Novelties in Dermatology
Usefulness of Photodynamic Therapy in the Management of Onychomycosis
Utilidad de la terapia fotodinámica en el manejo de la onicomicosis
a Sección de Microbiología, Hospital Royo Villanova, Zaragoza, Spain
b Instituto Aragonés de Ciencias de la Salud, Zaragoza, Spain
c Servicio de Microbiología, Hospital Universitario Miguel Servet, Zaragoza, Spain
d Universidad de Zaragoza, IIS Aragón, Zaragoza, Spain
e Servicio de Dermatología, Hospital San Jorge, Huesca, Spain
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La absorción de luz por un fotosensibilizador (FS) en su estado basal no excitado promueve un electrón a un orbital de mayor energía (FS basal excitado). A continuación, este puede volver a su estado basal por emisión de calor y/o fluorescencia o puede cambiar la orientación de su momento angular de espín (FS triplete excitado). El largo tiempo de vida del estado electrónico triplete favorece la formación de oxígeno singlete y/o radicales libres que dañan estructuras claves de la célula y finalmente causan su muerte. Finalizado el proceso el FS regresa a su estado fundamental, listo para realizar un nuevo ciclo fototerapéutico.</p>" ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "P. Robres, C. Aspiroz, A. Rezusta, Y. Gilaberte" "autores" => array:4 [ 0 => array:2 [ "nombre" => "P." "apellidos" => "Robres" ] 1 => array:2 [ "nombre" => "C." "apellidos" => "Aspiroz" ] 2 => array:2 [ "nombre" => "A." "apellidos" => "Rezusta" ] 3 => array:2 [ "nombre" => "Y." 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A, External ear tumor. B, Lower lip tumor.</p>" ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "T. Díaz-Corpas, M. Morales-Suárez-Varela, N. Rausell Fontestad, A. Fuertes Prósper, A. Marquina-Vila, E. Jordá-Cuevas" "autores" => array:6 [ 0 => array:2 [ "nombre" => "T." "apellidos" => "Díaz-Corpas" ] 1 => array:2 [ "nombre" => "M." "apellidos" => "Morales-Suárez-Varela" ] 2 => array:2 [ "nombre" => "N." "apellidos" => "Rausell Fontestad" ] 3 => array:2 [ "nombre" => "A." "apellidos" => "Fuertes Prósper" ] 4 => array:2 [ "nombre" => "A." "apellidos" => "Marquina-Vila" ] 5 => array:2 [ "nombre" => "E." 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Biopsy showing calcification of the medial layer of the vessels of the subcutaneous cell tissue (hematoxylin and eosin ×<span class="elsevierStyleHsp" style=""></span>200) (courtesy of Dr. Natalia Navas García).</p>" ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "D. Jiménez-Gallo, L. Ossorio-García, M. Linares-Barrios" "autores" => array:3 [ 0 => array:2 [ "nombre" => "D." "apellidos" => "Jiménez-Gallo" ] 1 => array:2 [ "nombre" => "L." "apellidos" => "Ossorio-García" ] 2 => array:2 [ "nombre" => "M." 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Robres, C. Aspiroz, A. Rezusta, Y. Gilaberte" "autores" => array:4 [ 0 => array:4 [ "nombre" => "P." "apellidos" => "Robres" "email" => array:1 [ 0 => "pilarrobres7@gmail.com" ] "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">*</span>" "identificador" => "cor0005" ] ] ] 1 => array:3 [ "nombre" => "C." "apellidos" => "Aspiroz" "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">b</span>" "identificador" => "aff0010" ] ] ] 2 => array:3 [ "nombre" => "A." "apellidos" => "Rezusta" "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">c</span>" "identificador" => "aff0015" ] 1 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">d</span>" "identificador" => "aff0020" ] ] ] 3 => array:3 [ "nombre" => "Y." "apellidos" => "Gilaberte" "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">b</span>" "identificador" => "aff0010" ] 1 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">e</span>" "identificador" => "aff0025" ] ] ] ] "afiliaciones" => array:5 [ 0 => array:3 [ "entidad" => "Sección de Microbiología, Hospital Royo Villanova, Zaragoza, Spain" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Instituto Aragonés de Ciencias de la Salud, Zaragoza, Spain" "etiqueta" => "b" "identificador" => "aff0010" ] 2 => array:3 [ "entidad" => "Servicio de Microbiología, Hospital Universitario Miguel Servet, Zaragoza, Spain" "etiqueta" => "c" "identificador" => "aff0015" ] 3 => array:3 [ "entidad" => "Universidad de Zaragoza, IIS Aragón, Zaragoza, Spain" "etiqueta" => "d" "identificador" => "aff0020" ] 4 => array:3 [ "entidad" => "Servicio de Dermatología, Hospital San Jorge, Huesca, Spain" "etiqueta" => "e" "identificador" => "aff0025" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Utilidad de la terapia fotodinámica en el manejo de la onicomicosis" ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0015" "etiqueta" => "Figure 3" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr3.jpeg" "Alto" => 672 "Ancho" => 1800 "Tamanyo" => 262704 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">White superficial onychomycosis caused by <span class="elsevierStyleItalic">Fusarium oxysporum</span>. Before (A) and 48 weeks (B) after completion of 3 treatment sessions at 1-week intervals of methyl aminolevulinate photodynamic therapy with 16% Aktilite (Photocure ASA, 37<span class="elsevierStyleHsp" style=""></span>J/cm<span class="elsevierStyleSup">2</span>). Prior to each PDT sessions the affected area was pretreated with 40% urea under occlusion for 3 nights and active mechanical removal of the nail plate just before the application of the photosensitizing agent.</p>" ] ] ] "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Onychomycosis is a fungal infection of the toenails or fingernails. It represents up to 50% of all onychopathies, and approximately 30% of all dermatomycosis.<a class="elsevierStyleCrossRef" href="#bib0235"><span class="elsevierStyleSup">1</span></a> The reported prevalence ranges from 2% to 40%, depending on the population studied and the diagnostic tools used. Onychomycosis is a common disease in adults<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">2</span></a> and is associated with different predisposing factors associated with occupation, social class, age, and climate, as well as a number of underlying diseases, including diabetes, peripheral vascular disease, immune deficiency, and psoriasis.<a class="elsevierStyleCrossRefs" href="#bib0240"><span class="elsevierStyleSup">2,3</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">Dermatophytes are the most common cause of onychomycosis, particularly <span class="elsevierStyleItalic">Trichophyton rubrum</span>, the most common etiologic agent.<a class="elsevierStyleCrossRefs" href="#bib0250"><span class="elsevierStyleSup">4–8</span></a> Non-dermatophyte filamentous fungi (<span class="elsevierStyleItalic">Fusarium</span>, <span class="elsevierStyleItalic">Aspergillus</span>, <span class="elsevierStyleItalic">Scopulariopsis</span>, and <span class="elsevierStyleItalic">Acremonium</span> species, etc.) cause between 2% and 13% of cases<a class="elsevierStyleCrossRefs" href="#bib0275"><span class="elsevierStyleSup">9–12</span></a> while yeasts are responsible for about 21% of onychomycosis, usually those affecting the fingernails.<a class="elsevierStyleCrossRefs" href="#bib0270"><span class="elsevierStyleSup">8,12</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">In terms of treatment, both lack of response (40%-70%)<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">2</span></a> and relapse or recurrence (20%-25%) are frequent in spite of the progress achieved with new antifungal agents.<a class="elsevierStyleCrossRef" href="#bib0295"><span class="elsevierStyleSup">13</span></a> Several factors lead to poor treatment outcomes: the difficulty of achieving penetration of the nail plate, lack of adherence to treatment (which lasts for months), the poor response of some fungi to antifungals, and individual susceptibility.<a class="elsevierStyleCrossRef" href="#bib0300"><span class="elsevierStyleSup">14</span></a> There is, therefore, a need to expand treatment options and reduce the adverse effects associated with treatment. Therapies based on devices<a class="elsevierStyleCrossRef" href="#bib0305"><span class="elsevierStyleSup">15</span></a> such as laser,<a class="elsevierStyleCrossRefs" href="#bib0310"><span class="elsevierStyleSup">16,17</span></a> iontophoresis,<a class="elsevierStyleCrossRef" href="#bib0320"><span class="elsevierStyleSup">18</span></a> and photodynamic therapy (PDT),<a class="elsevierStyleCrossRefs" href="#bib0325"><span class="elsevierStyleSup">19,20</span></a> can help overcome the limitations described above.</p><p id="par0020" class="elsevierStylePara elsevierViewall">PDT involves the use of photosensitizing agents that selectively localize in certain cells and produce cell death when activated with light of the appropriate wavelength in the presence of oxygen (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>).<a class="elsevierStyleCrossRef" href="#bib0335"><span class="elsevierStyleSup">21</span></a></p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0025" class="elsevierStylePara elsevierViewall">The use of PDT in the treatment of infections has given rise to antimicrobial PDT, an emerging field of research in the treatment of localized infections.