Organic cation transporters (OCTs) are responsible for the hepatic and renal transport of metformin. In this study we analyzed variants of OCT1 and OCT2 genes in 33 patients (24 responders and nine non-responders) based on the hypothesis that polymorphisms in both genes contribute to large interpatient variability in the clinical efficacy of metformin. The sequences of the 5¢-flanking and coding regions of the two genes of interest were screened by singlestrand conformation polymorphism (SSCP) analysis. To compare the causative factors between responders and non-responders, we performed stepwise discriminant functional analysis. Age, body mass index (BMI) and treatment with lipid-lowering agents were demonstrated as positive predictors, and two mutations in the OCT1 gene, -43T > G in intron 1 and 408Met > Val (1222A > G) in exon 7, were negative and positive predictors, respectively, for the efficacy of metformin; the predictive accuracy was 55.5% (P < 0.05). Subsequent study indicated that OCT1 mRNA levels tended to be lower in human livers with the 408Met (1222A) variant, though the differences did not reach the level of significance. In this study it is suggested that OCT1 and OCT2 gene polymorphisms have little contribution to the clinical efficacy of metformin.

Background-Hyperuricemia is common in chronic heart failure (CHF), and it is a strong independent marker of prognosis. Upregulated xanthine oxidase (XO) activity and impaired renal excretion have been shown to account for increased serum uric acid (UA) levels in CHF. Therapeutic interventions with allopurinol to reduce UA levels by XO inhibition have been shown to be beneficial. Discussions are ongoing whether UA itself is actively involved or it is a mere marker of upregulated XO activity within CHF pathophysiology. Therefore, the aim of this study was to test the effect of lowering UA by uricosuric treatment without XO inhibition on hemodynamic and metabolic characteristics of CHF. Impaired renal excretion of UA was taken into account. Methods and Results-Serum UA (SUA), urinary UA (uUA) excretion, and renal clearance test for UA (Cl UA ) were measured in 82 patients with CHF. SUA was significantly increased compared with controls of similar age (control, 5.45Ϯ0.70 mg/dL; New York Heart Association I, 6.48Ϯ1.70 mg/dL; New York Heart Association II, 7.34Ϯ1.94 mg/dL; New York Heart Association III, 7.61Ϯ2.11 mg/dL; PϽ0.01). Patients with CHF showed lower uUA excretion and Cl UA . On multivariate analysis, insulin, brain natriuretic peptide (PϽ0.01), and creatinine levels (Pϭ0.05) showed independent correlation with SUA. The treatment effect of the uricosuric agent benzbromarone was tested in 14 patients with CHF with hyperuricemia in a double-blind, placebo-controlled, randomized crossover study design. Benzbromarone significantly decreased SUA (PϽ0.01). Brain natriuretic peptide, left ventricular ejection fraction, and dimensions in echocardiographic assessment did not change after benzbromarone therapy. In contrast, fasting insulin (placebo, 18.8Ϯ8.9 U/mL; benzbromarone, 11.0Ϯ6.2 U/mL; PϽ0.05), homeostasis model assessment of insulin resistance index (placebo, 5.4Ϯ2.6; benzbromarone, 3.0Ϯ1.7; PϽ0.05), and tumor necrosis factor-␣ (placebo, 2.59Ϯ0.63 pg/mL; benzbromarone, 2.14Ϯ0.51 pg/mL; PϽ0.05) improved after benzbromarone, and the changes in tumor necrosis factor-␣ levels were correlated with reduction of SUA (PϽ0.05). Conclusions-These results show that UA lowering without XO inhibition may not have an effect on hemodynamic impairment in CHF pathophysiology. To the extent that these data are correct, this finding suggests that upregulated XO activity rather than UA itself is actively involved in hemodynamic impairment in CHF. Clinical Trial Registration-clinical trials.gov. Identifier: NCT00422318.(Circ Heart Fail. 2010;3:73-81.)

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It has been reported that the xanthine oxidase inhibitor, allopurinol, has a protective effect on ischemia - reperfusion injury, but the precise mechanism of its action is still unclear. Therefore, in the present study the mechanisms of the myocardial protection of allopurinol were evaluated in isolated perfused rat hearts. Allopurinol significantly inhibited myocardial xanthine oxidase activity, and improved left ventricular dysfunction after ischemia - reperfusion. In addition, the lactate dehydrogenase content in the coronary effluent obtained after reperfusion was significantly decreased. ATP, ADP, AMP and IMP significantly decreased, whereas inosine, hypoxanthine and xanthine significantly increased after ischemia in both the control and allopurinol groups. The concentration of xanthine was significantly decreased after ischemia - reperfusion in the allopurinol group; however, allopurinol did not affect the other purine metabolites. To evaluate the accumulation of oxidative stress, thiobarbituric acid reactive substances (TBARS) production in myocardial tissue was measured and allopurinol significantly decreased TBARS formation after ischemia - reperfusion. Finally, myocardial hydroxyl radicals were directly measured by electron spin resonance spectroscopy with the nitroxide radical 4-hydroxy-2, 2,6,6-tetramethyl-piperidine-N-oxyl. Hydroxyl radicals significantly increased immediately after reperfusion, but were significantly decreased in the allopurinol group. In conclusion, allopurinol reduced myocardial injury after ischemia-reperfusion by suppressing oxidative stress, but not by salvage of ATP. These findings may lead to the development of new therapeutic strategies for myocardial ischemia - reperfusion injury.