薬理と治療

We studied about the vasorelaxant effect of bonito extract on norepinephrine (NE)induced contract in rat isolated aorta. Furthermore, we attempted to clarify which component plays the major role in the vasodilating effect. Bonito extract concentration-dependently inhibited the contraction induced by NE in thoracic aortae with and without endothelium to a certain equally. In other words, the removal of the endothelium did not affect the relaxing effect of bonito extract upon NE-induced precontraction, suggesting the possibility that this action is related to the inhibitory effect on the constriction of blood vessels induced by NE via alpha adrenergic receptors. To investigate the identity of the active component, we examined the blood vessel-relaxing actions of three different fractions:total bonito extract, components with molecular weights below 1000(Mw<1000 fraction), and chemically-defined components. It was shown that total bonito extract, the Mw<1000 fraction and the mixture of chemically-defined compounds inhibited the contraction induced by NE in the thoracic aortae. The effect of mixture of chemically-defined compounds can contribute 59.2% of the effect of total bonito extract. From these results, it is also a possibility that the active component with molecular weight below 1000 is combination of histidine, carnosine and unknown peptides.

Objective To assess the efficacy and safety of long-term monotherapy with anagliptin administered before or after meals in Japanese patients with type 2 diabetes. Methods This was a multi-centre, 52-week, randomized, open-label, parallel-group study. Patients were randomized(1:1)to receive anagliptin(100 mg twice daily before meals, n=81)or anagliptin(100 mg twice daily after meals, n=70). After 16 weeks, patients who did not achieve the HbA1c goal(less than 6.9%)received the increased dose of anagliptin(200mg twice daily). The primary endpoint was the change from baseline in HbA1c at 12 weeks. Results Mean baseline age and HbA1c were 57.9 years and 8.2%, respectively. Baseline characteristics were similar in the two groups. After 12 weeks of treatment with anagliptin, mean changes from baseline in HbA1c were -0.63%(95%CI:-0.78, -0.48)when administered before meals versus -0.56%(95%CI:-0.69, -0.43)when administered after meals. Significant reductions from baseline in HbA1c were sustained through 52 weeks regardless of administration before or after meals. Anagliptin was generally well tolerated. Hypoglycaemic events were rare, and a drug-related hypoglycaemic event occurred in only one patient(0.7%). Conclusions Long-term monotherapy with anagliptin administered before or after meals significantly improved glycaemic control and was well tolerated in Japanese patients with type 2 diabetes.

Objective To assess the efficacy and safety of anagliptin added to biguanide, α-glucosidase inhibitor, sulfonylurea, or pioglitazone monotherapy in Japanese patients with type 2 diabetes. Methods In a randomized, double-blind, placebo-controlled trial, type 2 diabetic patients treated with biguanide(n=105), α-glucosidase inhibitor(n=94), sulfonylurea(n=136), or pioglitazone(n=102)monotherapy received either anagliptin 100 mg twice daily or placebo(2:1)for 12 weeks. Thereafter, all patients continued on anagliptin 100 mg twice daily in an open-label extension for 40 weeks. At week 28, patients who did not achieve the HbA1c goal (less than 6.9%)were placed on anagliptin 200 mg twice daily. The primary endpoint was the change in HbA1c from baseline(week 0)to the end of the double-blind period(week 12). Results Baseline characteristics of patients randomized to anagliptin vs. placebo were similar. After 12 weeks, a statistically significant reduction in HbA1c was observed in patients treated with anagliptin compared with a placebo treatment in all 4 add-on therapy groups;the mean placebo-adjusted changes in HbA1c were -1.07%(95% CI:-1.38, -0.75), -0.95%(95% CI:-1.19, -0.70), -0.79%(95% CI:-0.97, -0.59), and -0.84%(95% CI:-1.12, -0.54)in biguanide, α-glucosidase inhibitor, sulfonylurea, or pioglitazone treated patients, respectively. Significant reductions from baseline HbA1c were sustained through 52 weeks and anagliptin was generally well tolerated in all 4 groups. Hypoglycaemic events occurred more frequently in the anagliptin+sulfonylurea group compared with other groups. Drug-related hypoglycaemia events occurred in 10 patients(7.4%), but all events were considered mild. Conclusions Anagliptin added to biguanide, α-glucosidase inhibitor, sulfonylurea, or pioglitazone monotherapy significantly improved glycaemic control and was well tolerated in Japanese patients with type 2 diabetes.

