薬理と治療

We investigated the effects of tamsulosin and other α1−adrenoceptor antagonists on bladder function, especially spontaneous bladder contractions before micturition（premicturition contraction）, in conscious rats with bladder outlet obstruction induced by partial urethral ligation, and compared the results with the effects on intraurethral pressure response in anesthetized rats. In obstructed rats, α1−adrenoceptor antagonists tamsulosin, naftopidil, silodosin and urapidil and non−selective α−adrenoceptor antagonist phentolamine inhibited premicturition contractions in a dose−dependent fashion. In contrast, yohimbine, an α2−adrenoceptor antagonist, and atropine, a muscarinic receptor antagonist, hardly inhibited them. Moreover, tamsulosin and urapidil showed clearly inhibitory effects on increases in intraurethral pressure induced by phenylephrine, an α1−adrenoceptor agonist, in the same dose range as that at which they inhibited premicturition contractions, whereas naftopidil required somewhat higher doses to inhibit increases in intraurethral pressure than those at which it inhibited premicturition contractions. In contrast, silodosin required higher doses to inhibit premicturition contractions than those at which it inhibited increases in intraurethral pressure. In conclusion, premicturition contractions observed in obstructed rats were sensitive to α1−adrenoceptor antagonists, but not to α2−adrenoceptor or muscarinic receptor antagonists. Tamsulosin was shown to be effective against both premicturition contraction and intraurethral pressure response in the same dose range in rats. These results support the fact that tamsulosin has improved storage symptoms as well as voiding symptoms in patients with bladder outlet obstruction by blocking α1−adrenoceptors. （Jpn Pharmacol Ther 2008；36：381−92）KEY WORDS Tamsulosin, Naftopidil, Silodosin, Urapidil, α1−adrenoceptor, Intraurethral pressure, Premicturition contraction, Bladder outlet obstruction

【撤回論文】Objectives To study the tissue distribution and transfer into the fetus or milk of topiramate in rats. Methods ［14C］−topiramate was orally administered to male rats, and pregnant and lactating female rats at a dose of 40 mg／kg. Then, blood, tissues, fetus, and milk were collected and analyzed for radioactivity. Results Tissue concentrations of radioactivity in male rats showed the maximum levels in most tissues at 0.5 hours after administration. The concentration in the brain was 40−50％ of that in plasma up to 4 hours after administration, while the levels in other tissues were lower than or equal to the level in plasma. Radioactivity levels decreased to 1.4％ or lower of the maximum levels in all tissues at 72 hours. After administration to pregnant rats on the 19th day of gestation, radioactivity was transferred into the fetus. The concentration in the fetus was close to that in maternal plasma and decreased in parallel with the maternal plasma level. The concentration in milk reached the maximum level（24.32μg eq.／g）1.40 hours after administration to lactating rats on the 9th day after delivery, which levels decreasing faster than what was observed in plasma. The milk／plasma concentration ratio was 0.07−0.73 and decreased with time. Conclusions Topiramate was distributed into most tissues including the brain and transferred to the fetus and milk in rats. However, the elimination rate of concentrations in tissues, fetus and milk was faster than or equal to that in plasma. These data suggested topiramate did not remain in the body over a long period.（Jpn Pharmacol Ther 2008；36：393−9）KEY WORDS Topiramate, Distribution, Pregnancy, Milk, Pharmacokinetics

Background The standard formula tablets of warfarin potassium are hygroscopic and fragile. To improve these properties, we have developed tablets with new formulations. The bioequivalence of the new formula tablets was verified against the standard tablets. Methods Single oral doses of 0.5, 1 and 5 mg warfarin potassium tablets of either the new or the standard formula were given to 24 healthy adult volunteers under fasting conditions with a cross−over protocol. The geometric mean ratios for Cmax and AUC0−144 and their 90％ confidence intervals for the new tablets over the standard ones were calculated. Results The 90％ confidence intervals of the geometric mean ratios for Cmax and AUC0−144 obtained from 0.5, 1 and 5 mg tablets were within the range of 0.80−1.25 indicating bioequivalence of all dosages of new formula tablets. Linear relationships were observed between dose vs Cmax and dose vs AUC0−144. No serious adverse events were seen throughout the studies. Conclusions Because all the 0.5, 1 and 5 mg warfarin potassium tablets of new formula are bioequivalent to those of the standard formula, they can be replaced safely with the standard ones.（Jpn Pharmacol Ther 2008；36：401−9）KEY WORDS Warfarin，Bioequivalence study，Formulation，Pharmacokinetics

