國防藥學風華-兼論我的藥動研發

國防藥學風華－ 兼論我的藥動研發

胡 幼 圃講座教授 美國國家發明家學院院士/國防醫學院榮譽教授 中研院客座講座/台北醫學大學講座教授/台大兼任教授/清華大學兼任教授 113.8.4 國防醫學院傑出校友聯誼會

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現職：

簡 歷 胡幼圃 講座教授

•美國國家院士(發明家學院) •國防醫學院榮譽教授 •台北醫學大學講座教授 •中研院客座講座 •台灣大學醫學院兼任教授 •海峽兩岸醫藥衛生交流協會醫院藥學專委會榮譽主席(2018~) •清華大學兼任教授

學歷：

經歷：

專長：

•考試院考試委員(正部級) •行政院衛生署藥政處處長(1998～2002) 任內規劃、草擬通過“藥害救濟法”及“罕見疾病防治及 藥物法”；成立財團法人醫藥品查驗中心(CDE)及藥害救濟 基金會(TDRF) •世界衛生組織（WHO）藥物副作用中心顧問 •世界藥學會SIG法規組共同主席(2011~) •台北榮總醫學倫理委員會召集人(2022~) •藥事論壇講座常任主席(2004~ 逾100場) •中華生命科學與法律學會名譽理事長(2022~)

榮譽： •美國國家發明家學院院士 •美國藥學科學家學會會士 •亞洲藥學會學術研究獎– Ishidate Award(1998) •行政院衛福部一等衛生奬章(001號)(2014) •中華民國一等功績獎章(2014) •中華民國一等考銓獎章(2014)

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美國佛羅里達大學藥學院藥劑學組臨床 藥動學博士(1984) 新藥研發；藥政管理；生物科技；藥動 學及臨床藥理

研究及著作： 1.發明半乳糖單點定量法測定現存肝 功能(GSP and OGSP)，我國已上市 並列入歐美教科書及USFDA、 TFDA準則。 2.發明世界首例不成癮、止劇痛之新 成份新藥(納疼解)己於歐洲、我國及 新加坡、泰國、馬來西亞等國上市。 3.數件研發中的新藥(包括TB、NASH 、Non-toxic acetaminophen)於國內外 進行臨床phase II~III試驗。 4.已發表原始論文及專利共268篇，其 中國內、外專利已獲一百零八項。 2

國防醫學院(水源校區)大門 (大學62.7 ~ 66.7)

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我在國防醫學院所受的藥學科學家 或藥師之教育 藥學系、所 (

檢國 驗軍 中軍 心品

榮 民 製 藥 廠

景 德 製 藥 公 司

)

藥 品衛 製生 造實 研驗 究院 所

( (

郭紐 台約 銘藥 ，廠 林陸 淑常 如

研中 究華 基藥 金學 會

臨三 床軍 藥總 學醫 部院

)

)

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榮 藥民 劑總 部醫 院

永 信 藥 品 公 司

百年紀要 西元

民國

紀要

1902 年

民前10 年

北洋軍醫學堂創立於民前十年（清光緒廿八年）。

1908年

民前4年

正式成立藥科，招收第一期學生，修業三年。

1938年

民國27年

遷校廣西，藥科在桂林。

1939年

民國28年

藥科分七學系及藥品研究製造所。

1960年

民國49年

協助輔導會於學系成立榮民醫院聯合製藥廠。

1961年

民國50年

榮民藥廠於興隆路新建廠房。

1967年

民國56年

景德製藥公司建廠完成，為學生第二家實習藥廠。

1974年

民國63年

成立國軍藥品衛材檢驗中心。

1981年

民國70年

確立五組教學：天然物化學組、藥物化學組、藥劑學組、醫院藥學組、 藥品分析學組。

1984年

民國73年

藥學系主辦亞洲藥學會。

2000年

民國89年

國防醫學院與中正理工學院、國防管理學院合併成立國防大學。

2004年

民國93年

藥品研究製造所與學系合併。

2005年

民國94年

國防醫學院回復為獨立學院。

2015年

民國104年

大學部調整改制為六年學制(自P102開始)。

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本人自美返國(1984)任教，後奉國防部令，於1985~1991兼 任景德研究部主任，完成64個藥品(含二新藥)的研發、取證 Drug Product Approvals (Licensed) Granted from the Department of Health, ROC After completing the formulation studies and/or bioavailability studies (these were performed and funded during the period of Directorship of the Department of Research and Development, Kingdom Pharmaceutical Co., which has been the Teaching Pharmaceutical Plant of the National Defense Medical Center.), the following products have been marketed in Taiwan:

1.

3.

Cefuroxime Injention 750mg/vial Fosfomycin Injection 500mg

2.

4.

5.

Clobetasol propionate Cream 0.05%.

Niacotinic acid USP.

6.

7.

9.

11.

13.

15.

17.

19.

21.

23.

25.

27.

29.

Ampicillin Sodium Injection 1 Gm/vial Pirenzapin 2 HCl Inj. 10gm/2ml Fosfomycin Inj. 1Gm Polymagel 400 mg and dimethyl polysiloxan 25 mg Suspension.

Vigelor S.C. Tab. Dicloxacillin Cap. 125mg Kidoles Cap. 500mg APAP Elixir 160mg/5ml Cardionl Tab. Storage & Rinsing Sol'n Mitoxantrone dihydrochloride Inj. 20mg USP

Priziquantel Tablets 600mg Vit.A.(13.75 mg) and Vit. E. (70 mg) S. C. Tablets Compound Glcyrrhiza Mixture

8.

Gentamicin sulfate Injection 140n mg/ml.

10. Cersin Inj. 1gm/5ml 12. Metronidazole Inj. 5mg/ml 14. Cefamandole Inj. 1Gm 16. Clotrimazoleand Betamethasone dipropionate Cream.

18. Fenoverine 10 mg Cap. 20. Kingesic Cap. 65mg 22. APAC Elixir 24. Ascorbric acid eye Drops 26. Cleaning Sol'n "Kingdom" 28. Maxurine Tablet 30. Ambroxol Tablets 30mg

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本人自美返國(1984)任教，後奉國防部令，於1985~1991兼 任景德研究部主任，完成64個藥品(含二新藥)的研發、取證 31. Mitoxantrone Injection 2mg/mL 32. Clindamycin Cap. 150mg 34. Magnesium Sulfate 50% Injection 36. Sodium Chloride Injection. 23.5% 38. Lysine Aspirin 1 GM For Injection 40. Chloramphenicol Ophthalmic Solution 42. C.A.P. Cap 44. Amantadine Hydrochloride Cap. 100mg 46. Feldine Cap. 10mg 48. Acyclovir cream 5% 50. Sodium Acetate Inj. 4 mEq/ml 52. Penicillin G Procaine USP 54. Norfloxacin JP 56. Dice 25% w/v Emulsion 58. Deciro Cream 5% 60. Norfloxacin Tab. 100mg 62. Acyclovir Tab. 200mg 64. Famotidine Tab. 40mg

