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an antioxidant macromineral&#44; also has the advantages of being low in cost and easy to obtain&#46; Various agents such as contrast agents and chemotrophic agents reduce nephrotoxicity with these antioxidant effects&#46;<a class="elsevierStyleCrossRefs" href="#bib0295"><span class="elsevierStyleSup">15&#8211;18</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">GSH levels&#44; an endogenous antioxidant molecule&#44; are decreased with colistin treatment<a class="elsevierStyleCrossRefs" href="#bib0260"><span class="elsevierStyleSup">8&#44;12</span></a> and increased levels of MDA&#59; which are indicative of lipid peroxidation and increased in the case of oxidative damage&#46;<a class="elsevierStyleCrossRef" href="#bib0315"><span class="elsevierStyleSup">19</span></a> Therefore&#44; we examined whether magnesium had an antioxidant effect by analyzing different analytes such as GSH and MDA&#46; The effects of colistin on the kidney have been evaluated histopathologically in some studies&#46; The SQS system&#44; which is the sum of tubular damage in renal tissues and the percentage of tissue damage&#44; was used in these studies&#46;<a class="elsevierStyleCrossRefs" href="#bib0265"><span class="elsevierStyleSup">9&#44;13</span></a> We also planned to evaluate the colistin-induced renal tissue damage rate using this scoring system&#46;</p><p id="par0020" class="elsevierStylePara elsevierViewall">This study aimed to determine whether magnesium decreases nephrotoxicity caused by colistin&#44; which found to have an antioxidant effect in various drug studies of contrast and chemotherapeutic agents&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Methods</span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Animals</span><p id="par0025" class="elsevierStylePara elsevierViewall">The study was conducted in Sel&#231;uk University Experimental Medicine Application and Research Center with 30 male Wistar Albino rats weighing 300&#8211;350<span class="elsevierStyleHsp" style=""></span>g&#46; The study was approved by the ethics committee of the same center &#40;number&#58; 2019-46&#41;&#46; Rats were kept in cages at 21<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>1<span class="elsevierStyleHsp" style=""></span>&#176;C for 12<span class="elsevierStyleHsp" style=""></span>h in the light and 12<span class="elsevierStyleHsp" style=""></span>h in the dark and they were provided food and water&#46; To measure basal urea and creatinine levels&#44; 1<span class="elsevierStyleHsp" style=""></span>ml of blood was taken from the tail vein under anesthesia with 35<span class="elsevierStyleHsp" style=""></span>mg&#47;kg ketamine and 5<span class="elsevierStyleHsp" style=""></span>mg&#47;kg xylazine&#46;</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Drugs</span><p id="par0030" class="elsevierStylePara elsevierViewall">Colistimethate sodium was provided by Kocak Farma Pharmaceutical Company&#44; Istanbul&#44; Turkey &#40;Colimycin&#41;&#46; The drug contained 4&#44;500&#44;000<span class="elsevierStyleHsp" style=""></span>IU<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>384<span class="elsevierStyleHsp" style=""></span>mg colistimethate sodium and it had 150<span class="elsevierStyleHsp" style=""></span>mg of colistin base activity&#46; When it was reconstituted with 2<span class="elsevierStyleHsp" style=""></span>ml injection water&#44; a 1<span class="elsevierStyleHsp" style=""></span>ml solution contained 2&#44;250&#44;000<span class="elsevierStyleHsp" style=""></span>IU colistimethate sodium&#46; 15&#37; of magnesium sulfate &#40;1500<span class="elsevierStyleHsp" style=""></span>mg in 10<span class="elsevierStyleHsp" style=""></span>ml&#44; Kad&#305;k&#246;y&#44; Istanbul&#44; Turkey&#41; was used in the preparation of magnesium sulfate&#46;</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Experimental design</span><p id="par0035" class="elsevierStylePara elsevierViewall">Four groups were formed for the study&#58;<ul class="elsevierStyleList" id="lis0005"><li class="elsevierStyleListItem" id="lsti0005"><span class="elsevierStyleLabel">-</span><p id="par0040" class="elsevierStylePara elsevierViewall">The control group &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>6&#41; was given 2<span class="elsevierStyleHsp" style=""></span>ml&#47;kg&#47;day saline two times a day for seven days&#46;</p></li><li class="elsevierStyleListItem" id="lsti0010"><span class="elsevierStyleLabel">-</span><p id="par0045" class="elsevierStylePara elsevierViewall">Colistin group &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>8&#41; was given 300&#44;000<span class="elsevierStyleHsp" style=""></span>U&#47;kg&#47;day colistimetate sodium two times a day for seven days&#46;</p></li><li class="elsevierStyleListItem" id="lsti0015"><span class="elsevierStyleLabel">-</span><p id="par0050" class="elsevierStylePara elsevierViewall">Mg group &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>8&#41; was given magnesium sulfate intraperitoneally at a dose of 50<span class="elsevierStyleHsp" style=""></span>mg&#47;kg&#47;day two times a day for seven days&#46;</p></li><li class="elsevierStyleListItem" id="lsti0020"><span class="elsevierStyleLabel">-</span><p id="par0055" class="elsevierStylePara elsevierViewall">Mg<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>colistin &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>8&#41; was given intraperitoneal Mg sulfate at a dose of 50<span class="elsevierStyleHsp" style=""></span>mg&#47;kg&#47;day&#44; after 30<span class="elsevierStyleHsp" style=""></span>min&#44; 300&#44;000<span class="elsevierStyleHsp" style=""></span>U&#47;kg&#47;day of colistimethate sodium was administered two times a day for seven days&#46;</p></li></ul></p><p id="par0060" class="elsevierStylePara elsevierViewall">It could also be two doses with an interval of 8<span class="elsevierStyleHsp" style=""></span>h between the administration of doses&#46; On the seventh day&#44; rats were anesthetized with 90<span class="elsevierStyleHsp" style=""></span>mg&#47;kg ketamine and 10<span class="elsevierStyleHsp" style=""></span>mg&#47;kg xylazine 16<span class="elsevierStyleHsp" style=""></span>h after the last drug administration&#46; Right kidneys were fixed with 10&#37; formalin for histopathological examination and left kidneys were kept at &#8722;80<span class="elsevierStyleHsp" style=""></span>&#176;C for analysis of GSH and MDA levels at the tissue level&#46; Rats were sacrificed after taking 2<span class="elsevierStyleHsp" style=""></span>ml of intracardiac blood to analyze urea&#44; creatinine&#44; MDA&#44; and GSH analysis&#46;</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Biochemical measurements</span><p id="par0065" class="elsevierStylePara elsevierViewall">Biochemical analysis was performed by a blinded biochemist&#46;</p><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Blood samples</span><p id="par0070" class="elsevierStylePara elsevierViewall">Blood samples were taken into EDTA anticoagulant tubes and centrifuged at 3000 rpm for 10 min&#46; Plasma samples were collected for the analysis of MDA&#44; urea&#44; and creatinine samples were collected and washed three times with an ice-cold saline solution to obtain erythrocytes to test for GSH levels in the analysis of the red blood cells&#46;</p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Tissue collection and homogenization</span><p id="par0075" class="elsevierStylePara elsevierViewall">Kidney tissues were weighed&#44; recorded&#44; and divided into pieces and put into tubes&#46; Samples were placed in a Misonix Microson Ultrasonic Cell Disruptor with 150<span class="elsevierStyleHsp" style=""></span>mM KCl at 4<span class="elsevierStyleHsp" style=""></span>&#176;C to obtain 10&#37; homogenates&#46; MDA&#44; GSH&#44; and protein levels were analyzed in obtained homogenates&#46; GSH concentrations were analyzed according to the Ellmann method&#46; All analyses were carried out using spectrophotometrical techniques&#46;<a class="elsevierStyleCrossRef" href="#bib0320"><span class="elsevierStyleSup">20</span></a> The values were expressed as mg&#47;g protein in kidney tissue and mg&#47;g hemoglobin in the erythrocyte&#46; MDA concentrations were determined by the method of Uchiyama and Mihara with spectrophotometrical techniques&#46;<a class="elsevierStyleCrossRef" href="#bib0325"><span class="elsevierStyleSup">21</span></a> The values were expressed as nmol&#47;ml and nmol&#47;g tissue&#46; Blood hemoglobin concentrations were determined by Drabkin&#39;s method<a class="elsevierStyleCrossRef" href="#bib0330"><span class="elsevierStyleSup">22</span></a> and calculated as g&#47;dl&#46; Tissue protein concentrations were analyzed with a colorimetric test kit &#40;BioRad&#44; cat no&#58; 500-0002&#41; calculated as g&#47;dl&#46;</p><p id="par0080" class="elsevierStylePara elsevierViewall">Plasma urea was analyzed using a colorimetric test kit &#40;Elabsience Urea Kit&#44; cat no&#58; E-BC-K183-S&#41;&#46; The kit&#39;s detection range was 0&#46;114&#8211;30<span class="elsevierStyleHsp" style=""></span>mmol&#47;l&#44; inter-assay CV is 4&#46;7&#37;&#44; intra-assay CV is 4&#46;6&#37; and sensitivity 0&#46;114<span class="elsevierStyleHsp" style=""></span>mmol&#47;l&#46; Plasma creatinine levels were determined with the ELISA test kit &#40;Elabscience rat Creatinine&#44; cat no&#58; E-EL-0058&#41;&#46; The detection range was 1&#46;25&#8211;80<span class="elsevierStyleHsp" style=""></span>&#956;g&#47;ml&#44; and the sensitivity of the kit was 0&#46;75<span class="elsevierStyleHsp" style=""></span>&#956;g&#47;ml&#46; Plasma urea and creatinine concentrations were expressed as mg&#47;dl&#46; BMG LABTECH &#40;Germany&#41; and Rayto Microplate washer &#40;Elisa Washer&#41; &#40;RT-2600&#44; China&#41; were used for the analysis&#46;</p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Histopathological examination</span><p id="par0085" class="elsevierStylePara elsevierViewall">The right kidney tissues for histopathological examination were fixed after 24<span class="elsevierStyleHsp" style=""></span>h fixation in 10&#37; buffered formalin&#46; Microtome sections were taken from paraffin-block tissues and stained with hematoxylin&#8211;eosin &#40;HE&#41; and histochemical periodic acid Schiff &#40;PAS&#41; stains&#46; Histopathological assessment was performed by a blinded pathologist&#46; For each kidney tissue examined at 200&#215; magnification on light microscopic examination&#44; it was divided into three groups based on the tubular damage &#40;grade I&#44; grade II&#44; and grade III&#41;&#46; The tissue was divided into six scores based on the percentage of damage&#46; Percentage of affected area&#59; &#60;1&#37;&#44; 0&#59; 1&#8211;4&#37;&#44; 1&#59; 5&#8211;9&#37;&#44; 2&#59; 10&#8211;19&#37;&#44; 3&#59; 20&#8211;29&#37;&#44; 4&#59; 30&#8211;39&#37; 5&#59; &#8805;40&#37; were scored six&#46; These scores and grade grades were collected and divided into six groups using the SQS system within the scope of the kidney to be affected by the drug&#46; SQS &#43;1&#58; mild damage &#40;total score 1&#8211;14&#41;&#44; SQS &#43;2&#58; mild to moderate damage &#40;total score 15&#8211;29&#41;&#44; SQS &#43;3&#58; moderate damage &#40;total score 30&#8211;44&#41;&#44; SQS &#43;4&#58; moderate to severe damage &#40;total score 45&#8211;59&#41;&#44; SQS &#43;5&#58; severe damage &#40;total score 60&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0265"><span class="elsevierStyleSup">9&#44;13</span></a></p></span></span></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Power