<a class="elsevierStyleCrossRef" href="#bib0325"><span class="elsevierStyleSup">19</span></a> Several articles on in vitro and in vivo studies support the usefulness of PDT in the treatment of infections caused by viruses, bacteria, fungi, and parasites.<a class="elsevierStyleCrossRef" href="#bib0325"><span class="elsevierStyleSup">19</span></a> In such cases, PDT offers a number of advantages over traditional antimicrobial therapies. These include the following: 1) a broad spectrum of action; 2) effectiveness independent of patterns of antimicrobial resistance; 3) photoinactivation of the microorganisms—a multitarget process that makes the selection of photoresistant strains highly unlikely; 4) availability of formulations that allow specific delivery of the photosensitizer to the infected area and spare adjacent healthy tissue; 5) use of low cost light sources to activate a photosensitizing agent; and 6) compatibility with other antibiotic and antifungal drugs in combination therapies.</p><p id="par0030" class="elsevierStylePara elsevierViewall">The clinical indication of PDT as an antimicrobial has not, however, been approved to date and its application in this setting is anecdotal. In the specific case of fungal infections, mixed results have been reported in a series of cases of ringworm affecting hairless skin<a class="elsevierStyleCrossRef" href="#bib0340"><span class="elsevierStyleSup">22</span></a> and of candidiasis.<a class="elsevierStyleCrossRef" href="#bib0345"><span class="elsevierStyleSup">23</span></a> Since onychomycosis is a localized infection and because existing treatments are of limited effectiveness, it may be a cutaneous mycosis in which antimicrobial PDT could have a broader application.</p><p id="par0035" class="elsevierStylePara elsevierViewall">Our aim, in this review, is to provide answers to a series of questions about the basic in vitro and clinical in vivo evidence on the use of PDT in onychomycosis.</p><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Is PDT effective <span class="elsevierStyleItalic">in vitro</span> against the filamentous fungi that cause onychomycosis?</span><p id="par0040" class="elsevierStylePara elsevierViewall">The antifungal effectiveness of PDT has been assessed, in vitro, in different types of fungi using several different photosensitizers at different concentrations and light sources at various wavelengths. <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a> summarizes the most important studies.</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0045" class="elsevierStylePara elsevierViewall">In 1978, Propst and Lubin demonstrated that dermatophyte fungi might be photosensitive in vitro to heterocyclic dyes when they observed that proflavine and blue light (455<span class="elsevierStyleHsp" style=""></span>nm) were effective in killing both <span class="elsevierStyleItalic">Trichophyton mentagrophytes</span> and <span class="elsevierStyleItalic">Microsporum gypseum</span>.<a class="elsevierStyleCrossRef" href="#bib0350"><span class="elsevierStyleSup">24</span></a></p><p id="par0050" class="elsevierStylePara elsevierViewall">In 2 in vitro studies, Smijs et al.<a class="elsevierStyleCrossRefs" href="#bib0355"><span class="elsevierStyleSup">25,26</span></a> demonstrated the fungicidal effect of PDT on <span class="elsevierStyleItalic">T. rubrum</span> using porphyrin photosensitizers (Sylsens B and deuteroporfirín monomethylester) activated by broadband red or white light. They observed an effect that persisted several weeks after PDT. Moreover, it was seen at the different stages of fungal growth, although with interesting differences in sensitivity to the PDT: spores in suspension were more susceptible than fungal colonies in liquid culture.<a class="elsevierStyleCrossRef" href="#bib0360"><span class="elsevierStyleSup">26</span></a> The fact that PDT destroys the hyphae and inactivates the fungal spores is important in establishing its potential use as a treatment for superficial mycoses. In a clinical situation spores are responsible for the initiation of the infection and often persist and survive in the skin after treatment, favoring reinfection.</p><p id="par0055" class="elsevierStylePara elsevierViewall">The adhesion of dermatophytic fungi to keratinized tissue is essential in the pathogenesis of dermatophytosis. To investigate the outcomes of PDT in a situation similar to a clinical setting, Smijs et al. cultured <span class="elsevierStyleItalic">T. rubrum</span> in an ex vivo model using human stratum corneum.<a class="elsevierStyleCrossRef" href="#bib0365"><span class="elsevierStyleSup">27</span></a> Using this model they investigated the susceptibility of the fungus to PDT at different growth phases, demonstrating the importance in fungal virulence of adherence to a keratinized structure. They observed that, compared with the results of in vitro studies, the susceptibility of mature mycelia to PDT decreased while that of conidia did not. PDT using Sylsens B 160<span class="elsevierStyleHsp" style=""></span>μM and red light (108<span class="elsevierStyleHsp" style=""></span>J/cm<span class="elsevierStyleSup">2</span>) had a fungicidal effect in only 65% of cases, but this figure increased to 90% when a keratinase enzyme inhibitor was added to the incubation mixture. The same authors found that, when photodynamic inhibition was unsuccessful, the photosensitizer had not penetrated the fungal cell wall.</p><p id="par0060" class="elsevierStylePara elsevierViewall">Kamp et al.<a class="elsevierStyleCrossRef" href="#bib0370"><span class="elsevierStyleSup">28</span></a> observed a reduction of almost 50% in the growth of <span class="elsevierStyleItalic">T. rubrum</span> in vitro using 5-aminolevulinic acid (ALA) as a photosensitizer. The fungistatic effect could be due to the fact that ALA is a hydrophilic molecule. Consequently, its absorption and metabolism by <span class="elsevierStyleItalic">T. rubrum</span> was extremely slow: the first formation of protoporphyrin IX (PpIX) was observed only after 10 to 14 days of incubation. Increasing the lipophilicity of ALA by esterification is likely to improve its diffusion, uptake, and conversion by <span class="elsevierStyleItalic">T. rubrum</span>.<a class="elsevierStyleCrossRef" href="#bib0370"><span class="elsevierStyleSup">28</span></a></p><p id="par0065" class="elsevierStylePara elsevierViewall">Other authors have demonstrated the antifungal action of PDT in vitro using different photosensitizing agents, such as phenothiazines (Amorim et al.),<a class="elsevierStyleCrossRef" href="#bib0375"><span class="elsevierStyleSup">29</span></a> hypericin (Peace-Cristobal et al.),<a class="elsevierStyleCrossRef" href="#bib0380"><span class="elsevierStyleSup">30</span></a> and Rose Bengal (Morton et al.).<a class="elsevierStyleCrossRef" href="#bib0385"><span class="elsevierStyleSup">31</span></a></p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">What Clinical Evidence Supports the Use of Photodynamic Therapy in Onychomycosis?</span><p id="par0070" class="elsevierStylePara elsevierViewall">There is little clinical experience with the use of PDT in the treatment of onychomycosis and no standardized protocol exists. <a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a> lists the cases reported and clinical trials published to date. Most of these studies include patients in whom previous antifungal treatments had failed and patients who had underlying diseases that contraindicated oral treatment. All used a light source that emitted a wavelength in the red spectrum, which is not absorbed by hemoglobin and can penetrate more deeply into living tissue, a property that is particularly important in the treatment of nail infections. The lamp most often used in these studies was light emitting diode (LED) with a wavelength of 630<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>10<span class="elsevierStyleHsp" style=""></span>nm (Aktilite).<a class="elsevierStyleCrossRefs" href="#bib0340"><span class="elsevierStyleSup">22,32–35</span></a> LEDs are compact, require less energy to emit light at the desired wavelengths, do not cause thermal damage to biological tissues, and are made to produce multiple wavelengths.<a class="elsevierStyleCrossRef" href="#bib0360"><span class="elsevierStyleSup">26</span></a></p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia><p id="par0075" class="elsevierStylePara elsevierViewall">Although its effect in vitro is fungistatic, the photosensitizing agent most used in the literature was 20% ALA<a class="elsevierStyleCrossRefs" href="#bib0340"><span class="elsevierStyleSup">22,32</span></a> or its derivative 16% methyl-aminolevulinate (MAL).<a class="elsevierStyleCrossRefs" href="#bib0395"><span class="elsevierStyleSup">33–36</span></a> Both have been shown to be effective when applied topically, and have completely disappeared from the treated tissue within 24 to 48<span class="elsevierStyleHsp" style=""></span>hours of application.<a class="elsevierStyleCrossRef" href="#bib0345"><span class="elsevierStyleSup">23</span></a> Other photosensitizers used were 2% methylene blue<a class="elsevierStyleCrossRefs" href="#bib0415"><span class="elsevierStyleSup">37,38</span></a> and a hematoporphyrin derivative (Photogem).