32. Clindamycin Cap. 150mg 33. Sodium Chloride Injection 0.9% 35. Mannitol Injection 20% 37. Terfenadine Tablets 60mg 39. Erythromycin USP 41.Pilocarpine Ophthalmic Solution 1% 43. Pilocarpine Ophthalmic Solution 2% 45.Diclofenac Sodium E.C. Tablets 25mg 47. Diclofenac Sodium Injection 75mg/3ml 49. Acyclovir Ophthalmic Ointment 3% 51. Erythromyycin E.C. Cap. 250mg 53. B.Z.F.-F.C. Tablets 200mg 55. Erythromycin stearate USP 57. Benzyl Benzoate 25% Emulsion 59. Piracetam Cap. 500mg 61. Ciprofloxacin Tab. 100mg 63. Ranitidine Tab. 300mg

特別感謝金明儒董事長，張鍵官廠長及江樵熹品管主任的協助

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我也自75年到現在，113年，連續39年應聘 在台大教臨床藥動學(醫科，藥學系及研究所)

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台灣藥政管理體系 藥物研發

)

(BA/BE/cGMP/PIC/S)

(

新 藥 生 物 科 技

臨床試驗 (GCP)

藥物查 驗登記

(GLP) 臨床前試驗 衛生署核准 學

委 託 名 製 藥 造 、 檢 驗

藥物審議 委員會

醫藥品查驗 (安全監視) 中心

上市、行銷、廣告

醫院

藥局(房)

(醫藥分業)

不良反應申報系統 藥害救濟

保險制度

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藥物辨識系統

10

本人應衛署邀任藥政處長期間為建立我國 藥政體系推動的工作(依據衛生署資料) 幼圃于擔任衛生署藥政處長任內和藥政處同仁及在衛生署詹啟賢署 長(譚開元醫政處處長)支持下完成之重要施政: 1.制訂藥害救濟法，成立財團法人藥害救濟基金會 (TDRF)、建立 藥害救濟制度。 2.制訂罕見疾病防治及藥物法及相關規定並成立罕見藥物審查諮詢 委員會。 3.建立全國藥物不良反應通報系統並成立北中南東副作用申報中心。 4.任內設立財團法人醫藥品查驗中心-建立新藥審查專責二審制。 5.推動醫療器材GMP及對醫材重新分類分級 (Class I, II 及 III)與世界 接軌。 6.繼續推動全國醫藥分業，由北高二市推廣至全省二十縣市(特別感 謝省衛生處石曜堂處長的大力協助。

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本人應衛署邀任藥政處長期間為建立我國 藥政體系推動的工作(依據衛生署資料) 7.推動藥品全面確效，開展、建立cGMP製度。 8.健全我國臨床試驗體系 (成立9家臨床試驗中心、並將臨床試 驗IND醫院及衛生署同時送審、及推動臨床試驗查核制度及 保險制度)，公告銜接性臨床試驗辦法，考量人種因素，促進 我國民眾安全用藥。 9.成立藥政處第五科審查新興生物製劑及健全體外檢驗試劑之 查驗登記制度。 10.成立專責指示藥品審查諮詢委員會-推動指示藥品鬆綁。 11.簽署台瑞典及推動台歐盟合作換文-相互承認醫材品質認證。 12.推動國外藥廠查廠事宜，成立臺灣藥物品質協會(TPQRI)與國 際Product Quality Research Institute(PQRI)-協助衛生署，負 責開創國外查廠事宜。(鍾柄泓主任為第一任理事長) 13.七七公告、雙十二公告，開啟我國臨床試驗契機。 請勿轉載

2001藥害救濟基金會成立 請勿轉載

藥害救濟基金會成立15週年

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藥害救濟基金會成立20週年(獲頒特殊貢獻奬) 請勿轉載

1998醫藥品查驗中心(CDE)成立

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1999年11月11日余政道委員罕病法草案公布記者會 胡幼圃前處長說明立法精神

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103年衛生福利部一等專業奬章(衛福部001號)

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2008~2014擔任考試委員期間為健全軍、公、 教考銓制度(特別是醫事人員)所推動的工作 幼圃在擔任考試委員，和關中院長、吳錦霖副院長、委員 同仁及部會首長一起工作，其中已完成與生技醫藥相關的 部分工作，舉其大者包括： 1.已提高並提昇衛生福利部(含FDA)研究員員額(10人)及 職等，由10至11職等。 2.已適當增加全國各級衛生醫療機關適用醫事人員人事條 例的員額，使醫藥人員可不經公務員高考直接出任公職 ，減少外行人領導內行人的情況。 3.合理認定生技新藥條例中“政府研究機構及研究人員” 認定原則，使所長、院長等原列行政人員也屬生技法中 之研究人員，如此均可適用生技新藥條例。 4.協助完成將OSCE納入醫師考試第二試應考資格。 請勿轉載

2008~2014擔任考試委員期間為健全軍、公、教 考銓制度(特別是醫事人員)所推動的工作(續) 5.協助修訂公務員考試法第十九條，使具有國家考試及格之醫 事專技人員，經再考二科即可通過高考及格，不必重覆考專 技已考過之科目，使政府有可用有經驗之專技人員擔任公職 ，且避開專技人員為擔任公職需再重考全部專業科目。 6.藥師考試實施藥師考試分二階段考試 （一）建請教育部儘速完成適合我國國情之藥學教育體系。6 年制藥學教育最後2年應分為三個主要方向：(1)臨床藥學； (2)藥事行政與藥貿；(3)生技製藥或工業藥學。 7.醫師以外之醫事人員，藥師、護理師、醫檢師等，於醫院中 亦可經院長同意任師一級之職等。 8.提案修正教育人員任用條例，使全國教育人員借調至行政院 服務於法有據。

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國防醫學院司徒惠康院長頒發榮譽教授證書

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為感念藥學系師長，特捐助成立 “金鍾獎” 奬勵同學及補助學系學術活動 113年5月3日系務會議通過 113年 月 日第二次修正

一、主旨： 藥學系胡幼圃榮譽教授(P60)為紀念藥學系前主任金明儒教 授(P34)及鍾柄泓教授(P40)對母系之貢獻，特捐(募)款成立 金鍾獎。一則紀念金、鍾二主任對藥學系之貢獻，奬勵學 系教師致力研究、教學及鼓勵藥學系大學及研究所同學努 力向學，二則支援藥學系各項學術活動、研討會等費用。 二、經費來源及運用：(與捐款單位合辦) 由胡幼圃教授、欣耀生醫股份有限公司及財團法人國際教 育基金會前五年，每年至少捐贈新台幣壹佰萬元，款項指 定由藥學系組成管理小組，就上述指定用途規劃運用。

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Pharmacokinetic Basis of Novel Drug Design and Development 以藥物動力學為基礎的新藥研發 請勿轉載

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25

Ref: Stephen H. Curry, Hu O. Y.-P., Robin Whelpton, Neuromethods.

