総説・解説等

＜文献概要＞薬物の胎児移行性の指標である胎児血/母体血濃度比は,胎盤関門に発現するトランスポーターや受容体など,担体を介した胎盤透過の影響を強く受ける.たとえば,高分子である生物学的製剤は,サイズの大きさから多くは胎盤透過できないが,Fc受容体に認識される抗体医薬品は胎盤をトランスサイトーシスで透過するため,胎児移行性が高い.低分子薬物と高分子の生物学的製剤のそれぞれについて,胎盤関門を介した薬物の胎児移行制御メカニズムを紹介する.

Workshops are an important part of the IFPA annual meeting as they allow for discussion of specialized topics. At IFPA meeting 2012 there were twelve themed workshops, four of which are summarized in this report. These workshops related to various aspects of placental biology: 1) epigenetics and imprinting in the placenta; 2) growth factors and villous trophoblast differentiation; 3) role of the placenta in regulating fetal exposure to xenobiotics during pregnancy; 4) infection and the placenta.

Recent clinical research utilizing noninvasive functional measurement techniques has indicated that placebo effects might be therapeutically useful, because clear responses to placebo administration have been observed in patients' brains. Both physiological and mental states are affected by placebo and a role of brain receptor(s) was suggested. Factors influencing the placebo effect are the Pavlov reaction, expectation, cognition, and conditioning. Further, the nocebo effect is a negative reaction caused by anxiety, which acts as a confounding factor. Different outcomes may be obtained depending upon whether the placebo effect is evaluated in terms of objective or subjective responses. Correlation analyses of outcomes from various clinical trials indicate that placebo improves subjective response more effectively than objective parameters. Psychosocial care of patients is an important aspect of welfare, and a better understanding of the mechanism of the placebo effect will be helpful in this regard. Cognitive therapy is well known to be as efficacious as antidepressant medication for treating depression. Therefore, we studied the relationship between activity in the cerebral prefrontal area and counseling intervention. Aromatherapy is known to be effective to improve mood. We thus evaluated the influence of counseling on the efficacy of aromatherapy in healthy young women. Participants in a room filled with the fragrance of bergamot completed both a self-reported questionnaire (motivation, feeling of drowsiness and general fatigue) and multi-dimensional fatigue inventory-20 (MFI-20). Further, as an objective measure of changes in stress, blood flow in the inferior frontal cortex was evaluated by near-infrared spectroscopy (NIRS). MFI-20 showed that the combination of aromatherapy with counseling significantly improved both brain activity and motivation, as compared to aromatherapy alone, though the self-reported questionnaire showed no significant difference. Regional blood flow in the inferior frontal cortex was significantly decreased by exposure to aromatherapy with counseling, compared to aromatherapy alone (p<0.05). The value of the NIRS-derived laterality index (LI), which is considered to be a measure of stress, was decreased by aromatherapy with counseling. Thus, we confirmed that the combination of aromatherapy with counseling intervention significantly improved mood and stress. Our results also demonstrated that counseling intervention increased the effectiveness of aromatherapy.

慶應義塾大学薬学部における新型コロナウイルス感染症への対応をふり返る．教員に対しては遠隔授業に関する最新情報を共有し，学習管理システムや動画公開に関する講習会，著作権に関する研修会を実施した．新入生にはオンラインクラス会などで薬学部への入学を実感できるようにしたほか，6月から週1回対面による授業を実施して，学生同士のコミュニティ作りや教員への質問・相談ができる環境を構築した．遠隔授業に関するアンケートから学生が困っていることを抽出し，教員に確認を呼びかけた．「友人と相談できない，情報交換できない」と答えた回答者の割合は学年進行と共に低下する傾向があり，1年生への配慮が重要と考えた．遠隔授業は効率的，繰り返し視聴できるなど，学生は比較的良い印象で受け止めていることがわかった．今後は対面授業も組合せながら遠隔を含む授業をより効果的に活用し，薬学部における教育効果をさらに向上させたいと考える．

妊婦薬物治療は,母体及び胎児に対するリスクとベネフィットを考慮して行う。そのため胎児曝露量は重要であり,出産時の母体血及び臍帯血の薬物濃度比(in vivo F/M比)は,有用な指標となる。母体・胎児薬物移行性評価法としてヒト胎盤に薬物灌流を行うex vivoヒト胎盤灌流試験がある。ヒト胎盤に薬物の灌流を実験的に行い,母体-胎児間の薬物移行を検討する。大半の薬剤でex vivo試験で得られた母体-胎児濃度比(ex vivo F/M比)と,in vivo F/M比が一致することが報告されているが,digoxinなど一部の薬物では一致しない。筆者らは,既報のex vivoヒト胎盤灌流試験にファーマコメトリクス,すなわちモデリング・シミュレーション手法を応用し,この原因を明らかにすると共に,胎児曝露量を予測可能とした。本稿ではこの新たなヒト胎児曝露量予測法についてdigoxinを例に紹介する。(著者抄録)

© 2019 Workshops are an important part of the IFPA annual meeting as they allow for discussion of specialized topics. At IFPA meeting 2018 there were nine themed workshops, five of which are summarised in this report. These workshops discussed new perspectives and knowledge in the following areas of research: 1) preeclampsia; 2) abnormally invasive placenta; 3) placental infection; 4) gestational trophoblastic disease; 4) drug delivery to treat placental dysfunction.