<a class="elsevierStyleCrossRef" href="#bib0425"><span class="elsevierStyleSup">39</span></a></p><p id="par0080" class="elsevierStylePara elsevierViewall">Most authors report a clinical and microbiological cure rate of 90% to 100% following treatment; however, this percentage decreases on follow-up. The efficacy of PDT appears to depend on the pretreatment of the nail with urea and/or mechanical abrasion to increase its permeability to the photosensitizing agent<a class="elsevierStyleCrossRefs" href="#bib0340"><span class="elsevierStyleSup">22,32</span></a> and active removal of hyperkeratosis.<a class="elsevierStyleCrossRefs" href="#bib0340"><span class="elsevierStyleSup">22,36</span></a></p><p id="par0085" class="elsevierStylePara elsevierViewall">The first reported cases of onychomycosis treated with PDT were in 2008, when Watanabe et al.<a class="elsevierStyleCrossRef" href="#bib0390"><span class="elsevierStyleSup">32</span></a> treated 2 patients with distal and lateral subungual dermatophyte onychomycosis affecting the first toenail. In both of these patients, other antifungal treatments had been applied with no success. In both cases, the affected nails were pretreated with a 20% urea ointment for 10<span class="elsevierStyleHsp" style=""></span>hours to facilitate penetration of the photosensitizing agent ALA (incubated for 5<span class="elsevierStyleHsp" style=""></span>h). The diseased nails were then irradiated with pulsed laser light at a wavelength of 630<span class="elsevierStyleHsp" style=""></span>nm at 100<span class="elsevierStyleHsp" style=""></span>J/cm<span class="elsevierStyleSup">2</span>. Treatment was repeated once a week until clinical improvement was observed and no dermatophytes were detected by potassium hydroxide microscopy or by culture. The patients experienced mild pain during PDT, but this disappeared within a day. No recurrence (clinical or microbiological) was observed after 3 months in 1 of the 2 patients or on follow-up at 6 months in the other.</p><p id="par0090" class="elsevierStylePara elsevierViewall">Subsequently, Piraccini et al.<a class="elsevierStyleCrossRef" href="#bib0410"><span class="elsevierStyleSup">36</span></a> reported the case of a patient with onychomycosis caused by <span class="elsevierStyleItalic">T. rubrum</span> affecting the first toenails of both feet; topical antifungal treatment had proved unsuccessful and oral therapy was contraindicated. On the days preceding treatment, 40% urea was applied and nail hyperkeratosis was removed. On the day of PDT treatment, 16% MAL was applied and incubated under an occlusive dressing for 3<span class="elsevierStyleHsp" style=""></span>hours. The affected area was then irradiated with red light (Aktilite) (630<span class="elsevierStyleHsp" style=""></span>nm, 37<span class="elsevierStyleHsp" style=""></span>J/cm<span class="elsevierStyleSup">2</span>). Three PDT sessions separated by an interval of 15 days achieved clinical and mycological cure. No recurrence of the infection was observed on follow-up at 24 months.</p><p id="par0095" class="elsevierStylePara elsevierViewall">Aspiroz et al.<a class="elsevierStyleCrossRefs" href="#bib0395"><span class="elsevierStyleSup">33,34</span></a> and Gilaberte and colleagues,<a class="elsevierStyleCrossRef" href="#bib0405"><span class="elsevierStyleSup">35</span></a> using a protocol based on that of Piraccini et al,<a class="elsevierStyleCrossRef" href="#bib0410"><span class="elsevierStyleSup">36</span></a> treated several cases of onychomycosis caused by nondermatophyte molds (<span class="elsevierStyleItalic">Acremonium sclerotigenum</span>, <span class="elsevierStyleItalic">Fusarium oxysporum</span>, <span class="elsevierStyleItalic">Aspergillus terreus</span>) and yeasts (mixed infection with <span class="elsevierStyleItalic">Candida albicans</span> and <span class="elsevierStyleItalic">Malassezia furfur</span>). All these cases of fingernail infections treated successfully with PDT, provide further evidence to support the use of PDT in this type of onychomycosis when the response to oral and topical antifungal therapies is inadequate.<a class="elsevierStyleCrossRef" href="#bib0430"><span class="elsevierStyleSup">40</span></a></p><p id="par0100" class="elsevierStylePara elsevierViewall">Silva et al.<a class="elsevierStyleCrossRef" href="#bib0425"><span class="elsevierStyleSup">39</span></a> described the effective use of PDT with a hematoporphyrin derivative (Photogem) in the treatment of longstanding onychomycosis. The results of a culture performed after completion of treatment was negative, but there was no subsequent follow-up.</p><p id="par0105" class="elsevierStylePara elsevierViewall">To date, only 3 published clinical trials have been carried out. Sotiriou et al.<a class="elsevierStyleCrossRef" href="#bib0340"><span class="elsevierStyleSup">22</span></a> used 20% ALA and red light (40<span class="elsevierStyleHsp" style=""></span>J/cm<span class="elsevierStyleSup">2</span>, Waldmann PDT 1200) to treat 30 patients with distal and lateral subungual onychomycosis caused by <span class="elsevierStyleItalic">T. rubrum</span> in whom topical antifungal therapy had proved unsuccessful and there were confirmed contraindications to oral antifungal agents. In that study, 22 (73.3%) of the patients had involvement of the first toenail. The number of treatment sessions and the intervals between them were similar to those used by Piraccini et al., with the difference that treatment was preceded by 10 nights with 20% urea under occlusive dressing. On follow-up at 12 months, clinical and microbiological cure was observed in 13 patients (43.3%), no clinical signs were apparent in 5 (16.6%), and in the other 8 (26.6%) patients there were residual changes affecting less than 10% of the nail plate and the results of culture were negative. On follow-up at 18 months, 11 patients (36.6%) were still disease free; the recurrence in 2 cases may have been due to poor penetration of ALA or because only 1 nail was treated when several were infected.</p><p id="par0110" class="elsevierStylePara elsevierViewall">Figueiredo Souza and colleagues<a class="elsevierStyleCrossRefs" href="#bib0415"><span class="elsevierStyleSup">37,38</span></a> carried out 2 studies using methylene blue as the photosenstizing agent. One of them—the largest trial published to date—enrolled 80 patients with onychomycosis of different etiologies, including <span class="elsevierStyleItalic">T. rubrum</span>, <span class="elsevierStyleItalic">T. mentagrophytes</span>, <span class="elsevierStyleItalic">E. floccosum</span>, <span class="elsevierStyleItalic">Aspergillus</span> spp., <span class="elsevierStyleItalic">Candida</span> spp. and <span class="elsevierStyleItalic">Fusarium</span> spp.<a class="elsevierStyleCrossRef" href="#bib0415"><span class="elsevierStyleSup">37</span></a> In this 24-week blind study, patients were randomized to receive either PDT with 2% methylene blue at 15-day intervals or oral fluconazole. In both groups, patients with hyperkeratosis greater than 2<span class="elsevierStyleHsp" style=""></span>mm, longitudinal onychomycosis, or dermatophytomas were treated with mechanical abrasion of the nail to facilitate penetration of the photosensitizing agent. On completion of treatment, the cure rate was 90% in the group treated with PDT and methylene blue versus 45% in the group receiving oral fluconazole (<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span><<span class="elsevierStyleHsp" style=""></span>.002). After 12 months of follow-up, the cure rate in the PDT group was 80%, irrespective of whether or not the patients had received prior abrasion. The results of that study show that PDT can be an effective treatment for onychomycosis, regardless of the causative pathogen involved. However, the use of oral fluconazole as a comparator may have introduced a bias because this drug is less effective than terbinafine or itraconazole.<a class="elsevierStyleCrossRefs" href="#bib0435"><span class="elsevierStyleSup">41,42</span></a> The clinical cure rate of 90% is the highest obtained with PDT and is probably due to the use of mechanical abrasion in hyperkeratotic lesions and those with longitudinal spikes or dermatophytoma, features often associated with treatment failure.<a class="elsevierStyleCrossRef" href="#bib0445"><span class="elsevierStyleSup">43</span></a></p></span></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Conclusions</span><p id="par0115" class="elsevierStylePara elsevierViewall">PDT is an easily reproducible, well tolerated, local treatment that does not interact with other drugs and can be combined with any antifungal agent. It is a treatment option for longstanding onychomycosis that has not responded to the usual antifungal therapies and in patients who have an underlying disease, are receiving multiple medications, or do not wish to undertake a prolonged course of treatment.</p><p id="par0120" class="elsevierStylePara elsevierViewall">The variable results obtained in different clinical trials of PDT in onychomycosis may be explained by differences in the causal agent or by factors related to the technical protocol, such as the photosensitizing agent used, the number of sessions administered, pretreatment of the nails, the number of nails affected, and the severity of onychomycosis.