The Humana Press, Inc., 1988.

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Novel Plasma Protein Binding ( Hu ) Equation Calculation of Fraction Bound in Equilibrium Dialysis with Special Reference to Volume Shift, Drug Losses by Decomposition and Adsorption

CuVp Fu =

Ao ─ Aloss─ CuVb

Ref: Stephen H. Curry, Hu O. Y.-P., Robin Whelpton, Neuromethods.

The Humana Press, Inc., 1988.

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27

TDM of Cancer Chemotherapy Pharmacokinetic and Pharmacodynamic Studies with 4’-epi-doxorubicin in nasopharyngeal carcinoma patients Oliver Yoa-Pu Hu1, Shiu-Pei Chang1,2, Jer-Min Jame2, and Kuang-Yao Chen2

1 School of Pharmacy, National Defense Medical Center, Taipei, Taiwan, Republic of China 2.Cancer Therapy Center, Veterans General Hospital, Taipei, Taiwan, Republic of China

Ref : Cancer Chemother Pharmacol (1989) 24:332-337

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28

hr) after administering mg/m ) 2

Epirubicine Plasma concentration ( adjusted dose( ~

11 0 72 75

Patient Number 72 hrs’ Epirubicine plasma concertation after administering adjusted dose(75~110 mg/m2) among 38 Nasopharyngeal Carcinoma patients

Ref : Journal Med. Science, 13(2) : 77-96, 1992.

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Survival (%)

Time (month) After 6 years follow-up, complete responder’s survival rate are highly significant higher than partial responder and non-responder, (Breslow-test, p=0.037) 30 Ref : Journal Med. Science, 13(2) : 77-96, 1992.

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The Mechanism of Reducing Thiopentone Dose in Elderly Patients undergoing Surgery Shung-Tai Ho＊, Oliver Y. P. Hu＊＊, Li-Heng Pao ＊＊ Weber Ho ＊＊ ＊ and Shin-Chun Lee ＊＊ ＊＊ ＊ Department of Anesthesiology, National Defense Medical Center ＊＊ School of Pharmacy, National Defense Medical Center ＊＊ ＊ Department of Anesthesiology, Far Eastern Memorial Hospital ＊＊ ＊＊ Department of Surgery, National Defense Medical Center Taipei, Taiwan Republic of China

Ref : Proc. Natl., Sci. Counc. B. ROC Vol. 12, No, 1, 1988. pp.1-8.

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31

新藥研發的專業與查登機制的建立 發明unmet medical need 新藥上市 公 司 治 理 基醫 礎藥 科 學

教 學 、 研 究

研 發 團 隊 專 利 保 護

法 規

查 驗 登 記

擔 任 審 查 委 員

成 立新 藥藥 害研 基發 金 會

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談 判

成 立

技 轉 成 功 臨

IRB 床 CDE JIRB試

驗

臨 床 試 驗 體 系

寶塔式的研發成果

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Strategies for New Drug, New Diagnostic Kits Development and Its Applications in Taiwan— (Policy)、(Strategy)、(Tactics) 新藥研發之策略 — 政略、戰略、戰術 請勿轉載

用世界的難題 吸引世界級的人才

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已成功開發上市或進入臨床二、三 期的新藥 1. 長效(7天)止劇痛、不成癮新藥納疼解 (國科會計劃，歐 洲、我國等6國上市) 2. 肝剩餘功能測定新法GSP, OGSP收載於US FDA, Taiwan FDA Guidance及國際教科書，台灣上市，2023 ) 3. Acyclovir Transdermal for Herpes Zoster(國科會技轉 日本，台灣上市) 4. Safe Tynadol Hepatotoxicity free Acetaminophen (pivotal trial / 4~12g已完成，NDMC技轉欣耀生醫) 5. 脂肪肝炎用藥，SNP-630 MASH (II) (NDMC技轉欣耀 生醫) 6. 無肝毒性TB藥(phase III) 請勿轉載

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What’s the Problems for Pain Control Especially Moderate to Severe Pain : 1. Almost all the pain killer for moderate to severe pain are: (1) Narcotics with addiction (2) Respiratory suppression may cause death (3) possible vasodialation (4) Reduce GI motility (5) Convulsant effects 2. Not a moderate to severe (M/S) pain killer for post operation pain has a duration longer than one day.

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Pharmacokinetic Basis of Novel New Drug Design and Development

納疼解的開發 Topic Selection • Thousands of Diseases Just Several Kinds of Pain

• National Defense 請勿轉載

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Development of Non–addiction, Non–respiratory Depression, Once a Week, Novel Analgesic for Severe Pain

胡幼圃 教授 Prof. Oliver Yoa-Pu Hu, Ph. D., FNAI (USA), FAAPS (USA)

何善台 醫師 Shung-Tai Ho, Deputy Superintendent

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熊正輝 博士 Cheng-Huei Hsiong, Ph.D.

40

止痛藥理及副作用機轉 Opioid Receptor Major Subtypes (I) Receptor Subtypes Location

mu (μ)

μ1, μ2, μ3

Function

 brain μ1:  spinal cord  analgesia  peripheral  physical dependence  intestinal μ2: tract  respiratory depression  euphoria  reduced GI motility  physical dependence μ3:  possible vasodilation41

Ref : https://en.m.wikipedia.org/wiki/Opioid_receptor

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止痛藥理及副作用機轉 Opioid Receptor Major Subtypes (II) Receptor Subtypes Location kappa (κ) κ1, κ2, κ3  brain  spinal cord  peripheral

Ref : https://en.m.wikipedia.org/wiki/Opioid_receptor

Function  analgesia  anticonvulsant effects  depression  dissociative/hallucinogenic effects  sedation

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42

Cell Volume 172, Issues 1-2, p55–67.e15, 11 January 2018

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Polynalbuphine Ester

+ HCOO R

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Note : Thanks for the support from National Science Council (NT$8,300萬)

44

Drug Design : Multiple Warhead Missile Nose cone

Warheads

The original missile design has a single warhead inside the nose cone.

Ref : http://cn.nytimes.com/china/20150517/c17missiles/zh-hant/

The new model has multiple warheads that can be aimed independently.

