The present population pharmacokinetic analysis strongly indicates that fosfluconazole (and fluconazole) dosage should be optimized in terms of CLcr in critically ill patients.

SLCO1B3 699GG and 344TT genotypes are associated with non-response to IM, while ABCA3 4548-91 CC/CA genotypes are related to poor CMR in CML patients treated with standard-dose imatinib.

TNFA -308G >A polymorphism appear to be involved in regulation of gene expression independently of hyperglycemia and its interaction with pioglitazone may modify tALP, a important bone marker. IL6 -174G>C variant is related with reduced risk of postprandial hyperglycemia but not with mRNA expression or bone markers.

1422 Background: Imatinib Mesylate (IM) used in the treatment of CML, interacts with membrane efflux transporters such as ABCB1 and ABCG2, whereas the active uptake of IM into the cells is mediated by SLC22A1. The predictive value of these markers is still controversial. The altered expression of these genes could impact on intracellular concentration of IM and contribute to resistance. Aims: The aim of this study was to investigate ABCB1, ABCG2 and SLC22A1 gene expression as potential sources of resistance to imatinib in patients with CML Methods: One hundred and eighteen patients in chronic phase of CML, both genders with age range 18 to 80 were studied. All patients were initially treated with a standard dose of IM (400 mg/day) and divided in two groups according to response. The responder group comprised 70 patients who had a complete cytogenetic response within 18 months of treatment. The non-responder group comprised 48 patients who did not have a complete cytogenetic response with the initial dose (400 mg/day) of IM or who relapsed during treatment and were submitted to higher doses of 600 or 800 mg/day. Criteria of failed response to treatment were established by European LeukemiaNet. Patients with cytogenetic patterns other than the Philadelphia chromosome and patients with mutations in the BCR-ABL1 gene were excluded from this study. Major molecular response (MMR) was defined as a reduction of BCR-ABL1 transcripts levels to ≤ 0.1% in the peripheral blood standardized on the International scale. Complete molecular response (CMR) was defined as a reduction ≤ 0.032% BCR-ABL1 transcripts levels. Primary resistance and secondary resistance also were evaluated. Real-Time PCR was performed to evaluate the ABCB1, ABCG2 and SLC22A1 mRNA relative expression to control gene GAPDH. Results: Expression of ABCG2 in the non-responder group was higher than in the responder group (P=0.028). This result was influenced by patients with primary resistance (n= 34 p=0.029) but not secondary resistance (n=14 p=0.249) when compared with responders (n=70). ABCB1 and SLC22A1 expression were similar between responder and non-responder groups. Higher levels of SLC22A1 mRNA were found in patients who achieved MMR in the responder group (p=0.009). The elevated ABCG2 expression was also found in those who did not achieve MMR (p=0.027) when all patients were analyzed. None of studied genes was associated with CMR. Conclusions: The high expression of ABCG2 is related to primary resistance and SLC22A1 is positively associated with major molecular response to treatment with IM. Our data suggests that ABCG2 may be a mediator of IM resistance, whereas SLC22A1 could be a good predictor of response to IM therapy. Financing: Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP 2009/54184-0). Disclosures: No relevant conflicts of interest to declare.

An integrative analysis of miRNA and mRNA expression profiles in left ventricle (LV) of diabetes-induced rats was performed to elucidate the role of miRNAs and their mRNAs target in diabetic cardiomyopathy (DCM). mRNA (GSE4745) and miRNA (GSE44179) datasets were downloaded from Gene Expression Omnibus 2R (GEO2R) and differentially expressed mRNAs and miRNAs were selected. Cardiotoxicity-related mRNAs (n=7) were analyzed by Ingenuity Pathway Analyses 6 (IPA) and regulatory miRNAs (n=639) were identified using TargetScan 7.1. web dataset. The integrative analysis was performed between miRNAs differentially expressed in GSE44179 and regulatory TargetScan-detected miRNAs of mRNAs differentially expressed in GSE4745. and mRNAs were up-and-down regulated, respectively, in GSE4745 on days 3 and 42 after diabetes-induction. The regulatory miRNAs, rno-miR-877, rno-miR-320 and rno-miR-214 were down-regulated, and regulatory miRNAs, rno-miR-17, rno-miR-187, rno-miR-34a, rno-miR-322, rno-miR-188, rno-miR-532 and rno-miR-21, were up-regulated in GSE44179 dataset. These results are suggestive that and mRNAs and their regulatory miRNAs play a role in DCM pathogenesis and they may be potential circulating biomarkers to detect early cardiovascular complications in diabetic patients.