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          "en" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Main anti-inflammatory mechanisms of action of colchicine&#46;</p>"
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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Coronavirus &#40;COVID-19&#41; infection and the mortality associated with the acute respiratory distress syndrome &#40;hereafter referred to as ARDS&#41; poses a global public health challenge&#46;<a class="elsevierStyleCrossRef" href="#bib0145"><span class="elsevierStyleSup">1</span></a> To date&#44; it exceeds two and a half million infections worldwide with a mortality rate that is greater than 7&#46;08&#37;&#46; The increase in the spread and associated mortality poses a scenario where cost-effective therapeutic options to control the epidemic and decrease the number of deaths are urgently recommended to the international scientific community&#46; Several reports show that the common final event that increases mortality from COVID-19 infection is ARDS&#44; which results from an unmodulated inflammatory response and leads to death&#46;<a class="elsevierStyleCrossRefs" href="#bib0145"><span class="elsevierStyleSup">1&#44;2</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">It has been a challenge to identify targets where drugs will useful for controlling and treating the new coronavirus COVID-19 infection&#46; Currently several potential drugs are used at different stages of the disease&#59; however none of the therapies have been proven to be completely effective to date&#46;<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">3</span></a> One possible useful drug is colchicine&#44; a molecule commonly used to treat different diseases such as gout and some autoinflammatory syndromes such as Adult-onset Still&#39;s disease&#44; Beh&#231;et&#39;s disease or familial Mediterranean Fever as well cardiac conditions&#44; etc&#46;<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">4</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">Colchicine has been used for more than 10 years for symptomatic treatment of patients with iatrogenic allogenosis &#40;IA&#41;&#44; a disease caused by allogenic substances like modeling agents or biopolymers that are foreign to the body&#46;<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">5</span></a> Colchicine decreases the symptoms these patients have that are associated with inflammatory response&#44; and some clinical manifestations such as arthralgia&#44; headache&#44; and pulmonary infiltrates&#46; These patients experience clinical improvement&#44; and the manifestations decrease in frequency&#46;</p><p id="par0020" class="elsevierStylePara elsevierViewall">In the light of current information&#44; a summary of recent knowledge about colchicine mechanisms of action and metabolic pathways that might explain the immunomodulatory effects that lead to preventing ARDS associated with COVID-19 infection and its possible effects on viral replication and antigen presentation are presented&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Mechanisms of action</span><p id="par0025" class="elsevierStylePara elsevierViewall">Colchicine is a tricyclic alkaloid that is extracted from the plant Colchicum autumnale&#46; Colchicine acts as a potent inhibitor of tubulin polymerization&#46; The mechanism studied the most is colchicine&#39;s high affinity for binding to the &#946;-tubulin subunit to prevent it from assembling and thus block microtubule polymerization&#46;<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">6</span></a> Microtubules are the key piece of the cytoskeleton and are involved in multiple cellular processes such as maintaining the shape of the cell&#44; transferring intracellular substances&#44; secreting cytokines and chemokines&#44; cell migration&#44; regulating ion channels&#44; and cell division&#46; Colchicine is an antimitotic substance that blocks cell division during metaphase&#46;<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">6</span></a> It stimulates independent GTPase activity to promote the loss of the microtubule GTP cap and prevent assembly&#46; When colchicine binds to tubulin&#44; the straight conformation of the &#945;&#946;-tubulin heterodimeric subunits is lost resulting in curved tubulin heterodimers&#46; The lateral contacts between adjacent &#945;&#946;-subunits that are needed to maintain interaction between them is lost and&#44; as lateral contacts decrease&#44; microtubules disassemble&#46; Colchicine may also modify the voltage-dependent anion channels of mitochondrial membranes&#44; thereby limiting mitochondrial metabolism&#46;<a class="elsevierStyleCrossRef" href="#bib0175"><span class="elsevierStyleSup">7</span></a> Colchicine has an additional effect on the chemotaxis of inflammatory cells such as neutrophils and monocytes and on the intracellular transportation of vesicles such as endosomes and exosomes&#46; It also inhibits the expression of E-selectin&#44; an adhesion molecule important for binding leukocytes to endothelial cells and the recruitment of monocytes and neutrophils to inflamed tissue&#46; Finally&#44; colchicine reduces the neutrophil production of free radicals like superoxide&#46;<a class="elsevierStyleCrossRef" href="#bib0180"><span class="elsevierStyleSup">8</span></a> It has also been associated with disrupting inflammasome activation&#44; thereby suppressing caspase-1 activation and the subsequent release of IL-1&#946; and IL-18&#46;<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">9</span></a> The SARS-CoV-1 infection has been associated with inflammasome activation<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">10</span></a> by calcium ion transportation leading to IL-1-&#946; overproduction&#44;<a class="elsevierStyleCrossRef" href="#bib0195"><span class="elsevierStyleSup">11</span></a> direct caspase-1 activation&#44; or an enhanced potassium efflux<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">12</span></a> &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#46; Within the bloodstream&#44; &#8764;40&#37; of colchicine binds to albumin&#46; Peak plasma concentrations occur 1<span class="elsevierStyleHsp" style=""></span>h after administration and maximal anti-inflammatory effects develop over 24&#8211;48<span class="elsevierStyleHsp" style=""></span>h based on intra-leukocyte accumulation&#46; Colchicine reaches much higher concentrations within leukocytes than in plasma and persists there for several days after ingestion&#46; All of this explains in part its fast blockage of acute inflammatory diseases such as gout&#46;<a class="elsevierStyleCrossRef" href="#bib0205"><span class="elsevierStyleSup">13</span></a></p><elsevierMultimedia ident="fig0005"></elsevierMultimedia></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Metabolism and elimination</span><p id="par0030" class="elsevierStylePara elsevierViewall">Colchicine is eliminated from the body mainly through transportation by P-glycoprotein &#91;P-gp&#44; also known as multi-drug resistant protein 1 &#40;MDR1&#41; or ATP-binding cassette subfamily B member 1 &#40;ABCB1&#41;&#93; expressed in hepatocytes &#40;biliary excretion&#41;&#44; proximal renal tubules &#40;renal excretion&#41;&#44; enteric cells &#40;intestinal excretion&#41;&#44; monocytes&#44; and blood-brain barrier cells&#46; The P glycoprotein is encoded by the MDR1 gene&#44; and certain MDR1 polymorphisms are associated with increased P-gp expression&#47;activity and decreased serum colchicine concentrations&#46;<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">14</span></a> A smaller&#44; but significant quantity of absorbed colchicine is metabolized by hepatic P450 cytochrome CYP3A4&#44; or directly eliminated by the kidneys through glomerular filtration&#46; All of these mechanisms are vulnerable to drug interaction which can affect bloodstream levels&#46;<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">6</span></a></p><p id="par0035" class="elsevierStylePara elsevierViewall">In general&#44; colchicine has been safely administered&#46; However&#44; when there is an overdose&#44; toxicity includes neutropenia&#44; gastrointestinal upset&#44; bone marrow damage&#44; and anemia&#46; Colchicine&#39;s toxicity is due to its antimitotic properties&#46; It binds to tubulin in cells and causes impaired protein assembly&#44; mitotic arrest&#44; and multi-organ dysfunction but is safe when used according to the established therapeutic guidelines&#44; and toxicity is rare if the recommended doses are not exceeded&#46;<a class="elsevierStyleCrossRef" href="#bib0175"><span