analysis</span><p id="par0090" class="elsevierStylePara elsevierViewall">In the present study&#44; the sample size was calculated based on the &#8220;resource equation&#8221; proposed by Arifin and Zahiruddin&#46; The sample size in each group should be a minimum of 10&#47;<span class="elsevierStyleItalic">k</span><span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>1 and a maximum of 20&#47;<span class="elsevierStyleItalic">k</span><span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>1 &#40;<span class="elsevierStyleItalic">k</span> the number of groups&#41; in this equality&#46; Thereby&#44; we calculated the sample size of each group to be a minimum of four&#44; and a maximum of six&#46;<a class="elsevierStyleCrossRef" href="#bib0335"><span class="elsevierStyleSup">23</span></a></p></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Data analysis</span><p id="par0095" class="elsevierStylePara elsevierViewall">Data were analyzed using R Version 3&#46;6&#46;0 &#40;<a href="http://www.r-project.org/">www&#46;r-project&#46;org</a>&#41;&#46; Variables were described as mean<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>standard deviation or median &#40;interquartile range&#41;&#46; The two-way repeated-measures ANOVA was performed to assess the groups&#8217; effects and time on urea and creatinine values in rats&#46; The box-plot method showed that there were no extreme outliers&#46; Shapiro&#8211;Wilk&#39;s test of normality was used to analyze the distribution of data &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#41;&#46; Levene&#39;s test of homogeneity of variances found variances to be homogeneous &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#41;&#46; A Bonferroni adjustment was used for the interaction and main effects&#46; Because the plasma MDA was not normally distributed&#44; Kruskal&#8211;Wallis and Wilcoxon tests were used to compare groups and time effects&#44; respectively&#46; After the Kruskal&#8211;Wallis test results were significant&#44; the Conover-Iman posthoc test with Bonferroni adjustment was used for multiple comparisons&#46; One way ANOVA and Welch tests were used to compare groups in terms of GSH and MDA levels&#46; Tukey HSD and Games-Howell posthoc tests were used for multiple comparisons according to these parameters at T1 time&#46; Mann&#8211;Whitney-<span class="elsevierStyleItalic">U</span> test was used to compare groups according to the grade of renal histology&#44; renal affected area score&#44; and SQS&#46; A <span class="elsevierStyleItalic">p</span>-value of less than 0&#46;05 was considered as significant&#46;</p></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Results</span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Biochemical evaluations</span><p id="par0100" class="elsevierStylePara elsevierViewall">The effect of different study groups overtime on urea values was assessed&#46; There were significant main effects of group on the urea values and also there was a significant interaction between group and time on urea values in rats &#40;<span class="elsevierStyleItalic">F</span>&#40;3&#44;26&#41;<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>7&#46;114&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;001&#44; <span class="elsevierStyleItalic">&#951;</span><span class="elsevierStyleSup">2</span><span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;451&#41;&#46; The simple main effect of the group was not significant at the time point T0 &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;925&#41;&#46; It became significant at T1 &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;015&#41;&#46; The mean urea value was significantly higher in the control and colistin groups compared to Mg &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;013 and <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;001&#44; respectively&#41; and Mg<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>colistin &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;001 and <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;001&#44; respectively&#41; groups at T1&#46; Unlike the Mg &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;002&#41; and Mg<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>colistin &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;001&#41; groups&#44; the simple main effect of time was not significant in the control &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;999&#41; and colistin groups &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;999&#41;&#46; The Mg &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;001&#41; and Mg<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>colistin groups &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;001&#41; had significantly lower mean urea value at the T1 time point compared to T0 &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a> and <a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>A&#41;&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0105" class="elsevierStylePara elsevierViewall">The effect of different study groups overtime on creatinine values was evaluated&#46; There was a significant main effects of group &#40;<span class="elsevierStyleItalic">F</span>&#40;3&#44;26&#41;<span class="elsevierStyleMonospace">Y</span>&#61;<span class="elsevierStyleMonospace">Y</span>3&#46;294&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;036&#44; <span class="elsevierStyleItalic">&#951;</span><span class="elsevierStyleSup">2</span><span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;275&#41; and time &#40;<span class="elsevierStyleItalic">F</span>&#40;1&#44;26&#41;<span class="elsevierStyleMonospace">Y</span>&#61;<span class="elsevierStyleMonospace">Y</span>27&#46;334&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;001&#44; <span class="elsevierStyleItalic">&#951;</span><span class="elsevierStyleSup">2</span><span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;513&#41; on the creatinine values in rats&#44; and also a significant interaction between group and time on creatinine values in rats &#40;<span class="elsevierStyleItalic">F</span>&#40;3&#44;26&#41;<span class="elsevierStyleMonospace">Y</span>&#61;<span class="elsevierStyleMonospace">Y</span>3&#46;128&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;043&#44; <span class="elsevierStyleItalic">&#951;</span><span class="elsevierStyleSup">2</span><span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;265&#41;&#46; The simple main effect of the group was not significant at the time point T0 &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;280&#41;&#46; It was significant at T1 &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;012&#41;&#46; The colistin group had a significantly higher mean creatinine value than the Mg<span class="elsevierStyleMonospace">Y</span>&#43;<span class="elsevierStyleMonospace">Y</span>colistin &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;011&#41; group at T1&#46; The simple main effect of time was not significant in the control &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;572&#41; and Mg<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>colistin groups &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;999&#41;&#46; The mean creatinine value was significantly higher at the T1 time point compared with the T0 time point for colistin and Mg groups &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;005 and <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;020&#44; respectively&#41; &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a> and <a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>B&#41;&#46;</p></span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">MDA and GSH levels</span><p id="par0110" class="elsevierStylePara elsevierViewall">Plasma MDA values were significantly affected by groups at the T1 time &#40;<span class="elsevierStyleItalic">H</span>&#40;3&#41;<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>17&#46;502&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;001&#41;&#44; but not at T0 time &#40;<span class="elsevierStyleItalic">H</span>&#40;3&#41;<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;121&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;989&#41;&#46; The median plasma MDA value was significantly higher in the colistin group compared with the other &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;001&#41; groups at the T1 time point&#46; The median plasma MDA value was significantly higher at the T1 time point compared with the T0 time point for colistin&#44; Mg&#44; and Mg<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>colistin groups &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;014&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;021&#44; and <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;021&#44; respectively&#41; &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a> and <a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>C&#41;&#46; There was a significant difference between the groups&#8217; erythrocyte GSH levels &#40;<span class="elsevierStyleItalic">Welch F</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>32&#46;715&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;001&#41;&#46; The colistin group &#40;1&#46;99<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;39&#41; had significantly lower GSH erythrocyte values than the control &#40;17&#46;52<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>5&#46;61&#41; and Mg &#40;23&#46;75<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>8&#41; groups after treatment&#46; There was no significant difference between the colistin and Mg<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>colistin &#40;9&#46;72<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>8&#46;53&#41; groups&#46; Moreover&#44; GSH erythrocyte values in rats were significantly higher after treatment in the Mg group compared to the colistin and Mg<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>colistin groups&#46; There was no significant difference between the Mg and control groups &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a> and <a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>D&#41;&#46; There were no significant differences between the groups&#8217; &#40;<span class="elsevierStyleItalic">F</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>1&#46;816&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;169&#44; <span class="elsevierStyleItalic">F</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;802&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;504&#44; respectively&#41; kidney GSH and MDA levels &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#46;</p></span><span id="sec0075" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Histopathological findings</span><p id="par0115" class="elsevierStylePara elsevierViewall">Grade of renal histology&#44; renal affected area score&#44; and SQS in rats were significantly lower in the Mg<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>colistin group compared to the colistin group &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;035&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;001 and <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;001&#44; respectively&#41; &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a> and <a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>&#41;&#46; The light microscopic examination showed that the normal structure of the tubules was maintained in the control and Mg groups&#46; Damage to the tubular epithelium was prominent in the colistin