In 2007, ezetimibe（ZETIA Tablet）, an inhibitor of small intestinal cholesterol transport （Niemann Pick C1 Like 1）, became available in Japan. Ezetimibe was reported to lower plasma LDL cholesterol level by 20％ in Western countries, but little information is available in Japan. The purpose of this study is to investigate the effect of ezetimibe monotherapy on plasma lipids（particularly LDL cholesterol and remnant cholesterol）, glycemic control and adverse reactions in Japanese hyperlipidemic patients. Twenty five patients with hyperlipidemia（male n＝14, female n＝11）were studied. Ten patients had type 2 diabetes mellitus, and they were under stable glycemic control. All patients had normal renal and liver functions. Plasma lipids and other parameters were measured before and after the treatment. Plasma remnant cholesterol was determined as RLP−cholesterol（normal range＜5.2 mg／dL）. Ezetimibe（10 mg／day after breakfast）was administered over 3 months. It significantly reduced plasma total cholesterol by 19.6％（235→189 mg／dL）, plasma LDL−cholesterol by 25.2％（151→113 mg／dL）, and plasma remnant cholesterol by 39.2％（7.9→4.8 mg／dL）. It tended to reduce plasma triglyceride by 16.7％（141→118 mg／dL）and to raise plasma HDLcholesterol by 2 mg／dL （55→57 mg／dL）, but these differences were not statistically different. Fasting plasma glucose and HbA1c were not changed in all patients or in diabetic patients before and after the treatment. Plasma ALT, AST, γ−GTP, CPK and creatinine were not changed before and after the treatment, and no adverse reactions were observed over the study period. It is concluded that the ezetimibe monotherapy is very effective to reduce not only plasma LDL−cholesterol but also plasma remnant cholesterol in Japanese hyperlipidemic patients. Ezetimibe is suggested to protect atherosclerosis since increased remnant lipoproteins which underlie hyeprtriglyceridemia are strongly atherogenic as well as LDL. （Jpn Pharmacol Ther 2008；36：411−6） KEY WORDS Ezetimibe, Hyperlipidemia, Remnant cholesterol, LDL cholesterol, Effectiveness, Safety

Objectives Low glycemic index（GI）foods would prevent metabolic diseases. Soybean, which is categorized as low GI food, is recognized its health advantages. Recently, a nutrition bar combined soybean（Soy）has been on the market. The aims of the present study were to investigate Soy’s features of GI value（test1）,“second meal effect”to glucose tolerance （test2）, and dynamics of biochemical markers after ingestion of 80 kcal of Soy as a preliminary approach for diabetes care（test3）. Methods Healthy volunteers were recruited for each test. In the test1 and test3, glucose, insulin, triglyceride（TG：test3）, free fatty acid（FFA）, and amino acids（AA）in the blood were determined for 2−hr after ingestion of test foods. In the test2, blood glucose level was determined after ingestion of an identical meal, which was followed by 3−hr earlier test food ingestions. Soy was ingested as a test food in each test. Additionally, reference food was glucose in test1. Rice cracker（Rice）or non−meal in test2 and isoenergetic（80−kcal）wheat products in test3 were ingested for control trials. Results GI value of Soy was 6.2±1.8. Glycemic response after identical meal in test2 was lower in Soy than in Rice and non−meal. Serum TG and FFA were not changed and plasma AAs were maintained during the 2−hr in Soy（80−kcal）. Conclusions These findings suggested that the low GI value in Soy contributed to the“second meal effect”. Furthermore, the present study suggested that Soy has potential to an advantage for diabetes care.（Jpn Pharmacol Ther 2008；36：417−27） KEY WORDS Soybean nutrition bar, Glycemic index, Second meal effect, Diabetes