class="elsevierStyleSup">7</span></a></p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Clinical cases description&#58; Iatrogenic allogenosis patients infected with COVID19 under colchicine treatment</span><p id="par0040" class="elsevierStylePara elsevierViewall">Five cases with a clinical history of biopolymers in the gluteal region who developed IA and comorbidities with a high probability of an autoimmune&#47;inflammatory syndrome induced by adjuvants &#40;ASIA Syndrome&#41; or Schoenfeld&#39;s Syndrome are presented &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">15</span></a> Colchicine was used for the symptomatic management of the clinical manifestations of IA&#46; These patients were treated with an initial impregnation dose as is done in the management of an acute attack of gout&#58; First day&#58; 1<span class="elsevierStyleHsp" style=""></span>mg every 8<span class="elsevierStyleHsp" style=""></span>h&#46; Second day&#58; 1<span class="elsevierStyleHsp" style=""></span>mg every 12<span class="elsevierStyleHsp" style=""></span>h and from the third day on a maintenance dose of 0&#46;5&#8211;1<span class="elsevierStyleHsp" style=""></span>mg per day for 3&#8211;4 weeks until remission of symptoms&#46; This is repeated between 1 and 3 times a year depending on the reappearance of symptoms such as&#58; pain&#44; erythema&#44; arthralgia&#44; headache&#44; insomnia&#44; and depression&#46; In general&#44; control is regained over the inflammatory or autoimmune process that occurred in these patients&#46; A similar use has been shown and a favorable outcome has been achieved with colchicine in patients with foreign body granuloma as an inflammatory tissue reaction to exogenous material &#40;therapeutic embolization of the facial arteries&#41;&#44;<a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">16</span></a> or Granuloma faciale<a class="elsevierStyleCrossRef" href="#bib0225"><span class="elsevierStyleSup">17</span></a> and in cases of oleoma<a class="elsevierStyleCrossRef" href="#bib0230"><span class="elsevierStyleSup">18</span></a> &#40;a non-allergic&#44; foreign body type granulomatous reaction in response to oily exogenous substances injected into the dermis or subcutis for esthetical purposes&#41;&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0045" class="elsevierStylePara elsevierViewall">The five patients were diagnosed with IA and comorbidities &#40;age&#44; arterial hypertension&#44; diabetes&#44; hypothyroidism&#41; and were put under colchicine treatment for IA crisis 3 weeks ago&#46; These patients developed mild symptoms &#40;headache&#44; cough without dyspnea&#44; and arthralgias&#41; and were positive when tested for COVID-19 RT-PCRT&#46; However&#44; they did not need to be hospitalized for treatment&#46; It should be noted that three close contacts presented severe symptoms and died&#44; whereas other close contacts experienced mild symptoms&#46; Based on these cases&#44; we hypothesized a possible protective effect of colchicine among the IA patients who did not suffer a severe COVID-19 infection even though they had several comorbidities and a possible disrupted immune system because of ASIA Syndrome which has been reported to be a risk factor for patients with the new pandemic disease&#46;<a class="elsevierStyleCrossRef" href="#bib0235"><span class="elsevierStyleSup">19</span></a></p><p id="par0050" class="elsevierStylePara elsevierViewall">Recently&#44; Gandolfini et al&#46;<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">20</span></a> showed the possible colchicine therapeutic effect &#40;applied at 120<span class="elsevierStyleHsp" style=""></span>mg&#41; on a 52-year-old female who developed COVID-19 8 months after a kidney transplant&#46; The patient received antiviral therapy plus hydroxychloroquine&#46; After progressive worsening of respiratory conditions requiring non-invasive ventilation and being considered for intubation&#44; the antiviral therapy was ended&#44; and the patient was put on colchicine &#40;1<span class="elsevierStyleHsp" style=""></span>mg on day 8&#44; and 0&#46;5<span class="elsevierStyleHsp" style=""></span>mg&#47;day thereafter&#41; to reduce inflammation due to the unavailability of anti-IL-6 receptor mAb tocilizumab&#46; Authors concluded that the immunosuppression interruption combined with the anti-inflammatory effects of colchicine may have synergized with the antiviral therapy and hydroxychloroquine to lower viral replication and minimize the cytokine storm triggered by SARS-CoV-2&#46;</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Possible uses of colchicine to prevent acute respiratory distress syndrome &#40;ARDS&#41; in patients with COVID-19 infection</span><p id="par0055" class="elsevierStylePara elsevierViewall">Studies showing the behavior of the COVID-19 infection indicate that between 70 and 80&#37; of the infected population will have mild or moderate symptoms&#44; 15&#37; will have severe infections manifested by severe dyspnea with hypoxemia and pulmonary infiltrates&#44; and 5&#37; will have critical conditions with respiratory failure&#44; septic shock&#44; and multi-organ dysfunction&#46;<a class="elsevierStyleCrossRef" href="#bib0245"><span class="elsevierStyleSup">21</span></a> Patients in higher age groups &#40;over 60 years old&#41; and with associated comorbidities such as hypertension and diabetes have the highest mortality rates&#46;<a class="elsevierStyleCrossRef" href="#bib0250"><span class="elsevierStyleSup">22</span></a> Among the predictors of worse prognosis are the presence of dyspnea&#44; lymphopenia&#44; elevated neutrophils&#44; and decreased monocytes and platelets&#46; The CD4 and CD8 T lymphocyte count is lower&#44; and the ureic nitrogen and creatinine is higher&#46; In other words&#44; there is an evident suppression of cellular immunity along with a severe inflammatory reaction that can lead to death&#46; There is a greater proportion of dyspnea symptoms in patients who die compared to survivors who do not suffer fevers&#44; headaches&#44; and other symptoms &#40;<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>&#46;001&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0250"><span class="elsevierStyleSup">22</span></a> Other factors that are prevalent in patients who die from COVID-19 are a decrease in albumin&#44; an increase in lactate&#44; a slight decrease in the number of red cells and hemoglobin&#44; and an increase in lactic dehydrogenase&#46;<a class="elsevierStyleCrossRef" href="#bib0255"><span class="elsevierStyleSup">23</span></a> Among the predictors of the best prognosis are a high level of lymphocytes and female gender&#44; characteristics that appear in a greater proportion in the group of survivors&#46;</p><p id="par0060" class="elsevierStylePara elsevierViewall">ARDS appears to be the common final path leading to the death of the patient&#46; All patients die of respiratory failure thus indicating that the lungs are the target organ&#46; Furthermore&#44; when multiorgan failure occurs&#44; the most compromised organ after the lung is the heart followed by the kidney and liver&#46; There is elevated procalcitonin in 0&#46;5&#37; of the patients&#44; probably as an indicator of bacterial infection&#46; Patients who die have a severe inflammatory cascade which is reflected in increased C-reactive protein and serum amyloid A&#46;<a class="elsevierStyleCrossRefs" href="#bib0255"><span class="elsevierStyleSup">23&#44;24</span></a></p><p id="par0065" class="elsevierStylePara elsevierViewall">ARDS is believed to be the result of an injury to the alveolar epithelium and capillary endothelium with abnormalities in the immune system&#46; Neutrophils are recruited to the lungs by cytokines while toxic mediators such as oxygen free radicals and proteases are activated and released&#46;<a class="elsevierStyleCrossRef" href="#bib0265"><span class="elsevierStyleSup">25</span></a> Extensive production of free radicals exceeds the capacity of endogenous antioxidants and causes oxidative cell damage&#46; Factors such as endothelin-1&#44; angiotensin-2&#44; NF-kappa B&#44; and phospholipase A-2 increase vascular permeability and destroy microvascular architecture thus increasing inflammation and lung damage&#46;<a class="elsevierStyleCrossRef" href="#bib0265"><span class="elsevierStyleSup">25</span></a> This results in an influx of protein-rich fluid into the airspaces caused by increased permeability of the alveolar-capillary barrier&#46; Increased alveolar fluid reduces gas exchange through the alveolar-capillary membrane and results in hypoxemia and respiratory failure&#46; However&#44; no sensitive and specific clinical biomarkers for ARDS have been