Background Dipeptidyl peptidase－4 inhibitors exert various beneficial effects including lipid profile modification in addition to its glucose－lowering action. Several long－term trials with anagliptin have demonstrated a significant reduction in serum LDL－C level, suggesting a lipid－modulating action of this drug. Methods One monotherapy and 4 add－on therapy trials extending out to 52 weeks were included in this analysis. In the monotherapy trial, patients were randomized（1：1）to receive anagliptin 100 mg twice daily either before a meal or after a meal. In the add－on therapy trial, patients were randomized（2：1）to receive anagliptin 100 mg twice daily or placebo in addition to biguanide, α－glucosidase inhibitor, sulfonylurea, or pioglitazone therapy. After 12 weeks, all patients assigned to placebo received anagliptin 100 mg twice daily. During the follow－up periods, patients who did not achieve the HbA1c goal（less than 6.9％）were titrated to anagliptin 200 mg twice daily. Individual patient data obtained in these trials were applied to assess serum lipid profile as well as HbA1c level. Results Anagliptin treatment for 12 weeks showed a statistically significant reduction in LDL－C（－5.1％, p＝0.002）as well as HbA1c（－0.88％, p＜0.001）compared with placebo. The long－term treatment with anagliptin further decreased LDL－C level（－6.4％ at week 52 vs. week 0, p＜0.001）. The effect of anagliptin was more significant in patients with baseline LDL－C＞－ 140 mg／dL（mean：－13.9％ at week 52 vs. week 0, p＜0.001）. Anagliptin treatment for 52 weeks also reduced TG level（median：－16.1％ at week 52 vs. week 0, p＜0.001）in patients with baseline TG＞－150 mg／dL. Conclusions Long－term treatment with anagliptin reduced serum LDL－C and TG levels in addition to HbA1c reduction. This suggests that anagliptin may provide additional benefits beyond glucose lowering effect in type 2 diabetic patients with dyslipidemia.

Background L-Citrulline, a potent precursor of L-arginine, is an α-amino acid which is known to be effective in enhancing nitric oxide synthase-catalyzed nitric oxide production, which is involved in vasodilation. The objective of this study was to evaluate the effect of supplemented L-citrulline on swelling of the lower leg in females. Methods In a double-blind, randomized, placebo-controlled cross-over protocol, 11 healthy female volunteers(26.9±2.1 years old)received L-citrulline(3.2 g/day)or placebo for 5 days. On day 1(single administration)and day 5(continuous administration), the circumference of the lower leg and the pooled urine weight during long-term seating and oral water loading were measured. Results Long-term seating stress caused the leg swelling remarkably. Compared with the placebo trial, the increment in the circumference of the lower leg during long-term seating stress was significantly reduced in the L-citrulline trial. No significant change in the pooled urine weight was observed in the two trials. Conclusions These results indicate that L-citrulline supplementation is useful for reducing leg swelling induced by long-term seating stress in females, probably due to improving peripheral circulation without a diuretic effect.

Objectives We investigated the effect of test chocolate containing plant sterol on the serum cholesterol levels in subjects with borderline-high cholesterol or mild hypercholesterolemia. Methods Eighty nine subjects with borderline-high cholesterol or mild hypercholesterolemia(serum total cholesterol;200-240 mg/dL, serum LDL cholesterol;120-160 mg/dL)were randomly divided into four groups(a placebo group, chocolate containing 400 mg/day plant sterol group, chocolate containing 800 mg/day plant sterol group, chocolate containing 1200 mg/day plant sterol group, respectively). All groups took each chocolate(17.2 g)every day for 8 weeks.Results In 1200 mg/day group, average LDL cholesterol level at 8 weeks was significantly lower than that at baseline. Moreover, average LDL cholesterol level at 8 weeks was significantly lower than that of the placebo group. Any severe adverse effect was not observed in all the experimental groups. Conclusions The results suggest that chocolate containing 1200 mg/day plant sterol is useful for the reduction of LDL cholesterol levels without significant adverse effects in subjects with borderline-high cholesterol or with mild hypercholesterolemia(serum total cholesterol;200-240 mg/dL, serum LDL cholesterol;120-160 mg/dL)

Objectives In a randomized, placebo-controlled, double-blind study, we investigated the safety of excessive intake of chocolate containing plant sterol in subjects with borderlinehigh cholesterol or mild hypercholesterolemia(serum total cholesterol, 200-240 mg/dL and serum LDL cholesterol, 120-160 mg/dL)and subject within normal cholesterol(serum total cholesterol, less than 200 mg/dL or serum LDL cholesterol, less than 120 mg/dL). Methods Total forty-seven subjects, subjects with borderline-high cholesterol or mild hypercholesterolemia,(n=24)and subjects with normal cholesterol,(n=23)participated in the present study, and two groups of subjects were randomly assigned to one of two treatment groups:a test(chocolate containing plant sterol)group and a placebo group. Each group ingested test chocolate containing plant sterol(3600 mg;three times higher than the optical amount of 1200 mg/day in 12 pieces)or placebo for 4 weeks. The participants underwent blood, urine and physical examinations, and subjective and objective signs and symptoms were also examined during the experimental period. Results Preliminary analysis revealed that no differences in the results of parameters in blood, urine, physical examinations, and signs and symptoms, and thus, we evaluated the safety of the chocolate containing plant sterol by comparing the results of the test group (3600 mg/day)with those of the placebo group. No adverse events caused by test chocolate were observed based on blood chemistry, hematology, urine samples, physical examinations, and subjective sign and symptoms. Conclusions The present study demonstrated the safety of excessive intake of chocolate containing plant sterol in subjects with borderline-high cholesterol or mild hypercholesterolemia and within normal cholesterol.