著者
Hiroshi IWATA Yasuhiro TEZUKA Tepy USIA Shigetoshi KADOTA Akira HIRATSUKA Tadashi WATABE
出版者
和漢医薬学会
雑誌
Journal of Traditional Medicines (ISSN:18801447)
巻号頁・発行日
vol.21, no.1, pp.42-50, 2004 (Released:2007-09-21)
参考文献数
38
被引用文献数
7

78 種の生薬エキスについて,ヒト薬物代謝酵素シトクロム P450 3A4 (CYP3A4) および P450 2D6 (CYP2D6) に対する阻害作用を調べた。生薬エキス粉末からメタノール可溶性画分を調製し, 添加量 1.65 mg/mL で反応を行った。CYP3A4 の指標として用いたヒト肝ミクロソーム中のエリスロマイシン N-脱メチル化活性に対して 50 % 以上の阻害を示した生薬は 31 種であり, その中の 8 種 (白, 桂皮, 丁子, 羌活, 牡丹皮, 大黄, 蘇木, 五味子) が阻害率 90 % 以上を示した。 CYP3A4 活性に対する阻害の強さは, 蘇木, 大黄, 五味子, 羌活, 白の順であり, IC50 値は, それぞれ 43, 77, 127, 144 および 185 μg/mLであった。 一方, CYP2D6 の指標として用いたヒト肝ミクロソーム中のデキストロメトルファン O-脱メチル化活性に対して 50 % 以上の阻害を示した生薬は 28 種であり, その中の 13 種 (桂皮, 丁子, 黄連, 麻黄, 釣藤鈎, 羌活, 厚朴, 牡丹皮, 黄柏, 大黄, 蘇木, 防巳, 山椒) が阻害率 90 % 以上を示した。 CYP2D6 活性に対する阻害の強さは, 黄柏, 黄連, 防巳, 蘇木, 大黄の順であり, IC50 値は各々 4, 14, 40, 52 および 64 μg/mL であった。 これらの結果から, CYP3A4 あるいは CYP2D6 に対する阻害活性を示す生薬が複数存在することが明らかとなった。
著者
Hiroshi IWATA Yasuhiro TEZUKA Shigetoshi KADOTA Akira HIRATSUKA Tadashi WATABE
出版者
Medical and Pharmaceutical Society for WAKAN-YAKU
雑誌
Journal of Traditional Medicines (ISSN:18801447)
巻号頁・発行日
vol.21, no.6, pp.281-286, 2004 (Released:2007-12-28)
参考文献数
14
被引用文献数
3

26 種の生薬のシトクロム P450 3A4 (CYP3A4) 及び 2D6 (CYP2D6) に対する阻害作用を調べた。 生薬エキス粉末から調製されたメタノール可溶性画分を NADPH 生成系存在下, ヒト肝ミクロソームとプレインキュベーションした後の CYP3A4 の残存活性 (erythromycin N-demethylation 活性) と CYP2D6 の残存活性 (dextromethorphan O-demethylation 活性) を測定した。 その結果, 16 種の生薬がCYP3A4 活性をプレインキュベーション時間依存的に低下させた。 中でも, 呉茱萸による CYP3A4 活性の低下作用が最も顕著であった (30 分間プレインキュベーションした後の活性の残存率は 22.3%)。 次いで, 蘇木, 羌活, 五味子, 牛蒡子, 白, 大黄が顕著な低下を示した (30 分間プレインキュベーションした後の活性の残存率は, それぞれ 40.6, 41.2, 53.4, 47.1, 53.4, 59.2%)。 これら 7 種生薬による CYP3A4 活性低下作用は, CYP3A4 に対する不可逆的阻害剤である troleandomycin による残存率 (49.4%) に匹敵した。 CYP2D6 活性に対してプレインキュベーション時間依存的な活性の低下を示した生薬は, 5 種であった。 最も CYP2D6 活性の低下作用が大きかった生薬は, 羌活であり, 30 分間プレインキュベーションした後の活性の残存率は 61.9%であった。 以上の結果から, 呉茱萸, 蘇木, 羌活, 五味子, 牛蒡子, 白芷, 大黄等の複数の生薬エキス中に, CYP3A4 に対する metabolism-dependent inhibitor が含まれていることが示唆された。
著者
Junnichi Ishii Kosuke Kashiwabara Yukio Ozaki Hiroshi Takahashi Fumihiko Kitagawa Hideto Nishimura Hideki Ishii Satoshi Iimuro Hideki Kawai Takashi Muramatsu Hiroyuki Naruse Hiroshi Iwata Sadako Tanizawa-Motoyama Hiroyasu Ito Eiichi Watanabe Yutaka Matsuyama Yoshihiro Fukumoto Ichiro Sakuma Yoshihisa Nakagawa Kiyoshi Hibi Takafumi Hiro Seiji Hokimoto Katsumi Miyauchi Hiroshi Ohtsu Hideo Izawa Hisao Ogawa Hiroyuki Daida Hiroaki Shimokawa Yasushi Saito Takeshi Kimura Masunori Matsuzaki Ryozo Nagai
出版者
Japan Atherosclerosis Society
雑誌
Journal of Atherosclerosis and Thrombosis (ISSN:13403478)
巻号頁・発行日
vol.29, no.10, pp.1458-1474, 2022-10-01 (Released:2022-10-01)
参考文献数
33
被引用文献数
1 9

