In patients with atrial fibrillation, dabigatran given at a dose of 110 mg was associated with rates of stroke and systemic embolism that were similar to those associated with warfarin, as well as lower rates of major hemorrhage. Dabigatran administered at a dose of 150 mg, as compared with warfarin, was associated with lower rates of stroke and systemic embolism but similar rates of major hemorrhage. (ClinicalTrials.gov number, NCT00262600.)

従来，臨床には， 「薬のさじ加減」 ということばが ある．これは医師が薬の用量−反応関係を経験的に 取得し，個々の患者に対し適切な薬物選択と用量設 定を行うことを意味する．しかし，この方法は普遍 性に乏しく，black box が大きいため，危険性も潜 んでいる．近年，薬の適正使用が唱えられ，各患者 に応じた個別化治療を行うことが，有効性のみなら ず安全性のうえで欠かせないとされる．その手段と して，各患者における生体内での薬物の動きと効果 を理解することは重要である． 薬物動態学とは 薬物の生体内での流れ・運命を薬物動態という． 生体内に薬を投与すると，吸収・分布・代謝・排泄 を経て除去される．この過程で薬の一部が作用部位 に到達し，薬物受容体と結合し，薬理効果が出現す る．体液中の薬物濃度の時間的推移を速度論的に解 析し，薬物の生体内動態を研究する領域を薬物動態 学 （pharmacokinetics） と呼ぶ．一方，薬物が受容体 と結合し，薬理効果が出現するまでの領域を薬力学 （pharmacodynamics） と呼び，薬物動態学と作用部 位における薬物濃度によって密接にかかわってい る．個々の薬物反応には年齢，性別，遺伝的差異， 環境因子，食事，生活習慣，基礎疾患，併用薬など 様々な因子が薬物動態および薬力学の双方を介し て影響する． 薬物血中濃度モニタリング 抗不整脈薬は強力な薬理作用を有している反面， 重篤な副作用も合わせもっており，単なるさじ加減 では管理が難しい面がある．このため抗不整脈薬の 分野では，ジゴキシン，キニジンに代表されるよ うに古くから薬物動態の検討が行われ，薬物血中 濃度モニタリング （Therapeutic Drug Monitoring : TDM） を治療に応用してきた 1） ． 尿中未変化体排泄率の高い （腎排泄型） 薬は，腎機 能の変化で容易に血中濃度が変わる．一方，肝代謝 型の薬は代謝酵素活性の個人差に左右される．チト クロム P450 （CYP） 2D6 で代謝されるアプリンジン やプロパフェノン，ベプリジルは代謝能の飽和現象 から，用量と血中濃度は非線形関係にある．また， 複雑な薬物動態を特徴とするアミオダロンやベプリジ ルは， 同じ用量であっても個人あるいは投与期間によ り血中濃度は異なるため，TDM が必要とされよう． べプリジルは日本でのみ抗不整脈薬として使用さ れており，日本人における血中濃度と抗不整脈効果 や安全性に関する報告が出されている 2）-6） ．これ らのデータを基に， ベプリジルの治療域濃度は 250-800 ng/ml とされた．また，そのクリアランスは低 体重や加齢とともに低下することが示されており， 高齢者での低用量化が求められる． 7）, 8） P-糖蛋白の問題 P-糖 蛋 白 は， ア デ ノ シ ン 三 リ ン 酸 （adenosine triphosphate : ATP） に依存して有害物質 （陽イオン 東京女子医科大学循環器内科 志賀 剛

No abstract

Objectives-To explore the increased incidence of intravenous immunoglobulin (IVIG) resistance among San Diego County Kawasaki disease (KD) patients in 2006 and to evaluate a scoring system to predict IVIG-resistant patients with KD.Study design-We performed a retrospective review of patients with KD treated within 10 days of fever onset. Using multivariate analysis, independent predictors of IVIG-resistance were combined into a scoring system. 2006, 38.3 % of patients with KD in San Diego County were IVIG-resistant, a significant increase over previous years. IVIG-resistance was not associated with a particular brand or lot of IVIG. Resistant patients were diagnosed earlier, had higher % bands, and higher concentrations of C-reactive protein, alanine aminotransferase, and γ-glutamyl transferase (GGT). They also had lower platelet counts and age-adjusted hemoglobin (zHgb) concentrations and were more likely to have aneurysms (p=0.0008). A scoring system developed to predict IVIG-resistant patients using illness day, % bands, GGT, and zHgb, had a sensitivity of 73.3% and specificity of 61.9%. Results-InConclusions-An unexplained increase in IVIG-resistance was noted among patients with KD in San Diego County in 2006. Scoring systems based on demographic and laboratory data were insufficiently accurate to be clinically useful in our ethnically diverse population. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Keywords Conflict of Interests:The authors have no conflicts of interest to report. Kawasaki disease (KD), the leading cause of pediatric acquired heart disease in the United States and Japan, is an acute, systemic vasculitis. Treatment with a single dose of intravenous immunoglobulin (IVIG) and high-dose aspirin results in resolution of fever in most patients and significantly reduces the rate of coronary artery aneurysms (1). Despite this success, 10-20% of children will have persistent or recrudescent fever after their first infusion of IVIG (2-5). These patients are at increased risk of developing coronary artery abnormalities (5,6). Additional therapies used in these patients include retreatment with IVIG, immunomodulatory agents such as infliximab, high dose methylprednisolone, cyclophosphamide, and plasmapheresis. (7-11). Identification of patients who are likely to be IVIG-resistant would allow the use of additional therapies early in the course of their illness when prevention of coronary artery damage might still be possible. NIH Public AccessA number of recent studies from Asia have identified demographic and laboratory characteristics, including age...