</p><p id="par0125" class="elsevierStylePara elsevierViewall">Based on the above data and our own experience over 5 years (<a class="elsevierStyleCrossRefs" href="#fig0010">Figs. 2 and 3</a>), we believe that PDT can be a good treatment option for patients with onychomycosis of any etiology limited to a few nails when systemic treatment is contraindicated or low adherence to other treatments would be likely. When a subclinical infection is detected or clinical signs of ringworm on the hand or foot are observed, PDT should be complemented by the appropriate treatment.</p><elsevierMultimedia ident="fig0010"></elsevierMultimedia><elsevierMultimedia ident="fig0015"></elsevierMultimedia><p id="par0130" class="elsevierStylePara elsevierViewall"><a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a> provides details of the PDT protocol for onychomycosis used by our group, which has not been associated with significant adverse effects. An important aspect of this protocol is the pretreatment of the treatment area with 40% urea and mechanical removal of nail residue and hyperkeratotic areas, a procedure that appears to favor the penetration of the photosensitizer, thereby improving the clinical response to PDT. Further clinical trials are needed, not only to establish the real effectiveness of this treatment, but also to optimize the procedure and above all to determine which subgroups of patients may benefit from PDT.</p><elsevierMultimedia ident="tbl0015"></elsevierMultimedia></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Conflict of interests</span><p id="par0135" class="elsevierStylePara elsevierViewall">The authors declare no conflict of interest.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:9 [ 0 => array:3 [ "identificador" => "xres586241" "titulo" => "Abstract" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0005" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec602106" "titulo" => "Keywords" ] 2 => array:3 [ "identificador" => "xres586240" "titulo" => "Resumen" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0010" ] ] ] 3 => array:2 [ "identificador" => "xpalclavsec602105" "titulo" => "Palabras clave" ] 4 => array:3 [ "identificador" => "sec0005" "titulo" => "Introduction" "secciones" => array:2 [ 0 => array:2 [ "identificador" => "sec0010" "titulo" => "Is PDT effective in vitro against the filamentous fungi that cause onychomycosis?" ] 1 => array:2 [ "identificador" => "sec0015" "titulo" => "What Clinical Evidence Supports the Use of Photodynamic Therapy in Onychomycosis?" ] ] ] 5 => array:2 [ "identificador" => "sec0020" "titulo" => "Conclusions" ] 6 => array:2 [ "identificador" => "sec0025" "titulo" => "Conflict of interests" ] 7 => array:2 [ "identificador" => "xack197180" "titulo" => "Acknowledgments" ] 8 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2015-07-14" "fechaAceptado" => "2015-08-15" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec602106" "palabras" => array:5 [ 0 => "Photodynamic therapy" 1 => "Onychomycosis" 2 => "5-aminolevulinic acid" 3 => "5-methylaminolevulinic acid" 4 => "Methylene blue" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec602105" "palabras" => array:5 [ 0 => "Terapia fotodinámica" 1 => "Onicomicosis" 2 => "Ácido 5-aminolevulínico" 3 => "Ácido 5-metilaminolevulínico" 4 => "Azul de metileno" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:2 [ "titulo" => "Abstract" "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Onychomycosis, or fungal infection of the nails, is one of the most prevalent fungal diseases in the general population. Treatment is of limited effectiveness, tedious, and must be administered for long periods. Furthermore, systemic antifungal agents are associated with adverse effects. Photodynamic therapy (PDT) may prove to be a viable alternative in the treatment of superficial skin infections, including onychomycosis. We review articles relating to the usefulness of PDT in onychomycosis in both in vitro and in vivo settings and discuss the potential and limitations of various photosensitizing agents. In vivo, methylene blue and 5-aminolevulinic acid have led to cure rates in 80% and 43% of cases, respectively, at 12 months. Finally, based on data in the literature and our own experience, we propose a protocol of 3 PDT sessions, separated by an interval of 1 or 2 weeks, using methyl aminolevulinate 16% as a photosensitizing agent and red light (λ<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>630<span class="elsevierStyleHsp" style=""></span>nm, 37<span class="elsevierStyleHsp" style=""></span>J.cm<span class="elsevierStyleSup">−2</span>). Each session is preceded by the topical application of urea 40% over several days. Clinical trials are needed to optimize PDT protocols and to identify those patients who will benefit most from this treatment.</p></span>" ] "es" => array:2 [ "titulo" => "Resumen" "resumen" => "<span id="abst0010" class="elsevierStyleSection elsevierViewall"><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">La onicomicosis, o infección fúngica de las uñas, constituye una de las enfermedades micóticas más prevalentes en la población. Su tratamiento tiene una efectividad limitada, además de ser largo y tedioso y, en el caso de los antifúngicos sistémicos, no está exento de efectos adversos. La terapia fotodinámica (TFD) podría ser una buena alternativa para las infecciones cutáneas superficiales, entre ellas la onicomicosis.</p><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">El presente artículo revisa la experiencia publicada, tanto <span class="elsevierStyleItalic">in vitro</span> como <span class="elsevierStyleItalic">in vivo</span>, acerca de la utilidad de la TFD en las onicomicosis, mostrando el potencial de diversos fotosensibilizantes, así como sus limitaciones. Desde el punto de vista clínico el azul de metileno y el ácido 5-aminolevulínico muestran tasas de curación del 80% y el 43% respectivamente al año de seguimiento.</p><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Finalmente, basado en la bibliografía y en la propia experiencia, se propone un protocolo de 3 sesiones de TFD, usando metil-aminolevulinato 16% como fotosensibilizante y luz roja (λ<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>630<span class="elsevierStyleHsp" style=""></span>nm, 37<span class="elsevierStyleHsp" style=""></span>J.cm<span class="elsevierStyleSup">−2</span>), separadas por 1 o 2 semanas. Estas irán precedidas de la aplicación de urea 40% durante unos días. Nuevos ensayos clínicos deben optimizar los protocolos y establecer qué pacientes se benefician especialmente de recibir este tratamiento.</p></span>" ] ] "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "<p class="elsevierStyleNotepara" id="npar0020">Please cite this article as: Robres P, Aspiroz C, Rezusta A, Gilaberte Y. Utilidad de la terapia fotodinámica en el manejo de la onicomicosis. Actas Dermosifiliogr. 2015;106:795–805.</p>" ] ] "multimedia" => array:6 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 2048 "Ancho" => 2833 "Tamanyo" => 292561 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Modified Jablonski diagram: molecular basis and mechanism of action of photodynamic therapy. The absorption of light by a photosensitizer (PS) in its unexcited ground state promotes an electron to a higher energy orbit (PS excited singlet state). The PS may return to its ground state by emitting heat and/or fluorescence or may change the direction of its angular moment of spin (PS excited triplet state). The long life of the triplet electron state favors the formation of singlet oxygen and/or free radicals that damage key cell structures and eventually cause cell death. At the end of the process, the PS returns to its ground state, ready for a new phototherapeutic cycle.</p>" ] ] 1 => array:7 [ "identificador" => "fig0010" "etiqueta" => "Figure 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 559 "Ancho" => 1500 "Tamanyo" => 190431 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Distal and lateral subungual onychomycosis caused by <span class="elsevierStyleItalic">T. Mentagrophytes</span>. Before (A) and at 36 weeks (B) after treatment with 3 sessions at 1-week intervals of methyl aminolevulinate photodynamic therapy and 16% Aktilite (Photocure ASA, 37<span class="elsevierStyleHsp" style=""></span>J/cm<span class="elsevierStyleSup">2</span>). Prior to each PDT session the affected area was pretreated with 40% urea under occlusion for 5 consecutive nights.</p>" ] ] 2 => array:7 [ "identificador" => "fig0015" "etiqueta" => "Figure 3" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr3.jpeg" "Alto" => 672 "Ancho" => 1800 "Tamanyo" => 262704 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">White superficial onychomycosis caused by <span class="elsevierStyleItalic">Fusarium oxysporum</span>. Before (A) and 48 weeks (B) after completion of 3 treatment sessions at 1-week intervals of methyl aminolevulinate photodynamic therapy with 16% Aktilite (Photocure ASA, 37<span class="elsevierStyleHsp" style=""></span>J/cm<span class="elsevierStyleSup">2</span>). Prior to each PDT sessions the affected area was pretreated with 40% urea under occlusion for 3 nights and active mechanical removal of the nail plate just before the application of the photosensitizing agent.