Acetic acid and γ−Aminobutyric acid（GABA）are known that they both have hypotensive effect through different mechanisms. We investigated the effect of brown rice vinegar （unpolished rice vinegar）with high concentration of GABA, on blood pressure levels and its safety. A randomized double blind, placebo−controlled study was conducted on 71 subjects （average age：47.4±10.4, male：24, female：47）with mild hypertenion without treatment. The subjects were divided into three groups；placebo group, brown rice vinegar（with few GABA）group, brown rice vinegar with high concentration of GABA group. Subjects were given 7.5 mL of each drink per day for 12 weeks. Brown rice vinegar group took about 250 mg of acetic acid per day, and brown rice vinegar with high concentration of GABA group took about 270 mg of acetic acid and 15 mg of GABA. As a result, both brown rice vinegar with and without high concentration of GABA had significantly lower blood pressure than placebo. But, there was no significant difference in blood pressure between brown rice vinegar with and without high concentration of GABA. Therefore we could not clarify the primacy of brown rice vinegar with high concentration of GABA over brown rice vinegar on hypotensive effect. Also, the administration of the test diets for 12 weeks showed no adverse reactions in blood tests, urine tests and physical examinations. These results suggested that the brown rice vinegar with high concentration of GABA is useful for controlling blood pressure in mild hypertensive subjects without any adverse effects, as well as brown rice vinegar（with few GABA）.（Jpn Pharmacol Ther 2008；36：429−44）KEY WORDS Vinegar, Acetic Acid, γ−Aminobutyric acid（GABA）, Hypertension

Objectives In order to examine the effect of tea containing resistant maltodextrin on the elevation of serum triglyceride after intake of lipid, a human study was performed. Methods A food loading study with a load diet containing about 40 g of lipid was performed in 26 healthy male and female adults. The subjects were given tea containing 5.2 g（as dietary fiber）of resistant maltodextrin or tea without resistant maltodextrin（control drink）together with the load diet and blood samples were drawn at appropriate time points to analyze serum constituents. Results The value of postprandial serum triglyceride was significantly lower in intake of tea containing resistant maltodextrin compared with that in intake of the control drink. Conclusions The result indicated that tea containing resistant maltodextrin taken together with meal had the inhibitory effect on the postprandial serum triglyceride elevation. （Jpn Pharmacol Ther 2008；36：445−51）KEY WORDS Resistant maltodextrin，Postpradial serum triglyceride elevation，Remnantlike particle cholesterol，Tea beverage

We have evaluated nattokinase effects in 60 adult cardiovascular patients with warfarin by double blind method. Clinical symptoms（a short of breath, a walking condition, coldness of hand and foot, a color and gloss of skin）and the various biochemical data（APTT, PT, Ddimer, PIC, PAI−1, high sensitivity CRP）have improved in some of these patients with warfarin in spite of dosage of low dose（1700FU）or high dose（3400FU）of nattokinase. There are not recognized in side effect in all patients with nattokinase. Nattokinase might be useful in not only elderly patients with the low dose but also serious younger patient with the high dose. In conclusion, proper use of nattokinase could be suggested strongly effective, and safe in cardiac patient with warfarin.（Jpn Pharmacol Ther 2008；36：453−64） KEY WORDS Nattokinase, Warfarin, Combined effect, Cardiovascular patients

We examined the suppressive effects of tea catechins on physical fatigue by evaluating physical performance after their continuous intake. Eighteen healthy adults, consisting of 9 men and 9 women, underwent a crossover study, in which they consumed a beverage containing 540 mg of tea catechins and a placebo beverage for 4 weeks each, separated by a washout period of 4 weeks. Before and after the intake of each beverage, they were subjected to a physical workload on a bicycle ergometer for 4 hours at an intensity of 80％ of the heart rate, at the anaerobic threshold. After this activity, the subjects were allotted a recovery period of 4 hours. Before and after the activity and after the recovery period, physical performance was evaluated by the physical work capacity（PWC） test using an ergometer. At the same time, the level of fatigue was assessed subjectively by a visual analogue scale（VAS）, and changes in biomarkers were verified by blood, urine, and saliva tests. As a result, the level of physical performance was significantly higher, at 127.6±36.7 watts, in the tea catechin group than in the placebo group, at 119.2±38.5 watts. No significant difference in the level of fatigue, as assessed by the VAS test, was noted between the two groups. In terms of biomarkers, the reduction in serum triglycerides during the activity was inhibited more significantly in the tea catechin than in the placebo group, and the oxidative stress marker urinary 8−isoprostane tended to decrease in the former. These results suggest the involvement of oxidative stress and increased lipid metabolism in the action mechanism of tea catechins. Thus, the results of this study suggest that the continuous intake of a beverage containing 540 mg of tea catechins improves physical performance and reduces fatigue. （Jpn Pharmacol Ther 2008；36：465−78）KEY WORDS Physical fatigue, Catechin, Physical load, Performance, Biomarker