group &#40;<a class="elsevierStyleCrossRef" href="#fig0015">Fig&#46; 3</a>&#41;&#46;</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia><elsevierMultimedia ident="fig0010"></elsevierMultimedia><elsevierMultimedia ident="fig0015"></elsevierMultimedia></span></span><span id="sec0080" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Discussion</span><p id="par0120" class="elsevierStylePara elsevierViewall">Colistin has been increasingly used in recent times and is an important nephrotoxic&#46; The present study investigated if the toxic effects of colistin on the kidney decreased when it is combined with the antioxidant mineral Mg&#46; We found that the colistin<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>Mg group had lower urea and creatinine values and histopathological damage than the Mg group&#46; Additionally&#44; the colistin group had higher plasma MDA and GSH erythrocyte values than the other groups&#46;</p><p id="par0125" class="elsevierStylePara elsevierViewall">Colistin is filtered from glomeruli and secreted from tubules in the kidney&#46;<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">4</span></a> Its nephrotoxic effects are observed in the clinic as oliguria&#44; hematuria&#44; acute tubular necrosis&#46;<a class="elsevierStyleCrossRefs" href="#bib0340"><span class="elsevierStyleSup">24&#44;25</span></a> There are studies showing that oxidative stress plays a role in the formation of nephrotoxicity&#46;<a class="elsevierStyleCrossRefs" href="#bib0265"><span class="elsevierStyleSup">9&#44;12&#44;14&#44;19</span></a> It causes tubular lysis by causing the entrance of anion&#44; cation&#44; and water through tubular epithelial cell damage and affects in a similar way to bacteriostatic effect&#46; Colistin acts by displacing divalent cations Mg<span class="elsevierStyleSup">2&#43;</span> and Ca<span class="elsevierStyleSup">2&#43;</span> to disrupt the stability of the bacterial outer membrane&#46; Likewise&#44; it increases the permeability in tubules&#46;<a class="elsevierStyleCrossRef" href="#bib0350"><span class="elsevierStyleSup">26</span></a> Many reactive oxygen species that are formed in mitochondria result apoptosis and renal dysfunction&#46; Ozkan et al&#46; determined colistin-related in apoptosis to occur with the activation of caspase I and III&#46;<a class="elsevierStyleCrossRefs" href="#bib0355"><span class="elsevierStyleSup">27&#44;28</span></a> Many antioxidants have been studied to reduce the nephrotoxicity of colistin&#46;<a class="elsevierStyleCrossRefs" href="#bib0250"><span class="elsevierStyleSup">6&#44;10&#44;11&#44;13</span></a></p><p id="par0130" class="elsevierStylePara elsevierViewall">Magnesium is a mineral with vital functions such as transport function&#44; enzyme and signaling pathways&#44; energy metabolism&#44; and nucleic acid synthesis&#46;<a class="elsevierStyleCrossRef" href="#bib0365"><span class="elsevierStyleSup">29</span></a> It is an antioxidant and anti-inflammatory molecule&#46; It facilitates the intracellular calcium accumulation&#44; which we mentioned in the colistin nephrotoxicity&#44; by inhibiting the <span class="elsevierStyleSmallCaps">l</span>-type calcium channels&#46;<a class="elsevierStyleCrossRef" href="#bib0370"><span class="elsevierStyleSup">30</span></a> Magnesium was also found to decrease drug-related cardiotoxicity&#44; apoptosis&#44; and necrosis&#46;<a class="elsevierStyleCrossRef" href="#bib0375"><span class="elsevierStyleSup">31</span></a> Moreover&#44; various studies found this molecule to have antioxidant effects&#46; Administration of magnesium sulfate which has an antioxidant effect and dehydration in contrast-associated nephropathy reduced the risk of nephropathy&#46;<a class="elsevierStyleCrossRef" href="#bib0295"><span class="elsevierStyleSup">15</span></a> Another study indicated that contrast nephropathy was more common in patients with low magnesium levels&#46;<a class="elsevierStyleCrossRef" href="#bib0300"><span class="elsevierStyleSup">16</span></a> There are studies that show the effect of magnesium on nephropathy caused by some chemotherapeutic agents apart from contrast nephropathy&#46; In their experimental study&#44; Saito et al&#46; designed cisplatin nephrotoxicity and showed that giving magnesium to the rats decreased nephrotoxicity by reducing the cisplatin accumulation in the kidney&#46;<a class="elsevierStyleCrossRef" href="#bib0305"><span class="elsevierStyleSup">17</span></a> In a study conducted with people who received cisplatin chemotherapy&#44; the supplementation of magnesium to hydration reduced cisplatin nephrotoxicity&#46;<a class="elsevierStyleCrossRef" href="#bib0310"><span class="elsevierStyleSup">18</span></a> In another study performed on cyclosporine-treated mice&#44; magnesium supplementation had a renal protective effect by increasing nitric oxide synthase activity in the renal tissue&#46;<a class="elsevierStyleCrossRef" href="#bib0380"><span class="elsevierStyleSup">32</span></a></p><p id="par0135" class="elsevierStylePara elsevierViewall">Because there is no study examining the supplementation of Mg with colistin&#44; we referenced other studies for the Mg sulfate doses&#46; In their experiment to reduce the cardiotoxic effects of doxorubicin&#44; Khalilzadeh and colleagues gave rats 120<span class="elsevierStyleHsp" style=""></span>mg&#47;kg for two weeks and magnesium sulfate for three days a week as an IP and found that cardiotoxicity decreased&#46;<a class="elsevierStyleCrossRef" href="#bib0385"><span class="elsevierStyleSup">33</span></a> In another study&#44; nephrotoxicity was reduced by administering 40<span class="elsevierStyleHsp" style=""></span>mg&#47;kg Mg sulfate before cisplatin once a week for three weeks in rats given cisplatin&#46;<a class="elsevierStyleCrossRef" href="#bib0305"><span class="elsevierStyleSup">17</span></a> However&#44; higher magnesium doses were used in studies that assessed the effects of magnesium in rats with ischemic stroke and in Alzheimer&#39;s rat model&#46;<a class="elsevierStyleCrossRefs" href="#bib0390"><span class="elsevierStyleSup">34&#44;35</span></a></p><p id="par0140" class="elsevierStylePara elsevierViewall">In a review by Heybeli et al&#46; assessing the studies that involved colistin nephrotoxicity in rats&#44; it was observed that colistin was given at 300&#44;000&#8211;480&#44;000<span class="elsevierStyleHsp" style=""></span>IU&#47;kg&#47;day or 15&#8211;18<span class="elsevierStyleHsp" style=""></span>mg&#47;kg&#47;day or 36&#8211;84<span class="elsevierStyleHsp" style=""></span>mg&#47;kg cumulative doses because five of the eleven studies gave 300&#44;000<span class="elsevierStyleHsp" style=""></span>IU&#47;kg&#47;day&#46; In their article which was conducted in 2019 and included views of many institutions on the use of polymyxin&#44; Tsuji et al&#46; suggested 9&#44;000&#44;000<span class="elsevierStyleHsp" style=""></span>IU CMS maintenance dose to be systemically administered every 12&#8211;24<span class="elsevierStyleHsp" style=""></span>h after the 9&#44;000&#44;000<span class="elsevierStyleHsp" style=""></span>IU CMS loading dose and this was significantly lower than the dose &#40;300&#44;000<span class="elsevierStyleHsp" style=""></span>IU&#47;kg&#47;day&#41; we administered in the present study&#46;<a class="elsevierStyleCrossRef" href="#bib0400"><span class="elsevierStyleSup">36</span></a> The drug was provided for seven days in the majority of the studies&#46;<a class="elsevierStyleCrossRef" href="#bib0405"><span class="elsevierStyleSup">37</span></a> In their study in which they administered 300&#44;000<span class="elsevierStyleHsp" style=""></span>IU&#47;day CMS for six days&#44; Ozkan and Ozy&#305;lmaz determined that colistin caused a significant level of toxicity in the tissue and biochemical levels of the rats&#46;<a class="elsevierStyleCrossRefs" href="#bib0360"><span class="elsevierStyleSup">28&#44;38</span></a> Based on this study&#44; we administered colistin at a dose of 300&#44;000<span class="elsevierStyleHsp" style=""></span>IU&#47;kg&#47;day&#44; and for seven days&#46;</p><p id="par0145" class="elsevierStylePara elsevierViewall">We found that urea value decreased significantly in the Mg and Mg<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>colistin group&#44; creatinine value increased in the colistin and Mg groups and there was no significant increase in the control and Mg<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>colistin groups&#46; Although the decrease in the urea value of the Mg and Mg<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>colistin group supported the renal protective effect of magnesium&#44; it was also interesting to find that creatinine levels increased in the Mg group&#46; Cheungpasitporn et al&#46; showed that both hypomagnesemia and hypermagnesemia were associated with an increased risk of acute kidney disease&#46; They considered that overstimulated vasodilatation and vasoconstriction may be effective&#46;<a class="elsevierStyleCrossRef" href="#bib0415"><span class="elsevierStyleSup">39</span></a> Hypermagnesemia may occur in the group that was administered only magnesium and may cause creatinine value to be higher than the baseline&#46; The absence of histopathological changes in this group receiving magnesium alone may support the idea that a prerenal event may trigger an increase in creatinine&#46; Severe hypomagnesemia was detected in the colistin-treated groups in two studies in patients who were given colistin in the neonatal intensive care unit&#46;<a class="elsevierStyleCrossRefs" href="#bib0420"><span class="elsevierStyleSup">40&#44;41</span></a> Hypomagnesemia in the colistin group may lead to increased oxidative stress leading to renal toxicity&#46; Reduction of renal toxicity by adding magnesium to colistin may be a result of regulating hypomagnesemia with colistin&#46;</p><p id="par0150" class="elsevierStylePara elsevierViewall">MDA causes serious damage to the cell membrane structure&#46;<a class="elsevierStyleCrossRef" href="#bib0430"><span class="elsevierStyleSup">42</span></a> GSH is a tripeptide that reacts with hydrogen peroxide and organic acids and shows an antioxidant effec&#46;<a class="elsevierStyleCrossRef" href="#bib0435"><span class="elsevierStyleSup">43</span></a> In the study by Edrees et al&#46;&#44; concurrent administration of curcumin with colistin led to a decrease in the MDA level and an increase in GSH level in renal tissue&#46; Lee&#44; &#214;zkan&#44; and Ghlissi found that some antioxidant molecules used in their studies decreased the MDA levels compared to the colistin group&#46;<a class="elsevierStyleCrossRefs" href="#bib0255"><span class="elsevierStyleSup">7&#44;14&#44;44</span></a> Ozyilmaz et al&#46; found no change in the MDA level in plasma in the group given N-acetylcysteine together with colistin&#46;<a class="elsevierStyleCrossRef" href="#bib0410"><span class="elsevierStyleSup">38</span></a> We found that plasma MDA levels were significantly increased in the colistin group compared to the beginning of the experiment and compared to the other groups and decreased in the Mg and Mg<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>colistin groups&#46; While the colistin group had significantly lower erythrocyte GSH levels than the other groups&#44; Mg<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>colistin group was higher than the colistin group&#44; however&#59; it was not statistically significant&#46; Although renal GSH levels were the lowest in the colistin group renal MDA levels were the highest in the colistin group&#44; but it was not statistically significant&#46;</p><p