</a> The equatorial diameter of the lens also appears to increase with age, about 0.02 mm/year,<a class="elsevierStyleCrossRef" href="#bib0085">17</a> while the anterior curvature decreases with age.<a class="elsevierStyleCrossRefs" href="#bib0090">18,19</a>With age, free amino groups in the lens slowly react with reducing sugars and carbonyls, resulting in a slow and progressive glycation that cross-links, opacifies and densifies the crystallin proteins.<a class="elsevierStyleCrossRef" href="#bib0100">20</a> The non-enzymatic glycation of crystallin proteins is one of the main causes of the alteration of their stability and structure and of the covalent cross-linking, aggregation and insolubilization of crystallin proteins.<a class="elsevierStyleCrossRefs" href="#bib0105">21,22</a> Therefore, compounds that inhibit or alter advanced glycation end products (AGEs) may be effective in preventing age-associated structural alteration of the lens.<a class="elsevierStyleCrossRef" href="#bib0115">23</a>Crystalline hardening is caused by an increase in hydrophobic proteins.<a class="elsevierStyleCrossRefs" href="#bib0120">24,25</a> The main chemical modifications of the proteins are sulfhydryl oxidation, deamidation and the formation of PGA.<a class="elsevierStyleCrossRef" href="#bib0125">25</a> PGAs increase in concentration with aging,<a class="elsevierStyleCrossRef" href="#bib0110">22</a> producing a decrease in reduced glutathione, leading to oxidative damage and the formation of disulfide-bound protein agglutinins.<a class="elsevierStyleCrossRef" href="#bib0125">25</a> Replenishment of glutathione has been postulated as a strategy to reduce oxidative damage and delay lens hardening. Presbyopia is directly related to PGA levels, as they increase lens stiffness.<a class="elsevierStyleCrossRef" href="#bib0130">26</a> In addition, presbyopia is considered the earliest observable symptom of senile cataracts.<a class="elsevierStyleCrossRef" href="#bib0135">27</a>In short, the literature describes age-related changes in the 3 structures that make up the accommodative apparatus: the ciliary muscle, the lens and the zonule, evidencing a multifactorial basis.<a class="elsevierStyleCrossRefs" href="#bib0140">28–30</a>The ciliary muscle is a complex structure, with striated, smooth and cardiac fiber characteristics.<a class="elsevierStyleCrossRefs" href="#bib0055">11,31</a> With age there is an increase in intramuscular connective tissue.<a class="elsevierStyleCrossRef" href="#bib0035">7</a> Anatomically, it can be divided into 3 sections according to the orientation of its fibers: longitudinal, radial and circular.<a class="elsevierStyleCrossRef" href="#bib0160">32</a> The contraction of the ciliary muscle during accommodation causes a centripetal (inward, toward the center of the eye) and anterior (toward the cornea) movement of the ciliary muscle mass.<a class="elsevierStyleCrossRef" href="#bib0165">33</a> The longitudinal fibers are responsible for the anterior displacement of the muscle mass during contraction, while the radial and circular fibers are responsible for the inward movement of the muscle mass during contraction, with the circular fibers acting as a sphincter,<a class="elsevierStyleCrossRef" href="#bib0055">11</a> while the contractile response is thought to be greater temporally than nasally, possibly to align the lenticular axes during convergence.<a class="elsevierStyleCrossRef" href="#bib0060">12</a> Finally, the longitudinal fibers have continuity with the choroid posteriorly; this suggests that their contraction may have an effect on the choroid, displacing it anteriorly and perhaps modifying its thickness.<a class="elsevierStyleCrossRef" href="#bib0170">34</a>The role of convergence-accommodation synergy in near visual quality also remains to be elucidated. It is known that each diopter of accommodation is, in healthy subjects, a function of the diopters of convergence, but how does this relation change with age, what consequences does an alteration in this relation have in addition to possible strabismus, what ocular or extraocular diseases can affect it? This relationship seems to be important for accommodation and, therefore, for visual function. Its study can help us understand ocular physiology and, therefore, bring us closer to effective treatments for any related disease.A hitherto unexplained phenomenon is the increase in axial length with sustained accommodative effort, which returns to its baseline state 10 min after cessation of accommodation.<a class="elsevierStyleCrossRef" href="#bib0170">34</a> In a study with healthy subjects it was observed that axial length increased and choroidal thickness decreased transiently after prolonged accommodative effort. These changes were greater in myopic subjects.<a class="elsevierStyleCrossRef" href="#bib0170">34</a> In line with the increase in this axial length, Ni et al.<a class="elsevierStyleCrossRef" href="#bib0175">35</a> observed minimal but statistically significant changes in corneal volume during accommodation, observed by Scheimpflug imaging. These changes were observed especially in corneal volume and seem to favor near vision performance, especially by decreasing higher order aberrations.After presenting the state of knowledge on the anatomy and physiology of accommodation and presbyopia, we will now discuss the current pharmacological strategies for presbyopia correction. We have left aside surgical strategies because of their irreversibility and radically different mechanism of action, based on the presentation of multiple simultaneous focal points.Material and methodsA search was conducted in the following online search engines: PubMed, Embase, LILACS, IBECS and clinicaltrials.gov. The filters used were: humans, age over 18 years; languages: English, French, Spanish; type of study: clinical trial, randomized clinical trial, review, systematic review, meta-analysis. The terms entered were:<ul class="elsevierStyleList" id="lis0005"><li class="elsevierStyleListItem" id="lsti0005">1PubMed: (“Presbyopia”[MeSH]) AND (pharmacological treatment): 21 results. (“Presbyopia”[MeSH]) AND (drug therapy): 19 results.</li><li class="elsevierStyleListItem" id="lsti0010">2Embase: (“Presbyopia”) AND (“pharmacological treatment”): 146 results. (“Presbyopia”) AND (“drug therapy”): 146 results.</li><li class="elsevierStyleListItem" id="lsti0015">3LILACS: (presbyopia): 31 results.</li><li class="elsevierStyleListItem" id="lsti0020">4IBECS: (presbyopia): 80 results; (presbyopia) AND (drug therapy): 88 results; (presbyopia) AND (pharmacological treatment): 21 results.</li><li class="elsevierStyleListItem" id="lsti0025">5Clinicaltrials.gov: presbyopia: 62 results. Only completed studies with results were included.</li></ul>The titles of all the results were reviewed, discarding those that included the evaluation of surgical procedures, those that evaluated intraocular or extraocular lenses, trials with no published results, those with no abstract available, isolated clinical cases, that included the evaluation of non-pharmacological therapies, that evaluated monovision strategies, as well as epidemiological or economic impact studies, and epidemiological or economic impact studies. We excluded one clinical trial whose study population was only glaucomatous patients<a class="elsevierStyleCrossRef" href="#bib0180">36</a> because the purpose of this review was therapies applied to the general population.The objective was to find randomized clinical trials or meta-analyses that specifically evaluated the effect of pharmacological treatments on presbyopia. In the case of unpublished clinical trials, we rejected all those that did not present completed studies with results.We found a total of 15 randomized clinical trials with the following active ingredients (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>): pilocarpine hydrochloride 1.25% (GEMINI-1 and 2 studies, VIRGO study),<a class="elsevierStyleCrossRefs" href="#bib0185">37–39</a> carbachol plus brimonidine,<a class="elsevierStyleCrossRef" href="#bib0200">40</a> pilocarpine 1.25% plus diclofenac,<a class="elsevierStyleCrossRef" href="#bib0205">41</a> aceclidine plus tropicamide,<a class="elsevierStyleCrossRef" href="#bib0210">42</a> lipoic acid ester (also called UNR844 and EV06 compound),<a class="elsevierStyleCrossRefs" href="#bib0215">43–45</a> phentolamine (VEGA-1 study),<a class="elsevierStyleCrossRefs" href="#bib0230">46,47</a> phentolamine with pilocarpine,<a class="elsevierStyleCrossRefs" href="#bib0240">48–50</a> combination of AGN-190584 and AGN-199201.<a class="elsevierStyleCrossRef" href="#bib0255">51</a><elsevierMultimedia ident="tbl0005"></elsevierMultimedia>Twelve reviews by the following authors were found eligible for inclusion: Haghpanah and Alany,<a class="elsevierStyleCrossRef" href="#bib0260">52</a> Grzybowski et al.,<a class="elsevierStyleCrossRef" href="#bib0265">53</a> Rosenfield,<a class="elsevierStyleCrossRef" href="#bib0270">54</a> Orman and Benozzi,<a class="elsevierStyleCrossRefs" href="#bib0035">7,55</a> McDonald et al.,<a class="elsevierStyleCrossRef" href="#bib0280">56</a> Mercer et al.,<a class="elsevierStyleCrossRef" href="#bib0285">57</a> Montés-Mic ó and Charman,<a class="elsevierStyleCrossRef" href="#bib0290">58</a> Westheimer,<a class="elsevierStyleCrossRef" href="#bib0295">59</a> Castro-Castaneda et al.,<a class="elsevierStyleCrossRef" href="#bib0300">60</a> Lievens et al.<a class="elsevierStyleCrossRef" href="#bib0305">61</a> and Renna et al.<a class="elsevierStyleCrossRef" href="#bib0310">62</a> The reviews were searched exclusively for references to randomized clinical trials that had not been identified in the search engines.Results<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a> summarizes the active ingredients and characteristics of the clinical trials analyzed in this review. After reviewing the selected papers, we can draw some interesting conclusions. The “ideal” correction would be “one capable of restoring, in the pre-presbyopic stage, the optical dioptric range within which focusing is accurate. It should also be able to maintain this range for the remaining decades of the individual's life, without any further intervention, the eye being always emmetropic”.<a class="elsevierStyleCrossRef" href="#bib0180">36</a> Furthermore, it should be invisible to the external observer and changes in focus should occur synchrously with convergence and mild miosis. This clearly points to the ciliary system as a key element in achieving this presbyopia correction.<a class="elsevierStyleCrossRef" href="#bib0185">37</a>Currently there are different strategies aimed at correcting presbyopia from different mechanisms of action.<a class="elsevierStyleCrossRef" href="#bib0190">38</a> The pharmacological strategies include those that seek pseudoaccommodation, increasing the depth of focus by producing miosis, and those that seek to slow down the evolution towards rigidity of the nucleus and the crystalline capsule.<a class="elsevierStyleCrossRef" href="#bib0015">3</a> Pharmacological treatments are mostly in the research phase.<a class="elsevierStyleCrossRef" href="#bib0195">39</a> Their main disadvantages are the need for daily application, a limited action time of a few hours, and those based on altering lens sclerosis present doubts about their long-term safety.<a class="elsevierStyleCrossRef" href="#bib0035">7</a>Among the reviews analyzed, we found some retrospective or prospective nonrandomized studies that were not taken into account for this review. The randomized clinical trials mentioned in the review papers had been previously identified in the search engines. At present, we can say that there are basically 2 therapeutic strategies: pseudoaccommodation and lens flexibilization.PseudoaccommodationOptical instillation of parasympathomimetic drugs induces pupillary miosis that produces a pinhole effect, thereby increasing the depth of focus; however, this miosis also reduces the visual field. Pupil diameter is inversely proportional to depth of focus and directly proportional to visual field width. The minimum pupil size is considered to be 1.5 mm, below which the luminance reaching the retina is so low that it does not allow adequate contrast sensitivity and also produces many diffractive aberrations,<a class="elsevierStyleCrossRef" href="#bib0185">37</a> therefore, there is a limit to the ability of the pinhole effect to improve near vision.There are numerous studies under investigation and others already marketed with this pseudo-acommodative strategy. The main substances investigated for this purpose are: pilocarpine, aceclidine, brimonidine, phentolamine and carbachol. Pilocarpine 1.25% (Vuity®, Abvie, Dublin, Ireland) has been marketed in the United States since 2021. In the following section we will individually review the drugs of the study.Aceclidine is a nonselective partial muscarinic agonist of muscarinic receptors. In a 1990 study, Erickson-Lamy and Schroeder conducted a study in monkeys to study its effects on ocular pressure, finding an increase in the amplitude of accommodation of 5 Dp with aceclidine and of 19 Dp with pilocarpine.<a class="elsevierStyleCrossRef" href="#bib0315">63</a> This finding served as proof of concept for developing the pinhole effect as a treatment for presbyopia.Pilocarpine is a cholinergic muscarinic 5-receptor agonist. In December 2021, Allergan Inc. (Abvie) announced that the Food and Drug Administration had approved Vuity® (pilocarpine hydrochloride 1.25% ophthalmic solution, also called AGN-190584). This approval is the result of the GEMINI-1 and GEMINI-2 studies.<a class="elsevierStyleCrossRef" href="#bib0305">61</a> Pilocarpine 1.25% decreases pupil diameter by 50% after application.<a class="elsevierStyleCrossRef" href="#bib0185">37</a> These studies reported a significant improvement in near visual acuity (26 vs. 8% improvement of 3 lines in near vision) compared to placebo from the first hour to 6 h after its administration ; as the main adverse effect, mild headache was reported in 2% of cases, although the follow-up of this study was very short, only 30 days.<a class="elsevierStyleCrossRef" href="#bib0190">38</a> Neither was its effect studied in monthly optic conditions nor on activities such as driving.<a class="elsevierStyleCrossRef" href="#bib0190">38</a> The VIRGO study is a randomized phase 3 clinical trial of pilocarpine 1.25% versus placebo. A total of 230 patients received 2 drops per day for 15 days, and a statistically significant difference was found between the two groups. A 30% increase in the treatment group gained more than 3 lines in near vision with distance correction.