was read the article
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Martínez-Santamaría, S. Guerrero-Aspizua, M. Del Río" "autores" => array:3 [ 0 => array:2 [ "nombre" => "L." "apellidos" => "Martínez-Santamaría" ] 1 => array:2 [ "nombre" => "S." "apellidos" => "Guerrero-Aspizua" ] 2 => array:2 [ "nombre" => "M." "apellidos" => "Del Río" ] ] ] ] ] "idiomaDefecto" => "en" "Traduccion" => array:1 [ "es" => array:9 [ "pii" => "S0001731011001608" "doi" => "10.1016/j.ad.2011.03.006" "estado" => "S300" "subdocumento" => "" "abierto" => array:3 [ "ES" => true "ES2" => true "LATM" => true ] "gratuito" => true "lecturas" => array:1 [ "total" => 0 ] "idiomaDefecto" => "es" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S0001731011001608?idApp=UINPBA000044" ] ] "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S157821901200042X?idApp=UINPBA000044" "url" => "/15782190/0000010300000001/v1_201304241248/S157821901200042X/v1_201304241248/en/main.assets" ] "en" => array:13 [ "idiomaDefecto" => true "cabecera" => "<span class="elsevierStyleTextfn">Opinion Article</span>" "titulo" => "Methotrexate in Psoriasis: Do We Need to Give a Test Dose?" "tieneTextoCompleto" => true "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "1" "paginaFinal" => "4" ] ] "autores" => array:1 [ 0 => array:3 [ "autoresLista" => "G. Carretero-Hernández" "autores" => array:1 [ 0 => array:3 [ "nombre" => "G." "apellidos" => "Carretero-Hernández" "email" => array:1 [ 0 => "gcarrete@aedv.es" ] ] ] "afiliaciones" => array:1 [ 0 => array:1 [ "entidad" => "Servicio de Dermatología, Hospital Universitario de Gran Canaria, Las Palmas de Gran Canaria, Spain" ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Metotrexato en psoriasis: ¿es necesaria una dosis de prueba?" ] ] "textoCompleto" => "<span class="elsevierStyleSections"><p id="par0005" class="elsevierStylePara elsevierViewall">After more than 50 years’ experience with methotrexate and despite the lack of appropriate trials, the efficacy of this drug for treating psoriasis is unquestioned. However, the numerous guidelines and reviews on the use of methotrexate<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1–12</span></a> have not erased practitioners’ uneasiness about unforeseen potential side effects, resulting in considerable variation in the prescribing practices among physicians. One difference in practice is the use or not of a so-called ‘test dose’ (a lower initial dose given to assess the likelihood of an unexpected acute adverse event).</p><p id="par0010" class="elsevierStylePara elsevierViewall">Aminopterin was first used empirically for psoriasis and rheumatoid arthritis in 1951 by Gubner, an internist, and coworkers,<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">13</span></a> and in 1958 this drug was specifically mentioned as a treatment for psoriasis.<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">14</span></a> In 1972, the US Food and Drug Administration approved methotrexate for this indication. Dermatologists promptly began to assess the use of both aminopterin and methotrexate in this disease, testing twice weekly parenteral doses of 50–75<span class="elsevierStyleHsp" style=""></span>mg,<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a> very small daily doses for several consecutive days a month (0.5–0.6<span class="elsevierStyleHsp" style=""></span>mg every 4–6<span class="elsevierStyleHsp" style=""></span>h for 10<span class="elsevierStyleHsp" style=""></span>d/mo),<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">16</span></a> and topical application for psoriatic plaques.<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">17</span></a> After this initial stage, in 1969 the usefulness of a weekly dose was established,<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">18</span></a> and in 1971, the possibility of dividing the weekly dose into 3 doses administered at 12-h intervals (Weinstein's regimen) was suggested.