found&#46; Dyspnea is also a predictive element&#46;<a class="elsevierStyleCrossRef" href="#bib0265"><span class="elsevierStyleSup">25</span></a></p><p id="par0070" class="elsevierStylePara elsevierViewall">Efforts should focus on preventing the development of ARDS in patients with COVID-19 infections since once it occurs&#44; mortality is very high and our health systems do not have the capacity to care for as many critically ill patients as has been seen in Italy&#44; Spain and currently&#44; the USA&#46;</p><p id="par0075" class="elsevierStylePara elsevierViewall">Therefore&#44; we propose the use of colchicine in patients who are at risk of developing ARDS and who meet clinical and laboratory criteria that predict the appearance of ARDS&#46;</p><p id="par0080" class="elsevierStylePara elsevierViewall">A lot of attention has been given to the effects of colchicine on macrophages&#46; Colchicine has been shown to modulate lipopolysaccharide-induced secretion of tumor necrosis factor &#40;TNF&#41; by liver macrophages in a rat model&#46;<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">6</span></a> In a mouse brain macrophage cell line&#44; colchicine inhibited ATP-induced IL1&#946; release by preventing microtubule rearrangement and constraining activation of the Ras homolog gene family&#44; which contains the protein kinase &#40;ROCK&#41; pathway&#46; In the presence of colchicine&#44; mouse peritoneal macrophages showed less ATP-induced permeability to ethidium bromide and less formation of reactive species of oxygen &#40;ROS&#41;&#44; nitric oxide &#40;NO&#41;&#44; IL1&#946; release&#44; crystal-induced chemotactic factor&#44; myeloid inhibitory C type-like lectin&#44; toll-like receptors&#44; and vascular endothelial growth factor&#46;<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">6</span></a> All these compounds intervene to intensify the inflammatory process and are responsible for alveolar damage&#44; interstitial infiltration&#44; and lung collapse&#46; Colchicine can minimize such damage using different paths&#46;</p><p id="par0085" class="elsevierStylePara elsevierViewall">Colchicine has been studied as a possible treatment in other viral diseases&#46; Taking into consideration the promising anti-inflammatory property and good bioavailability of colchicine&#44; Lu et al&#46;<a class="elsevierStyleCrossRef" href="#bib0270"><span class="elsevierStyleSup">26</span></a> recently studied its role in inhibiting respiratory syncytial virus replication infection in vitro in BEAS-2B cells as well in vivo in neonatal rats&#46; They showed that colchicine inhibited RSV infection in neonatal rats through regulation of anti-oxidative factor production&#46; The expression of IFN-&#946;1 and RIG-I genes was also up-regulated in the RSV infected alveolar epithelial cells by treatment with colchicine&#46;</p><p id="par0090" class="elsevierStylePara elsevierViewall">An additional plausible link between the possible protective role for patients with COVID-19 and using colchicine is its effect on interferon mechanisms in viral infections that was studied decades ago&#46;<a class="elsevierStyleCrossRef" href="#bib0275"><span class="elsevierStyleSup">27</span></a> Reizin et al&#46;<a class="elsevierStyleCrossRef" href="#bib0280"><span class="elsevierStyleSup">28</span></a> demonstrated that colchicine inhibits interferon synthesis induced by the Lee strain of influenza B virus in chick embryo cells&#44; but it does not influence the release of preformed interferon from cells&#46; Colchicine was found to be most effective when it was introduced into the medium at early stages of infection&#46; It may also inhibit the formation of messenger RNA for interferonogenesis&#46;</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Colchicine clinical trials in COVID19</span><p id="par0095" class="elsevierStylePara elsevierViewall">Colchicine may be a good therapeutic option for COVID-19&#46; Currently&#44; there are only nine clinical trials considering the clinical utility of colchicine&#46; These include the Colchicine Coronavirus SARS-CoV2 Trial &#40;COLCORONA&#41; <a href="ctgov:NCT04322682">NCT04322682</a>&#44; the only trial recruiting patients&#44; the ECLA PHRI COLCOVID Trial <a href="ctgov:NCT04328480">NCT04328480</a>&#44; the GReek Study of the Effects of Colchicine on Covid-19 Complication Prevention &#40;GRECCO-19&#41; <a href="ctgov:NCT04326790">NCT04326790</a>&#44; the Colchicine to Reduce Myocardial Injury in COVID-19 &#40;COLHEART-19&#41; <a href="ctgov:NCT04355143">NCT04355143</a>&#44; and the Colchicine Counteracting Inflammation in COVID-19 Pneumonia <a href="ctgov:NCT04322565">NCT04322565</a> among others that will begin recruiting patients shortly&#46; Hopefully&#44; their results will come out soon&#46;</p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Conclusion</span><p id="par0100" class="elsevierStylePara elsevierViewall">The global medical community does not know whether rheumatic disease or immunosuppression increases the initial risk of COVID-19 infection&#46; It is not clear based upon current information whether the ingestion of colchicine by healthy patients may place the patient in an immunosuppressed condition&#46;</p><p id="par0105" class="elsevierStylePara elsevierViewall">Despite concerns that immunosuppressive drugs may increase the risk of complications for infected patients&#44; there is hope that the anti-inflammatory properties of these drugs may mitigate lung injury&#46; COVID-19 infection can give rise to what has been called &#8220;a cytokine storm&#8221; &#40;i&#46;e&#46; macrophage activation syndrome&#41;&#46; In such situations&#44; there is a massive release of various cytokines&#46; Therefore&#44; some of the biological immunosuppressive drugs used by rheumatologists may be effective in treating serious COVID-19 infections&#46;</p><p id="par0110" class="elsevierStylePara elsevierViewall">For instance&#44; interleukin blockers &#40;IL-1 and IL-6&#41; have been effective in ARDS&#46; There is also evidence that tumor necrosis factor &#40;TNF&#41; inhibitors may be effective&#46;</p><p id="par0115" class="elsevierStylePara elsevierViewall">In this respect&#44; in the risk-benefit and cost-effectiveness balance&#44; the administration of colchicine to healthy patients or those at risk of an ARDS complication should be evaluated&#46; The benefits exceed the risks of its use&#44; thus&#44; in an emergency situation caused by the current pandemic&#44; we would recommend using colchicine&#46;</p><p id="par0120" class="elsevierStylePara elsevierViewall">In this context&#44; the properties of colchicine&#44; as previously described&#44; can be used to decrease the risk of ARDS in patients with COVID-19 infection&#46; Given its relatively good safety record and tolerability profile when used carefully and appropriately&#44; it should be implemented through the proposed protocols&#46; This would provide an opportunity to decrease the results of the infection and allow for clinical observation&#46;</p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Conflict of interests</span><p id="par0125" class="elsevierStylePara elsevierViewall">The authors declare that there is no conflict of interests&#46;</p></span></span>"
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          "titulo" => "Introduction"
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          "titulo" => "Mechanisms of action"
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          "identificador" => "sec0015"
          "titulo" => "Metabolism and elimination"
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          "identificador" => "sec0020"
          "titulo" => "Clinical cases description&#58; Iatrogenic allogenosis patients infected with COVID19 under colchicine treatment"
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          "identificador" => "sec0025"
          "titulo" => "Possible uses of colchicine to prevent acute respiratory distress syndrome &#40;ARDS&#41; in patients with COVID-19 infection"
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          "identificador" => "sec0030"
          "titulo" => "Colchicine clinical trials in COVID19"
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          "titulo" => "Conclusion"
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          "titulo" => "References"
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    "fechaRecibido" => "2020-04-30"
    "fechaAceptado" => "2020-05-08"
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            0 => "COVID-19"
            1 => "SARS-CoV-2"
            2 => "Colchicine"
            3 => "Inflammasome"
            4 => "ARDS"