<a class="elsevierStyleCrossRef" href="#bib0195">39</a> Adverse effects were headache (8.8%), eye irritation (6.1%) and punctate keratitis (3.5%).However, continued use of pilocarpine, even at very low doses, has been associated with risk of chronic uveitis, posterior synechiae, tonic pupil, pigmentary dispersion<a class="elsevierStyleCrossRef" href="#bib0270">54</a> and retinal detachment,<a class="elsevierStyleCrossRef" href="#bib0320">64</a> to the point that the use of optical corticosteroids in conjunction with pilocarpine has been recommended to avoid these risks. Studies have also shown no clear improvement in spectacle independence with the use of pilocaripine,<a class="elsevierStyleCrossRef" href="#bib0270">54</a> probably due to the short time of action of the drug after instillation. Due to the mechanism of action it has been proposed that a sustained contraction of the ciliary muscle may lead to retinal detachment in predisposed eyes. Although this last statement has not been reported in clinical trials, it is an issue to be monitored in the case of continued use of these treatments.<a class="elsevierStyleCrossRef" href="#bib0295">59</a>Liquid Vision (PRX-100) is a formula combining aceclidine and tropicamide based on a miotic effect with minimal stimulation of accommodation, allowing a pinhole effect with miosis but without inducing ciliary spasm or optic myopic displacement that could alter distant vision. Aceclidine is a less potent muscarinic agonist than pilocarpine and carbachol. Tropicamide has the opposite effect to aceclidine; it has a much higher affinity for iris M3 receptors than other antimuscarinic agents and allows pupil dilation with minimal influence on accommodation.<a class="elsevierStyleCrossRef" href="#bib0325">65</a> A first pilot study with 9 participants revealed that the pupil reached a diameter of approximately 1.6 mm 30 min after instillation.<a class="elsevierStyleCrossRef" href="#bib0265">53</a> The Phase 2 clinical trial versus placebo verified the efficacy of PRX-100 in the treatment of incipient to moderate presbyopia in 58 patients.<a class="elsevierStyleCrossRef" href="#bib0210">42</a> The only adverse effects reported were headache (5%) and eye irritation (4%), similar to the rest of the miotics. Three visits were made and the results were evaluated one hour after instillation on each visit.In June 2021, LENZ announced its intention to submit a new drug application to the Food and Drug Administration and commence Phase 3 trials for LNZ100 (1.75% aceclidine) and LNZ101 (combination of 1.75% aceclidine and brimonidine).<a class="elsevierStyleCrossRef" href="#bib0210">42</a> Results are not yet available.Carbachol, like brimonidine, is a parasympathomimetic that activates muscarinic and nicotinic receptors. The combination of carbachol 2.25% and brimonidine 0.2% is also based on the pinhole effect. A randomized study in 48 presbyopic patients showed an improvement in near vision vs. placebo. The treatment group gained an average of 4 lines, one hour after instillation, without affecting far visual acuity.<a class="elsevierStyleCrossRef" href="#bib0200">40</a> Side effects were burning (3.3%), headache (10%) and mesopic visual difficulty (3.3%) during the first 2 weeks.<a class="elsevierStyleCrossRef" href="#bib0200">40</a> This is one of the studies with the longest follow-up time; at 3 months no serious adverse effects were observed.In the VEGA-1 study, 148 patients were randomized to receive a combination of phentolamine + pilocarpine or placebo. This was a multicenter, double-blind, phase 2b trial, where a statistically significant difference was observed between the placebo and treatment groups, with a higher percentage of patients improving 2 and 3 lines of near vision with its correction far vision. In this study, monocular and binocular gain was measured and a similar gain was observed (Katz et al.). The only adverse effects reported were hyperemia and ocular irritation. In contrast to other studies, no increased incidence of headache was observed.In another arm of the VEGA-1 study, 4 arms were assembled comparing isolated phentolamine, isolated pilocarpine, phentolamine + pilocarpine, and placebo (Pepose et al.). This was a randomized, multicenter, double-blind trial in which 150 patients were randomized. The results showed that those who received the combination of phentolamine and pilocarpine had the greatest improvement in their near corrected visual acuity 6 h after instillation (Pepose et al.). Adverse effects in this case did include headache for the combination of phentolamine and pilocarpine. Another publication reports these same results from the VEGA-1 study at 18 h after instillation (Brigell et al.), the follow-up period in all of them being no more than a few hours.A phase 2 clinical trial of oxymetazoline (AGN-199201) plus pilocarpine was conducted. Oxymetazoline is a sympathomimetic that would partially counteract the parasympathetic effect of pilocarpine. The intention of this association would be to allow a mild miosis without adverse effects on ciliary muscle traction. 151 patients between 40 and 55 years of age were selected, 4 treatment arms were created: placebo and 3 increasing concentrations of the combination of both drugs (low, medium and high according to the description of the trial). The study describes that up to 70% of patients had an improvement of 2 or more lines in uncorrected near visual acuity. Follow-up was 112 days and adverse effects were headache (12.2%), punctate keratitis (4.8%) and foreign body sensation (2.4%).<a class="elsevierStyleCrossRef" href="#bib0330">66</a>Lens flexibilizationAntioxidants applied topically are currently under research, having been shown to improve multiple ocular conditions: accommodation, cataract delay, glaucoma development, age-related macular degeneration and dry eye.<a class="elsevierStyleCrossRef" href="#bib0300">60</a> They constitute an interesting avenue of research in the subject under discussion.Hesperetin is a natural flavonoid that can prevent lens sclerosis and cataract formation attributable to aqueous water flow and PGA generation.<a class="elsevierStyleCrossRef" href="#bib0135">27</a> Experimental substances such as UNR844-Cl (formerly known as EV06) can replenish glutathione and decrease disulfide bonds in aged lens proteins.Deglycating enzymes are a novel strategy to try to make the lens more flexible and thus facilitate its malleability. Ex vivo treatment with fructosyl-α -L-amino acid oxidoreductase (deglycosylating) of lenses extracted from presbyopic patients results in a significant improvement in lens power. According to this ex vivo study, it can be concluded that fructosyl-α -L-amino acid oxidoreductase is able to break the cross-links between lens fibers and produce their deglycation, which increases their elasticity and malleability.<a class="elsevierStyleCrossRef" href="#bib0335">67</a>Lipoic acid ester, aggregalite 1 and 2, EV06 and oxymetazoline are molecules that appear to cause a decrease in lens protein disulfides, increasing lens elasticity.<a class="elsevierStyleCrossRef" href="#bib0145">29</a> EV06 (Novartis) is a 1.5% lipoic acid prodrug that may “soften” the lens, restoring the physiological response to the ciliary muscle. A randomized clinical trial compared EV06 with placebo in 75 patients.<a class="elsevierStyleCrossRef" href="#bib0220">44</a> An improvement in visual acuity (corrected for distance ition) was found compared to healthy controls. With a twice-daily application pattern, the benefit was observed to be maintained for 5–7 months with a 90-day treatment.<a class="elsevierStyleCrossRef" href="#bib0150">30</a> No serious adverse effects were reported; the mild ones were nasopharyngitis (16%), dysgeusia (14%), headache (8%) and eye irritation (6%).In another clinical trial with UNR844 (lipoic acid ester or EV06), with 50 patients, it was applied once daily for 90 days of treatment. A statistically significant improvement in near vision compared to placebo was observed. Fifty-one percent of the treatment group were able to improve more than 2 lines of vision compared to 21% of the control group. After 90 days of treatment, a 7-month follow-up was performed. The ocular adverse effects observed were mild, such as sensation of conjunctival hyperemia and pruritus. No worsening of distant vision and no systemic adverse effects were observed. This improvement occurred in both early and advanced stages of presbyopia.<a class="elsevierStyleCrossRef" href="#bib0225">45</a>DiscussionThe review provides relevant information on the epidemiology and physiology of presbyopia, as well as on therapeutic approaches based on pharmacological strategies. Currently, uncorrected presbyopia is the most common cause of treatable visual impairment worldwide and will remain so until 2050.<a class="elsevierStyleCrossRef" href="#bib0340">68</a> This problem is a major burden on productivity and quality of life, especially in developing countries, making the ease and low cost of correction a good argument for investing resources to address it. The new treatments already available from 2021 (Vuity®, Abvie) are one of the most novel aspects in ophthalmology in recent years.<a class="elsevierStyleCrossRef" href="#bib0335">67</a>Accommodation is a complex mechanism that is not fully elucidated and depends on the perfect coordination between different intraocular and extraocular structures. The key elements in accommodation appear to be changes in shape and position of the lens and pupillary diameter.To produce these lens changes, synkinesis of multiple structures must occur: sclera, ciliary body, zonule and iris sphincter. These changes are initiated in the midbrain by a stimulus from the optic nerve and are carried by the third cranial nerve to the long ciliary nerves.Current options include pharmacologic treatments, surgical and laser procedures. Surgical procedures based on phakic or pseudophakic intraocular lenses are an effective but invasive option with risks inherent to any intervention. This leads many patients to opt for less interventional options. As for the pharmacological approach, the proposed mechanisms of action include the pinhole effect and lens “softening”. Pupillary miotics increase the depth of focus creating a pinhole effect. Pure parasympathetic treatments may result in a decrease in pupillary size and myopic shift, compromising distance vision. It should also be noted that muscarinic stimulation can cause several adverse reactions related to uveitis and intraocular inflammation with its chronic use. Thus, other agents in combined use with parasympathomimetics were proposed to counteract these actions, including nonsteroidal anti-inflammatory drugs. Because of this, 2-drug combination formulations have been developed.Most studies include follow-up periods that are too short, some with only a single administration, and the longest follow-up periods are a few weeks.<a class="elsevierStyleCrossRef" href="#bib0345">69</a> Studies using the Benozzi method® have not been included in this review because they were not randomized. However, a brief mention should be made due to its frequency of administration and follow-up time: 2 times a day for 5 years.<a class="elsevierStyleCrossRef" href="#bib0350">70</a> The Benozzi method® (US 8,524,758 B2-EP1,938,839 B1) is a proprietary combination of pilocarpine and diclofenac. In 2 prospective case series studies, this author reported an improvement in near visual acuity without optical correction at 10 years of follow-up, no impairment in far visual acuity, and surface symptoms, headache and decreased mesopic contrast sensitivity as adverse effects.<a class="elsevierStyleCrossRefs" href="#bib0355">71,72</a> According to these publications, 70% of treated subjects achieved a visual acuity of J2 (Jaeger) without optical correction.In the clinical trials consulted, no serious adverse effects have been detected; however, there are some documented cases of retinal detachment associated with treatment for a few weeks with 1.25% pilocarpine,<a class="elsevierStyleCrossRefs" href="#bib0320">64,73</a> whose mechanism of action would be compatible with anterior displacement of the ciliary body. Although pilocarpine-based preparations have not been evaluated with continuous use for periods of time longer than 6 months, there are legitimate doubts about their long-term safety. The study with the largest sample size and follow-up time is the one published by Benozzi et al. with their own proprietary pilocarpine and diclofenac eye drops. In this study with 910 patients and a follow-up of 8 years, no case of retinal detachment or any other serious adverse effect was reported. Only transient dizziness, headache and eye irritation were reported.<a class="elsevierStyleCrossRef" href="#bib0360">72</a>The second approach to presbyopia treatment is based on “softening” the crystalline lens. EV06 is the only agent that has already been explored for this purpose, having obtained favorable results from 3 randomized clinical trials.The development of new therapeutic approaches depends on a thorough understanding of the phenomena of accommodation. Today it is not fully understood and there are conflicting theories about how it works. How it is triggered and how it is regulated in such a precise way also remains unclear. Advancing anatomic and physiolological knowledge about accommodation could aid in the development of new drugs or devices. For example, findings of vitreous, choroidal and scleral dynamics anteriorizing during accommodation allow us to take advantage of these structures to develop new treatments.