Tomi, Masatoshi

写真a

Affiliation

Faculty of Pharmacy, Department of Pharmacy 薬剤学講座 (Shiba-Kyoritsu)

Position

Professor

Related Websites

External Links

Profile Summary 【 Display / hide

  • 私たちは、胎児への薬物分布を制御する胎盤関門について研究しています。主に安全性の問題から、妊娠中疾患は薬物治療の貢献が不十分です。薬物の胎児影響は実験動物を用いて評価せざるを得ませんが、薬物の胎児移行性を規定する胎盤関門輸送体の中にはヒトだけにあるものや、ヒトとラットの間で発現量が異なるものがあり、ヒト胎児移行性の予測を困難にしています。私たちは、胎盤関門輸送体機能の種差を解明することなどを通じ、ヒト胎児中薬物濃度の予測精度を高め、妊婦で使用可能な薬物の選択肢を増やすことを目指しています。今後の医療は疾患の素因をあらかじめ摘み取る先制医療へとシフトしていきます。生活習慣病や精神・神経疾患の素因が形成される胎児の環境を直接的に制御するのは、胎盤関門です。胎盤関門機能の理解から、将来の疾患発症リスクを軽減する先制医療を実現させることが大きな目標です。

Career 【 Display / hide

  • 2001.04
    -
    2005.09

    Assistant Professor, Faculty of Pharmaceutical Sciences, Toyama Medical and Pharmaceutical University

  • 2005.10
    -
    2006.03

    Assistant Professor, Faculty of Pharmaceutical Sciences, University of Toyama

  • 2006.04
    -
    2008.12

    Postdoctoral Fellow, David Geffen School of Medicine, University of California, Los Angeles (UCLA)

  • 2009.01
    -
    2011.03

    Senior Assistant Professor, Faculty of Pharmacy, Keio University

  • 2011.04
    -
    2016.03

    Associate Professor, Faculty of Pharmacy, Keio University

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Academic Background 【 Display / hide

  • 1998.03

    Tohoku University, Faculty of Pharmaceutical Science, 薬学科

    University, Graduated

  • 2000.03

    Tohoku University, Graduate School, Division of Pharmaceutical Sciences, 分子生命薬学専攻

    Graduate School, Completed, Master's course

  • 2001.03

    Tohoku University, Graduate School, Division of Pharmaceutical Sciences, 生命薬学専攻

    Graduate School, Withdrawal before completion, Doctoral course

Academic Degrees 【 Display / hide

  • Ph.D.(Pharmaceutical Sciences), Tohoku University, Dissertation, 2004.01

Licenses and Qualifications 【 Display / hide

  • 薬剤師, 1999.02

 

Research Areas 【 Display / hide

  • Life Science / Clinical pharmacy

 

Books 【 Display / hide

  • 基礎と臨床の両側面からみた 胎盤学

    日本胎盤学会 (編集) 登美 斉俊, メジカルビュー, 2019.12

    Scope: 物質交換,  Contact page: 80-84

  • 薬の生体内運命 改訂7版

    丸山一雄 (編集) 登美斉俊, ネオメディカル, 2017.03

    Scope: 排泄,  Contact page: 112-134

  • スタンダード薬学シリーズⅡ 6 医療薬学 Ⅵ. 薬の生体内運命

    日本薬学会 (編集) 崔 吉道, 登美斉俊, 東京化学同人, 2016.12

    Scope: 胎盤関門の構造・機能と薬物の胎児への移行,  Contact page: 63-65

  • 薬剤学実験法必携マニュアル - Pharmaceutical Scientistのために Ⅱ 生物薬剤学

    日本薬剤学会出版委員会 (編集) 登美斉俊, 西村友宏, 南江堂, 2014.04

    Scope: 血液胎盤関門,  Contact page: 138-145

  • 薬の生体内運命 改訂5版

    中島恵美 (編集) 登美斉俊, ネオメディカル, 2013.03

    Scope: 薬の運命,  Contact page: 12-18

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Papers 【 Display / hide

  • Decellularized Organ-Derived Scaffold Is a Promising Carrier for Human Induced Pluripotent Stem Cells-Derived Hepatocytes

    Kojima H., Yagi H., Kushige H., Toda Y., Takayama K., Masuda S., Morisaku T., Tsuchida T., Kuroda K., Hirukawa K., Inui J., Nishi K., Nakano Y., Tanaka M., Hori S., Hasegawa Y., Abe Y., Kitago M., Adachi S., Tomi M., Matsuura K., Mizuguchi H., Kitagawa Y.