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45

An Innovative Cold Tail-Flick Test: Cold Ethanol Tail-Flick Test Kappa Receptor Efficacy Study Abstract An innovative antinociceptive test, the cold ethanol tail-flick test (CET), was developed for evaluating the actions of opioid analgesics. To select an optimal operation temperature range for the CET, temperatures from -5 degrees C to -30 degrees C were screened. After screening, temperatures ranging between -20 degrees C and -30 degrees C were both strong and effective enough to act as a noxious cold stimulus. In the following study, -20 degrees C was selected as the cold stimulus for the CET. The sensitivity and specificity of this test were challenged by opioid analgesics: an agonist (morphine) and two agonist-antagonists (buprenorphine and nalbuphine), two tranquilizers (droperidol and diazepam), and four nonopioid analgesics (acetaminophen, aspirin, indomethacin, and ketoprofen). The sensitivity of the CET was also compared with the assays using heat (radiant heat and hot water). The AD50 values determined by the CET for morphine, buprenorphine, and nalbuphine were 0.16 mg/kg, 0.22 micrograms/kg, and 0.19 mg/kg, respectively. Naloxone, an opioid antagonist, blocked the antinociceptive effects of these opioids which were determined by the CET. Furthermore, the tranquilizers and nonopioid analgesics did not show any activity in the CET. Our results show that not only can the CET assess the antinociceptive activity of both opioid agonist and mixed agonist-antagonist, it also possess the characteristics of sensitivity, specificity, simplicity, and reproducibility.

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Anesth. & Analg. 79:1-6, 1994.Wang J-J., Ho S-T., Chu K-M. and Hu O. Y-P.*

SDE 長效肌肉注射劑 (Formulation Studies)

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Note : Thanks for the support from National Science Council (NT$8,300萬)

47

Nalbuphine Conc.(ng/ml)

Nalbuphine in Beagle Dogs After IM 5 mg/kg of Nalbuphine-HCl or 30 mg/kg of SDE traditional nalbuphine-HCl SDE long-acting dosage form

1000

100

10 -1

0

1

2

3

4

5

Time(day)

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6

7

8

9

Toxicology – MPI (an US contract Lab.) 1. Acute intramuscular toxicity of SDE in rats – dose = 3, 30, 100, 300, 600, 1200 mg/kg, dosage form: 75 mg/ml oily solution

2. Acute intramuscular toxicity of SDE in dogs – dose = 3, 100, 300, dosage form: 75 mg/ml oily solution

3. 4-Week intramuscular toxicity of SDE in rats – dose = 30, 50, 100 mg/kg, dosage form: 75 mg/ml oily solution

4. 4-Week intramuscular toxicity of SDE in dogs

– dose = 10, 30, 60 mg/kg, dosage form: 75 mg/ml oily solution

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49

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50

Phase I Clinical Trial

A Phase I, Four Dose-Level Study to Assess the Safety, Tolerability and Pharmacokinetics of SDE 請勿轉載

51

Nalbuphine in Healthy Subjects After IM 17 mg of NH or 75, 100mg, 125 mg of SDE (II) 100

SDE 150mg(Taiwan) SDE 125mg (Taiwan) SDE 100mg (Taiwan) SDE 75mg (Taiwan) Nalbuphine-HCl 17mg (Taiwan)

Nalbuphine (ng/mL)

10

1

8 hrs post NH injection

0.1 0

48

96

144

192

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240

288

336

AUCinf of NH of Healthy Subjects after IM SDE 1600 1400 y = 10.495x - 15.718 r = 0.9938

AUCinf (h*ng/mL)

1200 1000 800 600 400 200 0 10

30

50

70

90

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Dose Equivalent to NH (mg)

110

130

150

Phase II / III Clinical Trial A Randomized, Double Blind, Placebocontrolled, Single Dose Study to Assess the Safety and Efficacy of Intramuscular SDE For Post-hemorrhoidectomy Pain Management

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Study Procedure Population：220 Hemorrhoid subjects (已排定要進行2或3處切除之痔瘡手術者) SDE/placebo single dose Chemistry/Hematology

手 術 D0

D-30

Screening Confirm Eligible, Arrange Surgery

D1

D2

D3

D4

D5

D6

需住院，Day 3出院 Ketorolac PCA

D7

D10

D7-10擇一天final visit Oral Ketorolac

Rescue Drug (Nalbuphine IV or IM) Injection site evaluation Vital signs evaluation

Primary Endpoint: VAS Assessment 55 before the first use of PCA Ketorolac, and at 1, 2, 3, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48 h after the surgery

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Nalbuphine concentration of subjects in SDE Phase I and Phase II / III study 20

SDE 150mg (Phase II/III/Taiwan)

Nalbuphine (ng/mL)

16

SDE 150mg (Phase I/Taiwan)

12

8

3 ng/mL

4

1 ng/mL 0 0

48

96

144

192 Time (hr)

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240

288

336 56

Primary Endpoint AUC0-48 of VAS Scores During 48 Hours After Hemorrhoid Operation Population

SDE

Active control

mITT N AUC0-48

103

106

209.9  111.3

253.5  108.5

AUC0-48 Data = Mean  SD 1ANOVA with treatment *Significant at 5% level

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p-value1

SDE-Active control LS-mean

0.0052*

-42.2

Secondary Endpoint 1 Amount of Ketorolac (mg) Administered by PCA Through 48 Hours After Hemorrhoid Operation Population

SDE

Active control

mITT(N)

103

106

NObs2

84

99

50.1  45.7

82.3  66.4

PCA consumption (mg)

PCA consumption Data = Mean  SD 1ANOVA with log-transformation of PCA consumption of treatment 2Number of observation *Significant at 5% level

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p-value1

0.0021*

Discussions – SDE’s AE Compare with Morphine’s AE Morphine

SDE

Indication

the relief of moderate to severe acute and chronic pain

the relief of moderate to severe acute and chronic pain

Gastrointestinal AE

Common (1% to 10%): Dry mouth, Vomiting (2.8%), nausea constipation, nausea, diarrhea, anorexia, (1.8%) abdominal pain, vomiting

Nervous system and general AE

Very common (10% or more): Drowsiness (28%) Common (1% to 10%): Dizziness, sedation, fever, anxiety, confusion, tremor, diaphoresis, lethargy, feeling of warmth

Respiratory depression, Chest pain, Other common Anemia, leukopenia, Rash, Peripheral AE (1% to 10%) edema

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Fever (16.5%), dizziness (6.4%)

No 59

Project Achievement •

Patents – 6 patents in 6 countries – – – – – –

•

Long Acting Analgesic Nalbuphine Polyester Derivative and Method of Use. ROC Patent: 118461, 2000.

Long Acting Analgesic Nalbuphine Polyester Derivative and Method of Use. U.S. Patent: 6,225,321, 2001.

Long Acting Analgesic Nalbuphine Polyester Derivative and Method of Use. European Patent:1149836, 2003.

Long analgesic acting nalbuphine polyester derivative and method of use. China Patent: ZL00108255.8, 2005.

Long analgesic acting nalbuphine polyester derivative and method of use. Japan Patent: 4024992, 2007.

Long analgesic acting nalbuphine polyester derivative and method of use. Korea Patent: 0534917, 2005.