<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">19</span></a> These prescription practices were an attempt to base dosing on the pharmacokinetics of methotrexate,<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">20</span></a> on studies of cell kinetics,<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">21</span></a> and on the unproven assumption that adverse gastrointestinal events would thereby be prevented or attenuated. Although minimum and maximum doses have not been universally established, the weekly administration of 7.5–25<span class="elsevierStyleHsp" style=""></span>mg is recommended as an effective therapeutic range in psoriasis.<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">The toxicity of methotrexate depends on the extracellular concentration of the drug and the period of exposure; toxicity for a given dose will therefore be proportional to the period of exposure to it. In theory, a toxic event can be anticipated by measuring blood levels of the drug (levels higher than 0.01<span class="elsevierStyleHsp" style=""></span>μmol/L after intramuscular injection of 10<span class="elsevierStyleHsp" style=""></span>mg should lead to suspicion of toxicity)<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">22</span></a>; however, we do not measure concentrations routinely.</p><p id="par0020" class="elsevierStylePara elsevierViewall">Most adverse reactions related to low-dose methotrexate (gastrointestinal and mucocutaneous) are mild, appear in the first 24–48<span class="elsevierStyleHsp" style=""></span>h after administration, and do not usually require interruption of the treatment. In some cases reactions can be attenuated by regulating or dividing the dose, by administering the drug intravenously at night, or by having the patient take folic acid supplements.<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">23</span></a> Gastrointestinal toxicity presents in 60% of patients as stomatitis, nausea, vomiting, indigestion, abdominal pain, dyspepsia, diarrhea, anorexia, and weight loss.<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">23</span></a> Aphthous stomatitis is associated with higher doses of methotrexate but folate supplements improve tolerance of the course of treatment.<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">24</span></a> The most severe toxicity associated with methotrexate is specific to certain organs and tissues, affecting the blood, liver, and lung; related mortality rates decrease in that order.<a class="elsevierStyleCrossRef" href="#bib0125"><span class="elsevierStyleSup">25</span></a> The development of toxicity is often associated with concomitant factors, accumulation of drugs or overdose, which are not fully understood.<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a> These factors must be remembered when selecting patients for treatment with methotrexate.</p><p id="par0025" class="elsevierStylePara elsevierViewall">However, a similar profile of adverse effects can also be seen with other drugs for which we do not consider test doses. For most dermatologists the test dose was handed down to us as clinical practice when we were residents, and we accepted it uncritically, presumably because it was a matter of prudence in the prescription of medication and out of respect for our superiors; that was the case for me and I believe my experience was typical. Why then do we not start with test doses of cyclosporin, nonsteroidal anti-inflammatory drugs (which, incidentally, cause more frequent adverse effects), tetracyclines, or any other drug we use routinely? Is it perhaps because hypersensitivity reactions to methotrexate, but not to cyclosporin, began to be reported at a certain historical moment? The initial trials and reports based on large patient series do not mention hypersensitivity reactions but rather toxicity associated with high doses and/or renal failure, and, in most cases, transitory transaminase elevation not requiring suspension of treatment.<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1,15,16,18,26</span></a> The test dose nonetheless continues to be recommended in most published guidelines, although I have found no documented account of its utility or trial evidence supporting it.