    Cells (Cells)  11 ( 8 )  2022.04

     View Summary

    Human induced pluripotent stem cells (hiPSCs) are a promising cell source for elucidating disease pathology and therapy. The mass supply of hiPSC-derived cells is technically feasible. Carriers that can contain a large number of hiPSC-derived cells and evaluate their functions in vivo-like environments will become increasingly important for understanding disease pathogenesis or treating end-stage organ failure. hiPSC-derived hepatocyte-like cells (hiPSC-HLCs; 5 × 108) were seeded into decellularized organ-derived scaffolds under circumfusion culture. The scaffolds were implanted into immunodeficient microminiature pigs to examine their applicability in vivo. The seeded hiPSC-HLCs demonstrated increased albumin secretion and up-regulated cytochrome P450 activities compared with those in standard two-dimensional culture conditions. Moreover, they showed long-term survival accompanied by neovascularization in vivo. The decellularized organ-derived scaffold is a promising carrier for hiPSC-derived cells for ex vivo and in vivo use and is an essential platform for regenerative medicine and research.

  • Limited Impact of Murine Placental MDR1 on Fetal Exposure of Certain Drugs Explained by Bypass Transfer Between Adjacent Syncytiotrophoblast Layers.

    Fujita A, Noguchi S, Hamada R, Inoue S, Shimada T, Katakura S, Maruyama T, Sai Y, Nishimura T, Tomi M

    Pharmaceutical research (Pharmaceutical Research)   2022.01

    Research paper (scientific journal), Accepted,  ISSN  0724-8741

     View Summary

    Purpose: Multidrug resistance protein 1 (MDR1) is located at the interface between two syncytiotrophoblast layers in rodent placenta, and may influence fetal drug distribution. Here, we quantitatively compare the functional impact per single MDR1 molecule of MDR1 at the placental barrier and blood-brain barrier in mice. Methods: MDR1A and MDR1B proteins were quantified by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Paclitaxel or digoxin was continuously administered to pregnant Mdr1a−/−/Mdr1b−/− or wild-type mice, and the drug concentrations in the maternal and fetal plasma and maternal brain were quantified by LC-MS/MS. Results: MDR1A and MDR1B proteins are expressed in the membrane of mouse placental labyrinth, and total MDR1 at the placental barrier amounts to about 30% of that at the blood-brain barrier. The fetal-to-maternal plasma concentration ratio of digoxin was only marginally affected in Mdr1a−/−/Mdr1b−/− mice, while that of paclitaxel showed a several-fold increase. No such difference between the two drugs was found in the maternal brain distribution. The impact per single MDR1 molecule on the fetal distribution of digoxin was calculated to be much lower than that on the brain distribution, but this was not the case for paclitaxel. Our pharmacokinetic model indicates that the impact of placental MDR1 is inversely correlated to the ratio of permeability through gap junctions connecting the two syncytiotrophoblast layers to passive diffusion permeability. Conclusion: Our findings indicate that murine placental MDR1 has a minimal influence on the fetal concentration of certain substrates, such as digoxin, due to bypass transfer, probably via connexin26 gap junctions.

  • Transplantation of Bioengineered Liver Capable of Extended Function in a Preclinical Liver Failure Model.

    Higashi H, Yagi H, Kuroda K, Tajima K, Kojima H, Nishi K, Morisaku T, Hirukawa K, Fukuda K, Matsubara K, Kitago M, Shinoda M, Obara H, Adachi S, Nishimura K, Natsume T, Tomi M, Soto-Gutierrez A, Kitagawa Y

    American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons (American Journal of Transplantation)  22 ( 3 ) 731 - 744 2021.12

    Research paper (scientific journal), Accepted,  ISSN  1600-6135

     View Summary

    Unlimited organ availability would represent a paradigm shift in transplantation. Long-term in vivo engraftment and function of scaled-up bioengineered liver grafts have not been previously reported. In this study, we describe a human-scale transplantable liver graft engineered on a porcine liver-derived scaffold. We repopulated the scaffold parenchyma with primary hepatocytes and the vascular system with endothelial cells. For in vivo functional testing, we performed auxiliary transplantation of the repopulated scaffold in pigs with induced liver failure. It was observed that the auxiliary bioengineered liver graft improved liver function for 28 days and exhibited upregulation of liver-specific genes. This study is the first of its kind to present 28 days of posttransplant evaluation of a bioengineered liver graft using a preclinical large animal model. Furthermore, it provides definitive evidence for the feasibility of engineering human-scale transplantable liver grafts for clinical applications.