</p>" ] ] 3 => array:7 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:2 [ "leyenda" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Abbreviations: ALA, 5-aminolevulinic acid; DPmme, deuteroporphyrin monomethylester; NS, not specified; Sylsens B, 5,10,15-Tris(4-methylpyridinium)-20-phenyl-[21H,23H]-porphine trichloride</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-with-role" title="table-head ; entry_with_role_rowhead " align="left" valign="top" scope="col">References \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col">Microorganism \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col">Photosensitizer \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " colspan="4" align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Light</th><th class="td" title="table-head " align="left" valign="top" scope="col">Effects of PDT \t\t\t\t\t\t\n \t\t\t\t</th></tr><tr title="table-row"><th class="td" title="table-head " align="" valign="top" scope="col" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="" valign="top" scope="col" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="" valign="top" scope="col" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">λ (nm) \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Dose (J/cm<span class="elsevierStyleSup">2</span>) \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Fluence (mW/cm<span class="elsevierStyleSup">2</span>) \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Source \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="" valign="top" scope="col" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Morton et al.,<a class="elsevierStyleCrossRef" href="#bib0385"><span class="elsevierStyleSup">31</span></a> (2014) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top"><span class="elsevierStyleItalic">T. rubrum</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Rose Bengal \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">530 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">24 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">13.4 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Three 3-watt H-HP803<span class="elsevierStyleHsp" style=""></span>PG LED modules \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">100% kill at a dose of 140<span class="elsevierStyleHsp" style=""></span>μM \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Paz-Cristobal et al.<a class="elsevierStyleCrossRef" href="#bib0380"><span class="elsevierStyleSup">30</span></a> (2014) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top"><span class="elsevierStyleItalic">T. rubrum</span><span class="elsevierStyleItalic">T. mentagrophytes</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Hypericin \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">602 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">37 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">10.3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">LED \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Fungicidal. 3 log reduction at doses of 10-50<span class="elsevierStyleHsp" style=""></span>μM \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Amorim et al.<a class="elsevierStyleCrossRef" href="#bib0375"><span class="elsevierStyleSup">29</span></a> (2012) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top"><span class="elsevierStyleItalic">T. rubrum</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Toluidine blue O \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">630 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">18-90 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">NS \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">LED \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Fungicidal at a dose of 25<span class="elsevierStyleHsp" style=""></span>μM and an energy density of 72<span class="elsevierStyleHsp" style=""></span>J/cm<span class="elsevierStyleSup">2</span> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Smijs et al.<a class="elsevierStyleCrossRef" href="#bib0450"><span class="elsevierStyleSup">44</span></a> (2009) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top"><span class="elsevierStyleItalic">T. rubrum</span>(ex vivo human stratum corneum model) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Sylsens B(pH 5.2) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">340-550 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">18 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">30 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">UV-A-1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Fungicidal. Fungal killCMI Sylsens B 10<span class="elsevierStyleHsp" style=""></span>μM with the clinical isolate 1<span class="elsevierStyleHsp" style=""></span>μM laboratory strain \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Smijs et al.<a class="elsevierStyleCrossRef" href="#bib0365"><span class="elsevierStyleSup">27</span></a> (2007) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top"><span class="elsevierStyleItalic">T. rubrum</span>(ex vivo human stratum corneum model) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Sylsens BDP mme \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">580-870 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">108 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">30 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Massive (no. 74900/21). 1<span class="elsevierStyleHsp" style=""></span>×<span class="elsevierStyleHsp" style=""></span>500W-230V-R7s, IP44 with a cut-off filter at 600<span class="elsevierStyleHsp" style=""></span>nm \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Fungicidal at different stages of conidial growth.Sylsens B:- 1<span class="elsevierStyleHsp" style=""></span>μM at 8<span class="elsevierStyleHsp" style=""></span>h- 5<span class="elsevierStyleHsp" style=""></span>μM at 17 and 24<span class="elsevierStyleHsp" style=""></span>hDP mme:- 80<span class="elsevierStyleHsp" style=""></span>μM at 8<span class="elsevierStyleHsp" style=""></span>h \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Donnelly et al.<a class="elsevierStyleCrossRef" href="#bib0455"><span class="elsevierStyleSup">45</span></a> (2005) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top"><span class="elsevierStyleItalic">Trichophyton interdigitale</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">ALA(0-100<span class="elsevierStyleHsp" style=""></span>mM) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">635 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">100 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">100 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Paterson Lamp (Phototherapeutics Ltd.) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Fungistatic ≤ 79% \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Kamp et al.<a class="elsevierStyleCrossRef" href="#bib0370"><span class="elsevierStyleSup">28</span></a> (2005) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top"><span class="elsevierStyleItalic">T. rubrum</span>(liquid culture medium) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">ALA(1-10<span class="elsevierStyleHsp" style=""></span>mmol l<span class="elsevierStyleSup">−1</span>) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">NS (white light) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">10<span class="elsevierStyleHsp" style=""></span>J for 60<span class="elsevierStyleHsp" style=""></span>min (≈128<span class="elsevierStyleHsp" style=""></span>J<span class="elsevierStyleHsp" style=""></span>cm<span class="elsevierStyleSup">−2</span>) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">36.8 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Quartz-halogen lamp Zeiss KL 2500 LCD \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Fungistatic: reductions in the number or the diameter of the colonies \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Smijs et al.<a class="elsevierStyleCrossRef" href="#bib0360"><span class="elsevierStyleSup">26</span></a> (2004) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top"><span class="elsevierStyleItalic">T. rubrum</span>(suspension culture of hyphae and microconidia) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Sylsens BDP mme \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">580-870 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">108 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">30 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Massive (no. 74900/21). 13 max. 500 W-230V-R7s, IP44 with a cut-off filter at 600<span class="elsevierStyleHsp" style=""></span>nm \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Fungicidal for microconidia:-Sylsens B 1<span class="elsevierStyleHsp" style=""></span>μM-DPmme >5<span class="elsevierStyleHsp" style=""></span>μMFungicidal for hyphae:-Sylsens B 10<span class="elsevierStyleHsp" style=""></span>μM-DPmme 40<span class="elsevierStyleHsp" style=""></span>μM \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Smijs et al.