Aim: We investigated the relationship between small dense low-density cholesterol (sdLDL-C) and risk of major adverse cardiovascular events (MACE) in patients treated with high- or low-dose statin therapy.Methods: This was a prospective case-cohort study within the Randomized Evaluation of Aggressive or Moderate Lipid-Lowering Therapy with Pitavastatin in Coronary Artery Disease (REAL-CAD) study, a randomized trial of high- or low-dose (4 or 1 mg/d pitavastatin, respectively) statin therapy, in patients with stable coronary artery disease (CAD). Serum sdLDL-C was determined using an automated homogenous assay at baseline (randomization after a rule-in period, >1 month with 1 mg/d pitavastatin) and 6 months after randomization, in 497 MACE cases, and 1543 participants randomly selected from the REAL-CAD study population.Results: High-dose pitavastatin reduced sdLDL-C by 20% than low-dose pitavastatin (p for interaction <0.001). Among patients receiving low-dose pitavastatin, baseline sdLDL-C demonstrated higher MACE risk independent of LDL-C (hazard ratio [95% confidence interval], 4th versus 1st quartile, 1.67 [1.04–2.68]; p for trend=0.034). High-dose (versus low-dose) pitavastatin reduced MACE risk by 46% in patients in the highest baseline sdLDL-C quartile (>34.3 mg/dL; 0.54 [0.36–0.81]; p=0.003), but increased relative risk by 40% in patients with 1st quartile (≤ 19.5 mg/dL; 1.40 [0.94–2.09]; p=0.099) and did not alter risk in those in 2nd and 3rd quartiles (p for interaction=0.002).Conclusions: These findings associate sdLDL-C and cardiovascular risk, independent of LDL-C, in statin-treated CAD patients. Notably, high-dose statin therapy reduces this risk in those with the highest baseline sdLDL-C.
著者
Toshiaki Toyota Takeshi Morimoto Satoshi Iimuro Retsu Fujita Hiroshi Iwata Katsumi Miyauchi Teruo Inoue Yoshihisa Nakagawa Yosuke Nishihata Hiroyuki Daida Yukio Ozaki Satoru Suwa Ichiro Sakuma Yutaka Furukawa Hiroki Shiomi Hirotoshi Watanabe Kyohei Yamaji Naritatsu Saito Masahiro Natsuaki Yasuo Ohashi Masunori Matsuzaki Ryozo Nagai Takeshi Kimura
出版者
The Japanese Circulation Society
雑誌
Circulation Journal (ISSN:13469843)
巻号頁・発行日
pp.CJ-22-0168, (Released:2022-09-14)
参考文献数
20

Background: The relationship between very low on-treatment low-density lipoprotein cholesterol (LDL-C) level and cardiovascular event risk is still unclear in patients receiving the same doses of statins.Methods and Results: From the REAL-CAD study comparing high-dose (4 mg/day) with low-dose (1 mg/day) pitavastatin therapy in patients with stable coronary artery disease, 11,105 patients with acceptable statin adherence were divided into 3 groups according to the on-treatment LDL-C level at 6 months (<70 mg/dL, 70–100 mg/dL, and ≥100 mg/dL). The primary outcome measure was a composite of cardiovascular death, non-fatal myocardial infarction, non-fatal ischemic stroke, or unstable angina requiring emergent admission. The adjusted risks of the LDL-C <70 mg/dL group relative to the LDL-C 70–100 mg/dL group (reference) was not significantly different for the primary outcome measure in both 1 mg/day and 4 mg/day strata (HR 0.84, 95% CI 0.58–1.18, P=0.32, and HR 1.25, 95% CI 0.88–1.79, P=0.22). The adjusted risk of the LDL-C ≥100 mg/dL group relative to the reference group was not significant for the primary outcome measure in the 1 mg/day stratum (HR 0.82, 95% CI 0.60–1.11, P=0.21), whereas it was highly significant in the 4 mg/day stratum (HR 3.32, 95% CI 2.08–5.17, P<0.001).Conclusions: A very low on-treatment LDL-C level (<70 mg/dL) was not associated with lower cardiovascular event risk compared with moderately low on-treatment LDL-C level (70–100 mg/dL) in patients receiving the same doses of statins.
著者
Hiroshi IWATA Nanami KATAYAMA Ken'ichi YAMAGUCHI
出版者
The Institute of Electronics, Information and Communication Engineers
雑誌
IEICE TRANSACTIONS on Information and Systems (ISSN:09168532)
巻号頁・発行日
vol.E100-D, no.6, pp.1182-1189, 2017-06-01

In accordance with Moore's law, recent design issues include shortening of time-to-market and detection of delay faults. Several studies with respect to formal techniques have examined the first issue. Using the equivalence checking, it is possible to identify whether large circuits are equivalent or not in a practical time frame. With respect to the latter issue, it is difficult to achieve 100% fault efficiency even for transition faults in full scan designs. This study involved proposing a redundant transition fault identification method using equivalence checking. The main concept of the proposed algorithm involved combining the following two known techniques, 1. modeling of a transition fault as a stuck-at fault with temporal expansion and 2. detection of a stuck-at fault by using equivalence checking tools. The experimental results indicated that the proposed redundant identification method using a formal approach achieved 100% fault efficiency for all benchmark circuits in a practical time even if a commercial ATPG tool was unable to achieve 100% fault efficiency for several circuits.