id="par0155" class="elsevierStylePara elsevierViewall">We found tubular injury&#44; renal involvement area&#44; and SQS were found to be high in the colistin-treated group&#44; while the histopathological changes were significantly decreased in the magnesium-treated and colistin-treated rats&#46; This was in line with previous studies&#46;<a class="elsevierStyleCrossRefs" href="#bib0265"><span class="elsevierStyleSup">9&#44;10&#44;13</span></a></p><p id="par0160" class="elsevierStylePara elsevierViewall">There were some limitations to our study&#46; We did not study the effects of different doses of magnesium and colistin&#46; The fact that we did not study serum magnesium levels at the beginning and end of the study was another limitation of this study&#46; However&#44; this study was the first to examine colistin nephrotoxicity with magnesium which is an easily accessed&#44; inexpensive molecule with many functions in the body&#46; We believe that comprehensive and more detailed studies should be conducted to investigate the relationship between magnesium and colistin nephrotoxicity&#46;</p></span><span id="sec0085" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Ethics standards</span><p id="par0165" class="elsevierStylePara elsevierViewall">The study was approved by the Ethics Advisory Committee Sel&#231;uk University Experimental Medicine Application and Research Center &#40;IRB approval number&#58; 2019-46&#41;&#46; All procedures performed in animal studies were in accordance with the ethical standards of the institution or practice in which the studies were conducted&#46;</p></span><span id="sec0090" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">Conflict of interest</span><p id="par0170" class="elsevierStylePara elsevierViewall">The authors have declared that no conflict of interest exists&#46;</p></span></span>"
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        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">The study aimed to investigate the role of magnesium sulfate prophylaxis in nephrotoxicity caused by colistin&#46; Thirty Wistar Albino rats were divided into four groups&#58; control&#44; colistin&#44; magnesium &#40;Mg&#41;&#44; and Mg<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>colistin&#46; The drugs were administered to the groups for seven days&#46; Urea-creatinine values were measured at the beginning &#40;T0&#41; and end &#40;T1&#41; of the study&#46; Malondialdehyde &#40;MDA&#41; levels were measured in plasma and kidney tissue&#44; glutathione &#40;GSH&#41; levels were analyzed in the erythrocyte and kidney tissues&#46; At the end of the study&#44; the semiquantitative score &#40;SQS&#41; was calculated by the histopathological examination of the kidneys&#46; Urea values significantly decreased in Mg and Mg<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>colistin groups compared to the baseline &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;013 and <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;001&#41;&#46; At the time of T1&#44; these groups had significantly lower urea values than the colistin and control groups&#46; Creatinine value was significantly increased in the colistin group compared to baseline &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;005&#41;&#44; the creatinine value in the colistin group was significantly higher than the Mg<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>colistin group &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;011&#41;&#46; Plasma MDA levels were significantly higher in the colistin group compared to the other groups at the time of T1 &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;001&#41;&#46; The Mg<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>colistin group had lower renal MDA levels than the colistin group&#46; The colistin group had significantly higher renal tubular grade &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;035&#41;&#44; renal affected area &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;001&#41;&#44; and SQS &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;001&#41; than the Mg<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>colistin group&#46; The results of the study suggested that Mg sulfate may have a nephrotoxicity-reducing effect on colistin&#46;</p></span>"
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        "resumen" => "<span id="abst0010" class="elsevierStyleSection elsevierViewall"><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">El objetivo del estudio fue investigar la funci&#243;n de la profilaxis con sulfato de magnesio en la nefrotoxicidad causada por la colistina&#46; Se dividieron 30 ratas Wistar albinas en 4 grupos&#58; control&#44; colistina&#44; magnesio &#40;Mg&#41; y Mg &#43; colistina&#46; Los f&#225;rmacos se administraron a los grupos durante 7 d&#237;as&#46; Los valores de urea-creatinina se midieron al principio &#40;T0&#41; y al final &#40;T1&#41; del estudio&#46; Se midieron los niveles de malondialdeh&#237;do &#40;MDA&#41; en el plasma y el tejido renal&#44; y se analizaron los niveles de glutati&#243;n &#40;GSH&#41; en los eritrocitos y el tejido renal&#46; Al final del estudio&#44; se calcul&#243; la puntuaci&#243;n semicuantitativa &#40;semiquantitative score &#91;SQS&#93;&#41; mediante el examen histopatol&#243;gico de los ri&#241;ones&#46; Los valores de urea disminuyeron significativamente en los grupos de Mg y Mg &#43; colistina en comparaci&#243;n con los valores iniciales &#40;p &#61; 0&#44;013 y p &#61; 0&#44;001&#41;&#46; En el momento del T1&#44; estos grupos ten&#237;an valores de urea significativamente m&#225;s bajos que los grupos de colistina y de control&#46; El valor de creatinina se increment&#243; significativamente en el grupo de colistina en comparaci&#243;n con el valor inicial &#40;p &#61; 0&#44;005&#41;&#59; el valor de creatinina en el grupo de colistina fue significativamente mayor que en el grupo de Mg &#43; colistina &#40;p &#61; 0&#44;011&#41;&#46; Los niveles de MDA en el plasma fueron significativamente m&#225;s altos en el grupo de colistina en comparaci&#243;n con los otros grupos en el momento del T1 &#40;p &#60; 0&#44;001&#41;&#46; El grupo de Mg &#43; colistina present&#243; niveles renales de MDA m&#225;s bajos que el grupo de colistina&#46; El grupo de colistina present&#243; un grado tubular renal &#40;p &#61; 0&#44;035&#41;&#44; un &#225;rea renal afectada &#40;p &#60; 0&#44;001&#41; y una SQS &#40;p &#61; 0&#44;001&#41; significativamente mayores que el grupo de Mg &#43; colistina&#46; Los resultados del estudio indicaron que el sulfato de Mg puede tener un efecto reductor de la nefrotoxicidad de la colistina&#46;</p></span>"
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Original article
Can magnesium sulfate prophylaxis reduce colistin nephrotoxicity?
¿Puede la profilaxis con sulfato de magnesio reducir la nefrotoxicidad de la colistina?
Yasemin Coşkun Yavuza,
Corresponding author
yasemincoskun@yahoo.com

Corresponding author.
, Nihal Cetinb, Esma Menevşec, Ahmet Cizmecioglud, Esin Celike, Zeynep Biyika, Can Sevincf, Serkan Yavuzg, Muslu Kazim Korezh, Lutfullah Altintepea
a Selcuk University Faculty of Medicine, Nephrology Department, Konya, Turkey
b Selcuk University Faculty of Medicine, Pharmacology Department, Konya, Turkey
c Selcuk University Faculty of Medicine, Biochemistry Department, Konya, Turkey
d Selcuk University Faculty of Medicine, Internal Medicine Department, Konya, Turkey
e Selcuk University Faculty of Medicine, Pathology Department, Konya, Turkey
f Ataturk University Faculty of Medicine, Nephrology Department, Erzurum, Turkey
g University of Healthy Sciences, Konya Training and Research Hospital, Department of Chest Disease, Konya, Turkey
h Selcuk University Faculty of Medicine, Biostatistics Department, Konya, Turkey
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        "titulo" => "&#191;Puede la profilaxis con sulfato de magnesio reducir la nefrotoxicidad de la colistina&#63;"
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          "en" => "<p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Comparison of renal histopathological scores in colistin and Mg<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>colistin groups&#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">Colistin has been out of trade since 1970&#44; however&#44; it is possible to see more of this drug due to the increasing gram-negative bacterial infections to multiple drug resistance&#46;<a class="elsevierStyleCrossRefs" href="#bib0225"><span class="elsevierStyleSup">1&#8211;3</span></a> It is used in the treatment of infections caused by carbapenem-resistant Enterobacteria&#44; <span class="elsevierStyleItalic">Acinetobacter baumannii</span>&#44; <span class="elsevierStyleItalic">Pseudomonas aeruginosa</span>&#46;<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">4</span></a> Renal failure occurs in 20&#8211;60&#37; of colistin users&#46;<a class="elsevierStyleCrossRef" href="#bib0245"><span class="elsevierStyleSup">5</span></a> The studies on antioxidant molecules such as hesperidin&#44;<a class="elsevierStyleCrossRef" href="#bib0250"><span class="elsevierStyleSup">6</span></a> black garlic extract&#44;<a class="elsevierStyleCrossRef" href="#bib0255"><span class="elsevierStyleSup">7</span></a> curcumin&#44;<a class="elsevierStyleCrossRef" href="#bib0260"><span class="elsevierStyleSup">8</span></a> N-acetylcysteine&#44;<a class="elsevierStyleCrossRef" href="#bib0265"><span class="elsevierStyleSup">9</span></a> ascorbic acid&#44;<a class="elsevierStyleCrossRef" href="#bib0270"><span class="elsevierStyleSup">10</span></a> melatonin&#44;<a class="elsevierStyleCrossRef" href="#bib0275"><span class="elsevierStyleSup">11</span></a> lycopene&#44;<a class="elsevierStyleCrossRef" href="#bib0280"><span class="elsevierStyleSup">12</span></a> luteolin&#44;<a class="elsevierStyleCrossRef" href="#bib0285"><span class="elsevierStyleSup">13</span></a> grape seed extract<a class="elsevierStyleCrossRef" href="#bib0290"><span class="elsevierStyleSup">14</span></a> found them to be effective in the prevention of colistin-induced nephropathy&#46;</p><p id="par0010" class="elsevierStylePara elsevierViewall">Magnesium&#44; an antioxidant macromineral&#44; also has the advantages of being low in cost and easy to obtain&#46; Various agents such as contrast agents and chemotrophic agents reduce nephrotoxicity with these antioxidant effects&#46;<a class="elsevierStyleCrossRefs" href="#bib0295"><span class="elsevierStyleSup">15&#8211;18</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">GSH levels&#44; an endogenous antioxidant molecule&#44; are decreased with colistin treatment<a class="elsevierStyleCrossRefs" href="#bib0260"><span class="elsevierStyleSup">8&#44;12</span></a> and increased levels of MDA&#59; which are indicative of lipid peroxidation and increased in the case of oxidative damage&#46;<a class="elsevierStyleCrossRef" href="#bib0315"><span class="elsevierStyleSup">19</span></a> Therefore&#44; we examined whether magnesium had an antioxidant effect by analyzing different analytes such as GSH and MDA&#46; The effects of colistin on the kidney have been evaluated histopathologically in some studies&#46; The SQS system&#44; which is the sum of tubular damage in renal tissues and the percentage of tissue damage&#44; was used in these studies&#46;<a class="elsevierStyleCrossRefs" href="#bib0265"><span class="elsevierStyleSup">9&#44;13</span></a> We also planned to evaluate the colistin-induced renal tissue damage rate using this scoring system&#46;</p><p id="par0020" class="elsevierStylePara elsevierViewall">This study