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            0 => "COVID-19"
            1 => "SARS-CoV-2"
            2 => "Colchicina"
            3 => "Inflamasoma"
            4 => "S&#237;ndrome de distr&#233;s respiratorio agudo"
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        "titulo" => "Abstract"
        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">COVID-19 is a newly emerged disease that has become a global public health challenge&#46; Due to a lack of knowledge about the virus&#44; a significant number of potential targets for using a particular drug have been proposed&#46; Five cases with a clinical history of biopolymers in the gluteal region that developed iatrogenic allogenosis &#40;IA&#41; are presented here&#46; The 5 cases were put under colchicine treatment for IA crisis and had non-specific symptoms &#40;headache&#44; cough without dyspnea&#44; and arthralgias&#41; with a positive SARS-CoV-2 test&#46; Their close contacts had mild to severe symptoms and three of them died&#46; In the SARS-CoV-2 infection different inflammatory pathways are altered where colchicine reduces cytokine levels as well as the activation of macrophages&#44; neutrophils&#44; and the inflammasome&#46; The possible mechanisms that colchicine may use to prevent acute respiratory distress syndrome &#40;ARDS&#41; in patients with COVID-19 infection are also reviewed in this article&#46;</p></span>"
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        "titulo" => "Resumen"
        "resumen" => "<span id="abst0010" class="elsevierStyleSection elsevierViewall"><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">COVID-19 es una enfermedad de aparici&#243;n reciente&#44; que se ha convertido en un reto global de salud p&#250;blica&#46; Debido a la falta de conocimiento acerca del virus&#44; se ha propuesto un n&#250;mero significativo de objetivos potenciales para utilizar un f&#225;rmaco en particular&#46; Presentamos 5 casos con historia cl&#237;nica de biopol&#237;meros en la regi&#243;n gl&#250;tea&#44; que desarrollaron alogenosis iatrog&#233;nica &#40;AI&#41;&#46; A los 5 casos se les administr&#243; tratamiento de colchicina debido a la crisis de AI&#44; no teniendo s&#237;ntomas espec&#237;ficos &#40;cefalea&#44; tos sin disnea y artralgias&#41;&#44; con resultado positivo en el test de SARS-CoV-2&#46; Sus contactos cercanos ten&#237;an s&#237;ntomas de leves a graves&#44; y 3 de ellos fallecieron&#46; En la infecci&#243;n por SARS-CoV-2 se alteran diferentes rutas inflamatorias&#44; en las que la colchicina reduce los niveles de citocinas y la activaci&#243;n de macr&#243;fagos&#44; neutr&#243;filos e inflamasoma&#46; Revisamos tambi&#233;n&#44; en este art&#237;culo&#44; los posibles mecanismos que puede utilizar colchicina para prevenir el s&#237;ndrome de distr&#233;s respiratorio agudo &#40;SDRA&#41; en pacientes con COVID-19&#46;</p></span>"
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          "leyenda" => "<p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Kg&#58; kilograms&#59; mg&#58; milligrams&#59; mcg&#58; micrograms&#59; ARDS&#58; acute respiratory distress syndrome&#59; ICU&#58; intensive care unit&#46;</p>"
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                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Case&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Age &#40;years&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Weight&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Colchicine dosage &#40;oral&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Years before of biopolymers injections&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Colchicine consumption before COVID-19 diagnosis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Comorbidities&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Clinical manifestation&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Close contact COVID-19 positive&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t">61&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t">68<span class="elsevierStyleHsp" style=""></span>kg&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;5<span class="elsevierStyleHsp" style=""></span>mg per day&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t">15&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">3 weeks&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Arterial hypertension treated with enalapril 10<span class="elsevierStyleHsp" style=""></span>mg&#47;day&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Subjective fever and headache during 5 days&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">68-Year-old aunt who lived with her&#44; with arterial hypertension&#46; She died in the ICU due to ARDS and multi-system failure&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">57&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">74<span class="elsevierStyleHsp" style=""></span>kg&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1<span class="elsevierStyleHsp" style=""></span>mg per day&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">12&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2 weeks before diagnosis and 1 week after&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">Type 2 diabetes treated with metformin&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">Headache during 3 days and dry cough without dyspnea&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">45-Year-old sister hospitalized for dyspnea&#44; did not require an ICU&#46;25-year-old cousin with mild cough and headache&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t">48&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t">66<span class="elsevierStyleHsp" style=""></span>kg&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;5<span class="elsevierStyleHsp" style=""></span>mg per day&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">8&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1 week&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Hypothyroidism treated with levothyroxine 100 mcg&#47;day&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">Headache during 5 days and mild cough&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Husband with headache and dry cough&#46; Children of 14 and 19 years old were asymptomatic&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t">4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t">38&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t">52<span class="elsevierStyleHsp" style=""></span>kg&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;5<span class="elsevierStyleHsp" style=""></span>mg per day&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t">6&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">3 weeks&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Fibromyalgia after biopolymers injections&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Dry cough without dyspnea&#46; Myalgias during 5 days&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">56-Year-old cousin died&#46; She does not live with her but has close contact &#40;birthday celebration&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t">5&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t">45&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">62<span class="elsevierStyleHsp" style=""></span>kg&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">0&#46;5<span class="elsevierStyleHsp" style=""></span>mg per day&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t">10&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">2 weeks&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t\ttop\n
                  \t\t\t\t">Hashimoto&#39;s thyroiditis&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t">Nonspecific arthralgias&#44; subjective fever&#44; and odynophagia&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">86-Year-old grandmother who lived with her&#44; with arterial hypertension died&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
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          "en" => "<p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Characteristics of patients with Colchicine treatment before COVID-19 diagnosis&#46;</p>"
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Special Article
Colchicine: A potential therapeutic tool against COVID-19. Experience of 5 patients
Colchicina: una herramienta terapéutica potencial frente a COVID-19. Experiencia en 5 pacientes
Giovanni Montealegre-Gómeza, Edgar Garavitob, Arley Gómez-Lópezc, Adriana Rojas-Villarragac, Rafael Parra-Medinac,d,
Autor para correspondencia
rafa.parram@gmail.com

Corresponding author.