<a class="elsevierStyleCrossRef" href="#bib0355"><span class="elsevierStyleSup">25</span></a> (2003) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top"><span class="elsevierStyleItalic">T. rubrum</span>(liquid culture medium) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Sylsens BDP mme \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">NS (white light) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">108 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">30 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Massive (no. 74900/21). 13 max. 500 W-230V-R7s, IP44 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Fungicidal (3<span class="elsevierStyleHsp" style=""></span>μg<span class="elsevierStyleHsp" style=""></span>mL<span class="elsevierStyleSup">−1</span>) with Sylsens B and DPmme.Fungistatic effect for 1 wk with phthalocyanines and Photofrin \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Ouf et al.<a class="elsevierStyleCrossRef" href="#bib0460"><span class="elsevierStyleSup">46</span></a> (2003) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top"><span class="elsevierStyleItalic">T. rubrum</span><span class="elsevierStyleItalic">T. verrucosum</span><span class="elsevierStyleItalic">T. violaceum</span><span class="elsevierStyleItalic">Microsporum canis</span><span class="elsevierStyleItalic">M. gypseum</span><span class="elsevierStyleItalic">Epidermophyton floccosum (spore solution)</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Hematoporphyrin derivative, methylene blue, toluidine blue \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">NS (visible light) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">72-144 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">40 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Oriel sun simulator \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Fungicidal with hematoporphyrin and methylene blue at 10<span class="elsevierStyleSup">−3</span><span class="elsevierStyleHsp" style=""></span>M for <span class="elsevierStyleItalic">M. canis</span>, <span class="elsevierStyleItalic">T. mentagrophytes</span> and <span class="elsevierStyleItalic">T. verrucossum</span> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Propst y Lubin<a class="elsevierStyleCrossRef" href="#bib0350"><span class="elsevierStyleSup">24</span></a> (1978) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top"><span class="elsevierStyleItalic">T. mentagrophytes</span><span class="elsevierStyleItalic">M. gypseum</span>(mixed suspension of spores and mycelia) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Methylene blue,neutral red, proflavine hemisulfate (3<span class="elsevierStyleHsp" style=""></span>mM) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">455 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">≈1.1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">≈1.8 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Blue light \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Fungicidal with proflavine (3<span class="elsevierStyleHsp" style=""></span>mM) \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab957282.png" ] ] ] ] "descripcion" => array:1 [ "en" => "<p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">In Vitro Research into the Use of Photodynamic Therapy in Filamentous Fungi.</p>" ] ] 4 => array:7 [ "identificador" => "tbl0010" "etiqueta" => "Table 2" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:3 [ "leyenda" => "<p id="spar0055" class="elsevierStyleSimplePara elsevierViewall">Abbreviations: ALA, 5-aminolevulinic acid; DTF, dermatophyte fungus; MAL, methyl aminolevulinate; NS, not specified.</p>" "tablatextoimagen" => array:2 [ 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="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">References \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Type of Onychomycosis \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Cases No. \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Causative Agent \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Site \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Urea Prior to PDT(%) \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Photosensitizer \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Incubation Time \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Watanabe D et al.<a class="elsevierStyleCrossRef" href="#bib0390"><span class="elsevierStyleSup">32</span></a> (2008) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Subungual, distal and lateral \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Unspecified DTF \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Nail of first toe \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Yes, 20% urea \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">20% ALA \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">5<span class="elsevierStyleHsp" style=""></span>h \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Sotiriou E et al.<a class="elsevierStyleCrossRef" href="#bib0340"><span class="elsevierStyleSup">22</span></a> (2010) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Subungual, distal and lateral \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">30 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top"><span class="elsevierStyleItalic">T. rubrum</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Nail of first toe (22 patients)Other toenail (8 patients) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Yes, 20% urea + mechanical abrasion \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">20% ALA \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">3<span class="elsevierStyleHsp" style=""></span>h \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Piraccini et al.<a class="elsevierStyleCrossRef" href="#bib0410"><span class="elsevierStyleSup">36</span></a> (2008) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Total onychodystrophyProximal subungual \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top"><span class="elsevierStyleItalic">T. rubrum</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Nails on first toes \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Yes, 40% urea+ mechanical abrasion \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">16% MAL \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">3<span class="elsevierStyleHsp" style=""></span>h \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Aspiroz et al.<a class="elsevierStyleCrossRef" href="#bib0400"><span class="elsevierStyleSup">34</span></a> (2011) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">White superficial \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top"><span class="elsevierStyleItalic">Acremonium sclerotigenum</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">5th fingernail \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">None \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">16% MAL (Metvix) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">4<span class="elsevierStyleHsp" style=""></span>h \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Gilaberte et al.<a class="elsevierStyleCrossRef" href="#bib0405"><span class="elsevierStyleSup">35</span></a> (2011) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Onychodystrophy \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top"><span class="elsevierStyleItalic">Fusarium oxysporum</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">4th fingernail \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Yes, 40% urea \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">16% MAL (Metvix) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">4<span class="elsevierStyleHsp" style=""></span>h \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Gilaberte et al.<a class="elsevierStyleCrossRef" href="#bib0405"><span class="elsevierStyleSup">35</span></a> (2011) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">White superficial \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top"><span class="elsevierStyleItalic">Aspergillus terreus</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1st to 5th fingernails \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Yes, 40% urea \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">16% MAL (Metvix) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">4<span class="elsevierStyleHsp" style=""></span>h \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Aspiroz et al.<a class="elsevierStyleCrossRef" href="#bib0395"><span class="elsevierStyleSup">33</span></a> (2011) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Onychodystrophy. Distal onycholysis \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top"><span class="elsevierStyleItalic">Candida albicans</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">+</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Malassezia furfur</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">3rd and 4th fingernails \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Yes, 40% urea \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">16% MAL (Metvix) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">3<span class="elsevierStyleHsp" style=""></span>h \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Silva et al.