aimed to determine whether magnesium decreases nephrotoxicity caused by colistin&#44; which found to have an antioxidant effect in various drug studies of contrast and chemotherapeutic agents&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Methods</span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Animals</span><p id="par0025" class="elsevierStylePara elsevierViewall">The study was conducted in Sel&#231;uk University Experimental Medicine Application and Research Center with 30 male Wistar Albino rats weighing 300&#8211;350<span class="elsevierStyleHsp" style=""></span>g&#46; The study was approved by the ethics committee of the same center &#40;number&#58; 2019-46&#41;&#46; Rats were kept in cages at 21<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>1<span class="elsevierStyleHsp" style=""></span>&#176;C for 12<span class="elsevierStyleHsp" style=""></span>h in the light and 12<span class="elsevierStyleHsp" style=""></span>h in the dark and they were provided food and water&#46; To measure basal urea and creatinine levels&#44; 1<span class="elsevierStyleHsp" style=""></span>ml of blood was taken from the tail vein under anesthesia with 35<span class="elsevierStyleHsp" style=""></span>mg&#47;kg ketamine and 5<span class="elsevierStyleHsp" style=""></span>mg&#47;kg xylazine&#46;</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Drugs</span><p id="par0030" class="elsevierStylePara elsevierViewall">Colistimethate sodium was provided by Kocak Farma Pharmaceutical Company&#44; Istanbul&#44; Turkey &#40;Colimycin&#41;&#46; The drug contained 4&#44;500&#44;000<span class="elsevierStyleHsp" style=""></span>IU<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>384<span class="elsevierStyleHsp" style=""></span>mg colistimethate sodium and it had 150<span class="elsevierStyleHsp" style=""></span>mg of colistin base activity&#46; When it was reconstituted with 2<span class="elsevierStyleHsp" style=""></span>ml injection water&#44; a 1<span class="elsevierStyleHsp" style=""></span>ml solution contained 2&#44;250&#44;000<span class="elsevierStyleHsp" style=""></span>IU colistimethate sodium&#46; 15&#37; of magnesium sulfate &#40;1500<span class="elsevierStyleHsp" style=""></span>mg in 10<span class="elsevierStyleHsp" style=""></span>ml&#44; Kad&#305;k&#246;y&#44; Istanbul&#44; Turkey&#41; was used in the preparation of magnesium sulfate&#46;</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Experimental design</span><p id="par0035" class="elsevierStylePara elsevierViewall">Four groups were formed for the study&#58;<ul class="elsevierStyleList" id="lis0005"><li class="elsevierStyleListItem" id="lsti0005"><span class="elsevierStyleLabel">-</span><p id="par0040" class="elsevierStylePara elsevierViewall">The control group &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>6&#41; was given 2<span class="elsevierStyleHsp" style=""></span>ml&#47;kg&#47;day saline two times a day for seven days&#46;</p></li><li class="elsevierStyleListItem" id="lsti0010"><span class="elsevierStyleLabel">-</span><p id="par0045" class="elsevierStylePara elsevierViewall">Colistin group &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>8&#41; was given 300&#44;000<span class="elsevierStyleHsp" style=""></span>U&#47;kg&#47;day colistimetate sodium two times a day for seven days&#46;</p></li><li class="elsevierStyleListItem" id="lsti0015"><span class="elsevierStyleLabel">-</span><p id="par0050" class="elsevierStylePara elsevierViewall">Mg group &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>8&#41; was given magnesium sulfate intraperitoneally at a dose of 50<span class="elsevierStyleHsp" style=""></span>mg&#47;kg&#47;day two times a day for seven days&#46;</p></li><li class="elsevierStyleListItem" id="lsti0020"><span class="elsevierStyleLabel">-</span><p id="par0055" class="elsevierStylePara elsevierViewall">Mg<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>colistin &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>8&#41; was given intraperitoneal Mg sulfate at a dose of 50<span class="elsevierStyleHsp" style=""></span>mg&#47;kg&#47;day&#44; after 30<span class="elsevierStyleHsp" style=""></span>min&#44; 300&#44;000<span class="elsevierStyleHsp" style=""></span>U&#47;kg&#47;day of colistimethate sodium was administered two times a day for seven days&#46;</p></li></ul></p><p id="par0060" class="elsevierStylePara elsevierViewall">It could also be two doses with an interval of 8<span class="elsevierStyleHsp" style=""></span>h between the administration of doses&#46; On the seventh day&#44; rats were anesthetized with 90<span class="elsevierStyleHsp" style=""></span>mg&#47;kg ketamine and 10<span class="elsevierStyleHsp" style=""></span>mg&#47;kg xylazine 16<span class="elsevierStyleHsp" style=""></span>h after the last drug administration&#46; Right kidneys were fixed with 10&#37; formalin for histopathological examination and left kidneys were kept at &#8722;80<span class="elsevierStyleHsp" style=""></span>&#176;C for analysis of GSH and MDA levels at the tissue level&#46; 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recorded&#44; and divided into pieces and put into tubes&#46; Samples were placed in a Misonix Microson Ultrasonic Cell Disruptor with 150<span class="elsevierStyleHsp" style=""></span>mM KCl at 4<span class="elsevierStyleHsp" style=""></span>&#176;C to obtain 10&#37; homogenates&#46; MDA&#44; GSH&#44; and protein levels were analyzed in obtained homogenates&#46; GSH concentrations were analyzed according to the Ellmann method&#46; All analyses were carried out using spectrophotometrical techniques&#46;<a class="elsevierStyleCrossRef" href="#bib0320"><span class="elsevierStyleSup">20</span></a> The values were expressed as mg&#47;g protein in kidney tissue and mg&#47;g hemoglobin in the erythrocyte&#46; MDA concentrations were determined by the method of Uchiyama and Mihara with spectrophotometrical techniques&#46;<a class="elsevierStyleCrossRef" href="#bib0325"><span class="elsevierStyleSup">21</span></a> The values were expressed as nmol&#47;ml and nmol&#47;g tissue&#46; Blood hemoglobin concentrations were determined by Drabkin&#39;s method<a class="elsevierStyleCrossRef" href="#bib0330"><span class="elsevierStyleSup">22</span></a> and calculated as g&#47;dl&#46; Tissue protein concentrations were analyzed with a colorimetric test kit &#40;BioRad&#44; cat no&#58; 500-0002&#41; calculated as g&#47;dl&#46;</p><p id="par0080" class="elsevierStylePara elsevierViewall">Plasma urea was analyzed using a colorimetric test kit &#40;Elabsience Urea Kit&#44; cat no&#58; E-BC-K183-S&#41;&#46; The kit&#39;s detection range was 0&#46;114&#8211;30<span class="elsevierStyleHsp" style=""></span>mmol&#47;l&#44; inter-assay CV is 4&#46;7&#37;&#44; intra-assay CV is 4&#46;6&#37; and sensitivity 0&#46;114<span class="elsevierStyleHsp" style=""></span>mmol&#47;l&#46; Plasma creatinine levels were determined with the ELISA test kit &#40;Elabscience rat Creatinine&#44; cat no&#58; E-EL-0058&#41;&#46; The detection range was 1&#46;25&#8211;80<span class="elsevierStyleHsp" style=""></span>&#956;g&#47;ml&#44; and the sensitivity of the kit was 0&#46;75<span class="elsevierStyleHsp" style=""></span>&#956;g&#47;ml&#46; Plasma urea and creatinine concentrations were expressed as mg&#47;dl&#46; BMG LABTECH &#40;Germany&#41; and Rayto Microplate washer &#40;Elisa Washer&#41; &#40;RT-2600&#44; China&#41; were used for the analysis&#46;</p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Histopathological examination</span><p id="par0085" class="elsevierStylePara elsevierViewall">The right kidney tissues for histopathological examination were fixed after 24<span class="elsevierStyleHsp" style=""></span>h fixation in 10&#37; buffered formalin&#46; Microtome sections were taken from paraffin-block tissues and stained with hematoxylin&#8211;eosin &#40;HE&#41; and histochemical periodic acid Schiff &#40;PAS&#41; stains&#46; Histopathological assessment was performed by a blinded pathologist&#46; For each kidney tissue examined at 200&#215; magnification on light microscopic examination&#44; it was divided into three groups based on the tubular damage &#40;grade I&#44; grade II&#44; and grade III&#41;&#46; The tissue was divided into six scores based on the percentage of damage&#46; Percentage of affected area&#59; &#60;1&#37;&#44; 0&#59; 1&#8211;4&#37;&#44; 1&#59; 5&#8211;9&#37;&#44; 2&#59; 10&#8211;19&#37;&#44; 3&#59; 20&#8211;29&#37;&#44; 4&#59; 30&#8211;39&#37; 5&#59; &#8805;40&#37; were scored six&#46; These scores and grade grades were collected and divided into six groups using the SQS system within the scope of the kidney to be affected by the drug&#46; SQS &#43;1&#58; mild damage &#40;total score 1&#8211;14&#41;&#44; SQS &#43;2&#58; mild to moderate damage &#40;total score 15&#8211;29&#41;&#44; SQS &#43;3&#58; moderate damage &#40;total score 30&#8211;44&#41;&#44; SQS &#43;4&#58; moderate to severe damage &#40;total score 45&#8211;59&#41;&#44; SQS &#43;5&#58; severe damage &#40;total score 60&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0265"><span class="elsevierStyleSup">9&#44;13</span></a></p></span></span></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Power analysis</span><p id="par0090" class="elsevierStylePara elsevierViewall">In the present study&#44; the sample size was calculated based on the &#8220;resource equation&#8221; proposed by Arifin and Zahiruddin&#46; The sample size in each group should be a minimum of 10&#47;<span class="elsevierStyleItalic">k</span><span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>1 and a maximum of 20&#47;<span class="elsevierStyleItalic">k</span><span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>1 &#40;<span class="elsevierStyleItalic">k</span> the number of groups&#41; in this equality&#46; Thereby&#44; we calculated the sample size of each group to be a minimum of four&#44; and a maximum of six&#46;<a class="elsevierStyleCrossRef" href="#bib0335"><span class="elsevierStyleSup">23</span></a></p></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Data analysis</span><p id="par0095" class="elsevierStylePara elsevierViewall">Data were analyzed using R Version 3&#46;6&#46;0 &#40;<a href="http://www.r-project.org/">www&#46;r-project&#46;org</a>&#41;&#46; Variables were described as mean<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>standard deviation or median &#40;interquartile range&#41;&#46; The two-way repeated-measures ANOVA was performed to assess the groups&#8217; effects and time on urea and creatinine values in rats&#46; The box-plot method showed that there were no extreme outliers&#46; Shapiro&#8211;Wilk&#39;s test of normality was used to analyze the distribution of data &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#41;&#46; Levene&#39;s test of homogeneity of variances found variances to be homogeneous &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#41;&#46; A Bonferroni adjustment was used for the interaction and main effects&#46; Because the plasma MDA was not normally distributed&#44; Kruskal&#8211;Wallis and Wilcoxon tests were used to compare groups and time effects&#44; respectively&#46; After the Kruskal&#8211;Wallis test results were significant&#44; the Conover-Iman posthoc test with Bonferroni adjustment was used for multiple comparisons&#46; One way ANOVA and Welch tests were used to compare groups in terms of GSH and MDA levels&#46; Tukey HSD and Games-Howell posthoc tests were used for multiple comparisons according to these parameters at T1 time&#46; Mann&#8211;Whitney-<span class="elsevierStyleItalic">U</span> test was used to compare groups according to the grade of renal