a Department of Plastic and Reconstructive Surgery, Hospital de San José, Fundación Universitaria de Ciencias de la Salud, Bogotá, Colombia
b Immunology Department, Fundación Universitaria de Ciencias de la Salud, Bogotá, Colombia
c Research Institute, Fundación Universitaria de Ciencias de la Salud, Bogotá, Colombia
d Department of Pathology, Fundación Universitaria de Ciencias de la Salud, Bogotá, Colombia
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    "cabecera" => "<span class="elsevierStyleTextfn">Special Article</span>"
    "titulo" => "Colchicine&#58; A potential therapeutic tool against COVID-19&#46; Experience of 5 patients"
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            "entidad" => "Department of Plastic and Reconstructive Surgery&#44; Hospital de San Jos&#233;&#44; Fundaci&#243;n Universitaria de Ciencias de la Salud&#44; Bogot&#225;&#44; Colombia"
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        "titulo" => "Colchicina&#58; una herramienta terap&#233;utica potencial frente a COVID-19&#46; Experiencia en 5 pacientes"
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          "en" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Main anti-inflammatory mechanisms of action of colchicine&#46;</p>"
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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Coronavirus &#40;COVID-19&#41; infection and the mortality associated with the acute respiratory distress syndrome &#40;hereafter referred to as ARDS&#41; poses a global public health challenge&#46;<a class="elsevierStyleCrossRef" href="#bib0145"><span class="elsevierStyleSup">1</span></a> To date&#44; it exceeds two and a half million infections worldwide with a mortality rate that is greater than 7&#46;08&#37;&#46; The increase in the spread and associated mortality poses a scenario where cost-effective therapeutic options to control the epidemic and decrease the number of deaths are urgently recommended to the international scientific community&#46; Several reports show that the common final event that increases mortality from COVID-19 infection is ARDS&#44; which results from an unmodulated inflammatory response and leads to death&#46;<a class="elsevierStyleCrossRefs" href="#bib0145"><span class="elsevierStyleSup">1&#44;2</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">It has been a challenge to identify targets where drugs will useful for controlling and treating the new coronavirus COVID-19 infection&#46; Currently several potential drugs are used at different stages of the disease&#59; however none of the therapies have been proven to be completely effective to date&#46;<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">3</span></a> One possible useful drug is colchicine&#44; a molecule commonly used to treat different diseases such as gout and some autoinflammatory syndromes such as Adult-onset Still&#39;s disease&#44; Beh&#231;et&#39;s disease or familial Mediterranean Fever as well cardiac conditions&#44; etc&#46;<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">4</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">Colchicine has been used for more than 10 years for symptomatic treatment of patients with iatrogenic allogenosis &#40;IA&#41;&#44; a disease caused by allogenic substances like modeling agents or biopolymers that are foreign to the body&#46;<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">5</span></a> Colchicine decreases the symptoms these patients have that are associated with inflammatory response&#44; and some clinical manifestations such as arthralgia&#44; headache&#44; and pulmonary infiltrates&#46; These patients experience clinical improvement&#44; and the manifestations decrease in frequency&#46;</p><p id="par0020" class="elsevierStylePara elsevierViewall">In the light of current information&#44; a summary of recent knowledge about colchicine mechanisms of action and metabolic pathways that might explain the immunomodulatory effects that lead to preventing ARDS associated with COVID-19 infection and its possible effects on viral replication and antigen presentation are presented&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Mechanisms of action</span><p id="par0025" class="elsevierStylePara elsevierViewall">Colchicine is a tricyclic alkaloid that is extracted from the plant Colchicum autumnale&#46; Colchicine acts as a potent inhibitor of tubulin polymerization&#46; The mechanism studied the most is colchicine&#39;s high affinity for binding to the &#946;-tubulin subunit to prevent it from assembling and thus block microtubule polymerization&#46;<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">6</span></a> Microtubules are the key piece of the cytoskeleton and are involved in multiple cellular processes such as maintaining the shape of the cell&#44; transferring intracellular substances&#44; secreting cytokines and chemokines&#44; cell migration&#44; regulating ion channels&#44; and cell division&#46; Colchicine is an antimitotic substance that blocks cell division during metaphase&#46;<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">6</span></a> It stimulates independent GTPase activity to promote the loss of the microtubule GTP cap and prevent assembly&#46; When colchicine binds to tubulin&#44; the straight conformation of the &#945;&#946;-tubulin heterodimeric subunits is lost resulting in curved tubulin heterodimers&#46; The lateral contacts between adjacent &#945;&#946;-subunits that are needed to maintain interaction between them is lost and&#44; as lateral contacts decrease&#44; microtubules disassemble&#46; Colchicine may also modify the voltage-dependent anion channels of mitochondrial membranes&#44; thereby limiting mitochondrial metabolism&#46;<a class="elsevierStyleCrossRef" href="#bib0175"><span class="elsevierStyleSup">7</span></a> Colchicine has an additional effect on the chemotaxis of inflammatory cells such as neutrophils and monocytes and on the intracellular transportation of vesicles such as endosomes and exosomes&#46; It also inhibits the expression of E-selectin&#44; an adhesion molecule important for binding leukocytes to endothelial cells and the recruitment of monocytes and neutrophils to inflamed tissue&#46; Finally&#44; colchicine reduces the neutrophil production of free radicals like superoxide&#46;<a class="elsevierStyleCrossRef" href="#bib0180"><span class="elsevierStyleSup">8</span></a> It has also been associated with disrupting inflammasome activation&#44; thereby suppressing caspase-1 activation and the subsequent release of IL-1&#946; and IL-18&#46;<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">9</span></a> The SARS-CoV-1 infection has been associated with inflammasome activation<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">10</span></a> by calcium ion transportation leading to IL-1-&#946; overproduction&#44;<a class="elsevierStyleCrossRef" href="#bib0195"><span class="elsevierStyleSup">11</span></a> direct caspase-1 activation&#44; or an enhanced potassium efflux<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">12</span></a> &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#46; Within the bloodstream&#44; &#8764;40&#37; of colchicine binds to albumin&#46; Peak plasma concentrations occur 1<span class="elsevierStyleHsp" style=""></span>h after administration and maximal anti-inflammatory effects develop over 24&#8211;48<span class="elsevierStyleHsp" style=""></span>h based on intra-leukocyte accumulation&#46; Colchicine reaches much higher concentrations within leukocytes than in plasma and persists there for several days after ingestion&#46; All of this explains in part its fast blockage of acute inflammatory diseases such as gout&#46;<a class="elsevierStyleCrossRef" href="#bib0205"><span class="elsevierStyleSup">13</span></a></p><elsevierMultimedia ident="fig0005"></elsevierMultimedia></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Metabolism and elimination</span><p id="par0030" class="elsevierStylePara elsevierViewall">Colchicine is eliminated from the body mainly through transportation by P-glycoprotein &#91;P-gp&#44; also known as multi-drug resistant protein 1 &#40;MDR1&#41; or ATP-binding cassette subfamily B member 1 &#40;ABCB1&#41;&#93; expressed in hepatocytes &#40;biliary excretion&#41;&#44; proximal renal tubules &#40;renal excretion&#41;&#44; enteric cells &#40;intestinal excretion&#41;&#44; monocytes&#44; and blood-brain barrier cells&#46; The P glycoprotein is encoded by the MDR1 gene&#44; and certain MDR1 polymorphisms are associated with increased P-gp expression&#47;activity and decreased serum colchicine concentrations&#46;<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">14</span></a> A smaller&#44; but significant quantity of absorbed colchicine is metabolized by hepatic P450 cytochrome CYP3A4&#44; or directly eliminated by the kidneys through glomerular filtration&#46; All of these mechanisms are vulnerable to drug interaction which can affect bloodstream levels&#46;<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">6</span></a></p><p id="par0035" class="elsevierStylePara