<a class="elsevierStyleCrossRef" href="#bib0425"><span class="elsevierStyleSup">39</span></a> (2013) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Subungual, distal and lateral. Onychodystrophy \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">NS \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">First toenail both feet both feet \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Yes, 20% urea<span class="elsevierStyleHsp" style=""></span>+<span class="elsevierStyleHsp" style=""></span>mechanical abrasion \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Hematoporphyrin derivative (Photogem 1<span class="elsevierStyleHsp" style=""></span>mL,<span class="elsevierStyleHsp" style=""></span>mg/mL) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1<span class="elsevierStyleHsp" style=""></span>h \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Figueiredo Souza et al.<a class="elsevierStyleCrossRef" href="#bib0415"><span class="elsevierStyleSup">37</span></a> (2014) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Subungual, distal and lateral \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">40 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top"><span class="elsevierStyleItalic">T. rubrum, T. mentagrophytes</span><span class="elsevierStyleItalic">E. floccosum</span><span class="elsevierStyleItalic">Aspergillus niger</span><span class="elsevierStyleItalic">Candida sp.</span><span class="elsevierStyleItalic">Fusarium sp.</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">NS \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Mechanical abrasion<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2% methylene blue aqueous solution \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">3<span class="elsevierStyleHsp" style=""></span>min \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Figueiredo Souza et al.<a class="elsevierStyleCrossRef" href="#bib0420"><span class="elsevierStyleSup">38</span></a> (2014) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Subungual, distal and lateral \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">22 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top"><span class="elsevierStyleItalic">T. rubrum</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">NS \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Mechanical abrasion<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2% methylene blue aqueous solution \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab957280.png" ] ] 1 => 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-with-role" title="table-head ; entry_with_role_rowhead " align="left" valign="top" scope="col">References \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col">Follow-up (mo) \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col">Quality of Evidence \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col">No.of PDT Sessions \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " colspan="4" align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Light</th><th class="td" title="table-head " align="left" valign="top" scope="col">Rate of Clinical or Microbiological Cure \t\t\t\t\t\t\n \t\t\t\t</th></tr><tr title="table-row"><th class="td" title="table-head " align="" valign="top" scope="col" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="" valign="top" scope="col" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="" valign="top" scope="col" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="" valign="top" scope="col" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">λ (nm) \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Fluence (J/cm<span class="elsevierStyleSup">2</span>) \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Irradiance (mW/cm<span class="elsevierStyleSup">2</span>) \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Source \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="" valign="top" scope="col" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Watanabe D et al.<a class="elsevierStyleCrossRef" href="#bib0390"><span class="elsevierStyleSup">32</span></a> (2008) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">3 and 6 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">III \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">6-7 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">630 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">100 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">NS \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Pulsed excimer dye laser (Hamamatsu Photonics KK) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2 (100%) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Sotiriou E et al.<a class="elsevierStyleCrossRef" href="#bib0340"><span class="elsevierStyleSup">22</span></a> (2010) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">12 and 18 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">II \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">570-670 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">40 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">40 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Waldmann PDT 1200 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">At 12 months follow-up: 43%At 18 months follow-up: 37% \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Piraccini et al.<a class="elsevierStyleCrossRef" href="#bib0410"><span class="elsevierStyleSup">36</span></a> (2008) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">24 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">III \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">630 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">37 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">NS \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Aktilite \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1 (100%) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Aspiroz et al.<a class="elsevierStyleCrossRef" href="#bib0400"><span class="elsevierStyleSup">34</span></a> (2011) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">3, 6, 9, and 12 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">III \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">630 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">37 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">NS \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Aktilite \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1 (100%) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Gilaberte et al.<a class="elsevierStyleCrossRef" href="#bib0405"><span class="elsevierStyleSup">35</span></a> (2011) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">6 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">III \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">630 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">37 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">NS \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Aktilite \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1 (100%) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Gilaberte et al.<a class="elsevierStyleCrossRef" href="#bib0405"><span class="elsevierStyleSup">35</span></a> (2011) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">6 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">III \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">630 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">37 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">NS \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Aktilite \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1 (100%) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Aspiroz et al.<a class="elsevierStyleCrossRef" href="#bib0395"><span class="elsevierStyleSup">33</span></a> (2011) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">6 and 18 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">III \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">630 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">37 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">NS \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Aktilite \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1 (100%) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Silva et al.<a class="elsevierStyleCrossRef" href="#bib0425"><span class="elsevierStyleSup">39</span></a> (2013) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">None \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">III \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">6 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">630 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">54 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">NS \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">LED \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1 (100%) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Figueiredo Souza et al.