histology&#44; renal affected area score&#44; and SQS&#46; A <span class="elsevierStyleItalic">p</span>-value of less than 0&#46;05 was considered as significant&#46;</p></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Results</span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Biochemical evaluations</span><p id="par0100" class="elsevierStylePara elsevierViewall">The effect of different study groups overtime on urea values was assessed&#46; There were significant main effects of group on the urea values and also there was a significant interaction between group and time on urea values in rats &#40;<span class="elsevierStyleItalic">F</span>&#40;3&#44;26&#41;<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>7&#46;114&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;001&#44; <span class="elsevierStyleItalic">&#951;</span><span class="elsevierStyleSup">2</span><span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;451&#41;&#46; The simple main effect of the group was not significant at the time point T0 &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;925&#41;&#46; It became significant at T1 &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;015&#41;&#46; The mean urea value was significantly higher in the control and colistin groups compared to Mg &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;013 and <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;001&#44; respectively&#41; and Mg<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>colistin &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;001 and <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;001&#44; respectively&#41; groups at T1&#46; Unlike the Mg &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;002&#41; and Mg<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>colistin &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;001&#41; groups&#44; the simple main effect of time was not significant in the control &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;999&#41; and colistin groups &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;999&#41;&#46; The Mg &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;001&#41; and Mg<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>colistin groups &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;001&#41; had significantly lower mean urea value at the T1 time point compared to T0 &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a> and <a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>A&#41;&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0105" class="elsevierStylePara elsevierViewall">The effect of different study groups overtime on creatinine values was evaluated&#46; There was a significant main effects of group &#40;<span class="elsevierStyleItalic">F</span>&#40;3&#44;26&#41;<span class="elsevierStyleMonospace">Y</span>&#61;<span class="elsevierStyleMonospace">Y</span>3&#46;294&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;036&#44; <span class="elsevierStyleItalic">&#951;</span><span class="elsevierStyleSup">2</span><span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;275&#41; and time &#40;<span class="elsevierStyleItalic">F</span>&#40;1&#44;26&#41;<span class="elsevierStyleMonospace">Y</span>&#61;<span class="elsevierStyleMonospace">Y</span>27&#46;334&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;001&#44; <span class="elsevierStyleItalic">&#951;</span><span class="elsevierStyleSup">2</span><span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;513&#41; on the creatinine values in rats&#44; and also a significant interaction between group and time on creatinine values in rats &#40;<span class="elsevierStyleItalic">F</span>&#40;3&#44;26&#41;<span class="elsevierStyleMonospace">Y</span>&#61;<span class="elsevierStyleMonospace">Y</span>3&#46;128&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;043&#44; <span class="elsevierStyleItalic">&#951;</span><span class="elsevierStyleSup">2</span><span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;265&#41;&#46; The simple main effect of the group was not significant at the time point T0 &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;280&#41;&#46; It was significant at T1 &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;012&#41;&#46; The colistin group had a significantly higher mean creatinine value than the Mg<span class="elsevierStyleMonospace">Y</span>&#43;<span class="elsevierStyleMonospace">Y</span>colistin &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;011&#41; group at T1&#46; The simple main effect of time was not significant in the control &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;572&#41; and Mg<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>colistin groups &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;999&#41;&#46; The mean creatinine value was significantly higher at the T1 time point compared with the T0 time point for colistin and Mg groups &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;005 and <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;020&#44; respectively&#41; &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a> and <a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>B&#41;&#46;</p></span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">MDA and GSH levels</span><p id="par0110" class="elsevierStylePara elsevierViewall">Plasma MDA values were significantly affected by groups at the T1 time &#40;<span class="elsevierStyleItalic">H</span>&#40;3&#41;<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>17&#46;502&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;001&#41;&#44; but not at T0 time &#40;<span class="elsevierStyleItalic">H</span>&#40;3&#41;<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;121&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;989&#41;&#46; The median plasma MDA value was significantly higher in the colistin group compared with the other &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;001&#41; groups at the T1 time point&#46; The median plasma MDA value was significantly higher at the T1 time point compared with the T0 time point for colistin&#44; Mg&#44; and Mg<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>colistin groups &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;014&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;021&#44; and <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;021&#44; respectively&#41; &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a> and <a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>C&#41;&#46; There was a significant difference between the groups&#8217; erythrocyte GSH levels &#40;<span class="elsevierStyleItalic">Welch F</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>32&#46;715&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;001&#41;&#46; The colistin group &#40;1&#46;99<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;39&#41; had significantly lower GSH erythrocyte values than the control &#40;17&#46;52<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>5&#46;61&#41; and Mg &#40;23&#46;75<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>8&#41; groups after treatment&#46; There was no significant difference between the colistin and Mg<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>colistin &#40;9&#46;72<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>8&#46;53&#41; groups&#46; Moreover&#44; GSH erythrocyte values in rats were significantly higher after treatment in the Mg group compared to the colistin and Mg<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>colistin groups&#46; There was no significant difference between the Mg and control groups &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a> and <a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>D&#41;&#46; There were no significant differences between the groups&#8217; &#40;<span class="elsevierStyleItalic">F</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>1&#46;816&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;169&#44; <span class="elsevierStyleItalic">F</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;802&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;504&#44; respectively&#41; kidney GSH and MDA levels &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#46;</p></span><span id="sec0075" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Histopathological findings</span><p id="par0115" class="elsevierStylePara elsevierViewall">Grade of renal histology&#44; renal affected area score&#44; and SQS in rats were significantly lower in the Mg<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>colistin group compared to the colistin group &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;035&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;001 and <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;001&#44; respectively&#41; &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a> and <a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>&#41;&#46; The light microscopic examination showed that the normal structure of the tubules was maintained in the control and Mg groups&#46; Damage to the tubular epithelium was prominent in the colistin group &#40;<a class="elsevierStyleCrossRef" href="#fig0015">Fig&#46; 3</a>&#41;&#46;</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia><elsevierMultimedia ident="fig0010"></elsevierMultimedia><elsevierMultimedia ident="fig0015"></elsevierMultimedia></span></span><span id="sec0080" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Discussion</span><p id="par0120" class="elsevierStylePara elsevierViewall">Colistin has been increasingly used in recent times and is an important nephrotoxic&#46; The present study investigated if the toxic effects of colistin on the kidney decreased when it is combined with the antioxidant mineral Mg&#46; We found that the colistin<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>Mg group had lower urea and creatinine values and histopathological damage than the Mg group&#46; Additionally&#44; the colistin group had higher plasma MDA and GSH erythrocyte values than the other groups&#46;</p><p id="par0125" class="elsevierStylePara elsevierViewall">Colistin is filtered from glomeruli and secreted from tubules in the kidney&#46;<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">4</span></a> Its nephrotoxic effects are observed in the clinic as oliguria&#44; hematuria&#44; acute tubular necrosis&#46;<a class="elsevierStyleCrossRefs" href="#bib0340"><span class="elsevierStyleSup">24&#44;25</span></a> There are studies showing that oxidative stress plays a role in the formation of nephrotoxicity&#46;<a class="elsevierStyleCrossRefs" href="#bib0265"><span class="elsevierStyleSup">9&#44;12&#44;14&#44;19</span></a> It causes tubular lysis by causing the entrance of anion&#44; cation&#44; and water through tubular epithelial cell damage and affects in a similar way to bacteriostatic effect&#46; Colistin acts by displacing divalent cations Mg<span class="elsevierStyleSup">2&#43;</span> and Ca<span class="elsevierStyleSup">2&#43;</span> to disrupt the stability of the bacterial outer membrane&#46; Likewise&#44; it increases the permeability in tubules&#46;<a class="elsevierStyleCrossRef" href="#bib0350"><span class="elsevierStyleSup">26</span></a> Many reactive oxygen species that are formed in mitochondria result apoptosis and renal dysfunction&#46; Ozkan et al&#46; determined colistin-related in apoptosis to occur with the activation of caspase I and III&#46;<a class="elsevierStyleCrossRefs" href="#bib0355"><span class="elsevierStyleSup">27&#44;28</span></a> Many antioxidants have been studied to reduce the