elsevierViewall">In general&#44; colchicine has been safely administered&#46; However&#44; when there is an overdose&#44; toxicity includes neutropenia&#44; gastrointestinal upset&#44; bone marrow damage&#44; and anemia&#46; Colchicine&#39;s toxicity is due to its antimitotic properties&#46; It binds to tubulin in cells and causes impaired protein assembly&#44; mitotic arrest&#44; and multi-organ dysfunction but is safe when used according to the established therapeutic guidelines&#44; and toxicity is rare if the recommended doses are not exceeded&#46;<a class="elsevierStyleCrossRef" href="#bib0175"><span class="elsevierStyleSup">7</span></a></p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Clinical cases description&#58; Iatrogenic allogenosis patients infected with COVID19 under colchicine treatment</span><p id="par0040" class="elsevierStylePara elsevierViewall">Five cases with a clinical history of biopolymers in the gluteal region who developed IA and comorbidities with a high probability of an autoimmune&#47;inflammatory syndrome induced by adjuvants &#40;ASIA Syndrome&#41; or Schoenfeld&#39;s Syndrome are presented &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">15</span></a> Colchicine was used for the symptomatic management of the clinical manifestations of IA&#46; These patients were treated with an initial impregnation dose as is done in the management of an acute attack of gout&#58; First day&#58; 1<span class="elsevierStyleHsp" style=""></span>mg every 8<span class="elsevierStyleHsp" style=""></span>h&#46; Second day&#58; 1<span class="elsevierStyleHsp" style=""></span>mg every 12<span class="elsevierStyleHsp" style=""></span>h and from the third day on a maintenance dose of 0&#46;5&#8211;1<span class="elsevierStyleHsp" style=""></span>mg per day for 3&#8211;4 weeks until remission of symptoms&#46; This is repeated between 1 and 3 times a year depending on the reappearance of symptoms such as&#58; pain&#44; erythema&#44; arthralgia&#44; headache&#44; insomnia&#44; and depression&#46; In general&#44; control is regained over the inflammatory or autoimmune process that occurred in these patients&#46; A similar use has been shown and a favorable outcome has been achieved with colchicine in patients with foreign body granuloma as an inflammatory tissue reaction to exogenous material &#40;therapeutic embolization of the facial arteries&#41;&#44;<a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">16</span></a> or Granuloma faciale<a class="elsevierStyleCrossRef" href="#bib0225"><span class="elsevierStyleSup">17</span></a> and in cases of oleoma<a class="elsevierStyleCrossRef" href="#bib0230"><span class="elsevierStyleSup">18</span></a> &#40;a non-allergic&#44; foreign body type granulomatous reaction in response to oily exogenous substances injected into the dermis or subcutis for esthetical purposes&#41;&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0045" class="elsevierStylePara elsevierViewall">The five patients were diagnosed with IA and comorbidities &#40;age&#44; arterial hypertension&#44; diabetes&#44; hypothyroidism&#41; and were put under colchicine treatment for IA crisis 3 weeks ago&#46; These patients developed mild symptoms &#40;headache&#44; cough without dyspnea&#44; and arthralgias&#41; and were positive when tested for COVID-19 RT-PCRT&#46; However&#44; they did not need to be hospitalized for treatment&#46; It should be noted that three close contacts presented severe symptoms and died&#44; whereas other close contacts experienced mild symptoms&#46; Based on these cases&#44; we hypothesized a possible protective effect of colchicine among the IA patients who did not suffer a severe COVID-19 infection even though they had several comorbidities and a possible disrupted immune system because of ASIA Syndrome which has been reported to be a risk factor for patients with the new pandemic disease&#46;<a class="elsevierStyleCrossRef" href="#bib0235"><span class="elsevierStyleSup">19</span></a></p><p id="par0050" class="elsevierStylePara elsevierViewall">Recently&#44; Gandolfini et al&#46;<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">20</span></a> showed the possible colchicine therapeutic effect &#40;applied at 120<span class="elsevierStyleHsp" style=""></span>mg&#41; on a 52-year-old female who developed COVID-19 8 months after a kidney transplant&#46; The patient received antiviral therapy plus hydroxychloroquine&#46; After progressive worsening of respiratory conditions requiring non-invasive ventilation and being considered for intubation&#44; the antiviral therapy was ended&#44; and the patient was put on colchicine &#40;1<span class="elsevierStyleHsp" style=""></span>mg on day 8&#44; and 0&#46;5<span class="elsevierStyleHsp" style=""></span>mg&#47;day thereafter&#41; to reduce inflammation due to the unavailability of anti-IL-6 receptor mAb tocilizumab&#46; Authors concluded that the immunosuppression interruption combined with the anti-inflammatory effects of colchicine may have synergized with the antiviral therapy and hydroxychloroquine to lower viral replication and minimize the cytokine storm triggered by SARS-CoV-2&#46;</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Possible uses of colchicine to prevent acute respiratory distress syndrome &#40;ARDS&#41; in patients with COVID-19 infection</span><p id="par0055" class="elsevierStylePara elsevierViewall">Studies showing the behavior of the COVID-19 infection indicate that between 70 and 80&#37; of the infected population will have mild or moderate symptoms&#44; 15&#37; will have severe infections manifested by severe dyspnea with hypoxemia and pulmonary infiltrates&#44; and 5&#37; will have critical conditions with respiratory failure&#44; septic shock&#44; and multi-organ dysfunction&#46;<a class="elsevierStyleCrossRef" href="#bib0245"><span class="elsevierStyleSup">21</span></a> Patients in higher age groups &#40;over 60 years old&#41; and with associated comorbidities such as hypertension and diabetes have the highest mortality rates&#46;<a class="elsevierStyleCrossRef" href="#bib0250"><span class="elsevierStyleSup">22</span></a> Among the predictors of worse prognosis are the presence of dyspnea&#44; lymphopenia&#44; elevated neutrophils&#44; and decreased monocytes and platelets&#46; The CD4 and CD8 T lymphocyte count is lower&#44; and the ureic nitrogen and creatinine is higher&#46; In other words&#44; there is an evident suppression of cellular immunity along with a severe inflammatory reaction that can lead to death&#46; There is a greater proportion of dyspnea symptoms in patients who die compared to survivors who do not suffer fevers&#44; headaches&#44; and other symptoms &#40;<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>&#46;001&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0250"><span class="elsevierStyleSup">22</span></a> Other factors that are prevalent in patients who die from COVID-19 are a decrease in albumin&#44; an increase in lactate&#44; a slight decrease in the number of red cells and hemoglobin&#44; and an increase in lactic dehydrogenase&#46;<a class="elsevierStyleCrossRef" href="#bib0255"><span class="elsevierStyleSup">23</span></a> Among the predictors of the best prognosis are a high level of lymphocytes and female gender&#44; characteristics that appear in a greater proportion in the group of survivors&#46;</p><p id="par0060" class="elsevierStylePara elsevierViewall">ARDS appears to be the common final path leading to the death of the patient&#46; All patients die of respiratory failure thus indicating that the lungs are the target organ&#46; Furthermore&#44; when multiorgan failure occurs&#44; the most compromised organ after the lung is the heart followed by the kidney and liver&#46; There is elevated procalcitonin in 0&#46;5&#37; of the patients&#44; probably as an indicator of bacterial infection&#46; Patients who die have a severe inflammatory cascade which is reflected in increased C-reactive protein and serum amyloid A&#46;<a class="elsevierStyleCrossRefs" href="#bib0255"><span class="elsevierStyleSup">23&#44;24</span></a></p><p id="par0065" class="elsevierStylePara elsevierViewall">ARDS is believed to be the result of an injury to the alveolar epithelium and capillary endothelium with abnormalities in the immune system&#46; Neutrophils are recruited to the lungs by cytokines while toxic mediators such as oxygen free radicals and proteases are activated and released&#46;<a class="elsevierStyleCrossRef" href="#bib0265"><span class="elsevierStyleSup">25</span></a> Extensive production of free radicals exceeds the capacity of endogenous antioxidants and causes oxidative cell damage&#46; Factors such as endothelin-1&#44; angiotensin-2&#44; NF-kappa B&#44; and phospholipase A-2 increase vascular permeability and destroy microvascular architecture thus increasing inflammation and lung damage&#46;<a class="elsevierStyleCrossRef" href="#bib0265"><span class="elsevierStyleSup">25</span></a> This results in an influx of protein-rich fluid into the airspaces caused by increased permeability of the alveolar-capillary barrier&#46; Increased