</p><p id="par0030" class="elsevierStylePara elsevierViewall">In my opinion, none of the toxicities associated with methotrexate can be considered hypersensitivity reactions, except for methotrexate-associated pneumonitis, which normally appears several weeks after treatment begins (nearly always after the full dose is reached). The test dose can therefore not be used as an excuse for preventing this serious, though unusual, toxic event. From a theoretical standpoint, assessing a test dose is more relevant in cases where methotrexate is being reintroduced, as allergic hypersensitivity could be expected then rather than at the start of treatment. Interestingly, the general assumption on reintroducing the drug is that the previous experience is sufficient indication of safety and no test dose is needed. However, the literature offers mainly reports of anaphylactoid reactions after high doses in patients who had previously been exposed to methotrexate.</p><p id="par0035" class="elsevierStylePara elsevierViewall">Acute hypersensitivity reactions—though we have no accurate catalog of exactly what to look for, whether anaphylaxis, urticaria, toxic hepatitis, bone marrow aplasia, or toxic epidermal necrolysis—have been sporadically described in the literature almost exclusively in oncology or rheumatology patients who are taking concomitant medications and high doses of parenteral methotrexate; the vast majority of these patients had been previously exposed to the drug.<a class="elsevierStyleCrossRefs" href="#bib0135"><span class="elsevierStyleSup">27–30</span></a> Very few cases of these reactions have been described after the initial dose and this is also true for patients with a severe underlying disease other than psoriasis and who are taking other medications. (We do note, however, a report of mild, transient purpura after a test dose of 7.5<span class="elsevierStyleHsp" style=""></span>mg<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">31</span></a>.) The available evidence therefore suggests that hypersensitivity reactions have mostly been described in patients who have previously taken high doses of methotrexate and have oncologic and/or rheumatologic disorders. This is not the situation for our patients taking low doses of methotrexate for psoriasis, however. Similarly, leukopenia or pancytopenia are reactions that have been described mainly in patients with underlying conditions (especially those with associated renal failure and in hemodialysis) or in cases of overdose.</p><p id="par0040" class="elsevierStylePara elsevierViewall">What then is the purpose of a test dose? Solely for the sake of argument, we note that a test dose is indicated for the prevention of a possible non-dose-dependent hypersensitivity reaction, which might be severe and which could be watched for; or we might attenuate a reaction's seriousness by administering a small dose. Next, my understanding is that we must abandon claiming that the prevention of possible adverse events related to drug accumulation is a criterion for deciding to use a test dose, given that a test occurs at the start of treatment. A survey of the Spanish Psoriasis Group of the Spanish Academy of Dermatology (AEDV), carried out when the association's guidelines on methotrexate use in psoriasis<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a> were being drafted, included a question about the respondents’ experience with test dosing. The answers we received were extremely varied: some respondents did not use one while others did—expressing fear of bone marrow aplasia, acute hepatitis, acute urticarial reaction—or “just in case of any unexpected reaction.” None of the respondents had ever witnessed such a reaction among their patients, however.</p><p id="par0045" class="elsevierStylePara elsevierViewall">The only unexpected reaction to methotrexate in psoriasis I have seen was plaque erosion after the first few doses of the drug (hypersensitivity?). This reaction is certainly not serious and is only remarkable because of the need to recognize it as what it really is in order to avoid interpreting it as a lack of response to methotrexate and then try raising the dose, thereby leading to acute toxicity due to overdose (a practice error, as a higher dose would not be indicated).