<a class="elsevierStyleCrossRef" href="#bib0415"><span class="elsevierStyleSup">37</span></a> (2014) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1 and 12 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">II-I \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">12 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">630 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">18 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">100 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">LED \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">At the end of treatment: 90%At 12 months follow-up: 80% \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Figueiredo Souza et al.<a class="elsevierStyleCrossRef" href="#bib0420"><span class="elsevierStyleSup">38</span></a> (2014) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">1 and 12 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">12 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">630 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">36 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">100 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">LED \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Mild to moderate onychomycosis: 100%Severe onychomycosis: 63.3% \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab957281.png" ] ] ] "notaPie" => array:1 [ 0 => array:3 [ "identificador" => "tblfn0005" "etiqueta" => "a" "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Mechanical abrasion of the nail when hyperkeratosis ><span class="elsevierStyleHsp" style=""></span>2<span class="elsevierStyleHsp" style=""></span>mm or in the presence of a longitudinal streak or dermatophytoma.</p>" ] ] ] "descripcion" => array:1 [ "en" => "<p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">Studies of Onychomycosis Treated with Photodynamic Therapy.</p>" ] ] 5 => array:7 [ "identificador" => "tbl0015" "etiqueta" => "Table 3" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:2 [ "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=""><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleBold">Days Before Treatment</span> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Apply 40% urea under occlusive dressing 12-24</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">h. Care should be taken not to macerate the periungual skin excessively:</span> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>In toenails or fingernails with hyperkeratosis<span class="elsevierStyleHsp" style=""></span>><span class="elsevierStyleHsp" style=""></span>2<span class="elsevierStyleHsp" style=""></span>mm the softening treatment should be applied daily for 5 days prior to photodynamic therapy<a class="elsevierStyleCrossRef" href="#tblfn0010"><span class="elsevierStyleSup">a</span></a><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>In fingernails or toenails with hyperkeratosis<span class="elsevierStyleHsp" style=""></span><<span class="elsevierStyleHsp" style=""></span>2<span class="elsevierStyleHsp" style=""></span>mm, 2 or 3 days of softening treatment with urea is sufficient<a class="elsevierStyleCrossRef" href="#tblfn0010"><span class="elsevierStyleSup">a</span></a> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleBold">Day of Treatment</span> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">1. Clean the urea residue from the nail plate and surrounding skin using 70% alcohol.</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">2. Remove nail debris and hyperkeratotic mechanically from treatment areas with a scalpel or abrasive tool, such as a file (recommended, could improve the results).</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">3. Clean nail plate and surrounding skin with 70% alcohol.</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">4. Apply the photosensitizer to the nail and periungual area (use a tongue depressor or finger to aid application).</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">5. Cover the whole area with a plastic occlusive dressing and with an opaque dressing to protect area from light for 3</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">h in the case of 16% 5-methyl aminolevulinate acid (Metvix).</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">6. Irradiate with LED 635</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">nm (Aktilite) at a fluence of 37</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">J/cm</span><span class="elsevierStyleSup"><span class="elsevierStyleItalic">2</span></span>.<span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">7. Protect the treated area from light for <span class="elsevierStyleSup">24</span>h–<span class="elsevierStyleSup">48</span>h</span>.<span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">8. Repeat the procedure every 1-2 weeks for up to 3 sessions.</span><a class="elsevierStyleCrossRef" href="#tblfn0015"><span class="elsevierStyleSup">b</span></a> \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab957279.png" ] ] ] "notaPie" => array:2 [ 0 => array:3 [ "identificador" => "tblfn0010" "etiqueta" => "a" "nota" => "<p class="elsevierStyleNotepara" id="npar0010">Care should be taken not to damage the periungual excessively with the urea because such damage could increase the pain of PDT during irradiation.</p>" ] 1 => array:3 [ "identificador" => "tblfn0015" "etiqueta" => "b" "nota" => "<p class="elsevierStyleNotepara" id="npar0015">The process can be repeated if necessary.</p>" ] ] ] "descripcion" => array:1 [ "en" => "<p id="spar0060" class="elsevierStyleSimplePara elsevierViewall">Protocol for Photodynamic Therapy in the Treatment of Onychomycosis.</p>" ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:46 [ 0 => array:3 [ "identificador" => "bib0235" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Onychomycosis: Treatment, quality of life, and economic issues" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => "B. 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| 2024 Septiembre | 135 | 29 | 164 |
| 2024 Agosto | 156 | 74 | 230 |
| 2024 Julio | 115 | 46 | 161 |
| 2024 Junio | 114 | 73 | 187 |
| 2024 Mayo | 96 | 48 | 144 |
| 2024 Abril | 117 | 39 | 156 |
| 2024 Marzo | 128 | 38 | 166 |
| 2024 Febrero | 125 | 41 | 166 |
| 2024 Enero | 98 | 43 | 141 |
| 2023 Diciembre | 104 | 29 | 133 |
| 2023 Noviembre | 91 | 32 | 123 |
| 2023 Octubre | 114 | 35 | 149 |
| 2023 Septiembre | 111 | 36 | 147 |
| 2023 Agosto | 61 | 22 | 83 |
| 2023 Julio | 67 | 47 | 114 |
| 2023 Junio | 73 | 31 | 104 |
| 2023 Mayo | 97 | 34 | 131 |
| 2023 Abril | 73 | 43 | 116 |
| 2023 Marzo | 98 | 45 | 143 |
| 2023 Febrero | 76 | 31 | 107 |
| 2023 Enero | 79 | 33 | 112 |
| 2022 Diciembre | 75 | 48 | 123 |
| 2022 Noviembre | 74 | 32 | 106 |
| 2022 Octubre | 33 | 48 | 81 |
| 2022 Septiembre | 35 | 59 | 94 |
| 2022 Agosto | 32 | 41 | 73 |
| 2022 Julio | 43 | 70 | 113 |
| 2022 Junio | 21 | 44 | 65 |
| 2022 Mayo | 39 | 49 | 88 |
| 2022 Abril | 75 | 72 | 147 |
| 2022 Marzo | 71 | 75 | 146 |
| 2022 Febrero | 55 | 45 | 100 |
| 2022 Enero | 71 | 50 | 121 |
| 2021 Diciembre | 46 | 57 | 103 |
| 2021 Noviembre | 55 | 55 | 110 |
| 2021 Octubre | 161 | 88 | 249 |
| 2021 Septiembre | 288 | 76 | 364 |
| 2021 Agosto | 84 | 81 | 165 |
| 2021 Julio | 59 | 64 | 123 |
| 2021 Junio | 66 | 67 | 133 |
| 2021 Mayo | 74 | 57 | 131 |
| 2021 Abril | 146 | 98 | 244 |
| 2021 Marzo | 88 | 61 | 149 |
| 2021 Febrero | 64 | 53 | 117 |
| 2021 Enero | 67 | 61 | 128 |
| 2020 Diciembre | 50 | 38 | 88 |
| 2020 Noviembre | 43 | 29 | 72 |
| 2020 Octubre | 38 | 14 | 52 |
| 2020 Septiembre | 50 | 17 | 67 |
| 2020 Agosto | 30 | 30 | 60 |
| 2020 Julio | 52 | 21 | 73 |
| 2020 Junio | 45 | 30 | 75 |
| 2020 Mayo | 31 | 20 | 51 |
| 2020 Abril | 43 | 28 | 71 |
| 2020 Marzo | 34 | 22 | 56 |
| 2020 Febrero | 2 | 2 | 4 |
| 2020 Enero | 0 | 6 | 6 |
| 2019 Diciembre | 4 | 9 | 13 |
| 2019 Noviembre | 0 | 2 | 2 |
| 2019 Octubre | 0 | 1 | 1 |
| 2019 Septiembre | 4 | 1 | 5 |
| 2019 Agosto | 0 | 1 | 1 |
| 2019 Julio | 0 | 5 | 5 |
| 2019 Junio | 2 | 6 | 8 |
| 2019 Mayo | 2 | 25 | 27 |
| 2019 Abril | 1 | 3 | 4 |
| 2019 Marzo | 2 | 6 | 8 |
| 2019 Enero | 2 | 0 | 2 |
| 2018 Diciembre | 1 | 0 | 1 |
| 2018 Noviembre | 1 | 0 | 1 |
| 2018 Octubre | 10 | 0 | 10 |
| 2018 Septiembre | 13 | 1 | 14 |
| 2018 Agosto | 0 | 5 | 5 |
| 2018 Julio | 0 | 1 | 1 |
| 2018 Junio | 0 | 1 | 1 |
| 2018 Mayo | 0 | 4 | 4 |
| 2018 Abril | 0 | 1 | 1 |
| 2018 Marzo | 3 | 4 | 7 |
| 2018 Febrero | 42 | 4 | 46 |
| 2018 Enero | 37 | 13 | 50 |
| 2017 Diciembre | 48 | 14 | 62 |
| 2017 Noviembre | 37 | 8 | 45 |
| 2017 Octubre | 45 | 10 | 55 |
| 2017 Septiembre | 28 | 15 | 43 |
| 2017 Agosto | 37 | 7 | 44 |
| 2017 Julio | 30 | 13 | 43 |
| 2017 Junio | 43 | 23 | 66 |
| 2017 Mayo | 61 | 24 | 85 |
| 2017 Abril | 39 | 21 | 60 |
| 2017 Marzo | 25 | 43 | 68 |
| 2017 Febrero | 87 | 30 | 117 |
| 2017 Enero | 26 | 17 | 43 |
| 2016 Diciembre | 53 | 40 | 93 |
| 2016 Noviembre | 57 | 29 | 86 |
| 2016 Octubre | 40 | 44 | 84 |
| 2016 Septiembre | 0 | 6 | 6 |
| 2016 Agosto | 0 | 2 | 2 |
| 2016 Julio | 0 | 2 | 2 |
| 2016 Junio | 2 | 33 | 35 |
| 2016 Mayo | 0 | 7 | 7 |
| 2016 Abril | 0 | 12 | 12 |
| 2016 Marzo | 0 | 15 | 15 |
| 2016 Febrero | 0 | 21 | 21 |
| 2016 Enero | 0 | 12 | 12 |
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