Published paper - The Effect of Aging on the Pharmacokinetics of Nalbuphine in Rabbits. Biopharmaceutics and Drug Disposition, 16 : 695-703, 1995.

- Determination of Nalbuphine by High-performance Liquid Chromatography with Ultraviolet Detection : Application to Human and Rabbit Pharmacokinetic Studies. Journal of Chromatography B, 678 :289-296, 1996.

- Controlled Release of Nalbuphine Prodrug from Biodegradable Polymeric Matrices: Influence of Prodrug Hydrophilicity and Polymer Composition. International Journal of Pharmaceutics, 172: 1725 1998.

- Mucoadhesive Buccal Disks for Novel Nalbuphine Pro-drug Controlled Delivery: Effect of Formulation Variables on Drug Release and Mucoadhesive Performance. International Journal of Pharmaceutics., 177: 201-209 ,1999.

- High-performance method for the Simultaneous Determination of Nalbuphine and its Pro-drug, Sebacoyl Dinalbuphine Ester, in Dog Plasma and Application to Phamacokinetic Studies in Dogs.

Journal of Chromatography 746 :241-247, 2000.

- Delivery of Nalbuphine and its Pro-drugs Across Skins by Passive Diffusion and Iontophoresis.

Journal of Controlled Release. 1-8, 2000.

- Controlled Release of Nalbuphine Propionate from Biodegradable Microspheres: in vitro and in vivo studies. International Journal of Pharmaceuties 220 : 91-99,2002.

- Transdermal Delivery of Nalbuphine and Nalbuphine Pivalate from Hydrogels by Passive Diffusion and Iontophoresis. Arzneimittel-Forshung Drug Reserch 51:408-413, 2002.

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Project Achievement •

Published paper - The analgesic effect of nalbuphine and its long-acting pro-drug, nalbuphine arachidicate, in rats.

Formos J Surg 35:283-289, 2002 - The Analgesic Effect of Nalbuphine and Its Long-acting Pro-drug, Nalbuphine Pivalate, in Rats. Acta Anaesthesiol Sin 40: 191-195, 2002.

- The Selection of Oil for the Preparation of Long-acting Nalbuphine. Chin J Pain 13(1): 18-22, 2003 - The Analgesic Effect of Nalbuphine and Its Pro-drug, Nalbuphine Benzoate, in Rats, Chin J Pain 13(1):11-17, 2003 - The Method for Synthesizing Nalbuphine Esters. Chin J Pain 13(1):23-28, 2003 - Biodegradable Polymeric Microspheres for Nalbuphine Pro-drug Controlled Delivery: in Vitro Characterization and in Vivo Pharmacokinetic Studies. International Journal of Pharmaceutics.

7441:1-9, 2003.

- The Antinociceptive Effect of Nalbuphine and Its Long-Acting Esters in Rats. Anesth Analg, 97:806809, 2003.

- The Antinociceptive Effect of a Long-acting Nalbuphine Preparation in Rabbits. Acta Anaesthesiol Sin, 41:99-103, 2003.

- Antinociceptive Effect of a Novel Long-Acting Nalbuphine Preparation. British Journal of Anaesthesia 92 (5): 712-715, 2004.

- In Vitro and In Vivo Evaluation of the Metabolism and Pharmacokinetics of Sebacoyl Dinalbuphine.

Drug Metabolism and Disposition, 33(3): 395- 402, 2005.

- The effects of electrically assisted methods on transdermal delivery of nalbuphine benzoate and sebacoyl dinalbuphine ester from solutions and hydrogels. International Journal of Pharmaceuics.

297(1-2):162-171, 2005.

- Submicron lipid emulsion as a drug delivery system for nalbuphine and its prodrugs. Journal of Controlled Release 115:140-149,2006.

- Simultaneous determination of nalbuphine and its prodrug sebacoly dinalbuphine ester in human plasma by ultra-performance liquid chromatography-tandem mass spectrometry and its application to pharmacokinetic study in humans. Biomedical Chromatography. 27：831-837,2013.

•

IND –

•

US: SDE, IND No. 56,367; Taiwan, Phase I: No. 0970344666 ; , Phase II/III : No. 1025005668 , Taiwan

NDA approved 2018, 歐、亞、台灣6國上市

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致謝 Acknowledgement 一、基礎團隊名單 國防/三總 胡幼圃 、張溫良、鮑 力恆、熊正輝 、王騰 旭、蔡昌晏、石東原、 何欣恬、黃北緯 、劉 宏達 、楊蘋 、田巧 怡 、楊莞鈴、黃俐瑛、 魏嘉虹

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63

致謝 Acknowledgement 二、SDE臨床團隊名單 三總大腸 直腸外科 : 饒樹文醫師

林口長庚 直肛科： 王正儀醫師

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基隆長庚 直肛科： 范仲維醫師

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USFDA推薦之快速精準測量 (Point-of-Care, POC)肝功能之新法 及其應用 Novel Point - of - Care system for fast and quantitative measurement of liver function and its applications 請勿轉載

Residual Liver Function – GSP Method

Development of Diagnostic Kit for Residual Liver Function – GSP Method

胡幼圃 教授 Prof. Oliver Yoa-Pu Hu, Ph. D., FNAI (USA), FAAPS (USA)

唐鴻舜 醫師 Hung-Shang Tang, Deputy Superintendent

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66

Comparison of Various Quantitative Liver Function Tests Method

Advantages

Disadvantages

Child-Pugh

Simple, convenient, semi- quantitative

Qualitative.

The Child-Pugh classification uses factors such as ascites and encephalopathy to evaluate liver function; therefore, it is mainly used to assess severe dysfunction.

ICG

Quantitative

i.v. bolus, complex (many blood sampling), foreign compound, blood flow only.

GSP (Galactose)

1. Simple (single blood sampling)

3 min i.v. Bolus, fasting.

2. Quantitative, blood flow and enzyme activity, not affected by CYP or conjugated metabolic system 3. Use strip to rapid detect QLFT, Point-ofCare 4. Galactose is a natural and safe compound 5. The GSP and OGSP tests appeared to be more appropriate than the Child-Pugh and MELD scores for patients with liver dysfunction across the entire normal-to-severe spectrum.

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Galactose Metabolized in Liver Becomes Glucose-1-Phosphate Then Produced ATP, Not Glucose (Diabetes Mellitus Patient Can Use)

Galactose

90% galactose metabolized in the liver

1. Galactose is extensively metabolized by liver - reflect the CLint 2. Galactose is highly extracted by liver – reflect the QH, hepatic blood flow. When not saturated.