alveolar fluid reduces gas exchange through the alveolar-capillary membrane and results in hypoxemia and respiratory failure&#46; However&#44; no sensitive and specific clinical biomarkers for ARDS have been found&#46; Dyspnea is also a predictive element&#46;<a class="elsevierStyleCrossRef" href="#bib0265"><span class="elsevierStyleSup">25</span></a></p><p id="par0070" class="elsevierStylePara elsevierViewall">Efforts should focus on preventing the development of ARDS in patients with COVID-19 infections since once it occurs&#44; mortality is very high and our health systems do not have the capacity to care for as many critically ill patients as has been seen in Italy&#44; Spain and currently&#44; the USA&#46;</p><p id="par0075" class="elsevierStylePara elsevierViewall">Therefore&#44; we propose the use of colchicine in patients who are at risk of developing ARDS and who meet clinical and laboratory criteria that predict the appearance of ARDS&#46;</p><p id="par0080" class="elsevierStylePara elsevierViewall">A lot of attention has been given to the effects of colchicine on macrophages&#46; Colchicine has been shown to modulate lipopolysaccharide-induced secretion of tumor necrosis factor &#40;TNF&#41; by liver macrophages in a rat model&#46;<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">6</span></a> In a mouse brain macrophage cell line&#44; colchicine inhibited ATP-induced IL1&#946; release by preventing microtubule rearrangement and constraining activation of the Ras homolog gene family&#44; which contains the protein kinase &#40;ROCK&#41; pathway&#46; In the presence of colchicine&#44; mouse peritoneal macrophages showed less ATP-induced permeability to ethidium bromide and less formation of reactive species of oxygen &#40;ROS&#41;&#44; nitric oxide &#40;NO&#41;&#44; IL1&#946; release&#44; crystal-induced chemotactic factor&#44; myeloid inhibitory C type-like lectin&#44; toll-like receptors&#44; and vascular endothelial growth factor&#46;<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">6</span></a> All these compounds intervene to intensify the inflammatory process and are responsible for alveolar damage&#44; interstitial infiltration&#44; and lung collapse&#46; Colchicine can minimize such damage using different paths&#46;</p><p id="par0085" class="elsevierStylePara elsevierViewall">Colchicine has been studied as a possible treatment in other viral diseases&#46; Taking into consideration the promising anti-inflammatory property and good bioavailability of colchicine&#44; Lu et al&#46;<a class="elsevierStyleCrossRef" href="#bib0270"><span class="elsevierStyleSup">26</span></a> recently studied its role in inhibiting respiratory syncytial virus replication infection in vitro in BEAS-2B cells as well in vivo in neonatal rats&#46; They showed that colchicine inhibited RSV infection in neonatal rats through regulation of anti-oxidative factor production&#46; The expression of IFN-&#946;1 and RIG-I genes was also up-regulated in the RSV infected alveolar epithelial cells by treatment with colchicine&#46;</p><p id="par0090" class="elsevierStylePara elsevierViewall">An additional plausible link between the possible protective role for patients with COVID-19 and using colchicine is its effect on interferon mechanisms in viral infections that was studied decades ago&#46;<a class="elsevierStyleCrossRef" href="#bib0275"><span class="elsevierStyleSup">27</span></a> Reizin et al&#46;<a class="elsevierStyleCrossRef" href="#bib0280"><span class="elsevierStyleSup">28</span></a> demonstrated that colchicine inhibits interferon synthesis induced by the Lee strain of influenza B virus in chick embryo cells&#44; but it does not influence the release of preformed interferon from cells&#46; Colchicine was found to be most effective when it was introduced into the medium at early stages of infection&#46; It may also inhibit the formation of messenger RNA for interferonogenesis&#46;</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Colchicine clinical trials in COVID19</span><p id="par0095" class="elsevierStylePara elsevierViewall">Colchicine may be a good therapeutic option for COVID-19&#46; Currently&#44; there are only nine clinical trials considering the clinical utility of colchicine&#46; These include the Colchicine Coronavirus SARS-CoV2 Trial &#40;COLCORONA&#41; <a href="ctgov:NCT04322682">NCT04322682</a>&#44; the only trial recruiting patients&#44; the ECLA PHRI COLCOVID Trial <a href="ctgov:NCT04328480">NCT04328480</a>&#44; the GReek Study of the Effects of Colchicine on Covid-19 Complication Prevention &#40;GRECCO-19&#41; <a href="ctgov:NCT04326790">NCT04326790</a>&#44; the Colchicine to Reduce Myocardial Injury in COVID-19 &#40;COLHEART-19&#41; <a href="ctgov:NCT04355143">NCT04355143</a>&#44; and the Colchicine Counteracting Inflammation in COVID-19 Pneumonia <a href="ctgov:NCT04322565">NCT04322565</a> among others that will begin recruiting patients shortly&#46; Hopefully&#44; their results will come out soon&#46;</p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Conclusion</span><p id="par0100" class="elsevierStylePara elsevierViewall">The global medical community does not know whether rheumatic disease or immunosuppression increases the initial risk of COVID-19 infection&#46; It is not clear based upon current information whether the ingestion of colchicine by healthy patients may place the patient in an immunosuppressed condition&#46;</p><p id="par0105" class="elsevierStylePara elsevierViewall">Despite concerns that immunosuppressive drugs may increase the risk of complications for infected patients&#44; there is hope that the anti-inflammatory properties of these drugs may mitigate lung injury&#46; COVID-19 infection can give rise to what has been called &#8220;a cytokine storm&#8221; &#40;i&#46;e&#46; macrophage activation syndrome&#41;&#46; In such situations&#44; there is a massive release of various cytokines&#46; Therefore&#44; some of the biological immunosuppressive drugs used by rheumatologists may be effective in treating serious COVID-19 infections&#46;</p><p id="par0110" class="elsevierStylePara elsevierViewall">For instance&#44; interleukin blockers &#40;IL-1 and IL-6&#41; have been effective in ARDS&#46; There is also evidence that tumor necrosis factor &#40;TNF&#41; inhibitors may be effective&#46;</p><p id="par0115" class="elsevierStylePara elsevierViewall">In this respect&#44; in the risk-benefit and cost-effectiveness balance&#44; the administration of colchicine to healthy patients or those at risk of an ARDS complication should be evaluated&#46; The benefits exceed the risks of its use&#44; thus&#44; in an emergency situation caused by the current pandemic&#44; we would recommend using colchicine&#46;</p><p id="par0120" class="elsevierStylePara elsevierViewall">In this context&#44; the properties of colchicine&#44; as previously described&#44; can be used to decrease the risk of ARDS in patients with COVID-19 infection&#46; Given its relatively good safety record and tolerability profile when used carefully and appropriately&#44; it should be implemented through the proposed protocols&#46; This would provide an opportunity to decrease the results of the infection and allow for clinical observation&#46;</p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Conflict of interests</span><p id="par0125" class="elsevierStylePara elsevierViewall">The authors declare that there is no conflict of interests&#46;</p></span></span>"
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          "titulo" => "Keywords"
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          "titulo" => "Palabras clave"
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          "titulo" => "Introduction"
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        5 => array:2 [
          "identificador" => "sec0010"
          "titulo" => "Mechanisms of action"
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        6 => array:2 [
          "identificador" => "sec0015"
          "titulo" => "Metabolism and elimination"
        ]
        7 => array:2 [
          "identificador" => "sec0020"
          "titulo" => "Clinical cases description&#58; Iatrogenic allogenosis patients infected with COVID19 under colchicine treatment"
        ]
        8 => array:2 [
          "identificador" => "sec0025"
          "titulo" => "Possible uses of colchicine to prevent acute respiratory distress syndrome &#40;ARDS&#41; in patients with COVID-19 infection"
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        9 => array:2 [
          "identificador" => "sec0030"
          "titulo" => "Colchicine clinical trials in COVID19"
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          "identificador" => "sec0035"
          "titulo" => "Conclusion"
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          "identificador" => "sec0040"
          "titulo" => "Conflict of interests"
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        12 => array:1 [
          "titulo" => "References"
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    "pdfFichero" => "main.pdf"