  • Transplacental pharmacokinetic model of digoxin based on ex vivo human placental perfusion study

    Kurosawa K, Noguchi S, Nishimura T, Tomi M, Chiba K

    Drug metabolism and disposition: the biological fate of chemicals (Drug Metabolism and Disposition)  50 ( 3 ) 287 - 298 2021.12

    Research paper (scientific journal), Accepted,  ISSN  0090-9556

     View Summary

    Digoxin is used as first-line therapy to treat fetal supraventricular tachycardia; however, because of the narrow therapeutic window, it is essential to estimate digoxin exposure in the fetus. The data from ex vivo human placental perfusion study are used to predict in vivo fetal exposure noninvasively, but the ex vivo fetal-to-maternal concentration (F:M) ratios observed in digoxin perfusion studies were much lower than those in vivo. In the present study, we developed a human transplacental pharmacokinetic model of digoxin using previously reported ex vivo human placental perfusion data. The model consists of maternal intervillous, fetal capillary, non-perfused tissue, and syncytiotrophoblast compartments, with multidrug resistance protein (MDR) 1 and influx transporter at the microvillous membrane (MVM) and influx and efflux transporters at the basal plasma membrane (BM). The model-predicted F:M ratio was 0.66, which is consistent with the mean in vivo value of 0.77 (95% confidence interval: 0.64-0.91). The time to achieve the steady state from the ex vivo perfusion study was estimated as 1,500 minutes, which is considerably longer than the reported ex vivo experimental durations, and this difference is considered to account for the inconsistency between ex vivo and in vivo F:M ratios. Reported digoxin concentrations in a drug-drug interaction study with MDR1 inhibitors quinidine and verapamil were consistent with the profiles simulated by our model incorporating inhibition of efflux transporter at the BM in addition to MVM. Our modeling and simulation approach should be a powerful tool to predict fetal exposure and DDIs in human placenta. SIGNIFICANCE STATEMENT We developed a human transplacental pharmacokinetic model of digoxin based on ex vivo human placental perfusion studies in order to resolve inconsistencies between reported ex vivo and in vivo fetal-to-maternal concentration ratios. The model successfully predicted the in vivo fetal exposure to digoxin and the drug-drug interactions of digoxin and P-glycoprotein/multidrug resistance protein 1 inhibitors in human placenta.

  • Role of Uptake Transporters OAT4, OATP2A1, and OATP1A2 in Human Placental Bio-disposition of Pravastatin

    Fokina V.M., Patrikeeva S., Wang X.m., Noguchi S., Tomi M., König J., Ahmed M.S., Nanovskaya T.

    Journal of Pharmaceutical Sciences (Journal of Pharmaceutical Sciences)  111 ( 2 ) 505 - 516 2021.09

    Research paper (scientific journal), Accepted,  ISSN  00223549

     View Summary

    Pravastatin is currently under evaluation for prevention of preeclampsia. Factors contributing to placental disposition of pravastatin are important in assessment of potential undesirable fetal effects. The purpose of this study was to identify the uptake transporters that contribute to the placental disposition of pravastatin. Our data revealed the expression of organic anion transporting polypeptide 1A2 (OATP1A2) and OATP2A1 in the apical, and OATP2B1 and OATP5A1 in the basolateral membranes of the placenta, while organic anion transporter 4 (OAT4) exhibited higher expression in basolateral membrane but was detected in both membranes. Preloading placental membrane vesicles with glutarate increased the uptake of pravastatin suggesting involvement of glutarate-dependent transporters such as OAT4. In the HEK293 cells overexpressing individual uptake transporters, OATP2A1, OATP1A2 and OAT4 were determined to accept pravastatin as a substrate at physiological pH, while the uptake of pravastatin by OATP2B1 (known to interact with pravastatin at acidic pH) and OATP5A1 was not detected at pH 7.4. These findings led us to propose that OATP1A2 and OATP2A1 are responsible for the placental uptake of pravastatin from the maternal circulation, while OAT4 mediates the passage of the drug across placental basolateral membrane in the fetal-to-maternal direction.