<a class="elsevierStyleCrossRef" href="#bib0370">74</a>The limitations of the present review include publication bias if we consider that studies based on pseudoaccommodation or relaxation that have not demonstrated positive results are unlikely to have been published. There are case series and retrospective cohort studies with other treatments, but these have been discarded in order to focus on drugs that have already shown results in randomized clinical trials. The authors have only been able to review articles in English, Spanish or French, so language in turn constitutes a bias in the review.ConclusionsPharmacological treatment of presbyopia may become a reality in clinical practice in the next few years. Possible future lines of research could focus on a combination of synergic strategies (pseudo-accommodation + lens flexibilization) that reduce adverse effects without diminshing efficacy. Also intraocular administration could be an advantage in achieving independence from instillation of drops.There is no doubt that the pharmacologic treatment of presbyopia is an interesting therapeutic approach. More randomized, quality studies with longer follow-up time are needed to evaluate its safety and efficacy, especially with continued use.FinancingNone.Conflict of interestNone." "textoCompletoSecciones" => array:1 [ "secciones" => array:12 [ 0 => array:3 [ "identificador" => "xres2214462" "titulo" => "Abstract" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0005" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec1856565" "titulo" => "Keywords" ] 2 => array:3 [ "identificador" => "xres2214461" "titulo" => "Resumen" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0010" ] ] ] 3 => array:2 [ "identificador" => "xpalclavsec1856566" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 5 => array:2 [ "identificador" => "sec0010" "titulo" => "Material and methods" ] 6 => array:3 [ "identificador" => "sec0015" "titulo" => "Results" "secciones" => array:2 [ 0 => array:2 [ "identificador" => "sec0020" "titulo" => "Pseudoaccommodation" ] 1 => array:2 [ "identificador" => "sec0025" "titulo" => "Lens flexibilization" ] ] ] 7 => array:2 [ "identificador" => "sec0030" "titulo" => "Discussion" ] 8 => array:2 [ "identificador" => "sec0035" "titulo" => "Conclusions" ] 9 => array:2 [ "identificador" => "sec0040" "titulo" => "Financing" ] 10 => array:2 [ "identificador" => "sec0045" "titulo" => "Conflict of interest" ] 11 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2023-10-12" "fechaAceptado" => "2024-03-10" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec1856565" "palabras" => array:4 [ 0 => "Presbyopia" 1 => "Accomodation" 2 => "Ciliary muscle" 3 => "Parasympathetic-mimetics" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec1856566" "palabras" => array:4 [ 0 => "Presbicia" 1 => "Acomodación" 2 => "Músculo ciliar" 3 => "Parasimpaticomiméticos" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:2 [ "titulo" => "Abstract" "resumen" => "Presbyopia affects between 1.7 and 2 billion people worldwide. Presbyopia significantly impacts productivity and quality of life in both developed and developing countries. During accommodation, the human eye changes its dioptric power by altering the shape of the lens, but the exact nature of this change has not been fully explained. Recently, topical treatments have been marketed for the treatment of presbyopia and others are under investigation.In order to prepare a review of these novel therapies, we searched the major biomedical search engines. We found 15 randomized clinical trials and 12 reviews that met our review criteria. There are two different strategies for this purpose, the pinhole effect that increases depth of focus and “crystalline lens relaxation” for which parasympathetic mimetics and lens oxidation intermediates have been used. The results are generally favorable in terms of improvement of near visual acuity, although the follow-up period of the studies is short. These are novel strategies in the early stages of research that could be useful in the treatment of presbyopia." ] "es" => array:2 [ "titulo" => "Resumen" "resumen" => "La presbicia afecta entre 1700 y 2000 millones de personas en todo el mundo. La presbicia impacta significativamente la productividad y la calidad de vida tanto en países desarrollados como en vías de desarrollo. Durante la acomodación, el ojo humano cambia su potencia dióptrica alterando la forma del cristalino, pero la naturaleza exacta de este cambio no ha sido completamente explicada. Recientemente han sido comercializados tratamientos tópicos para el tratamiento de la presbicia y existen otros en investigación.Con el objetivo de elaborar una revisión sobre estas terapias novedosas se realizó una búsqueda en los principales buscadores biomédicos. Se encontraron 15 ensayos clínicos aleatorizados y 12 revisiones que cumplían nuestros criterios de revisión. Existen dos estrategias diferentes con este fin, el efecto estenopeico que aumenta la profundidad de foco y la «flexibilización cristaliniana» para lo cual se han empleado parasimpático miméticos e intermediarios de la oxidación del cristalino. Los resultados son en general favorables en cuanto a la mejoría de la agudeza visual cercana, si bien el periodo de seguimiento de los estudios es corto. Se trata de estrategias novedosas en fases iniciales de investigación que podrían tener su utilidad para el tratamiento de la presbicia." ] ] "multimedia" => array:1 [ 0 => array:8 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0005" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "leyenda" => "NVADC: near visual acuity with distance correction; FAOD: fructosyl-α -L-amino acid oxidoreductase." "tablatextoimagen" => array:1 [ 0 => array:2 [ "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" style="border-bottom: 2px solid black">Drug \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" style="border-bottom: 2px solid black">Mechanism of action \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" style="border-bottom: 2px solid black">Type of study \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" style="border-bottom: 2px solid black">Results \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" style="border-bottom: 2px solid black">Follow-up \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" style="border-bottom: 2px solid black">Adverse effects (frequency) \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-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Optimized formulation of pilocarpine chloride 0.125% (AGN-190584) (AGN-190584)<a class="elsevierStyleCrossRefs" href="#bib0185">37,38</a> \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="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Pseudoaccommodation pseudoaccommodation/ pinhole effect \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="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Phase 3 clinical trial (GEMINI) \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="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Improvement of NVADC without affecting distant vision \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="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">30 days \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="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Headache (14%), eye irritation (4%), eye irritation (4%). \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Pilocarpine 1.25%.<a class="elsevierStyleCrossRef" href="#bib0195">39</a> \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="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Pseudoaccommodation pseudoaccommodation/ pinhole effect \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="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Phase 3 (VIRGO) \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="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">NVADC Improvement \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="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">14 days \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="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Headache (8.8%) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Pilocarpine + diclofenac<a class="elsevierStyleCrossRef" href="#bib0205">41</a> \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="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Pseudoaccommodation pseudoaccommodation/ pinhole effect \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="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Clinical trial: pilocarpine vs. diclofenac vs. pilocarpine vs. diclofenac (control group) \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="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">3-line improvement in NVADC in 46% pilocarpine, 46% pilocarpine + diclofenac vs. 16% control \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="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Single dose, 1 h post-treatment. \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="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Headache (9%), conjunctival hyperemia (5%) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Liquid Vision (PRX-100: aceclidine + tropicamide)<a class="elsevierStyleCrossRefs" href="#bib0210">42,53,65</a> \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="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Pseudoaccommodation pseudoaccommodation/ pinhole effect \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="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">PRX-100 vs. aceclidine vs. placebo clinical trial \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="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Near visual acuity J1, 3 lines with respect to placebo \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="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Single dose, 1 h post-treatment. \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="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Hyperemia (5%) and headache (5%) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Carbachol 2.25% + brimonidine 0.2%.<a class="elsevierStyleCrossRef" href="#bib0200">40</a> \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="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Pseudoaccommodation pseudoaccommodation/ pinhole effect \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="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Clinical trial vs. placebo \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="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">NVADC improvement over placebo \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="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">3 months \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="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Eye irritation and headache (6%) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Phentolamine 0.75%.<a class="elsevierStyleCrossRefs" href="#bib0230">46,47</a> \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="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Pinhole effect (1.5 mm) \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="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Placebo clinical trial (VEGA-1) \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="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">NVADC improvement over placebo \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="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">12 h \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="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">No difference with respect to placebo \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Phentolamine with pilocarpine<a class="elsevierStyleCrossRefs" href="#bib0240">48–50</a> \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="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Pseudoaccommodation pseudoaccommodation/ pinhole effect \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="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Clinical trial vs. placebo \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="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">NVADC improvement with respect to placebo without affecting distant vision \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="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">6 h \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="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Eye irritation and hyperemia (4%–6%) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Oxymetazoline (various concentrations) + pilocarpine 1.25%.<a class="elsevierStyleCrossRef" href="#bib0330">66</a> \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="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Pseudoaccommodation pseudoaccommodation/ pinhole effect \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="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Pseudoaccommodation and crystalline flexibilization \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="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Gain of about 5 letters not dose-dependent \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="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">112 days \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="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Headache (12.2%), punctate keratitis (4.8%) and foreign body sensation (2.4%). \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">UNR844 (lipoic acid derivative)<a class="elsevierStyleCrossRefs" href="#bib0215">43–45</a> \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="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Lens flexibilization \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="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Clinical trial vs. placebo \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="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">25% of those treated achieve good NVADC \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="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">3 months \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="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Dysgeusia, headache, blepharitis (3%–5%) \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab3611589.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Summary of drugs with completed and published studies." ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:74 [ 0 => array:3 [ "identificador" => "bib0005" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Restoration of accommodation" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => "A. Glasser" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1097/01.icu.0000193069.32369.e1" "Revista" => array:6 [ "tituloSerie" => "Curr Opin Ophthalmol." "fecha" => "2006" "volumen" => "17" "paginaInicial" => "12" "paginaFinal" => "18" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/16436919" "web" => "Medline" ] ] ] ] ] ] ] ] 1 => array:3 [ "identificador" => "bib0010" "etiqueta" => "2" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Global prevalence of presbyopia and vision impairment from uncorrected presbyopia: systematic review, meta-analysis, and modelling" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "T.R. Fricke" 1 => "N. Tahhan" 2 => "S. Resnikoff" 3 => "E. Papas" 4 => "A. Burnett" 5 => "S.M. Ho" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.ophtha.2018.04.013" "Revista" => array:6 [ "tituloSerie" => "Ophthalmology." 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Pharmacological treatments for the correction of presbyopia

Estrategias farmacológicas para la corrección de la presbicia

H. Fernández Jiménez-Ortiz

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hector_fernan@hotmail.com

Corresponding author.

