A Study to Explore the Role of IDH1 (R132) Mutation on Imatinib Toxicity and Effect of ABCG2/OCT1 Expression on N-Desmethyl Imatinib Plasma Level in Egyptian Chronic Myeloid Leukemia Patients.

Imatinib mesylate (IM) is the gold standard for treatment of Chronic Myeloid Leukemia (CML). This study aimed to gain more knowledge of the altered PK, pharmacogenetic factors, and gene expression leading to variable IM levels. Fifty patients with chronic phase-CML were enrolled in this study and divided as 25 responders and 25 non-responders (patients are directly recruited after response assessment). HPLC/MS/MS was used to determine trough and peak concentration of imatinib and N-desmethyl imatinib in the blood. PCR-RFLP technique was used to detect IDH1 gene mutation (R132). The median value of IM trough level was significantly higher, the P/T ratio was significantly lower and the α-1-acid glycoprotein (AGP) was significantly higher among responders compared to non-responders (P=0.007, 0.009 and 0.048, respectively). Higher N-desmethyl imatinib peak plasma concentration was observed with low mRNA expression of ABCG2 and OCT1 (P=0.01 and 0.037, respectively). IDH1 R132 gene mutation was associated with a significant increase in toxicities (P=0.028). In conclusion, IM trough level, P/T ratio and AGP was significantly higher in responders. In addition, ABCG2 and OCT1 gene expression may affect the interindividual PK variation. Although a prospective study with a larger patient population is necessary to validate these findings. IDH1 mutation is a predictor of increased toxicity with IM treatment.

Effect of surgically-induced weight loss on inflammatory mediators and peripheral blood monocyte CD11b expression in morbid obesity.

Obesity is characterized by a state of chronic mild inflammation, with raised circulating levels of inflammatory markers. Expression and release of inflammation-related adipokines, generally, rise as adipose tissue expands. In the present study we evaluated the level of serum mediators concerned in inflammation and monocyte activation (TNF-alpha, hs-CRP, MCP-1) together with percentage of CD11-b expression on monocytes in a group of morbidly obese individuals (n = 20) before and (3-6 months) after restrictive surgery, and in 15 healthy normal weight individuals. Serum MCP-1, TNF-alpha and hs-CRP were assayed by enzymatic immunoassay, while the percentage of CD11b expression on monocytes was assayed by flow cytometry. The total lipid profile and random blood glucose levels were also assessed. Morbidly obese individuals ( before surgical weight loss) had significantly increased levels of MCP-1, TNF-alpha, hs-CRP, CD11b expression on monocytes as compared to controls (P < 0.01). Levels of MCP-1, TNF-alpha, hs-CRP were significantly decreased 3 to 6 months after restrictive surgery than before the operation (P < 0.01). hs-CRP, MCP-1 and TNF-alpha were positively correlated versus each other. TNF-alpha and hs-CRP also showed positive correlation with the body mass index. Our data suggested that the studied serum and monocyte parameters may link obesity with systemic inflammation and metabolic disorders. The interactions of MCP-1, CD11b and other inflammatory parameters might provide the basis for development of new therapies for this syndrome.