nephrotoxicity of colistin&#46;<a class="elsevierStyleCrossRefs" href="#bib0250"><span class="elsevierStyleSup">6&#44;10&#44;11&#44;13</span></a></p><p id="par0130" class="elsevierStylePara elsevierViewall">Magnesium is a mineral with vital functions such as transport function&#44; enzyme and signaling pathways&#44; energy metabolism&#44; and nucleic acid synthesis&#46;<a class="elsevierStyleCrossRef" href="#bib0365"><span class="elsevierStyleSup">29</span></a> It is an antioxidant and anti-inflammatory molecule&#46; It facilitates the intracellular calcium accumulation&#44; which we mentioned in the colistin nephrotoxicity&#44; by inhibiting the <span class="elsevierStyleSmallCaps">l</span>-type calcium channels&#46;<a class="elsevierStyleCrossRef" href="#bib0370"><span class="elsevierStyleSup">30</span></a> Magnesium was also found to decrease drug-related cardiotoxicity&#44; apoptosis&#44; and necrosis&#46;<a class="elsevierStyleCrossRef" href="#bib0375"><span class="elsevierStyleSup">31</span></a> Moreover&#44; various studies found this molecule to have antioxidant effects&#46; Administration of magnesium sulfate which has an antioxidant effect and dehydration in contrast-associated nephropathy reduced the risk of nephropathy&#46;<a class="elsevierStyleCrossRef" href="#bib0295"><span class="elsevierStyleSup">15</span></a> Another study indicated that contrast nephropathy was more common in patients with low magnesium levels&#46;<a class="elsevierStyleCrossRef" href="#bib0300"><span class="elsevierStyleSup">16</span></a> There are studies that show the effect of magnesium on nephropathy caused by some chemotherapeutic agents apart from contrast nephropathy&#46; In their experimental study&#44; Saito et al&#46; designed cisplatin nephrotoxicity and showed that giving magnesium to the rats decreased nephrotoxicity by reducing the cisplatin accumulation in the kidney&#46;<a class="elsevierStyleCrossRef" href="#bib0305"><span class="elsevierStyleSup">17</span></a> In a study conducted with people who received cisplatin chemotherapy&#44; the supplementation of magnesium to hydration reduced cisplatin nephrotoxicity&#46;<a class="elsevierStyleCrossRef" href="#bib0310"><span class="elsevierStyleSup">18</span></a> In another study performed on cyclosporine-treated mice&#44; magnesium supplementation had a renal protective effect by increasing nitric oxide synthase activity in the renal tissue&#46;<a class="elsevierStyleCrossRef" href="#bib0380"><span class="elsevierStyleSup">32</span></a></p><p id="par0135" class="elsevierStylePara elsevierViewall">Because there is no study examining the supplementation of Mg with colistin&#44; we referenced other studies for the Mg sulfate doses&#46; In their experiment to reduce the cardiotoxic effects of doxorubicin&#44; Khalilzadeh and colleagues gave rats 120<span class="elsevierStyleHsp" style=""></span>mg&#47;kg for two weeks and magnesium sulfate for three days a week as an IP and found that cardiotoxicity decreased&#46;<a class="elsevierStyleCrossRef" href="#bib0385"><span class="elsevierStyleSup">33</span></a> In another study&#44; nephrotoxicity was reduced by administering 40<span class="elsevierStyleHsp" style=""></span>mg&#47;kg Mg sulfate before cisplatin once a week for three weeks in rats given cisplatin&#46;<a class="elsevierStyleCrossRef" href="#bib0305"><span class="elsevierStyleSup">17</span></a> However&#44; higher magnesium doses were used in studies that assessed the effects of magnesium in rats with ischemic stroke and in Alzheimer&#39;s rat model&#46;<a class="elsevierStyleCrossRefs" href="#bib0390"><span class="elsevierStyleSup">34&#44;35</span></a></p><p id="par0140" class="elsevierStylePara elsevierViewall">In a review by Heybeli et al&#46; assessing the studies that involved colistin nephrotoxicity in rats&#44; it was observed that colistin was given at 300&#44;000&#8211;480&#44;000<span class="elsevierStyleHsp" style=""></span>IU&#47;kg&#47;day or 15&#8211;18<span class="elsevierStyleHsp" style=""></span>mg&#47;kg&#47;day or 36&#8211;84<span class="elsevierStyleHsp" style=""></span>mg&#47;kg cumulative doses because five of the eleven studies gave 300&#44;000<span class="elsevierStyleHsp" style=""></span>IU&#47;kg&#47;day&#46; In their article which was conducted in 2019 and included views of many institutions on the use of polymyxin&#44; Tsuji et al&#46; suggested 9&#44;000&#44;000<span class="elsevierStyleHsp" style=""></span>IU CMS maintenance dose to be systemically administered every 12&#8211;24<span class="elsevierStyleHsp" style=""></span>h after the 9&#44;000&#44;000<span class="elsevierStyleHsp" style=""></span>IU CMS loading dose and this was significantly lower than the dose &#40;300&#44;000<span class="elsevierStyleHsp" style=""></span>IU&#47;kg&#47;day&#41; we administered in the present study&#46;<a class="elsevierStyleCrossRef" href="#bib0400"><span class="elsevierStyleSup">36</span></a> The drug was provided for seven days in the majority of the studies&#46;<a class="elsevierStyleCrossRef" href="#bib0405"><span class="elsevierStyleSup">37</span></a> In their study in which they administered 300&#44;000<span class="elsevierStyleHsp" style=""></span>IU&#47;day CMS for six days&#44; Ozkan and Ozy&#305;lmaz determined that colistin caused a significant level of toxicity in the tissue and biochemical levels of the rats&#46;<a class="elsevierStyleCrossRefs" href="#bib0360"><span class="elsevierStyleSup">28&#44;38</span></a> Based on this study&#44; we administered colistin at a dose of 300&#44;000<span class="elsevierStyleHsp" style=""></span>IU&#47;kg&#47;day&#44; and for seven days&#46;</p><p id="par0145" class="elsevierStylePara elsevierViewall">We found that urea value decreased significantly in the Mg and Mg<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>colistin group&#44; creatinine value increased in the colistin and Mg groups and there was no significant increase in the control and Mg<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>colistin groups&#46; Although the decrease in the urea value of the Mg and Mg<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>colistin group supported the renal protective effect of magnesium&#44; it was also interesting to find that creatinine levels increased in the Mg group&#46; Cheungpasitporn et al&#46; showed that both hypomagnesemia and hypermagnesemia were associated with an increased risk of acute kidney disease&#46; They considered that overstimulated vasodilatation and vasoconstriction may be effective&#46;<a class="elsevierStyleCrossRef" href="#bib0415"><span class="elsevierStyleSup">39</span></a> Hypermagnesemia may occur in the group that was administered only magnesium and may cause creatinine value to be higher than the baseline&#46; The absence of histopathological changes in this group receiving magnesium alone may support the idea that a prerenal event may trigger an increase in creatinine&#46; Severe hypomagnesemia was detected in the colistin-treated groups in two studies in patients who were given colistin in the neonatal intensive care unit&#46;<a class="elsevierStyleCrossRefs" href="#bib0420"><span class="elsevierStyleSup">40&#44;41</span></a> Hypomagnesemia in the colistin group may lead to increased oxidative stress leading to renal toxicity&#46; Reduction of renal toxicity by adding magnesium to colistin may be a result of regulating hypomagnesemia with colistin&#46;</p><p id="par0150" class="elsevierStylePara elsevierViewall">MDA causes serious damage to the cell membrane structure&#46;<a class="elsevierStyleCrossRef" href="#bib0430"><span class="elsevierStyleSup">42</span></a> GSH is a tripeptide that reacts with hydrogen peroxide and organic acids and shows an antioxidant effec&#46;<a class="elsevierStyleCrossRef" href="#bib0435"><span class="elsevierStyleSup">43</span></a> In the study by Edrees et al&#46;&#44; concurrent administration of curcumin with colistin led to a decrease in the MDA level and an increase in GSH level in renal tissue&#46; Lee&#44; &#214;zkan&#44; and Ghlissi found that some antioxidant molecules used in their studies decreased the MDA levels compared to the colistin group&#46;<a class="elsevierStyleCrossRefs" href="#bib0255"><span class="elsevierStyleSup">7&#44;14&#44;44</span></a> Ozyilmaz et al&#46; found no change in the MDA level in plasma in the group given N-acetylcysteine together with colistin&#46;<a class="elsevierStyleCrossRef" href="#bib0410"><span class="elsevierStyleSup">38</span></a> We found that plasma MDA levels were significantly increased in the colistin group compared to the beginning of the experiment and compared to the other groups and decreased in the Mg and Mg<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>colistin groups&#46; While the colistin group had significantly lower erythrocyte GSH levels than the other groups&#44; Mg<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>colistin group was higher than the colistin group&#44; however&#59; it was not statistically significant&#46; Although renal GSH levels were the lowest in the colistin group renal MDA levels were the highest in the colistin group&#44; but it was not statistically significant&#46;</p><p id="par0155" class="elsevierStylePara elsevierViewall">We found tubular injury&#44; renal involvement area&#44; and SQS were found to be high in the colistin-treated group&#44; while the histopathological changes were significantly decreased in the magnesium-treated and colistin-treated rats&#46; This was in line with previous studies&#46;<a class="elsevierStyleCrossRefs" href="#bib0265"><span class="elsevierStyleSup">9&#44;10&#44;13</span></a></p><p id="par0160" class="elsevierStylePara elsevierViewall">There were some limitations to our study&#46; We did not study the effects of different doses of magnesium and colistin&#46; The fact that we did not study serum magnesium levels at the beginning and end of the study was another limitation of this study&#46; However&#44; this study was the first to examine colistin nephrotoxicity with magnesium which is an easily accessed&#44; inexpensive molecule with many functions in the body&#46; We believe that comprehensive and more detailed studies should be conducted to investigate the relationship between magnesium and colistin nephrotoxicity&#46;</p></span><span id="sec0085" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Ethics standards</span><p id="par0165" class="elsevierStylePara elsevierViewall">The study was approved by the Ethics Advisory Committee Sel&#231;uk University Experimental Medicine Application and Research Center &#40;IRB approval number&#58; 2019-46&#41;&#46; All procedures performed in animal studies were in accordance with the ethical standards of the institution or practice in which the studies were conducted&#46;</p></span><span id="sec0090" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">Conflict of interest</span><p id="par0170" class="elsevierStylePara elsevierViewall">The authors have declared that no conflict of interest exists&#46;</p></span></span>"
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          "titulo" => "Palabras clave"
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        4 => array:2 [
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          "titulo" => "Introduction"
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          "titulo" => "Methods"
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            0 => array:2 [
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              "titulo" => "Animals"
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            1 => array:2 [