, N. Toledano Fernández

Servicio de Oftalmología, Hospital Universitario de Fuenlabrada, Fuenlabrada, Madrid, Spain

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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Presbyopia&#44; from the Greek <span class="elsevierStyleItalic">presbys&#44;</span> meaning &#8220;old&#44;&#8221; and <span class="elsevierStyleItalic">ops&#44;</span> meaning &#8220;to see as&#44;&#8221; is the inability to focus on near objects due to aging&#46; The most widely accepted definition of presbyopia is&#58; &#8220;A refractive condition in which the accommodative ability of the eye is insufficient for near vision work due to aging&#8221;&#46;<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">It affects every individual from the fifth or sixth decade of life onwards &#40;1&#46;7 and 2&#46;1 billion people worldwide&#41; and its incidence is increasing due to the aging of the population&#46;<a class="elsevierStyleCrossRefs" href="#bib0010"><span class="elsevierStyleSup">2&#44;3</span></a> Dependence on glasses is one of the main causes of loss of quality of life in people over 45 years of age&#46;<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a> Forty-five percent of said population do not have access to effective treatment&#44; especially in rural areas of developing countries&#46;<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> Presbyopia significantly impacts productivity and quality of life in both developed and developing countries&#44;<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a> although the impact is greater in the latter&#46;<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">During accommodation&#44; the eye changes its optical power by altering the shape of the lens&#44; but the exact mechanism of this phenomenon has not been fully explained&#46;<a class="elsevierStyleCrossRefs" href="#bib0025"><span class="elsevierStyleSup">5&#44;6</span></a></p><p id="par0020" class="elsevierStylePara elsevierViewall">There are several conflicting theories that attempt to explain this process&#46; For accommodation to occur effectively&#44; 3 phenomena must occur&#58; change in lens shape&#44; decrease in pupillary diameter and convergence&#46;<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a> In 1864&#44; Donders proposed that this is due to a decrease in the contracting force of the ciliary muscle with age&#44; and Helmholtz in 1855 suggested that the cause was &#8220;sclerosis&#8221; of the lens&#44; which causes it to become less malleable with age&#46;<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a> According to this theory&#44; accommodation occurs as a result of the elasticity of the lens &#40;possibly also of the vitreous&#41;&#44; which allows the lens to expand and thus increase its optical dioptric power when the zonular tension decreases&#46; As the lens changes with age&#44; the ability to expand and increase its refractive power is progressively lost&#46; Possibly&#44; a combination of these 2 mechanisms determines the natural evolution and course of presbyopia&#46;</p><p id="par0025" class="elsevierStylePara elsevierViewall">However&#44; both Helmholtz and Donders&#39; theories were challenged by Schachar&#44;<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a> who showed that the longitudinal muscle fibers of the ciliary muscle produce more tension in the equatorial zonula&#44; relaxing the anterior and posterior fibers thereof&#46; This distribution of forces causes an increase in the equatorial diameter of the lens&#44; decreasing the peripheral volume and increasing the central volume&#46; This latter increase creates an increase in the anterior and posterior curvature of the lens which increases its optical dioptric power&#46; According to Schachar&#44; accommodation occurs as a result of an asymmetry in the force exerted by the ciliary muscle on the lens&#44; with more central and less peripheral traction&#44; increasing the curvature and&#44; therefore&#44; the optical dioptric power of the lens&#46;<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a> In turn&#44; according to this theory&#44; presbyopia is the result of age-related reduction of the circumlental space &#40;the distance between the inner apex of the ciliary muscle and the lens equator&#41;&#44; due to the increase in the equatorial diameter of the lens&#44; which shortens the length of the muscle fibers and&#44; therefore&#44; does not allow this asymmetry in the traction that would cause accommodation&#46;<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a> This theory also failed to be unanimously accepted and illustrates the difficulty of defining the ultimate causes of presbyopia&#46;</p><p id="par0030" class="elsevierStylePara elsevierViewall">Experimental MRI studies have observed an anterior displacement of the ciliary body during accommodation&#46;<a class="elsevierStyleCrossRefs" href="#bib0055"><span class="elsevierStyleSup">11&#44;12</span></a> This continuous displacement would push the pupillary margin and iris root forward&#44; reducing the zonular tension at rest and allowing the lens to adopt a thicker and more curved shape&#44; thereby reducing the accommodative response of the lens&#46;<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a> In fact&#44; relocation of the anterior uveal tract to a more posterior position after cataract surgery appears to support this hypothesis&#46;<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">13</span></a></p><p id="par0035" class="elsevierStylePara elsevierViewall">The elasticity of the lens is critical for accommodation&#44; which depends on the displacement of cytosol in the fibers to increase the refractive index of the lens&#46;<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a> As the latter continues to grow with age&#44; there are not enough reducing enzymes to maintain the flow of cytosol&#46;<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">14</span></a> This leads to a loss of lens elasticity and dynamic refractive power during accommodation&#46;<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">14</span></a></p><p id="par0040" class="elsevierStylePara elsevierViewall">The decrease in the amplitude of accommodation is progressive from infancy and its degree can be determined as a function of age &#40;amplitude of accommodation&#8239;&#61;&#8239;26&#46;45&#8211;13&#46;82 log of age&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a> However&#44; ciliary muscle contraction does not decrease with age or implantation of an intraocular lens&#46;<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a> In addition&#44; the diameter of the ciliary muscle decreases with advancing age and this also does not appear to be altered by the implantation of an intraocular lens&#46;<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a></p><p id="par0045" class="elsevierStylePara elsevierViewall">The origin of the lens is ectodermal and&#44; like all ectodermal structures&#44; it continues to grow throughout life&#46; However&#44; the sclera&#44; which is of mesodermal origin&#44; does not increase after the age of 13&#46; The lens continues to grow throughout life due to the addition of new epithelial cells&#46;<a class="elsevierStyleCrossRefs" href="#bib0075"><span class="elsevierStyleSup">15&#8211;17</span></a> The equatorial diameter of the lens also appears to increase with age&#44; about 0&#46;02&#8239;mm&#47;year&#44;<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">17</span></a> while the anterior curvature decreases with age&#46;<a class="elsevierStyleCrossRefs" href="#bib0090"><span class="elsevierStyleSup">18&#44;19</span></a></p><p id="par0050" class="elsevierStylePara elsevierViewall">With age&#44; free amino groups in the lens slowly react with reducing sugars and carbonyls&#44; resulting in a slow and progressive glycation that cross-links&#44; opacifies and densifies the crystallin proteins&#46;<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">20</span></a> The non-enzymatic glycation of crystallin proteins is one of the main causes of the alteration of their stability and structure and of the covalent cross-linking&#44; aggregation and insolubilization of crystallin proteins&#46;<a class="elsevierStyleCrossRefs" href="#bib0105"><span class="elsevierStyleSup">21&#44;22</span></a> Therefore&#44; compounds that inhibit or alter advanced glycation end products &#40;AGEs&#41; may be effective in preventing age-associated structural alteration of the lens&#46;<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">23</span></a></p><p id="par0055" class="elsevierStylePara elsevierViewall">Crystalline hardening is caused by an increase in hydrophobic proteins&#46;<a class="elsevierStyleCrossRefs" href="#bib0120"><span class="elsevierStyleSup">24&#44;25</span></a> The main chemical modifications of the proteins are sulfhydryl oxidation&#44; deamidation and the formation of PGA&#46;<a class="elsevierStyleCrossRef" href="#bib0125"><span class="elsevierStyleSup">25</span></a> PGAs increase in concentration with aging&#44;<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">22</span></a> producing a decrease in reduced glutathione&#44; leading to oxidative damage and the formation of disulfide-bound protein agglutinins&#46;<a class="elsevierStyleCrossRef" href="#bib0125"><span class="elsevierStyleSup">25</span></a> Replenishment of glutathione has been postulated as a strategy to reduce oxidative damage and delay lens hardening&#46; Presbyopia is directly related to PGA levels&#44; as they increase lens stiffness&#46;<a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">26</span></a> In addition&#44; presbyopia is considered the earliest observable symptom of senile cataracts&#46;<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">27</span></a></p><p id="par0060" class="elsevierStylePara elsevierViewall">In short&#44; the literature describes age-related changes in the 3 structures that make up the accommodative apparatus&#58; the ciliary muscle&#44; the lens and the zonule&#44; evidencing a multifactorial basis&#46;<a class="elsevierStyleCrossRefs" href="#bib0140"><span class="elsevierStyleSup">28&#8211;30</span></a></p><p id="par0065" class="elsevierStylePara elsevierViewall">The ciliary muscle is a complex structure&#44; with striated&#44; smooth and cardiac fiber characteristics&#46;<a class="elsevierStyleCrossRefs" href="#bib0055"><span class="elsevierStyleSup">11&#44;31</span></a> With age there is an increase in intramuscular connective tissue&#46;<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a> Anatomically&#44; it can be divided into 3 sections according to the orientation of its fibers&#58; longitudinal&#44; radial and circular&#46;<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">32</span></a> The contraction of the ciliary muscle during accommodation causes a centripetal &#40;inward&#44; toward the center of the eye&#41; and anterior &#40;toward the cornea&#41; movement of the ciliary muscle mass&#46;<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">33</span></a> The longitudinal fibers are responsible for the anterior displacement of the muscle mass during contraction&#44; while the radial and circular fibers are responsible for the inward movement of the muscle mass during contraction&#44; with the circular fibers acting as a sphincter&#44;<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a> while the contractile response is thought to be greater temporally than nasally&#44; possibly to align the lenticular axes during convergence&#46;<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a> Finally&#44; the longitudinal fibers have continuity with the choroid posteriorly&#59; this suggests that their contraction may have an effect on the choroid&#44; displacing it anteriorly and perhaps modifying its thickness&#46;<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">34</span></a></p><p