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Papers, etc., Registered in KOARA 【 Display / hide

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Reviews, Commentaries, etc. 【 Display / hide

  • 【妊娠・授乳中の薬剤の安全性について科学する】薬物の胎児移行性評価と薬物療法

    登美 斉俊

    Precision Medicine ((株)北隆館)  4 ( 10 ) 918 - 921 2021.09

    ISSN  2434-3625

     View Summary

    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)

  • Faculty challenges during the SARS-CoV-2 pandemic and the results of student questionnaires for the implementation of online and face-to-face classes

    Ishikawa Satoko, Inoue Kae, Tomi Masatoshi

    Japanese Journal of Pharmaceutical Education (Japan Society for Pharmaceutical Education)  5 ( 0 ) n/a 2021

    ISSN  2432-4124

     View Summary

    <p>Review of the challenges posed by the SARS-CoV-2 pandemic at Keio University Faculty of Pharmacy. We shared the latest information needed to conduct online classes with faculty and staff, held seminars on using learning management systems, creating video content, and for copyright adherence of educational materials. For freshmen of the Faculty of Pharmacy, an online communication session was held in April of 2020 and a subsequent environment for conducting face-to-face classes once a week was implemented from June of 2020. At our campus, students were able to participate more actively as college students, have interactions with their peers, ask questions, and consult with the faculty. From questionnaires about online classes, problems facing the students were identified and presented to our faculty for purposes of improving learning content. The number of students who chose the option "I don't have an opportunity to talk with my friends" tends to decrease as the academic year of education rises. Hence, more consideration should be given particularly to the first-year students. All students tended to have relatively good impressions about online classes due to the efficiency and ability for repeated viewing of lecture content. We would like to utilize the knowledge acquired from the past 10 months to provide more effective classes and further enhance the educational impact at the Faculty of Pharmacy.</p>

  • 【周産期の薬】産科編 総論 薬物の経胎盤透過

    登美 斉俊

    周産期医学 ((株)東京医学社)  50 ( 増刊 ) 46 - 48 2020.12

    ISSN  0386-9881

  • 【「今さら聞けない」をスッキリ解消する 妊娠・授乳と薬】[妊娠と薬]薬物の胎児移行性を規定するメカニズム

    登美 斉俊, 野村 岳広

    薬事 ((株)じほう)  62 ( 4 ) 729 - 734 2020.03

    ISSN  0016-5980

     View Summary

    <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)

  • 【「今さら聞けない」をスッキリ解消する 妊娠・授乳と薬】[妊娠と薬]胎盤透過と薬物選択

    登美 斉俊, 植田 有美

    薬事 ((株)じほう)  62 ( 4 ) 735 - 739 2020.03

    ISSN  0016-5980

     View Summary

    <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)

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Presentations 【 Display / hide

  • 副作用報告頻度に基づく低胎児毒性アンジオテンシンII受容体拮抗薬の探索と低胎盤透過性の要因

    西村 友宏, 石川 優, 野口 幸希, 登美 斉俊

    第41回日本妊娠高血圧学会学術集会 (奈良) , 

    2021.12

    Oral presentation (invited, special)

  • タダラフィルおよびシルデナフィルのマウス胎仔移行性比較と胎盤透過制御機構

    石井 まり, 西村 友宏, 野口 幸希, 田中 博明, 池田 智明, 登美 斉俊

    第41回日本妊娠高血圧学会学術集会 (奈良) , 

    2021.12

    Oral presentation (general)

  • LIN28A発現抑制を介したmiR-126によるJEG-3細胞の浸潤抑制

    野口 幸希, 潘 暁楽, 安藤 美鈴, 西村 友宏, 登美 斉俊

    第29回日本胎盤学会学術集会 (Web) , 

    2021.11

    Oral presentation (general)

  • マウス胎盤におけるPGE2受容体の発現解析

    高橋 駿太, 稲垣 舞, 野口 幸希, 西村 友宏, 登美 斉俊

    第29回日本胎盤学会学術集会 (Web) , 

    2021.11

    Oral presentation (general)

  • Ex vivoヒト胎盤灌流試験を用いたジゴキシンのヒト胎盤薬物動態モデル

    黒沢 健, 千葉 康司, 野口 幸希, 西村 友宏, 登美 斉俊

    日本薬物動態学会第36回年会 (Web) , 

    2021.11

    Poster presentation

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Research Projects of Competitive Funds, etc. 【 Display / hide

  • 輸送分子種差と遊離形濃度に基づくヒト胎児への経胎盤薬物曝露量予測モデルの構築

    2021.04
    -
    2024.03

    Keio University, Grants-in-Aid for Scientific Research, Grant-in-Aid for Scientific Research (B), No Setting

