日本小児循環器学会雑誌 Pediatric Cardiology and Cardiac Surgery

Online ISSN: 2187-2988 Print ISSN: 0911-1794
特定非営利活動法人日本小児循環器学会 Japanese Society of Pediatric Cardiology and Cardiac Surgery
〒162-0801東京都新宿区山吹町358-5アカデミーセンター Japanese Society of Pediatric Cardiology and Cardiac Surgery Academy Center, 358-5 Yamabuki-cho, Shinju-ku, Tokyo 162-0801, Japan
Pediatric Cardiology and Cardiac Surgery 31(4): 157-183 (2015)


小児期肺動脈性高血圧の正しく的確な治療戦略The Real World of Medical Treatment of Pulmonary Arterial HypertensionSmall Evidence, but Heavy Cornerstone

東邦大学医療センター大森病院小児医療センター小児科Department of Pediatrics, Children's Medical Center, Toho University Omori Medical Center ◇ 〒143-8541 東京都大田区大森西六丁目11番1号6-11-1 Omori-Nishi, Ota-ku, Tokyo 143-8541, Japan

発行日:2015年7月1日Published: July 1, 2015

小児期PAHの薬物療法を行うにあたって,臨床医は小児は成人と異なり様々な特色があることを再認識しなければならない.すなわち,代謝酵素活性(p450など),受容体の濃度(密度)や感受性,器官の機能発達(特に腎臓と肝臓,心筋代謝),体脂肪の容積,蛋白(アルブミン)結合率,血中蛋白濃度,分散容積,薬物動態PKや薬力学PD,一定の年齢だけ反応する臓器(動脈管など),薬理遺伝子的背景,遺伝子多型などによる個人差,特異体質,薬物相互作用,生体内活性物質(サイトカイン,ホルモン,伝達物質,カテコラミンなど)の影響である.特に小児期の重症疾患に対しては,“Right drug for the Right patient at Right time”という諺に準じて,その個人に見合った慎重なcase by caseの薬剤選択を心掛けなくてはいけない.小児期の肺高血圧治療薬には,NO-cGMP経路,PGI2-cAMP経路,エンドセリン受容体拮抗薬(ERA)の三大肺血管作動薬を使用する.小児では,世界的にもほとんどがoff-labelの状態で使用されている.しかし肺血管拡張作用以外の,細胞増殖抑制作用,線維化・肥大抑制作用,抗酸化ストレス・抗炎症作用を秘め,長期にわたって血管壁に抗リモデリン作用を発揮する薬剤を選択したい.また特発性(遺伝性,家族性)と二次性肺高血圧(左心不全,膠原病関連,呼吸器関連,肺血栓塞栓関連,そして新生児期肺高血圧など)では,3大治療薬が持つPDE5阻害作用,PGI2産生促進作用,エンドセリン受容体拮抗作用などの有効性もそれぞれ異なると予想される.本稿では,治療薬の小児期でのエビデンスを紹介しながら,最適の治療法を推奨したい.

A variety of pulmonary vasodilators are now on the market; however, little is known about their use in children, as over the past two decades, only a limited number of clinical pediatric trials have been conducted in the US and EU. Pulmonary arterial hypertension (PAH) is a rare disease characterized by sustained elevation of pulmonary vascular resistance and pressure, resulting in refractory right ventricular dysfunction. Clinical trials using agents that act on three major pathways, prostacyclin PGI2/cAMP, NO/cGMP activation by phosphodiesterase (PDE)-5 inhibitors, and suppression of the activity of endothelin (ET)-1 by ET receptor antagonists (ERAs), have been performed mainly in adults. Most pediatric cardiologists treat PAH in children by conversion of normal adult dosages. However, such dosage modification in children is not always safe or effective. In addition, management of pediatric PAH is complex because of the variety of formulations, classes, and nature of the three major types of agent. The current trend in drug therapy for PAH recommends a so-called combination therapy; however, any pulmonary vasodilative agent has not been approved by their efficacy and safety for background disease-related PAH. PGI2 or epoprostenol (Flolan, GSK) has been recommended in NYHA-FC III and IV. However, some cases have been withdrawn from continuous infusion of Flolan in combination with inhaled PG12 (iloprost, treprostinil), subcutaneous PG12 (treprostinil), oral PGI2, (beraprost), ERA (bosetan, ambrisentan), or PDE5-I (sildenafil, tadalafil). Careful consideration and assessment of PK/PD and interactions of each class of drug are essential in children with PAH on a case-by-case basis. Clinical trials of bosentan, ambrisentan, sildenafil, and tadalafil for children have been conducted in Japan since 2012; however, no conclusive results have been obtained till date. In general, the efficacy and side effects seem to be similar to those in adults. Other critical drugs used in the treatment of PAH include sGC agonists; riociguat, a Rho-kinase inhibitor; Fasudil macitentan Opsumit, and inhaled iloprost, all of which have undergone clinical trials in adults. This chapter presents the current standard for medications used for pediatric PAH.

Key words: pulmonary arterial hypertension; pediatric patients; prostacyclin; phosphodiesterase5-inhibitor; endothelin receptor blockade

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