id="par0070" class="elsevierStylePara elsevierViewall">The role of convergence-accommodation synergy in near visual quality also remains to be elucidated&#46; It is known that each diopter of accommodation is&#44; in healthy subjects&#44; a function of the diopters of convergence&#44; but how does this relation change with age&#44; what consequences does an alteration in this relation have in addition to possible strabismus&#44; what ocular or extraocular diseases can affect it&#63; This relationship seems to be important for accommodation and&#44; therefore&#44; for visual function&#46; Its study can help us understand ocular physiology and&#44; therefore&#44; bring us closer to effective treatments for any related disease&#46;</p><p id="par0075" class="elsevierStylePara elsevierViewall">A hitherto unexplained phenomenon is the increase in axial length with sustained accommodative effort&#44; which returns to its baseline state 10&#8239;min after cessation of accommodation&#46;<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">34</span></a> In a study with healthy subjects it was observed that axial length increased and choroidal thickness decreased transiently after prolonged accommodative effort&#46; These changes were greater in myopic subjects&#46;<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">34</span></a> In line with the increase in this axial length&#44; Ni et al&#46;<a class="elsevierStyleCrossRef" href="#bib0175"><span class="elsevierStyleSup">35</span></a> observed minimal but statistically significant changes in corneal volume during accommodation&#44; observed by Scheimpflug imaging&#46; These changes were observed especially in corneal volume and seem to favor near vision performance&#44; especially by decreasing higher order aberrations&#46;</p><p id="par0080" class="elsevierStylePara elsevierViewall">After presenting the state of knowledge on the anatomy and physiology of accommodation and presbyopia&#44; we will now discuss the current pharmacological strategies for presbyopia correction&#46; We have left aside surgical strategies because of their irreversibility and radically different mechanism of action&#44; based on the presentation of multiple simultaneous focal points&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Material and methods</span><p id="par0085" class="elsevierStylePara elsevierViewall">A search was conducted in the following online search engines&#58; PubMed&#44; Embase&#44; LILACS&#44; IBECS and clinicaltrials&#46;gov&#46; The filters used were&#58; humans&#44; age over 18 years&#59; languages&#58; English&#44; French&#44; Spanish&#59; type of study&#58; clinical trial&#44; randomized clinical trial&#44; review&#44; systematic review&#44; meta-analysis&#46; The terms entered were&#58;<ul class="elsevierStyleList" id="lis0005"><li class="elsevierStyleListItem" id="lsti0005"><span class="elsevierStyleLabel">1</span><p id="par0090" class="elsevierStylePara elsevierViewall">PubMed&#58; &#40;&#8220;Presbyopia&#8221;&#91;MeSH&#93;&#41; AND &#40;pharmacological treatment&#41;&#58; 21 results&#46; &#40;&#8220;Presbyopia&#8221;&#91;MeSH&#93;&#41; AND &#40;drug therapy&#41;&#58; 19 results&#46;</p></li><li class="elsevierStyleListItem" id="lsti0010"><span class="elsevierStyleLabel">2</span><p id="par0095" class="elsevierStylePara elsevierViewall">Embase&#58; &#40;&#8220;Presbyopia&#8221;&#41; AND &#40;&#8220;pharmacological treatment&#8221;&#41;&#58; 146 results&#46; &#40;&#8220;Presbyopia&#8221;&#41; AND &#40;&#8220;drug therapy&#8221;&#41;&#58; 146 results&#46;</p></li><li class="elsevierStyleListItem" id="lsti0015"><span class="elsevierStyleLabel">3</span><p id="par0100" class="elsevierStylePara elsevierViewall">LILACS&#58; &#40;presbyopia&#41;&#58; 31 results&#46;</p></li><li class="elsevierStyleListItem" id="lsti0020"><span class="elsevierStyleLabel">4</span><p id="par0105" class="elsevierStylePara elsevierViewall">IBECS&#58; &#40;presbyopia&#41;&#58; 80 results&#59; &#40;presbyopia&#41; AND &#40;drug therapy&#41;&#58; 88 results&#59; &#40;presbyopia&#41; AND &#40;pharmacological treatment&#41;&#58; 21 results&#46;</p></li><li class="elsevierStyleListItem" id="lsti0025"><span class="elsevierStyleLabel">5</span><p id="par0110" class="elsevierStylePara elsevierViewall">Clinicaltrials&#46;gov&#58; presbyopia&#58; 62 results&#46; Only completed studies with results were included&#46;</p></li></ul></p><p id="par0115" class="elsevierStylePara elsevierViewall">The titles of all the results were reviewed&#44; discarding those that included the evaluation of surgical procedures&#44; those that evaluated intraocular or extraocular lenses&#44; trials with no published results&#44; those with no abstract available&#44; isolated clinical cases&#44; that included the evaluation of non-pharmacological therapies&#44; that evaluated monovision strategies&#44; as well as epidemiological or economic impact studies&#44; and epidemiological or economic impact studies&#46; We excluded one clinical trial whose study population was only glaucomatous patients<a class="elsevierStyleCrossRef" href="#bib0180"><span class="elsevierStyleSup">36</span></a> because the purpose of this review was therapies applied to the general population&#46;</p><p id="par0120" class="elsevierStylePara elsevierViewall">The objective was to find randomized clinical trials or meta-analyses that specifically evaluated the effect of pharmacological treatments on presbyopia&#46; In the case of unpublished clinical trials&#44; we rejected all those that did not present completed studies with results&#46;</p><p id="par0125" class="elsevierStylePara elsevierViewall">We found a total of 15 randomized clinical trials with the following active ingredients &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#58; pilocarpine hydrochloride 1&#46;25&#37; &#40;GEMINI-1 and 2 studies&#44; VIRGO study&#41;&#44;<a class="elsevierStyleCrossRefs" href="#bib0185"><span class="elsevierStyleSup">37&#8211;39</span></a> carbachol plus brimonidine&#44;<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">40</span></a> pilocarpine 1&#46;25&#37; plus diclofenac&#44;<a class="elsevierStyleCrossRef" href="#bib0205"><span class="elsevierStyleSup">41</span></a> aceclidine plus tropicamide&#44;<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">42</span></a> lipoic acid ester &#40;also called UNR844 and EV06 compound&#41;&#44;<a class="elsevierStyleCrossRefs" href="#bib0215"><span class="elsevierStyleSup">43&#8211;45</span></a> phentolamine &#40;VEGA-1 study&#41;&#44;<a class="elsevierStyleCrossRefs" href="#bib0230"><span class="elsevierStyleSup">46&#44;47</span></a> phentolamine with pilocarpine&#44;<a class="elsevierStyleCrossRefs" href="#bib0240"><span class="elsevierStyleSup">48&#8211;50</span></a> combination of AGN-190584 and AGN-199201&#46;<a class="elsevierStyleCrossRef" href="#bib0255"><span class="elsevierStyleSup">51</span></a></p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0130" class="elsevierStylePara elsevierViewall">Twelve reviews by the following authors were found eligible for inclusion&#58; Haghpanah and Alany&#44;<a class="elsevierStyleCrossRef" href="#bib0260"><span class="elsevierStyleSup">52</span></a> Grzybowski et al&#46;&#44;<a class="elsevierStyleCrossRef" href="#bib0265"><span class="elsevierStyleSup">53</span></a> Rosenfield&#44;<a class="elsevierStyleCrossRef" href="#bib0270"><span class="elsevierStyleSup">54</span></a> Orman and Benozzi&#44;<a class="elsevierStyleCrossRefs" href="#bib0035"><span class="elsevierStyleSup">7&#44;55</span></a> McDonald et al&#46;&#44;<a class="elsevierStyleCrossRef" href="#bib0280"><span class="elsevierStyleSup">56</span></a> Mercer et al&#46;&#44;<a class="elsevierStyleCrossRef" href="#bib0285"><span class="elsevierStyleSup">57</span></a> Mont&#233;s-Mic &#243; and Charman&#44;<a class="elsevierStyleCrossRef" href="#bib0290"><span class="elsevierStyleSup">58</span></a> Westheimer&#44;<a class="elsevierStyleCrossRef" href="#bib0295"><span class="elsevierStyleSup">59</span></a> Castro-Castaneda et al&#46;&#44;<a class="elsevierStyleCrossRef" href="#bib0300"><span class="elsevierStyleSup">60</span></a> Lievens et al&#46;<a class="elsevierStyleCrossRef" href="#bib0305"><span class="elsevierStyleSup">61</span></a> and Renna et al&#46;<a class="elsevierStyleCrossRef" href="#bib0310"><span class="elsevierStyleSup">62</span></a> The reviews were searched exclusively for references to randomized clinical trials that had not been identified in the search engines&#46;</p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Results</span><p id="par0135" class="elsevierStylePara elsevierViewall"><a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a> summarizes the active ingredients and characteristics of the clinical trials analyzed in this review&#46; After reviewing the selected papers&#44; we can draw some interesting conclusions&#46; The &#8220;ideal&#8221; correction would be &#8220;one capable of restoring&#44; in the pre-presbyopic stage&#44; the optical dioptric range within which focusing is accurate&#46; It should also be able to maintain this range for the remaining decades of the individual&#39;s life&#44; without any further intervention&#44; the eye being always emmetropic&#8221;&#46;<a class="elsevierStyleCrossRef" href="#bib0180"><span class="elsevierStyleSup">36</span></a> Furthermore&#44; it should be invisible to the external observer and changes in focus should occur synchrously with convergence and mild miosis&#46; This clearly points to the ciliary system as a key element in achieving this presbyopia correction&#46;<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">37</span></a></p><p id="par0140" class="elsevierStylePara elsevierViewall">Currently there are different strategies aimed at correcting presbyopia from different mechanisms of action&#46;<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">38</span></a> The pharmacological strategies include those that seek pseudoaccommodation&#44; increasing the depth of focus by producing miosis&#44; and those that seek to slow down the evolution towards rigidity of the nucleus and the crystalline capsule&#46;<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a> Pharmacological treatments are mostly in the research phase&#46;<a class="elsevierStyleCrossRef" href="#bib0195"><span class="elsevierStyleSup">39</span></a> Their main disadvantages are the need for daily application&#44; a limited action time of a few hours&#44; and those based on altering lens sclerosis present doubts about their long-term safety&#46;<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a></p><p id="par0145" class="elsevierStylePara elsevierViewall">Among the reviews analyzed&#44; we found some retrospective or prospective nonrandomized studies that were not taken into account for this review&#46; The randomized clinical trials mentioned in the review papers had been previously identified in the search engines&#46; At present&#44; we can say that there are basically 2 therapeutic strategies&#58; pseudoaccommodation and lens flexibilization&#46;</p><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Pseudoaccommodation</span><p id="par0150" class="elsevierStylePara elsevierViewall">Optical instillation of parasympathomimetic drugs induces pupillary miosis that produces a pinhole effect&#44; thereby increasing the depth of focus&#59; however&#44; this miosis also reduces the visual field&#46; Pupil diameter is inversely proportional to depth of focus and directly proportional to visual field width&#46; The minimum pupil size is considered to be 1&#46;5&#8239;mm&#44; below which the luminance reaching the retina is so low that it does not allow adequate contrast sensitivity and also produces many diffractive aberrations&#44;<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">37</span></a> therefore&#44; there is a limit to the ability of the pinhole effect to improve near vision&#46;</p><p id="par0155" class="elsevierStylePara