     View Summary

    胎児血中薬物濃度は妊婦への薬物治療において重要な指標であるが、ヒトで実測可能な薬物は限られる。本研究では、ヒト胎盤灌流およびラットでの薬物の胎児移行性評価から、ヒト胎児移行性を定量的に予測することを目指している。具体的には、定常状態での遊離形薬物濃度比を基準とし、実験手法の差や輸送体の種差を克服可能な胎盤透過の薬物動態モデルを構築することを目指す。

  • 胎盤エクソソームのウイルス型膜融合を介した妊婦薬物動態の統合制御

    2020.07
    -
    2022.03

    Keio University, Challenging Research (Exploratory), No Setting

     View Summary

    妊婦への薬物治療を妨げる一因は、妊娠進行に伴う薬物動態変動の評価が難しい点である。本課題を克服するには、妊娠に伴う薬物動態変動を規定する機構を解明し、その変化をモニター可能な技術を確立することが必要である。本研究では、薬物代謝酵素やトランスポーター発現に及ぼす胎盤エクソソーム中miRNAの影響を分子機構として解明し、胎盤による妊婦薬物動態の統合調節機構を明らかにすることを目指す。

  • Significance of a balanced tryptophan diet for supporting fetal growth

    2018.04
    -
    2021.03

    MEXT,JSPS, Grant-in-Aid for Scientific Research, Tomi Masatoshi, Grant-in-Aid for Scientific Research (B), Principal investigator

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    The purpose of the present study was to clarify the transporters mediating the fetal transfer of tryptophan and examine the importance of an adequate supply of tryptophan into the fetus. This study described the amount and localization of LAT1 protein, a transporter for large neutral amino acids including tryptophan, at the placental barrier. It is also observed that the tissue distribution of LAT1 substrate is suppressed by an increase of LAT1-substrate amino acids in the plasma. For serotonin, we have clarified OCTN1 protein accepts it as a substrate and is expressed at the placental barrier at term. However, the effect of tryptophan imbalance in the diet was negligible in the plasma concentration of amino acids.

  • Functional expression of sensing foctors against maternal osmotic stress in the placenta

    2015.04
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    2018.03

    Keio University, NISHIMURA Tomohiro, Grant-in-Aid for Scientific Research (C), No Setting

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    Placenta is an interface between mother and fetus and it has a role of nutrients transfer. The placenta has the function mitigating the osmotic stress exposed from maternal blood. Part of amino acid is transferred via amino acid transport system A from mother to fetus in the placenta. In this study, we clarified that expression of the system A molecule can be more quickly increased in response to the osmotic stress than other molecules and we investigated how the system A molecules is induced by hypertonic stress.

  • Medication for pregnant women based on 'barrier transition' behavior in feto-placental circulation

    2015.04
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    2017.03

    MEXT,JSPS, Grant-in-Aid for Scientific Research, Tomi Masatoshi, Grant-in-Aid for Challenging Exploratory Research, Principal investigator

     View Summary

    We have clarified the developmental change in the placental transporters such as glucose transporter 1 (GLUT1) and monocarboxylate transporter 1 (MCT1), while the expressions of ABC transporters such as MDR1 and BCRP were unchanged during pregnancy. We also found a placenta-derived miRNA which may work for maturation of both placental and blood-brain barrier. These observations are helpful for examining the interorgan network in the fetoplacental circulation for establishing and managing barriers in the placenta and the brain.

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Awards 【 Display / hide

  • 2019 Top Reviewer

    2019, Journal of Pharmaceutical Sciences

    Type of Award: Honored in official journal of a scientific society, scientific journal

  • 2018 Top Reviewer

    2018, Journal of Pharmaceutical Sciences

    Type of Award: Honored in official journal of a scientific society, scientific journal

  • 2017 Top Reviewer

    2017, Journal of Pharmaceutical Sciences

    Type of Award: Honored in official journal of a scientific society, scientific journal

  • 日本薬剤学会奨励賞

    2015, The Academy of Pharmaceutical Science and Technology, Japan, 関門トランスポーターによる薬物組織分布制御機構の研究

    Type of Award: Award from Japanese society, conference, symposium, etc.

  • 学部長賞

    2015, 慶應義塾大学薬学部

    Type of Award: Keio commendation etc.

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Courses Taught 【 Display / hide

  • STUDY OF MAJOR FIELD: (PHARMACEUTICS)

    2022

  • SEMINAR: (PHARMACEUTICS)

    2022

  • RESEARCH FRONTIERS IN BIOMEDICAL SCIENCE

    2022

  • RESEARCH FOR BACHELOR'S THESIS 1

    2022

  • PRE-CLINICAL TRAINING FOR HOSPITAL & COMMUNITY PHARMACY

    2022

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