3. When galactose saturated, the clearance will reflect the hepatic enzymes activities.

CLH  QH 

fu  CLint QH  fu  CLint

CLint reflect the hepatic enzymes activities QH reflect the hepatic flow

ADP ATP

68

Glycolysis pathway

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Hepatic Clearance Correlated with Hepatic Blood Flow and Enzymes Activities • Galactose is extensively metabolized by liver - reflect the CLint • Galactose is highly extracted by liver – reflect the QH

fu  CLint CLH  QH  QH  fu  CLint CLint reflect the hepatic enzymes activities QH reflect the hepatic flow

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69

Assessment of Liver Function Using a Novel Galactose Single Point Method

Tang HS and Hu OYP, Digestion 1992;52:222-231

Fig.2. The galactose saturation time period in normal volunteers (a) and patients with cirrhosis (b) obtained from each person’s galactose concentration timeFig2. curve after quick saturstion intravenous Thereceiving galactose administration of 0.5 g/kg galactose. time period in normal Fig.3. Difference of galactose blood concentration at different time point (a) between volunteers and51 normal healthy volunteers and 36 patients with cirrhosis after 0.5 g/kg galactose was infused intravenously for 3 min.

The concentration 40, 50 and 60 min after infusion give highly significant difference between these two groups.

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Point of Care, Clinically Useful Galactose Single Point (GSP) and Oral GSP (OGSP) Method • Oral 0.5g/kg or i.v. infused (3~5min.) of galactose, and measuring whole blood galactose concentration at 60 minutes.

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Point of Care, Clinically Useful Galactose Single Point (GSP) and Oral GSP (OGSP) Method Galactose Monitoring System Can Rapid Detect Quantitative Liver Function ( QLF )

可居家自我量測

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GSP Method Has Been Recommended by U.S. FDA

Guidance for Industry Pharmacokinetics in Patients with Impaired Hepatic Function: Study Design, Data Analysis, and Impact on Dosing and Labeling U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER) Center for Biologics Evaluation and Research (CBER) May 2003 Clinical Pharmacology 73

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Confidential and not for distribution

半乳糖單點法測定人肝臟剩餘功能 Assessment of Liver Function Using a Novel Galactose Single Point (GSP) Method

Guidance for Industry, Pharmacokinetics in Patients with Impaired Hepatic Function: Study Design, Data Analysis, and Impact on Dosing and Labeling U.S. FDA May 2003 肝功能不全病患的藥動學試驗基準 －臨床試驗設計、數據分析以及對劑量調整與標示的影響 行政院衛生署 中華民國九十年七月 Tang HS and Hu OYP, Digestion 1992; 52(3): 222-231

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肝功能不全病患的藥動學試驗基準 －臨床試驗設計、數據分析以及對劑量 調整與標示的影響 肝功能評估-推薦方法之一 2、半乳糖單點法（Galactose Single Point, GSP） 本法乃是由唐鴻舜及胡幼圃發表於1992年之Digestion期刊中。GSP為於空腹時， 三分鐘快速靜脈輸注0.5 g/kg的半乳糖，經過60分鐘後，測量受試者血中半乳糖的 濃度，即為其GSP值（單位為g/ml）。血中半乳糖濃度，和肝功能異常有靈敏的 相關性，且實驗數據顯示GSP值與肝功能異常的程度有非常顯著的關係。因此， 可經由受試者的GSP值來評估其肝臟的剩餘功能，評估方法如下： (1)GSP值小於280g/ml：肝功能正常或受損輕微。 (2)GSP值介於280與480g/ml之間：肝功能受損為中度（可能為慢性肝炎患者）。 (3)GSP值大於480g/ml：肝功能受損較嚴重（可能為肝硬化或肝癌患者）。

Tang HS and Hu OYP, Digestion 1992; 52(3): 222-231

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75

International Popular Textbook Has Been Recommended (I)

76

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International Popular Textbook Has Been Recommended (II)

2010.11

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半乳糖單點快速測量系統之用途 醫院、診所

社區藥局

1. 提供專業人員為受檢者口服飲用半乳糖 1. 提供受檢者於藥局、 快速監控肝功能或肝臟血流及肝酵素。 居家使用，口服飲 2. 提供專業人員為受檢者以注射半乳糖， 用半乳糖，快速篩 快速精準定量病患肝功能受損程度。 檢肝功能、肝臟血 3. 可應用於多種肝功能不全的病人，如肝 流及肝酵素。若肝 切除術前後、各種肝病的進程，換肝前 功能不正常可以盡 後及肝功能不全的病人。 快就醫。 4. 用於調整藥物劑量(如：抗癲癇 2. 應用於多種肝功能 phenytoin, 降血脂statins, 抗生素 不全的病人、慢性 cefoperazone …等)之用途。 肝炎、各種肝病的 5. 篩檢先天半乳糖血症的Type 2(半乳糖 進程。 激酶缺乏)。

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Preoperative Galactose Elimination Capacity Predicts Complications and Survival After Hepatic Resection

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Ann Surg 2002; 235(1): 77-85

79

Published GSP Application Papers (I) 1. Hung-Shang Tang and Oliver Yoa-Pu Hu. Assessment of Liver Function Using a Novel Galactose Single Point Method.

Digestion 1992; 52: 222-231.

2. Oliver Yoa-Pu Hu, Hung-Shang Tang and Ching-Ling Chang. The Influence of Chronic Lobular Hepatitis on Pharmacokinetics of Cefoperazone -A Novel Galactose Single-Point Method as A Measure of Residual Liver Function.

Biopharmaceutics and Drug Disposition 1994; 15: 563-576.

3. Oliver Yoa-Pu Hu, Teh-Min Hu and Hung-Shang Tang. Determination of Galactose in Human Blood by High-Performance Liquid Chromatography: Comparison with Enzymatic Method and Application to the Pharmacokinetic Study of Galactose in Patients with Liver Dysfunction. Journal of Pharmaceutical Sciences 1995; 84(2): 231-235.

4. Oliver Yoa-Pu Hu, Hung-Shang Tang, Tuzen-Yen Sheeng, Tung-Chao Chen and Stephen H. Curry. Pharmacokinetics of Promazine in Patients with Hepatic Cirrhosis–Correlation with a Novel Galactose Single Point Method. Journal of Pharmaceutical Sciences 1995; 84(1): 111-114.

5. Oliver Yoa-Pu Hu, Hung-Shang Tang and Ching-Ling Chang. Novel Galactose Single Point Method as a Measure of Residual Liver Function: Example of Cefoperazone Kinetics in Patients with Liver Cirrhosis. Journal of Clinical Pharmacology 1995; 35: 250-258.

6. Hung-Shang Tang, Oliver Yoa-Pu Hu, Feng-Chen Wu, Ton-Ho Young, Teh-Min Hu and You-Chen Chao. Prognostic Value of Galactose Elimination Capacity in Patients with Cirrhosis Based on a Serial Determination. Journal Med Sciences 1996; 16(5): 295 -305.