elsevierViewall">There are numerous studies under investigation and others already marketed with this pseudo-acommodative strategy&#46; The main substances investigated for this purpose are&#58; pilocarpine&#44; aceclidine&#44; brimonidine&#44; phentolamine and carbachol&#46; Pilocarpine 1&#46;25&#37; &#40;Vuity&#174;&#44; Abvie&#44; Dublin&#44; Ireland&#41; has been marketed in the United States since 2021&#46; In the following section we will individually review the drugs of the study&#46;</p><p id="par0160" class="elsevierStylePara elsevierViewall">Aceclidine is a nonselective partial muscarinic agonist of muscarinic receptors&#46; In a 1990 study&#44; Erickson-Lamy and Schroeder conducted a study in monkeys to study its effects on ocular pressure&#44; finding an increase in the amplitude of accommodation of 5 Dp with aceclidine and of 19 Dp with pilocarpine&#46;<a class="elsevierStyleCrossRef" href="#bib0315"><span class="elsevierStyleSup">63</span></a> This finding served as proof of concept for developing the pinhole effect as a treatment for presbyopia&#46;</p><p id="par0165" class="elsevierStylePara elsevierViewall">Pilocarpine is a cholinergic muscarinic 5-receptor agonist&#46; In December 2021&#44; Allergan Inc&#46; &#40;Abvie&#41; announced that the Food and Drug Administration had approved Vuity&#174; &#40;pilocarpine hydrochloride 1&#46;25&#37; ophthalmic solution&#44; also called AGN-190584&#41;&#46; This approval is the result of the GEMINI-1 and GEMINI-2 studies&#46;<a class="elsevierStyleCrossRef" href="#bib0305"><span class="elsevierStyleSup">61</span></a> Pilocarpine 1&#46;25&#37; decreases pupil diameter by 50&#37; after application&#46;<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">37</span></a> These studies reported a significant improvement in near visual acuity &#40;26 vs&#46; 8&#37; improvement of 3 lines in near vision&#41; compared to placebo from the first hour to 6&#8239;h after its administration &#59; as the main adverse effect&#44; mild headache was reported in 2&#37; of cases&#44; although the follow-up of this study was very short&#44; only 30 days&#46;<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">38</span></a> Neither was its effect studied in monthly optic conditions nor on activities such as driving&#46;<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">38</span></a> The VIRGO study is a randomized phase 3 clinical trial of pilocarpine 1&#46;25&#37; versus placebo&#46; A total of 230 patients received 2 drops per day for 15 days&#44; and a statistically significant difference was found between the two groups&#46; A 30&#37; increase in the treatment group gained more than 3 lines in near vision with distance correction&#46;<a class="elsevierStyleCrossRef" href="#bib0195"><span class="elsevierStyleSup">39</span></a> Adverse effects were headache &#40;8&#46;8&#37;&#41;&#44; eye irritation &#40;6&#46;1&#37;&#41; and punctate keratitis &#40;3&#46;5&#37;&#41;&#46;</p><p id="par0170" class="elsevierStylePara elsevierViewall">However&#44; continued use of pilocarpine&#44; even at very low doses&#44; has been associated with risk of chronic uveitis&#44; posterior synechiae&#44; tonic pupil&#44; pigmentary dispersion<a class="elsevierStyleCrossRef" href="#bib0270"><span class="elsevierStyleSup">54</span></a> and retinal detachment&#44;<a class="elsevierStyleCrossRef" href="#bib0320"><span class="elsevierStyleSup">64</span></a> to the point that the use of optical corticosteroids in conjunction with pilocarpine has been recommended to avoid these risks&#46; Studies have also shown no clear improvement in spectacle independence with the use of pilocaripine&#44;<a class="elsevierStyleCrossRef" href="#bib0270"><span class="elsevierStyleSup">54</span></a> probably due to the short time of action of the drug after instillation&#46; Due to the mechanism of action it has been proposed that a sustained contraction of the ciliary muscle may lead to retinal detachment in predisposed eyes&#46; Although this last statement has not been reported in clinical trials&#44; it is an issue to be monitored in the case of continued use of these treatments&#46;<a class="elsevierStyleCrossRef" href="#bib0295"><span class="elsevierStyleSup">59</span></a></p><p id="par0175" class="elsevierStylePara elsevierViewall">Liquid Vision &#40;PRX-100&#41; is a formula combining aceclidine and tropicamide based on a miotic effect with minimal stimulation of accommodation&#44; allowing a pinhole effect with miosis but without inducing ciliary spasm or optic myopic displacement that could alter distant vision&#46; Aceclidine is a less potent muscarinic agonist than pilocarpine and carbachol&#46; Tropicamide has the opposite effect to aceclidine&#59; it has a much higher affinity for iris M3 receptors than other antimuscarinic agents and allows pupil dilation with minimal influence on accommodation&#46;<a class="elsevierStyleCrossRef" href="#bib0325"><span class="elsevierStyleSup">65</span></a> A first pilot study with 9 participants revealed that the pupil reached a diameter of approximately 1&#46;6&#8239;mm 30&#8239;min after instillation&#46;<a class="elsevierStyleCrossRef" href="#bib0265"><span class="elsevierStyleSup">53</span></a> The Phase 2 clinical trial versus placebo verified the efficacy of PRX-100 in the treatment of incipient to moderate presbyopia in 58 patients&#46;<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">42</span></a> The only adverse effects reported were headache &#40;5&#37;&#41; and eye irritation &#40;4&#37;&#41;&#44; similar to the rest of the miotics&#46; Three visits were made and the results were evaluated one hour after instillation on each visit&#46;</p><p id="par0180" class="elsevierStylePara elsevierViewall">In June 2021&#44; LENZ announced its intention to submit a new drug application to the Food and Drug Administration and commence Phase 3 trials for LNZ100 &#40;1&#46;75&#37; aceclidine&#41; and LNZ101 &#40;combination of 1&#46;75&#37; aceclidine and brimonidine&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">42</span></a> Results are not yet available&#46;</p><p id="par0185" class="elsevierStylePara elsevierViewall">Carbachol&#44; like brimonidine&#44; is a parasympathomimetic that activates muscarinic and nicotinic receptors&#46; The combination of carbachol 2&#46;25&#37; and brimonidine 0&#46;2&#37; is also based on the pinhole effect&#46; A randomized study in 48 presbyopic patients showed an improvement in near vision vs&#46; placebo&#46; The treatment group gained an average of 4 lines&#44; one hour after instillation&#44; without affecting far visual acuity&#46;<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">40</span></a> Side effects were burning &#40;3&#46;3&#37;&#41;&#44; headache &#40;10&#37;&#41; and mesopic visual difficulty &#40;3&#46;3&#37;&#41; during the first 2 weeks&#46;<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">40</span></a> This is one of the studies with the longest follow-up time&#59; at 3 months no serious adverse effects were observed&#46;</p><p id="par0190" class="elsevierStylePara elsevierViewall">In the VEGA-1 study&#44; 148 patients were randomized to receive a combination of phentolamine&#8239;&#43;&#8239;pilocarpine or placebo&#46; This was a multicenter&#44; double-blind&#44; phase 2b trial&#44; where a statistically significant difference was observed between the placebo and treatment groups&#44; with a higher percentage of patients improving 2 and 3 lines of near vision with its correction far vision&#46; In this study&#44; monocular and binocular gain was measured and a similar gain was observed &#40;Katz et al&#46;&#41;&#46; The only adverse effects reported were hyperemia and ocular irritation&#46; In contrast to other studies&#44; no increased incidence of headache was observed&#46;</p><p id="par0195" class="elsevierStylePara elsevierViewall">In another arm of the VEGA-1 study&#44; 4 arms were assembled comparing isolated phentolamine&#44; isolated pilocarpine&#44; phentolamine&#8239;&#43;&#8239;pilocarpine&#44; and placebo &#40;Pepose et al&#46;&#41;&#46; This was a randomized&#44; multicenter&#44; double-blind trial in which 150 patients were randomized&#46; The results showed that those who received the combination of phentolamine and pilocarpine had the greatest improvement in their near corrected visual acuity 6&#8239;h after instillation &#40;Pepose et al&#46;&#41;&#46; Adverse effects in this case did include headache for the combination of phentolamine and pilocarpine&#46; Another publication reports these same results from the VEGA-1 study at 18&#8239;h after instillation &#40;Brigell et al&#46;&#41;&#44; the follow-up period in all of them being no more than a few hours&#46;</p><p id="par0200" class="elsevierStylePara elsevierViewall">A phase 2 clinical trial of oxymetazoline &#40;AGN-199201&#41; plus pilocarpine was conducted&#46; Oxymetazoline is a sympathomimetic that would partially counteract the parasympathetic effect of pilocarpine&#46; The intention of this association would be to allow a mild miosis without adverse effects on ciliary muscle traction&#46; 151 patients between 40 and 55 years of age were selected&#44; 4 treatment arms were created&#58; placebo and 3 increasing concentrations of the combination of both drugs &#40;low&#44; medium and high according to the description of the trial&#41;&#46; The study describes that up to 70&#37; of patients had an improvement of 2 or more lines in uncorrected near visual acuity&#46; Follow-up was 112 days and adverse effects were headache &#40;12&#46;2&#37;&#41;&#44; punctate keratitis &#40;4&#46;8&#37;&#41; and foreign body sensation &#40;2&#46;4&#37;&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0330"><span class="elsevierStyleSup">66</span></a></p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Lens flexibilization</span><p id="par0205" class="elsevierStylePara elsevierViewall">Antioxidants applied topically are currently under research&#44; having been shown to improve multiple ocular conditions&#58; accommodation&#44; cataract delay&#44; glaucoma development&#44; age-related macular degeneration and dry eye&#46;<a class="elsevierStyleCrossRef" href="#bib0300"><span class="elsevierStyleSup">60</span></a> They constitute an interesting avenue of research in the subject under discussion&#46;</p><p id="par0210" class="elsevierStylePara elsevierViewall">Hesperetin is a natural flavonoid that can prevent lens sclerosis and cataract formation attributable to aqueous water flow and PGA generation&#46;<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">27</span></a> Experimental substances such as UNR844-Cl &#40;formerly known as EV06&#41; can replenish glutathione and decrease disulfide bonds in aged lens proteins&#46;</p><p id="par0215" class="elsevierStylePara elsevierViewall">Deglycating enzymes are a novel strategy to try to make the lens more flexible and thus facilitate its malleability&#46; <span class="elsevierStyleItalic">Ex vivo</span> treatment with fructosyl-&#945; -L-amino acid oxidoreductase &#40;deglycosylating&#41; of lenses extracted from presbyopic patients results in a significant improvement in lens power&#46; According to this <span class="elsevierStyleItalic">ex vivo</span> study&#44; it can be concluded that fructosyl-&#945; -L-amino acid oxidoreductase is able to break the cross-links between lens fibers and produce their deglycation&#44; which increases their elasticity and malleability&#46;<a class="elsevierStyleCrossRef" href="#bib0335"><span class="elsevierStyleSup">67</span></a></p><p id="par0220" class="elsevierStylePara elsevierViewall">Lipoic acid ester&#44; aggregalite 1 and 2&#44; EV06 and oxymetazoline are molecules that appear to cause a decrease in lens protein disulfides&#44; increasing lens elasticity&#46;<a class="elsevierStyleCrossRef" href="#bib0145"><span class="elsevierStyleSup">29</span></a> EV06 &#40;Novartis&#41; is a 1&#46;5&#37; lipoic acid prodrug that may &#8220;soften&#8221; the lens&#44; restoring the physiological response to the ciliary muscle&#46; A randomized clinical trial compared EV06 with placebo in 75 patients&#46;<a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">44</span></a> An improvement in visual acuity &#40;corrected for distance ition&#41; was found compared to healthy controls&#46; With a twice-daily application pattern&#44; the benefit was observed to be maintained for 5&#8211;7 months with a 90-day treatment&#46;<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">30</span></a> No serious adverse effects were reported&#59; the mild ones were nasopharyngitis &#40;16&#37;&#41;&#44; dysgeusia &#40;14&#37;&#41;&#44; headache &#40;8&#37;&#41; and eye irritation &#40;6&#37;&#41;&#46;</p><p id="par0225" class="elsevierStylePara elsevierViewall">In another clinical trial with UNR844 &#40;lipoic acid ester or EV06&#41;&#44; with 50 patients&#44; it was applied once daily for 90 days of treatment&#46; A statistically significant improvement in near vision compared to placebo was observed&#46; Fifty-one percent of the treatment group were able to improve more than 2 lines of vision compared to 21&#37; of the control group&#46; After 90 days of treatment&#44; a 7-month follow-up was performed&#46; The ocular adverse effects observed were mild&#44; such as sensation of conjunctival hyperemia and pruritus&#46; No worsening of distant vision and no systemic adverse effects were observed&#46; This improvement occurred in both early and advanced stages of presbyopia&#46;<a class="elsevierStyleCrossRef" href="#bib0225"><span class="elsevierStyleSup">45</span></a></p></span></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Discussion</span><p id="par0230" class="elsevierStylePara elsevierViewall">The review provides relevant information on the epidemiology and physiology of presbyopia&#44; as well as on therapeutic approaches based on pharmacological strategies&#46; Currently&#44; uncorrected presbyopia is the most common cause of treatable visual impairment worldwide and will remain so until 2050&#46;<a class="elsevierStyleCrossRef" href="#bib0340"><span class="elsevierStyleSup">68</span></a> This problem is a major burden on productivity and quality of life&#44; especially in developing countries&#44; making the ease and low cost of correction a good argument for investing resources to address it&#46; The new treatments already available from 2021 &#40;Vuity&#174;&#44; Abvie&#41; are one of the most novel aspects in ophthalmology in recent years&#46;<a class="elsevierStyleCrossRef" href="#bib0335"><span class="elsevierStyleSup">67</span></a></p><p id="par0235" class="elsevierStylePara elsevierViewall">Accommodation is a complex mechanism that is not fully elucidated and depends on the perfect coordination between different intraocular and extraocular structures&#46; The key elements in accommodation appear to be changes in shape and position of the lens and pupillary diameter&#46;</p><p id="par0240" class="elsevierStylePara elsevierViewall">To produce these lens changes&#44; synkinesis of multiple structures must occur&#58; sclera&#44; ciliary body&#44; zonule and iris sphincter&#46; These changes are initiated in the midbrain by a stimulus from the optic nerve and are carried by the third cranial nerve to the long ciliary nerves&#46;</p><p id="par0245" class="elsevierStylePara elsevierViewall">Current options include pharmacologic treatments&#44; surgical and laser procedures&#46; Surgical procedures based on phakic or pseudophakic intraocular lenses are an effective but invasive option with risks inherent to any intervention&#46; This leads many patients to opt for less interventional options&#46; As for the pharmacological approach&#44; the proposed mechanisms of action include the pinhole effect and lens &#8220;softening&#8221;&#46; Pupillary miotics increase the depth of focus creating a pinhole effect&#46; Pure parasympathetic treatments may result in a decrease in pupillary size and myopic shift&#44; compromising distance vision&#46; It should also be noted that muscarinic stimulation can cause several adverse reactions related to uveitis and intraocular inflammation with its chronic use&#46; Thus&#44; other agents in combined use with parasympathomimetics were proposed to counteract these actions&#44; including nonsteroidal anti-inflammatory drugs&#46; Because of this&#44; 2-drug combination formulations have been developed&#46;</p><p id="par0250" class="elsevierStylePara elsevierViewall">Most studies include follow-up periods that are too short&#44; some with only a single administration&#44; and the longest follow-up periods are a few weeks&#46;<a class="elsevierStyleCrossRef" href="#bib0345"><span class="elsevierStyleSup">69</span></a> Studies using the Benozzi method&#174; have not been included in this review because they were not randomized&#46; However&#44; a brief mention should be made due to its frequency of administration and follow-up time&#58; 2 times a day for 5 years&#46;<a class="elsevierStyleCrossRef" href="#bib0350"><span class="elsevierStyleSup">70</span></a> The Benozzi method&#174; &#40;US 8&#44;524&#44;758 B2-EP1&#44;938&#44;839 B1&#41; is a proprietary combination of pilocarpine and diclofenac&#46; In 2 prospective case series studies&#44; this author reported an improvement in near visual acuity without optical correction at 10 years of follow-up&#44; no impairment in far visual acuity&#44; and surface symptoms&#44; headache and decreased mesopic contrast sensitivity as adverse effects&#46;<a class="elsevierStyleCrossRefs" href="#bib0355"><span class="elsevierStyleSup">71&#44;72</span></a> According to these publications&#44; 70&#37; of treated subjects achieved a visual acuity of J2 &#40;Jaeger&#41; without optical correction&#46;</p><p id="par0255" class="elsevierStylePara elsevierViewall">In the clinical trials consulted&#44; no serious adverse effects have been detected&#59; however&#44; there are some documented cases of retinal detachment associated with treatment for a few weeks with 1&#46;25&#37; pilocarpine&#44;<a class="elsevierStyleCrossRefs" href="#bib0320"><span class="elsevierStyleSup">64&#44;73</span></a> whose mechanism of action would be compatible with anterior displacement of the ciliary body&#46; Although pilocarpine-based preparations have not been evaluated with continuous use for periods of time longer than 6 months&#44; there are legitimate doubts about their long-term safety&#46; The study with the largest sample size and follow-up time is the one published by Benozzi et al&#46; with their own proprietary pilocarpine and diclofenac eye drops&#46; In this study with 910 patients and a follow-up of 8 years&#44; no case of retinal detachment or any other serious adverse effect was reported&#46; Only transient dizziness&#44; headache and eye irritation were reported&#46;<a class="elsevierStyleCrossRef" href="#bib0360"><span class="elsevierStyleSup">72</span></a></p><p id="par0260" class="elsevierStylePara elsevierViewall">The second approach to presbyopia treatment is based on &#8220;softening&#8221; the crystalline lens&#46; EV06 is the only agent that has already been explored for this purpose&#44; having obtained favorable results from 3 randomized clinical trials&#46;</p><p id="par0265" class="elsevierStylePara elsevierViewall">The development of new therapeutic approaches depends on a thorough understanding of the phenomena of accommodation&#46; Today it is not fully understood and there are conflicting theories about how it works&#46; How it is triggered and how it is regulated in such a precise way also remains unclear&#46; Advancing anatomic and physiolological knowledge about accommodation could aid in the development of new drugs or devices&#46; For example&#44; findings of vitreous&#44; choroidal and scleral dynamics anteriorizing during accommodation allow us to take advantage of these structures to develop new treatments&#46;<a class="elsevierStyleCrossRef" href="#bib0370"><span class="elsevierStyleSup">74</span></a></p><p id="par0270" class="elsevierStylePara elsevierViewall">The limitations of the present review include publication bias if we consider that studies based on pseudoaccommodation or relaxation that have not demonstrated positive results are unlikely to have been published&#46; There are case series and retrospective cohort studies with other treatments&#44; but these have been discarded in order to focus on drugs that have already shown results in randomized clinical trials&#46; The authors have only been able to review articles in English&#44; Spanish or French&#44; so language in turn constitutes a bias in the review&#46;</p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Conclusions</span><p id="par0275" class="elsevierStylePara elsevierViewall">Pharmacological treatment of presbyopia may become a reality in clinical practice in the next few years&#46; Possible future lines of research could focus on a combination of synergic strategies &#40;pseudo-accommodation&#8239;&#43;&#8239;lens flexibilization&#41; that reduce adverse effects without diminshing efficacy&#46; Also intraocular administration could be an advantage in achieving independence from instillation of drops&#46;</p><p id="par0280" class="elsevierStylePara elsevierViewall">There is no doubt that the pharmacologic treatment of presbyopia is an interesting therapeutic approach&#46; More randomized&#44; quality studies with longer follow-up time are needed to evaluate its safety and efficacy&#44; especially with continued use&#46;</p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Financing</span><p id="par0285" class="elsevierStylePara elsevierViewall">None&#46;</p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Conflict of interest</span><p id="par0290" class="elsevierStylePara elsevierViewall">None&#46;</p></span></span>"
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          "titulo" => "Material and methods"
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        6 => array:3 [
          "identificador" => "sec0015"
          "titulo" => "Results"
          "secciones" => array:2 [
            0 => array:2 [
              "identificador" => "sec0020"
              "titulo" => "Pseudoaccommodation"
            ]
            1 => array:2 [
              "identificador" => "sec0025"
              "titulo" => "Lens flexibilization"
            ]
          ]
        ]
        7 => array:2 [
          "identificador" => "sec0030"
          "titulo" => "Discussion"
        ]
        8 => array:2 [
          "identificador" => "sec0035"
          "titulo" => "Conclusions"
        ]
        9 => array:2 [
          "identificador" => "sec0040"
          "titulo" => "Financing"
        ]
        10 => array:2 [
          "identificador" => "sec0045"
          "titulo" => "Conflict of interest"
        ]
        11 => array:1 [
          "titulo" => "References"
        ]
      ]
    ]
    "pdfFichero" => "main.pdf"
    "tienePdf" => true
    "fechaRecibido" => "2023-10-12"
    "fechaAceptado" => "2024-03-10"
    "PalabrasClave" => array:2 [
      "en" => array:1 [
        0 => array:4 [
          "clase" => "keyword"
          "titulo" => "Keywords"
          "identificador" => "xpalclavsec1856565"
          "palabras" => array:4 [
            0 => "Presbyopia"
            1 => "Accomodation"
            2 => "Ciliary muscle"
            3 => "Parasympathetic-mimetics"
          ]
        ]
      ]
      "es" => array:1 [
        0 => array:4 [
          "clase" => "keyword"
          "titulo" => "Palabras clave"
          "identificador" => "xpalclavsec1856566"
          "palabras" => array:4 [
            0 => "Presbicia"
            1 => "Acomodaci&#243;n"
            2 => "M&#250;sculo ciliar"
            3 => "Parasimpaticomim&#233;ticos"
          ]
        ]
      ]
    ]
    "tieneResumen" => true
    "resumen" => array:2 [
      "en" => array:2 [
        "titulo" => "Abstract"