</p><p id="par0050" class="elsevierStylePara elsevierViewall">What constitutes a test dose? That there is also variation in what practitioners consider to be a test dose was also evident in the survey mentioned above, in which respondents chose 2.5<span class="elsevierStyleHsp" style=""></span>mg, 5<span class="elsevierStyleHsp" style=""></span>mg, 7.5<span class="elsevierStyleHsp" style=""></span>mg, and 10<span class="elsevierStyleHsp" style=""></span>mg for such doses. Several guidelines suggest a test dose of 5–10<span class="elsevierStyleHsp" style=""></span>mg, or a lower one of 2.5<span class="elsevierStyleHsp" style=""></span>mg in a ‘susceptible patient’.<a class="elsevierStyleCrossRefs" href="#bib0050"><span class="elsevierStyleSup">10,11</span></a> The prescribing information for oral and injectable forms of methotrexate recommends an initial dose of 7.5<span class="elsevierStyleHsp" style=""></span>mg and 10<span class="elsevierStyleHsp" style=""></span>mg,<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">32</span></a> respectively, without explicitly defining it as a test dose.</p><p id="par0055" class="elsevierStylePara elsevierViewall">Still, doses of 7.5<span class="elsevierStyleHsp" style=""></span>mg and higher are already within the therapeutic range (7.5–25<span class="elsevierStyleHsp" style=""></span>mg/wk) for psoriasis. Is 7.5<span class="elsevierStyleHsp" style=""></span>mg the test dose when wanting to prescribe 15 or 20<span class="elsevierStyleHsp" style=""></span>mg? And what if I want to administer a 7.5-mg dose directly? What is, in principle, the dose I eventually want to reach? No studies give guidance on a theoretically optimal dose, and methotrexate is not prescribed according to weight. The precautionary measure of administering low doses would be more valid for patients with underlying risks (due to comorbidity, age, or concomitant medication).</p><p id="par0060" class="elsevierStylePara elsevierViewall">A lower initial dose must not be confused with a test dose. The intention in the first instance is to discover the minimum effective dose rather than to prevent toxic reactions: the minimum effective dose and the test dose are not one and the same. The purpose of the test dose is to prevent an immediate acute adverse reaction that could be severe. If the reaction is idiosyncratic or the result of hypersensitivity, I believe it will matter little whether the dose is of 2.5<span class="elsevierStyleHsp" style=""></span>mg, 5<span class="elsevierStyleHsp" style=""></span>mg, 7.5<span class="elsevierStyleHsp" style=""></span>mg, or 15<span class="elsevierStyleHsp" style=""></span>mg, since the problem stems from an individual's genetic makeup and metabolism of a drug and on the molecular structure of the drug itself. Moreover, any of these doses is far lower than those that had been administered in the reported cases of hypersensitivity reactions. If the intention of a test is to prevent dose-dependent toxicity, then indeed, establishing the minimum effective dose could be considered. How can we be sure that a single dose of 2.5<span class="elsevierStyleHsp" style=""></span>mg will be safe and that a reaction will not develop after the second, third, or ninth dose? Rather than accepting the test dose as a routine practice, it would be more reasonable to maintain a low dose divided into several weekly intakes and to speak of a test or induction phase rather than a test dose.</p><p id="par0065" class="elsevierStylePara elsevierViewall">Personally, I do not prescribe test doses, instead starting patients on an initial dose of 15<span class="elsevierStyleHsp" style=""></span>mg if they have no comorbidities associated with increased risk when taking this drug.<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a> I have observed no severe acute toxicity from this initial dose<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">33</span></a> and consider it the optimal one for predicting the efficacy that can be expected from continuing treatment. This dose has been suggested on the basis of findings from trials that compared biologic agents to methotrexate, according to Dr Kristian Reich, speaking at the 2010 annual congress of the European Academy of Dermatology and Venereology in Gothenburg, Sweden.