7. Hung-Shang Tang, Oliver Yoa-Pu Hu, You-Chen Chao, Ton-Ho Young and Teh-Min Hu. The Clinical Significance of Assay Serum Collagen IV 7S Collagen in Patients with Hepatitis B-Related Liver Disease. Journal Med Sciences 1998; 18(5): 306-315.

8. Ton-Ho Young, Hung-Shang Tang, Herng-Sheng Lee, Cheng-Huei Hsiong and Oliver Yoa-Pu Hu. Effects of Hyperglycemia on Quantitative Liver Functions by the Galactose Load Test in Diabetic Rats. Metabolism Clinical and Experimental 2007; 56: 1265-1269.

9. Ton-Ho Young, Hung-Shang Tang, You-Chen Chao, Herng-Sheng Lee, Cheng-Huei Hsiong, Li-Heng Pao and Oliver YoaPu Hu. Quantitative Rat Liver Function Test by Galactose Single Point Method. Laboratory Animals 2008; 42: 495-504.

10. Chung-Jung Lin, Ming-Fang Yen, Oliver Yoa-Pu Hu, Min-Shung Lin, Cheng-Huei Hsiong, Chin-Chuan Hung and HorngHuei Liou. Association of Galactose Single-Point Test Levels and Phenytoin Metabolic Polymorphisms with Gingival 80 Hyperplasia in Patients Receiving Long-Term Phenytoin Therapy. Pharmacotherapy 2008; 28(1): 35-41.

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Published GSP Application Papers (II) 11.

12.

13.

14.

15.

16.

17.

18.

19.

Jr-Ting Lee, Li-Heng Pao, Meei-Shyuan Lee, Jiunn-Wang Liao, Chi-Min Shih, Cheng- Huei Hsiong, Fon-Yi Yin, TungYuan Shih and Oliver Yoa-Pu Hu. A New Approach to Facilitate Diagnosis of Nonalcoholic Fatty Liver Disease Through a Galactose Single Point Method. Digestive and Liver Disease 2013; 45: 134-141.

Tung-Yuan Shih, Chien-Yi Pai, Ping Yang, Wen-Liang Chang, Ning-Chi Wang and Oliver Yoa-Pu Hu. A Novel Mechanism Underlies the Hepatotoxicity of Pyrazinamide. Antimicrobial Agents and Chemotherapy 2013;57(4):16851690.

Tung-Yuan Shih, Ton-Ho Young, Herng-Sheng Lee, Chung-Bao Hsieh and Oliver Yoa-Pu Hu. Protective Effect of Kaempferol on Isoniazid and Rifampicin-Induced Hepatotoxicity. AAPS J 2013; 15(3): 753-762.

Tung-Yuan Shih, Shan-Chu Ho, Cheng-Huei Hsiong, Tien-Yu Huang and Oliver Yoa-Pu Hu. Selected Pharmaceutical Excipient Prevent Isoniazid and Rifampicin Induced Hepatotoxicity. Curr Drug Metab 2013; 14(6)：720-728.

Yi-Chou Hou, Wen-Chih Liu, Min-Tser Liao, Kuo-Cheng Lu, Lan Lo, Heng-Chih Pan, Chia-Chao Wu, Oliver Yoa-Pu Hu and Hung-Shang Tang. Long-Term and Short-Term Effects of Hemodialysis on Liver Function Evaluated Using the Galactose Single-Point Test. Scientific World Journal 2014; 2014: 260939.

Kuo-Ming Yu, Ping Yang, Tien-Yu Huang, Thomas Yen-Shih Shen, Johnson Yiu-Nam Lau, Oliver Yoa-Pu Hu. A Novel Galactose Electrochemical Biosensor Intended for Point-of-Care Measurement of Quantitative Liver Function Using Galactose Single-Point Test. Anal Bioanal Chem 2022 ;414(14): 4067-4077.

Tung-Yuan Shih, Ton-Ho Young, Tien-Yu Huang, Hong-Shun Tang, Hsin-Tien Ho, Ping Yang, Johnson Yiu-Nam Lau and Oliver Yoa-Pu Hu. Galactose Single Point Method as a Safe, Simple, High-Sensitive Quantitative Liver Function Assessment in Patients with Non-alcoholic Fatty Liver Disease. GUT 2024. (submitted) Tung-Yuan Shih, Wan-Ling Yang, Pei-Wei Huang, Cheng-Huei Hsiong, Te-Yu Lin, Kai-Min Chu, Oliver Yoa-Pu Hu. Pain Relief with a Novel Acetaminophen Formulation Without Fear of Hepatotoxicity. Hepatology 2024. (submitted) Tien-Yu Huang, Hsuan-Hwai Lin, Ping Yang, Kuo-Ming Yu, Johnson Yiu-Nam Lau and Oliver Yoa-Pu Hu. Quantitative Measurement of Liver Dysfunction by an Oral Point-of-Care Galactose Single-Point Method. Journal of Gastroenterology 2024. (submitted)

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Table1. Top-50 Selling Drugs from the 2017 Data (Drugs Avoid or Withhold )-1 Product Name

Active liver Ingred metabolis ient m

2. Opdivo Nivolu mab

Main Therape utic Indicatio n

Opdivo is Oncology not extensively metabolize d in the liver. 約有 67 % Cardiovas 經由肝臟酵 -cular 素CYP3A4、 Diseases CYP3A5 和 CYP2J2 代 謝

16.

Xarelto

Rivaro xaban

17.

Crestor

Rosuva CYP2C9 statin 10% Calciu m

Cardiovas cular Diseases

2017 Revenue in Millions (USD)

“Warnings and precautions” and “contraindications” for any liver impairment

4,948

Immune-mediated hepatitis: Monitor for changes in liver function. Withhold for moderate and permanently discontinue for severe or life-threatening transaminase or total bilirubin elevation.

Dose modification

2,500

Use in Patients with Hepatic Impairment • Avoid the use of XARELTO in patients with moderate and severe hepatic impairment or with any hepatic disease associated with coagulopathy.

Hepatic impairment: • Avoid use in patients with moderate and severe hepatic impairment or with any degree of hepatic disease associated with coagulopathy.

Hepatic Impairment Crestor is contraindicated in patients with active liver disease. Chronic alcohol liver disease ; Crestor should be used with caution in these patients.

82

2,365

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臨床藥物治療監測 (TDM) (1) 111年 醫院開 肝代謝 肝功能劑量調整 Drug 立次數 排名 valproate 幾乎完全由 Mild to moderate 2. Valproic 肝臟代謝 acid impairment: Not (Depakene) recommended for use in hepatic disease 5. Phenytoin Phenytoin is Has liver disease, the dose of primarily phenytoin may need to be metabolized by the adjusted to avoid potential liver, specifically by toxicity or insufficient the enzyme CYP2C9 therapeutic effects.

Tacrolimus主要由肝 (Micromedex: severe (Child6. Tacrolimus 1 臟細胞色素CYP3A4 Pugh score 10 or greater): 酵素代謝 May require lower doses 90%是經由肝臟 肝臟疾病使用Theophylline 7.

