Antioxidants have been proposed to have antiatherogenic potential by their inhibition of low density lipoprotein (LDL) oxidation. Here, we report an antioxidant, BO-653 (2,3-dihydro-5-hydroxy-2,2-dipentyl-4,6-di-tert-butylbenzofuran), designed to exhibit antioxidative potency comparable to that of ␣-tocopherol, but yet possess a high degree of lipophilicity comparable to that of probucol. BO-653 exhibits a high affinity for LDL and is well distributed in aortic vessels in vivo. In atherosclerosis models of rabbits and mice, BO-653 has been shown to be able to suppress the formation of atherosclerotic lesions without untoward side effects. Specifically, there was no reduction of high density lipoprotein levels. This antioxidant provides additional evidence in support of the oxidized-LDL hypothesis, and itself is a promising candidate antioxidant for clinical use.

Tofogliflozin is a selective oral inhibitor of sodium-glucose co-transporter 2 for treatment of type 2 diabetes mellitus. The pharmacokinetics, pharmacodynamics, and safety of tofogliflozin were investigated in healthy male subjects. Three studies were conducted: single-ascending dose study (10-640 mg) in 56 Japanese and 24 Caucasian subjects; multiple-ascending dose study (2.5-80 mg once daily for 7 days) in 24 Japanese subjects; and food-effect study (20-40 mg) in 30 Japanese subjects. Tofogliflozin was absorbed rapidly and eliminated from the systemic circulation with a t of 5-6 h. Exposure increased dose-proportionally up to 320 mg. Body weight-corrected exposure was similar between Japanese and Caucasian subjects. Urinary excretion of tofogliflozin ranged from 17.1 to 27.4% of dose. Tofogliflozin did not accumulate with once daily administration. Food intake decreased C by approximately 30% but did not change AUC. Tofogliflozin caused dose-dependent daily urinary glucose excretion (UGE), but food intake condition at administration did not affect it. The exposure-response relationship between plasma average concentration of tofogliflozin (C) and UGE fitted E model well. There were no serious adverse events leading to discontinuation or episodes of hypoglycemia. Single and multiple administration of tofogliflozin were generally well tolerated. Exposure to tofogliflozin was dose-proportional up to 320 mg and did not accumulate with multiple once-a-day administration. The model suggests more than 100 ng/mL C corresponding to the dose of between 20 and 40 mg leads to almost maximum effect of tofogliflozin.

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