<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">34</span></a></p><p id="par0070" class="elsevierStylePara elsevierViewall">In my opinion the main issue in the management of methotrexate therapy is not about dosing regimens; rather, we should be concerned with evaluating patients before starting treatment and following them closely (including monitoring laboratory test results), as we have recommended.<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a> Early reviews of the use of aminopterin and methotrexate in psoriasis indicated that the possible adverse reactions encountered were related to renal or hepatic failure and rarely to hypersensitivity.<a class="elsevierStyleCrossRefs" href="#bib0175"><span class="elsevierStyleSup">35,36</span></a> When the use of methotrexate is considered, contraindications and special precautions for this drug must be carefully assessed. Any previous relative contraindication experienced by the patient will certainly influence the choice of dose, follow-up, and safety regimens.<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a> However, this presupposes a standardized management of methotrexate similar to that of other antipsoriatic drugs, with no resort to a test dose based on uneasiness which neither experience nor evidence justifies.</p><p id="par0075" class="elsevierStylePara elsevierViewall">Perhaps the reason for ongoing debate lies in the lack of randomized clinical trials. Methotrexate is an old drug that appeared in another era. The lack of appropriate clinical trials was denounced decades ago,<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">37</span></a> yet trials have not been widely or systematically performed for this drug as they have been for cyclosporin and biologic agents, drugs for which a test dose has not been suggested even though their potential to cause very serious adverse events is acknowledged.</p><p id="par0080" class="elsevierStylePara elsevierViewall">Methotrexate has been the target of myths and groundless fears (high risk of pulmonary and hepatic toxicity, mutagenic potential, etc.), which have gradually faded or diminished after decades of experience.<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">38</span></a> In any case, discussions about the initial dose are not as important as the need for prompt patient evaluation and later clinical vigilance once methotrexate has been prescribed, irrespective of the initial dose.</p><p id="par0085" class="elsevierStylePara elsevierViewall">In summary, I believe that when prescribing methotrexate in psoriasis we should consider therapeutic range; patient selection; the so-called attack, or loading, dose as well as the maintenance dose; and follow-up. A test dose, on the other hand, should not be used for fear of the unknown or figments of our imagination. Methotrexate should receive the same medical, pharmacologic, and pharmacovigilance treatment as any other drug and not be subjected to a verdict of guilty without trial.</p><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Conflicts of Interest</span><p id="par0090" class="elsevierStylePara elsevierViewall">The author declares that he has no conflicts of interest with regard to this opinion article. However, he has received fees for speaking at conferences, conducting clinical trials, or otherwise serving as a consultant from the following laboratories: Novartis, Leo-Pharma, MSD, Abbott, Pfizer, and Janssen-Cilag.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:2 [ 0 => array:2 [ "identificador" => "sec0005" "titulo" => "Conflicts of Interest" ] 1 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "<p class="elsevierStyleNotepara">Please cite this article as: Carretero-Hernández G. Metotrexato en psoriasis: ¿es necesaria una dosis de prueba?. Actas Dermosifiliogr.2012;103:1-4.</p>" ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:38 [ 0 => array:3 [ "identificador" => "bib0005" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Methotrexate for psoriasis" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ 0 => "R.B. Rees" 1 => "J.H. Beenett" 2 => "H.I. Maibach" 3 => "H.L. 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Year/Month | Html | Total | |
---|---|---|---|
2024 November | 9 | 6 | 15 |
2024 October | 96 | 47 | 143 |