CYP3A4及CYP1A2 須小心 Theophylline 83 代謝

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Table1. Summary of Drug Avoid in Cirrhosis-4

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MASH New drug to treat NASH: SNP-6

熊正輝 博士 Cheng-Huei Hsiong, Ph.D.

何欣恬 博士 Hsin-Tien Ho, Ph.D.

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Pathogenesis of fatty liver disease High fat diet, metabolic syndrome

Acetaldehyde

Acetyl CoA Free fatty acid

Alcohol Hepatic enzyme

Lipid peroxidation

Triglyceride (accumulation)

Simple fatty liver

Toxic metabolites ROS

Cell damage, steatohepatitis

Cirrhosis

Hepatoma

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Comparison of the Efficacy of oral SNP-6 and the front runner - Elafibranor (Genfit)*

Fig. Changes from baseline in ALT in treatment groups. Results are expressed in mean values of changes from baseline during treatment with placebo (n=77), elafibranor 80 mg (n=82), elafibranor 120 mg (n=78) and SNP-6 (n=17). Error bars represent 95% CIs. ALT, alanine aminotransferase. *Elafibranor data is adapted from the GOLDEN-505 trial published in Gastroenterology 2016;150:1147–1159

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Liver Disease Research (Basic R&D Team)

何欣恬 博士 Hsin-Tien Ho, Ph.D.

陳欣蔚 博士 Shin-Wei Chen, Ph.D.

曹昌輝 博士 Chang-Hui Tsao, Ph.D.

徐袁章 博士 Yuan-Chang Hsu, Ph.D.

Postdoc, National Defense Medical Center, Taiwan Ph.D., Graduate institute of Life Sciences, National Defense Medical Center, Taiwan

CTO, I Care You Biotech, Taiwan Ph.D., Graduate School of Science, The University of Tokyo, Japan

Postdoc, VIB-KU Leuven Center for Brain & Disease Research, Belgium Ph.D., Graduate institute of Life Sciences, National Defense Medical Center, Taiwan

Pharm/Tox Reviewer Division of New Drugs, Center for Drug Evaluation, Taiwan Ph.D., The Institute of Basic Medical Sciences, National Cheng Kung University, Taiwan

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Liver Disease Research (Clinical Team)

施宇隆 醫師 Yu-Lueng Shih, MD, Ph.D.

黃天佑 醫師 Tien-Yu Huang, MD, Ph.D.

方文輝 醫師 Wen-Hui Fang, MD

1. Associate professor 2. Attending Physician, Division of Gastroenterology 3. Superintendent of the Tri-Service General Hospital Penghu Branch

1. Associate professor 2. Attending Physician, Division of Gastroenterology 3. Director of the Endoscopy center

1. Director of the Family and Community Health Department and International Medical Service Center 2. Associate professor

劉昌憲 醫師 Chang-Hsien Liu, MD 1. Director of the Radiological Diagnosis Department 2. Assistant professor

林榮鈞 醫師 Jung-Chun Lin, MD, Ph.D. 1. Attending Physician, Division of Gastroenterology 2. Assistant professor

林德宇 醫師 Te-Yu Lin, MD Attending Physician, Division of Infectious Diseases and Tropical Medicine

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向芝薇 醫師 Chih-Weim Hsiang, MD Attending Physician, Department of Radiology 89

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Pain Control Research (Clinical Team)

陳威明 醫師 Wei-Ming Chen, MD, Ph.D. 1. Superintendent of Taipei Veterans General Hospital, Taiwan 2. Professor of Orthopaedics 3. President Elect Asia Pacific Musculoskeletal Tumour Society

林育寬 醫師 Yu-Kuan Lin, MD 1. Division of Joint Reconstruction 2. Department of Orthopaedics and Traumatology, Taipei Veterans General Hospital, Taiwan

陳正豐 醫師 Cheng-Fong Chen, M.D., Ph.D.

宋俊松 醫師 Chun-Sung Sung, MD, Ph.D.

1. Division of Joint Reconstruction 2. Department of Orthopaedics and Traumatology, Taipei Veterans General Hospital, Taiwan 3. Associate professor

1. Attending Physician and Director of Pain Management, Department of Anesthesiology, Taipei Veterans General Hospital, Taiwan 2. Associate professor

王永志 醫師 Yung-Chih Wang, MD 1. Attending Physician 2. Division of Infectious Diseases and Tropical Medicine, Tri-Service General Hospital, Taipei, Taiwan.

3. Associate professor

林德宇 醫師 Te-Yu Lin, MD 1. Attending Physician 2. Division of Infectious Diseases and Tropical Medicine, Tri-Service General Hospital, Taipei, Taiwan.

3. Associate professor

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蔡尚聞 醫師 91 Shang-Wen Tsai, MD 1. Division of Joint Reconstruction 2. Department of Orthopaedics and Traumatology, Taipei Veterans General Hospital, Taiwan

Pain Research (Clinical Team)

王永志 醫師 Yung-Chih Wang, MD, Ph.D. 1. Associate professor 2. Attending Physician, Division of Infectious Diseases and Tropical Medicine

黃獻皞 醫師 Hsien-Hao Huang, MD, Ph.D. 1. Assistant Professor 2. Attending doctor, Department of Emergency Medicine, Taipei Veterans General Hospital

徐德福 醫師 Teh-Fu Hsu, MD. 1. Attending Physician 2. Assistant professor, School of Medicine, National YangMing University

吳明玲 醫師 Ming-Ling Wu, MD, Ph.D. Attending Physician, Department of Occupational Medicine and Clinical Toxicology, Taipei Veterans General Hospital

朱豐沅 醫師 Feng-Yuan Chu, MD, Ph.D. Attending Physician

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92

我的斜槓人生

考試委員 生命科技法律學會榮譽理事長

世界藥學會共同主席 世界衛生組織顧問 任內規劃、草擬通過罕見疾病防治及藥物法

數項新藥國際上市 美國國家發明家學院院士 美國藥學科學家學會院士 論文及專利268篇 教學研究 臨床藥理 藥理專業

成立藥害基金會

成立CDE 藥政處長 行政管理

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人生快樂 快樂人生 Live Happy Happy Life

if 請勿轉載

94

民國93年-113年 辦理全國藥事論壇講 座逾110場，參與人員 共19,379人

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國防藥學風華－ 兼論我的藥動研發 胡 幼 圃講座教授 美國國家發明家學院院士/台北醫學大學 中研院客座講座/國防醫學院榮譽教授/台大兼任教授 113.8.4

Tel: 02-8792-3100 ext. 18211, 18176 FAX: 02-8792-4859 E-mail: hyp@ndmctsgh.edu.tw 96 Add: 114台北市內湖區民權東路六段161號9樓9302室 請勿轉載