Objective: Administration of angiotensin II receptor blocker (ARB) to pregnant women is contraindicated due to the risk of inducing oligohydramnios. However, it is unclear if the ARBs on the market uniformly induce oligohydramnios. The aim of this study was to find an ARB that is less likely to develop oligohydramnios based on the frequency of side effects registered in the US Food and Drug Administration Adverse Event Reporting System (FAERS) and to show the mechanism of the lower risk of developing oligohydramnios in non-clinical studies.Methods: We searched for cases registered in FAERS from 2004 to 2017, investigated the frequency of adverse event records of patients taking ARB showing oligohydramnios, and compared them among ARB drugs. We compared the antihypertensive effect of the selected ARBs and their fetal transfer in the model rats of hypertensive disorder of pregnancy with administration of L-NAME, a nonselective nitric oxide synthase inhibitor. The transport activity of organic anion transporting polypeptide (OATP) 2B1 was evaluated by using HEK293 cells transiently transfected with cDNA of human OATP2B1. The drug concentrations were measured by liquid chromatography with tandem mass spectrometry.Results: Of the 6 ARBs investigated, olmesartan had the highest frequency of oligohydramnios, and irbesartan had the lowest frequency, with a 25-fold difference in reporting frequency. In pregnant hypertensive rats, both olmesartan and irbesartan showed remarkable antihypertensive effect, while only irbesartan showed the effect of improving fetal growth failure. Ratio of the plasma concentration in the fetus to that in the dam (F/M ratio) was measured. The F/M ratios of olmesartan and irbesartan were about 1.6 and 0.28, respectively, indicating that fetal transfer of irbesartan is relatively limited due to the flux in the placenta. OATP2B1 is one of drug transporters which is known to be expressed in the fetal-facing membrane in syncytiotrophoblasts. When the transport activity of both drugs by OATP2B1 was examined, it was shown that only irbesartan was transported.Conclusion: The records in the database implied that irbesartan has a low risk of increasing amniotic fluid volume among the ARB drugs. Irbesartan showed lower fetal transfer at least in rats than olmesartan and irbesartan is a substrate of OATP2B1, indicating that irbesartan may be excreted by placental OATP2B1 from fetal plasma to maternal plasma.

薬物の胎児移行性を評価し、その機構を理解するには、定常状態における胎児血/母体血濃度比を基準とすることが重要である。定常状態における濃度比に影響するのは薬物の脂溶性やタンパク結合率に限らず、むしろトランスポーターを介した透過クリアランスによる影響が大きい。本稿では、妊婦に用いられる薬物として血糖降下薬や甲状腺機能亢進症治療薬、ジゴキシンに焦点を当て、定常状態における濃度比に基づく胎児移行性評価と、胎児移行に果たす胎盤トランスポーターの役割、胎児への影響について概説する。(著者抄録)

＜Points＞▼母体の治療には胎盤透過性の低い薬物がより望ましく、インスリンやヘパリンなどの高分子医薬品や、プレドニゾロンのように胎盤での代謝を強く受ける薬物が代表例である。▼胎児の経胎盤治療にはチアマゾールやベタメタゾン、ジゴキシンなど、一定の胎盤透過性を有した薬物が用いられている。▼胎盤透過する薬物の胎児への影響や胎盤透過性は妊娠進行に伴い変動することがあり、チアマゾールのように妊娠初期は禁忌でも、妊娠中後期には用いられる場合がある。(著者抄録)

＜Points＞▼薬物が胎盤関門を介して胎児に移行する速度は、受動拡散による透過の場合、脂溶性に依存するが、定常状態における胎児血中濃度が移行速度に比例して高くなるわけではない。▼血漿タンパク結合した薬物は胎盤関門を透過できないが、血漿タンパク結合率は100%ではない。遊離形薬物は胎盤関門を透過できるため、血漿タンパク結合率が高い薬物であっても、定常状態においては胎児血中の遊離形薬物濃度が母体血並みに高くなっている可能性は十分にある。▼胎盤関門において、母体側細胞膜の頂端膜と胎児側細胞膜の基底細胞膜には、それぞれトランスポーターが極性をもって局在し、基質薬物の胎児血への移行速度と、定常状態における胎児血中濃度の両方を規定する。(著者抄録)