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              "titulo" => "Biochemical measurements"
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                0 => array:2 [
                  "identificador" => "sec0035"
                  "titulo" => "Blood samples"
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                1 => array:2 [
                  "identificador" => "sec0040"
                  "titulo" => "Tissue collection and homogenization"
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                  "titulo" => "Histopathological examination"
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          "titulo" => "Power analysis"
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          "titulo" => "Results"
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            0 => array:2 [
              "identificador" => "sec0065"
              "titulo" => "Biochemical evaluations"
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            1 => array:2 [
              "identificador" => "sec0070"
              "titulo" => "MDA and GSH levels"
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              "titulo" => "Histopathological findings"
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    "pdfFichero" => "main.pdf"
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    "fechaRecibido" => "2020-06-23"
    "fechaAceptado" => "2020-11-19"
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          "clase" => "keyword"
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            0 => "Colistin"
            1 => "Magnesium"
            2 => "Nephrotoxicity"
            3 => "Oxidative stress"
            4 => "Rat model"
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            0 => "Colistina"
            1 => "Magnesio"
            2 => "Nefrotoxicidad"
            3 => "Estr&#233;s oxidativo"
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        "titulo" => "Abstract"
        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">The study aimed to investigate the role of magnesium sulfate prophylaxis in nephrotoxicity caused by colistin&#46; Thirty Wistar Albino rats were divided into four groups&#58; control&#44; colistin&#44; magnesium &#40;Mg&#41;&#44; and Mg<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>colistin&#46; The drugs were administered to the groups for seven days&#46; Urea-creatinine values were measured at the beginning &#40;T0&#41; and end &#40;T1&#41; of the study&#46; Malondialdehyde &#40;MDA&#41; levels were measured in plasma and kidney tissue&#44; glutathione &#40;GSH&#41; levels were analyzed in the erythrocyte and kidney tissues&#46; At the end of the study&#44; the semiquantitative score &#40;SQS&#41; was calculated by the histopathological examination of the kidneys&#46; Urea values significantly decreased in Mg and Mg<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>colistin groups compared to the baseline &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;013 and <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;001&#41;&#46; At the time of T1&#44; these groups had significantly lower urea values than the colistin and control groups&#46; Creatinine value was significantly increased in the colistin group compared to baseline &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;005&#41;&#44; the creatinine value in the colistin group was significantly higher than the Mg<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>colistin group &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;011&#41;&#46; Plasma MDA levels were significantly higher in the colistin group compared to the other groups at the time of T1 &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;001&#41;&#46; The Mg<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>colistin group had lower renal MDA levels than the colistin group&#46; The colistin group had significantly higher renal tubular grade &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;035&#41;&#44; renal affected area &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;001&#41;&#44; and SQS &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;001&#41; than the Mg<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>colistin group&#46; The results of the study suggested that Mg sulfate may have a nephrotoxicity-reducing effect on colistin&#46;</p></span>"
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        "resumen" => "<span id="abst0010" class="elsevierStyleSection elsevierViewall"><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">El objetivo del estudio fue investigar la funci&#243;n de la profilaxis con sulfato de magnesio en la nefrotoxicidad causada por la colistina&#46; Se dividieron 30 ratas Wistar albinas en 4 grupos&#58; control&#44; colistina&#44; magnesio &#40;Mg&#41; y Mg &#43; colistina&#46; Los f&#225;rmacos se administraron a los grupos durante 7 d&#237;as&#46; Los valores de urea-creatinina se midieron al principio &#40;T0&#41; y al final &#40;T1&#41; del estudio&#46; Se midieron los niveles de malondialdeh&#237;do &#40;MDA&#41; en el plasma y el tejido renal&#44; y se analizaron los niveles de glutati&#243;n &#40;GSH&#41; en los eritrocitos y el tejido renal&#46; Al final del estudio&#44; se calcul&#243; la puntuaci&#243;n semicuantitativa &#40;semiquantitative score &#91;SQS&#93;&#41; mediante el examen histopatol&#243;gico de los ri&#241;ones&#46; Los valores de urea disminuyeron significativamente en los grupos de Mg y Mg &#43; colistina en comparaci&#243;n con los valores iniciales &#40;p &#61; 0&#44;013 y p &#61; 0&#44;001&#41;&#46; En el momento del T1&#44; estos grupos ten&#237;an valores de urea significativamente m&#225;s bajos que los grupos de colistina y de control&#46; El valor de creatinina se increment&#243; significativamente en el grupo de colistina en comparaci&#243;n con el valor inicial &#40;p &#61; 0&#44;005&#41;&#59; el valor de creatinina en el grupo de colistina fue significativamente mayor que en el grupo de Mg &#43; colistina &#40;p &#61; 0&#44;011&#41;&#46; Los niveles de MDA en el plasma fueron significativamente m&#225;s altos en el grupo de colistina en comparaci&#243;n con los otros grupos en el momento del T1 &#40;p &#60; 0&#44;001&#41;&#46; El grupo de Mg &#43; colistina present&#243; niveles renales de MDA m&#225;s bajos que el grupo de colistina&#46; El grupo de colistina present&#243; un grado tubular renal &#40;p &#61; 0&#44;035&#41;&#44; un &#225;rea renal afectada &#40;p &#60; 0&#44;001&#41; y una SQS &#40;p &#61; 0&#44;001&#41; significativamente mayores que el grupo de Mg &#43; colistina&#46; Los resultados del estudio indicaron que el sulfato de Mg puede tener un efecto reductor de la nefrotoxicidad de la colistina&#46;</p></span>"
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          "en" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Comparison of urea&#44; creatinine&#44; MDA&#44; and GSH levels within and between groups&#46;</p>"
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          "en" => "<p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Comparison of renal histopathological scores in colistin and Mg<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>colistin groups&#46;</p>"
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          "en" => "<p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Histopathological examination image&#46; a&#58; Tubular epithelium lumen spill &#40;arrow&#41; &#40;HE 200&#215;&#41;&#59; b&#58; vacuolar degeneration in tubulepitel cells &#40;arrow&#41; &#40;HE 200&#215;&#41;&#59; c&#58; tubular epithelium necrosis &#40;ring&#41; &#40;HE 200&#215;&#41;&#59; d&#58; tubular epithelial cells degeneration at the brushy edge &#40;arrow&#41; &#40;PAS 200&#215;&#41;&#59; e&#58; eosinophilic cytoplasm cells &#40;ring&#41; with picnotic nuclei laying tubules &#40;HE 200&#215;&#41;&#46;</p>"
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          "leyenda" => "<p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Values are presented as mean<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>standard deviation or median &#40;interquartile range&#41;&#44; ns&#58; not significant&#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" scope="col" style="border-bottom: 2px solid black">Groups</th><th class="td" title="\n
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                  \t\t\t\t" scope="col"><span class="elsevierStyleItalic">p</span>-Value&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th></tr><tr title="table-row"><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="center" valign="\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Control &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>6&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Colistin &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>8&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Mg &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>8&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Mg<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>colistin &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>8&#41;&nbsp;\t\t\t\t\t\t\n
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                    0 => array:2 [
                      "titulo" => "Colistin&#58; the revival of polymyxins for the management of multidrug-resistant gram-negative bacterial infections"
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                        0 => array:2 [
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                          "autores" => array:2 [
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                    0 => array:2 [
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                        "paginaInicial" => "1333"
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                      "titulo" => "Colistin&#58; how should it be dosed for the critically ill&#63;"
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                          "autores" => array:2 [
                            0 => "C&#46;B&#46; Landersdorfer"
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                    0 => array:2 [
                      "doi" => "10.1055/s-0034-1398390"
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                        "tituloSerie" => "Semin Respir Crit Care Med"
                        "fecha" => "2015"
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                      "titulo" => "Colistin&#58; the re-emerging antibiotic for multidrug-resistant Gram-negative bacterial infections"
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                          "etal" => true
                          "autores" => array:6 [
                            0 => "J&#46; Li"
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                            2 => "J&#46;D&#46; Turnidge"
                            3 => "R&#46;W&#46; Milne"
                            4 => "K&#46; Coulthard"
                            5 => "C&#46;R&#46; Rayner"
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                    0 => array:2 [
                      "doi" => "10.1016/S1473-3099(06)70580-1"
                      "Revista" => array:6 [
                        "tituloSerie" => "Lancet Infect Dis"
                        "fecha" => "2006"
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                        "paginaInicial" => "589"
                        "paginaFinal" => "601"
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Article information
ISSN: 20132514
Original language: English
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