2024 September | 122 | 37 | 159 |
2024 August | 110 | 47 | 157 |
2024 July | 100 | 30 | 130 |
2024 June | 107 | 35 | 142 |
2024 May | 100 | 42 | 142 |
2024 April | 90 | 29 | 119 |
2024 March | 82 | 21 | 103 |
2024 February | 82 | 29 | 111 |
2024 January | 90 | 34 | 124 |
2023 December | 63 | 24 | 87 |
2023 November | 70 | 22 | 92 |
2023 October | 53 | 26 | 79 |
2023 September | 60 | 40 | 100 |
2023 August | 46 | 21 | 67 |
2023 July | 64 | 31 | 95 |
2023 June | 56 | 18 | 74 |
2023 May | 66 | 27 | 93 |
2023 April | 71 | 20 | 91 |
2023 March | 83 | 29 | 112 |
2023 February | 41 | 42 | 83 |
2023 January | 43 | 50 | 93 |
2022 December | 66 | 45 | 111 |
2022 November | 42 | 32 | 74 |
2022 October | 21 | 31 | 52 |
2022 September | 23 | 51 | 74 |
2022 August | 13 | 32 | 45 |
2022 July | 20 | 43 | 63 |
2022 June | 33 | 32 | 65 |
2022 May | 74 | 61 | 135 |
2022 April | 104 | 39 | 143 |
2022 March | 133 | 53 | 186 |
2022 February | 124 | 34 | 158 |
2022 January | 138 | 45 | 183 |
2021 December | 81 | 42 | 123 |
2021 November | 119 | 43 | 162 |
2021 October | 101 | 52 | 153 |
2021 September | 79 | 39 | 118 |
2021 August | 89 | 39 | 128 |
2021 July | 73 | 23 | 96 |
2021 June | 83 | 29 | 112 |
2021 May | 129 | 54 | 183 |
2021 April | 204 | 70 | 274 |
2021 March | 142 | 31 | 173 |
2021 February | 117 | 46 | 163 |
2021 January | 79 | 18 | 97 |
2020 December | 65 | 22 | 87 |
2020 November | 52 | 34 | 86 |
2020 October | 52 | 28 | 80 |
2020 September | 40 | 21 | 61 |
2020 August | 46 | 31 | 77 |
2020 July | 42 | 26 | 68 |
2020 June | 45 | 28 | 73 |
2020 May | 42 | 31 | 73 |
2020 April | 41 | 35 | 76 |
2020 March | 21 | 19 | 40 |
2020 February | 8 | 15 | 23 |
2020 January | 6 | 13 | 19 |
2019 December | 8 | 31 | 39 |
2019 November | 4 | 9 | 13 |
2019 October | 0 | 15 | 15 |
2019 September | 4 | 11 | 15 |
2019 August | 4 | 18 | 22 |
2019 July | 4 | 22 | 26 |
2019 June | 6 | 33 | 39 |
2019 May | 4 | 150 | 154 |
2019 April | 2 | 61 | 63 |
2019 March | 4 | 38 | 42 |
2019 February | 0 | 22 | 22 |
2019 January | 4 | 17 | 21 |
2018 December | 3 | 24 | 27 |
2018 November | 0 | 3 | 3 |
2018 October | 3 | 0 | 3 |
2018 September | 4 | 13 | 17 |
2018 August | 0 | 28 | 28 |
2018 July | 0 | 40 | 40 |
2018 June | 0 | 19 | 19 |
2018 May | 0 | 1 | 1 |
2018 March | 1 | 13 | 14 |
2018 February | 82 | 21 | 103 |
2018 January | 109 | 15 | 124 |
2017 December | 92 | 25 | 117 |
2017 November | 112 | 20 | 132 |
2017 October | 101 | 23 | 124 |
2017 September | 82 | 19 | 101 |
2017 August | 86 | 47 | 133 |
2017 July | 82 | 22 | 104 |
2017 June | 132 | 36 | 168 |
2017 May | 115 | 25 | 140 |
2017 April | 120 | 44 | 164 |
2017 March | 165 | 64 | 229 |
2017 February | 330 | 34 | 364 |
2017 January | 125 | 30 | 155 |
2016 December | 119 | 17 | 136 |
2016 November | 165 | 19 | 184 |
2016 October | 191 | 22 | 213 |
2016 September | 244 | 29 | 273 |
2016 August | 165 | 28 | 193 |
2016 July | 175 | 21 | 196 |
2016 June | 7 | 6 | 13 |
2016 May | 10 | 4 | 14 |
2016 April | 7 | 1 | 8 |
2016 March | 5 | 1 | 6 |
2016 February | 8 | 30 | 38 |
2016 January | 8 | 23 | 31 |
2015 December | 11 | 17 | 28 |
2015 November | 16 | 19 | 35 |
2015 October | 15 | 1 | 16 |
2015 September | 6 | 22 | 28 |
2015 August | 10 | 1 | 11 |
2015 July | 107 | 10 | 117 |
2015 June | 83 | 7 | 90 |
2015 May | 126 | 7 | 133 |
2015 April | 94 | 10 | 104 |
2015 March | 123 | 9 | 132 |
2015 February | 99 | 15 | 114 |
2015 January | 73 | 7 | 80 |
2014 December | 86 | 10 | 96 |
2014 November | 50 | 9 | 59 |
2014 October | 66 | 18 | 84 |
2014 September | 56 | 14 | 70 |
2014 August | 64 | 15 | 79 |
2014 July | 61 | 16 | 77 |
2014 June | 102 | 20 | 122 |
2014 May | 80 | 17 | 97 |
2014 April | 81 | 9 | 90 |
2014 March | 94 | 19 | 113 |
2014 February | 50 | 28 | 78 |
2014 January | 62 | 28 | 90 |
2013 December | 37 | 22 | 59 |
2013 November | 28 | 17 | 45 |
2013 October | 12 | 15 | 27 |
2013 September | 9 | 13 | 22 |
2013 August | 12 | 38 | 50 |
2013 July | 15 | 28 | 43 |
2013 June | 13 | 64 | 77 |
2013 May | 15 | 29 | 44 |
2013 April | 7 | 29 | 36 |
2013 March | 18 | 17 | 35 |
2013 February | 39 | 7 | 46 |
2013 January | 43 | 17 | 60 |
2012 December | 24 | 11 | 35 |
2012 November | 2 | 4 | 6 |
2012 October | 9 | 11 | 20 |
2012 September | 0 | 7 | 7 |
2012 August | 1 | 0 | 1 |