        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Presbyopia affects between 1&#46;7 and 2 billion people worldwide&#46; Presbyopia significantly impacts productivity and quality of life in both developed and developing countries&#46; During accommodation&#44; the human eye changes its dioptric power by altering the shape of the lens&#44; but the exact nature of this change has not been fully explained&#46; Recently&#44; topical treatments have been marketed for the treatment of presbyopia and others are under investigation&#46;</p><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">In order to prepare a review of these novel therapies&#44; we searched the major biomedical search engines&#46; We found 15 randomized clinical trials and 12 reviews that met our review criteria&#46; There are two different strategies for this purpose&#44; the pinhole effect that increases depth of focus and &#8220;crystalline lens relaxation&#8221; for which parasympathetic mimetics and lens oxidation intermediates have been used&#46; The results are generally favorable in terms of improvement of near visual acuity&#44; although the follow-up period of the studies is short&#46; These are novel strategies in the early stages of research that could be useful in the treatment of presbyopia&#46;</p></span>"
      ]
      "es" => array:2 [
        "titulo" => "Resumen"
        "resumen" => "<span id="abst0010" class="elsevierStyleSection elsevierViewall"><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">La presbicia afecta entre 1700 y 2000 millones de personas en todo el mundo&#46; La presbicia impacta significativamente la productividad y la calidad de vida tanto en pa&#237;ses desarrollados como en v&#237;as de desarrollo&#46; Durante la acomodaci&#243;n&#44; el ojo humano cambia su potencia di&#243;ptrica alterando la forma del cristalino&#44; pero la naturaleza exacta de este cambio no ha sido completamente explicada&#46; Recientemente han sido comercializados tratamientos t&#243;picos para el tratamiento de la presbicia y existen otros en investigaci&#243;n&#46;</p><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Con el objetivo de elaborar una revisi&#243;n sobre estas terapias novedosas se realiz&#243; una b&#250;squeda en los principales buscadores biom&#233;dicos&#46; Se encontraron 15 ensayos cl&#237;nicos aleatorizados y 12 revisiones que cumpl&#237;an nuestros criterios de revisi&#243;n&#46; Existen dos estrategias diferentes con este fin&#44; el efecto estenopeico que aumenta la profundidad de foco y la &#171;flexibilizaci&#243;n cristaliniana&#187; para lo cual se han empleado parasimp&#225;tico mim&#233;ticos e intermediarios de la oxidaci&#243;n del cristalino&#46; Los resultados son en general favorables en cuanto a la mejor&#237;a de la agudeza visual cercana&#44; si bien el periodo de seguimiento de los estudios es corto&#46; Se trata de estrategias novedosas en fases iniciales de investigaci&#243;n que podr&#237;an tener su utilidad para el tratamiento de la presbicia&#46;</p></span>"
      ]
    ]
    "multimedia" => array:1 [
      0 => array:8 [
        "identificador" => "tbl0005"
        "etiqueta" => "Table 1"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "detalles" => array:1 [
          0 => array:3 [
            "identificador" => "at0005"
            "detalle" => "Table "
            "rol" => "short"
          ]
        ]
        "tabla" => array:2 [
          "leyenda" => "<p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">NVADC&#58; near visual acuity with distance correction&#59; FAOD&#58; fructosyl-&#945; -L-amino acid oxidoreductase&#46;</p>"
          "tablatextoimagen" => array:1 [
            0 => array:2 [
              "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" style="border-bottom: 2px solid black">Drug&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" style="border-bottom: 2px solid black">Mechanism of action&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" style="border-bottom: 2px solid black">Type of study&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" style="border-bottom: 2px solid black">Results&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" style="border-bottom: 2px solid black">Follow-up&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" style="border-bottom: 2px solid black">Adverse effects &#40;frequency&#41;&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-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Optimized formulation of pilocarpine chloride 0&#46;125&#37; &#40;AGN-190584&#41; &#40;AGN-190584&#41;<a class="elsevierStyleCrossRefs" href="#bib0185"><span class="elsevierStyleSup">37&#44;38</span></a>&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Pseudoaccommodation pseudoaccommodation&#47; pinhole effect&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Phase 3 clinical trial &#40;GEMINI&#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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Improvement of NVADC without affecting distant vision&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">30 days&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Headache &#40;14&#37;&#41;&#44; eye irritation &#40;4&#37;&#41;&#44; eye irritation &#40;4&#37;&#41;&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Pilocarpine 1&#46;25&#37;&#46;<a class="elsevierStyleCrossRef" href="#bib0195"><span class="elsevierStyleSup">39</span></a>&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Pseudoaccommodation pseudoaccommodation&#47; pinhole effect&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Phase 3 &#40;VIRGO&#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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">NVADC Improvement&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">14 days&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Headache &#40;8&#46;8&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Pilocarpine&#8239;&#43;&#8239;diclofenac<a class="elsevierStyleCrossRef" href="#bib0205"><span class="elsevierStyleSup">41</span></a>&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Pseudoaccommodation pseudoaccommodation&#47; pinhole effect&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Clinical trial&#58; pilocarpine vs&#46; diclofenac vs&#46; pilocarpine vs&#46; diclofenac &#40;control group&#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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">3-line improvement in NVADC in 46&#37; pilocarpine&#44; 46&#37; pilocarpine&#8239;&#43;&#8239;diclofenac vs&#46; 16&#37; control&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Single dose&#44; 1&#8239;h post-treatment&#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  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Headache &#40;9&#37;&#41;&#44; conjunctival hyperemia &#40;5&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Liquid Vision &#40;PRX-100&#58; aceclidine&#8239;&#43;&#8239;tropicamide&#41;<a class="elsevierStyleCrossRefs" href="#bib0210"><span class="elsevierStyleSup">42&#44;53&#44;65</span></a>&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Pseudoaccommodation pseudoaccommodation&#47; pinhole effect&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">PRX-100 vs&#46; aceclidine vs&#46; placebo clinical trial&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Near visual acuity J1&#44; 3 lines with respect to placebo&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Single dose&#44; 1&#8239;h post-treatment&#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  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Hyperemia &#40;5&#37;&#41; and headache &#40;5&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Carbachol 2&#46;25&#37; &#43; brimonidine 0&#46;2&#37;&#46;<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">40</span></a>&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Pseudoaccommodation pseudoaccommodation&#47; pinhole effect&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Clinical trial vs&#46; placebo&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">NVADC improvement over placebo&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">3 months&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Eye irritation and headache &#40;6&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Phentolamine 0&#46;75&#37;&#46;<a class="elsevierStyleCrossRefs" href="#bib0230"><span class="elsevierStyleSup">46&#44;47</span></a>&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Pinhole effect &#40;1&#46;5&#8239;mm&#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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Placebo clinical trial &#40;VEGA-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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">NVADC improvement over placebo&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">12 h&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">No difference with respect to placebo&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Phentolamine with pilocarpine<a class="elsevierStyleCrossRefs" href="#bib0240"><span class="elsevierStyleSup">48&#8211;50</span></a>&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Pseudoaccommodation pseudoaccommodation&#47; pinhole effect&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Clinical trial vs&#46; placebo&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">NVADC improvement with respect to placebo without affecting distant vision&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">6&#8239;h&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Eye irritation and hyperemia &#40;4&#37;&#8211;6&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Oxymetazoline &#40;various concentrations&#41; &#43; pilocarpine 1&#46;25&#37;&#46;<a class="elsevierStyleCrossRef" href="#bib0330"><span class="elsevierStyleSup">66</span></a>&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="left" valign="\n
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                  \t\t\t\t">Pseudoaccommodation pseudoaccommodation&#47; pinhole effect&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">Pseudoaccommodation and crystalline flexibilization&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
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                  \t\t\t\t">Gain of about 5 letters not dose-dependent&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
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                  \t\t\t\t">112 days&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
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                  \t\t\t\t">Headache &#40;12&#46;2&#37;&#41;&#44; punctate keratitis &#40;4&#46;8&#37;&#41; and foreign body sensation &#40;2&#46;4&#37;&#41;&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
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                  \t\t\t\t">UNR844 &#40;lipoic acid derivative&#41;<a class="elsevierStyleCrossRefs" href="#bib0215"><span class="elsevierStyleSup">43&#8211;45</span></a>&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="left" valign="\n
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                  \t\t\t\t">Lens flexibilization&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
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                  \t\t\t\t">Clinical trial vs&#46; placebo&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">25&#37; of those treated achieve good NVADC&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">3 months&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="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Dysgeusia&#44; headache&#44; blepharitis &#40;3&#37;&#8211;5&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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Article information

ISSN: 21735794
Original language: English

DOI:10.1016/j.oftale.2024.04.008

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