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    "fechaRecibido" => "2020-04-30"
    "fechaAceptado" => "2020-05-08"
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          "clase" => "keyword"
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          "palabras" => array:5 [
            0 => "COVID-19"
            1 => "SARS-CoV-2"
            2 => "Colchicine"
            3 => "Inflammasome"
            4 => "ARDS"
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        0 => array:4 [
          "clase" => "keyword"
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          "identificador" => "xpalclavsec1403267"
          "palabras" => array:5 [
            0 => "COVID-19"
            1 => "SARS-CoV-2"
            2 => "Colchicina"
            3 => "Inflamasoma"
            4 => "S&#237;ndrome de distr&#233;s respiratorio agudo"
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    "resumen" => array:2 [
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        "titulo" => "Abstract"
        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">COVID-19 is a newly emerged disease that has become a global public health challenge&#46; Due to a lack of knowledge about the virus&#44; a significant number of potential targets for using a particular drug have been proposed&#46; Five cases with a clinical history of biopolymers in the gluteal region that developed iatrogenic allogenosis &#40;IA&#41; are presented here&#46; The 5 cases were put under colchicine treatment for IA crisis and had non-specific symptoms &#40;headache&#44; cough without dyspnea&#44; and arthralgias&#41; with a positive SARS-CoV-2 test&#46; Their close contacts had mild to severe symptoms and three of them died&#46; In the SARS-CoV-2 infection different inflammatory pathways are altered where colchicine reduces cytokine levels as well as the activation of macrophages&#44; neutrophils&#44; and the inflammasome&#46; The possible mechanisms that colchicine may use to prevent acute respiratory distress syndrome &#40;ARDS&#41; in patients with COVID-19 infection are also reviewed in this article&#46;</p></span>"
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        "titulo" => "Resumen"
        "resumen" => "<span id="abst0010" class="elsevierStyleSection elsevierViewall"><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">COVID-19 es una enfermedad de aparici&#243;n reciente&#44; que se ha convertido en un reto global de salud p&#250;blica&#46; Debido a la falta de conocimiento acerca del virus&#44; se ha propuesto un n&#250;mero significativo de objetivos potenciales para utilizar un f&#225;rmaco en particular&#46; Presentamos 5 casos con historia cl&#237;nica de biopol&#237;meros en la regi&#243;n gl&#250;tea&#44; que desarrollaron alogenosis iatrog&#233;nica &#40;AI&#41;&#46; A los 5 casos se les administr&#243; tratamiento de colchicina debido a la crisis de AI&#44; no teniendo s&#237;ntomas espec&#237;ficos &#40;cefalea&#44; tos sin disnea y artralgias&#41;&#44; con resultado positivo en el test de SARS-CoV-2&#46; Sus contactos cercanos ten&#237;an s&#237;ntomas de leves a graves&#44; y 3 de ellos fallecieron&#46; En la infecci&#243;n por SARS-CoV-2 se alteran diferentes rutas inflamatorias&#44; en las que la colchicina reduce los niveles de citocinas y la activaci&#243;n de macr&#243;fagos&#44; neutr&#243;filos e inflamasoma&#46; Revisamos tambi&#233;n&#44; en este art&#237;culo&#44; los posibles mecanismos que puede utilizar colchicina para prevenir el s&#237;ndrome de distr&#233;s respiratorio agudo &#40;SDRA&#41; en pacientes con COVID-19&#46;</p></span>"
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          "en" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Main anti-inflammatory mechanisms of action of colchicine&#46;</p>"
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          "leyenda" => "<p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Kg&#58; kilograms&#59; mg&#58; milligrams&#59; mcg&#58; micrograms&#59; ARDS&#58; acute respiratory distress syndrome&#59; ICU&#58; intensive care unit&#46;</p>"
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                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
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                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Case&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Age &#40;years&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Weight&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Colchicine dosage &#40;oral&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Years before of biopolymers injections&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Colchicine consumption before COVID-19 diagnosis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Comorbidities&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Clinical manifestation&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Close contact COVID-19 positive&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="\n
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                  \t\t\t\t">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">61&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">68<span class="elsevierStyleHsp" style=""></span>kg&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;5<span class="elsevierStyleHsp" style=""></span>mg per day&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">15&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">3 weeks&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Arterial hypertension treated with enalapril 10<span class="elsevierStyleHsp" style=""></span>mg&#47;day&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Subjective fever and headache during 5 days&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">68-Year-old aunt who lived with her&#44; with arterial hypertension&#46; She died in the ICU due to ARDS and multi-system failure&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">57&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">74<span class="elsevierStyleHsp" style=""></span>kg&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1<span class="elsevierStyleHsp" style=""></span>mg per day&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">12&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2 weeks before diagnosis and 1 week after&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Type 2 diabetes treated with metformin&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Headache during 3 days and dry cough without dyspnea&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">45-Year-old sister hospitalized for dyspnea&#44; did not require an ICU&#46;25-year-old cousin with mild cough and headache&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t">48&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">66<span class="elsevierStyleHsp" style=""></span>kg&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;5<span class="elsevierStyleHsp" style=""></span>mg per day&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">8&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1 week&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Hypothyroidism treated with levothyroxine 100 mcg&#47;day&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Headache during 5 days and mild cough&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Husband with headache and dry cough&#46; Children of 14 and 19 years old were asymptomatic&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">38&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t">52<span class="elsevierStyleHsp" style=""></span>kg&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;5<span class="elsevierStyleHsp" style=""></span>mg per day&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">6&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">3 weeks&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">Fibromyalgia after biopolymers injections&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Dry cough without dyspnea&#46; Myalgias during 5 days&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">56-Year-old cousin died&#46; She does not live with her but has close contact &#40;birthday celebration&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t">5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t">45&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t">62<span class="elsevierStyleHsp" style=""></span>kg&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">0&#46;5<span class="elsevierStyleHsp" style=""></span>mg per day&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t">10&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">2 weeks&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">Hashimoto&#39;s thyroiditis&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">Nonspecific arthralgias&#44; subjective fever&#44; and odynophagia&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">86-Year-old grandmother who lived with her&#44; with arterial hypertension died&nbsp;\t\t\t\t\t\t\n
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