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Acetogenins In Vivo re: Wu - (p 22-36)

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Information about Acetogenins In Vivo re: Wu - (p 22-36)
Health & Medicine

Published on January 26, 2009

Author: benrock

Source: slideshare.net

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Herbal Medicine Development in Taiwan and the Research for WYC-01 and WYC-02 Yang-Chang Wu Graduate Institute of Natural Products Kaohsiung Medical University Kaohsiung, Taiwan 1 ICSB, University of Mississippi, May 3, 2007

WHA No. 56.31 Resolution • WHA No. 56.31 resolution urges member countries to adjust, adopt and implement the “ WHO traditional medicine strategy”. • As the basis of national planning, there are four main goals including: – – – – Policymaking Enhancement of safety Efficacy and quality Ensuring availability and promotion of proper use Reference: abstracted from the China Journal of Traditional Medicine, 2002 2 ICSB, University of Mississippi, May 3, 2007

ICSB, University of Mississippi, May 3, 2007 3 The Global Trend of Traditional Medicine WHO traditional Medicine Strategy 2002-2005 • Traditional Chinese Medicine (TCM) & Complementary and Alternative Medicine (CAM) – Integrate with national health care systems – Promote the safety, efficacy and quality – Increase the availability and affordability – Promote therapeutically sound use of appropriate of TCM/CAM Reference: WHO Traditional Medicine Strategy 2002-2005, 2002

ICSB, University of Mississippi, May 3, 2007 4 The Developing Dynamics and Trend of Traditional Medicine (TM) in the World – TM/CAM integrated into national health care systems where appropriate – Safety, efficacy, and quality of TM/CAM enhanced – Availability and affordability of TM/CAM enhanced – Rational use of TM/CAM by providers and consumers promoted • WHO Medicines strategy 2004-2007

ICSB, University of Mississippi, May 3, 2007 5 Recognition of WHO on Traditional Medicine Development (Current Traditional Medicine Conditions in Taiwan) (I) • Statistics and data released by official WHO organizations indicate that , so far, Taiwan, China, North Korea, Korea, and Vietnam have established a completely integrated health care system with regards to traditional medicine.

Recognition of WHO on Traditional Medicine Development (Current Traditional Medicine Conditions in Taiwan) (II) • The National Medicinal Policy recognizes traditional medicine and its practitioners; it allows traditional medicinal products to become register and regulated and, it also allows traditional medicine to be practiced by hospitals and public/private clinics. • Traditional medicine is covered by health insurance and related researches and education will be made possible to all. 6 ICSB, University of Mississippi, May 3, 2007

Recognition of WHO on Traditional Medicine Development (Current Traditional Medicine Conditions in Taiwan) (III) • 25 countries have created state policies concerning the development of traditional medicine • Nearly 70 countries have stipulated laws and regulation for the registration of medicinal herbal products. 7 ICSB, University of Mississippi, May 3, 2007

Important Development and Achievement of Committee on Chinese Medicine and Pharmacy (CCMP), Taiwan in Recent Years 8 ICSB, University of Mississippi, May 3, 2007

The modernization and internalization of TCM Provide a safe development for TCM environment of doctor consultation and medication for public 5-year plan: Establishment of an environment for safe use of TCM Follow the global trend and accelerate the The proposal to promote TCM modernization and internationalization Establish clinical teaching program for TCM Integration of CMP modernization and internalization and Research on Genome of TCM 9 ICSB, University of Mississippi, May 3, 2007

ICSB, University of Mississippi, May 3, 2007 10 Important achievement in recent years (I) • The Chinese medicine has been incorporated into the National Health Insurance. • Complete standards and regulations of Chinese medicine education , certification , preclinical training , and accreditation are well established. • Te overall practice of GMP in Chinese medicine had been reached by Sep. 2005

Important achievement in recent years (II) • The “unified formula” of Chinese medicine are announced and implemented. • Enhancing clinical teaching quality of Chinese medicine • Planning of appraisal of affiliated Chinese medicine departments in Chinese medicine hospitals and regular hospitals • Improving Chinese medicine personnel quality • 13 Clinical trial centers for Chinese medicine are constructed. 11 ICSB, University of Mississippi, May 3, 2007

Important achievement in recent years (III) • Announcement of Pharmaceutical Affairs regulations • Conducting supervision program on illegal advertisement in print media with a total of 1379 cases supervised and 222 cases in violation. • Consigning a total of 73 research programs on Chinese medicine and subsidizing 2 academic interchange programs across the Strait in 2006 12 ICSB, University of Mississippi, May 3, 2007

Important achievement in recent years (IV) • Conducting Program of Chinese Medicine Health Security Protection Network Technology • Aggressively promoting academic Chinese medicine and held 4 international symposiums • Putting Chinese medicine evidence medicine research into practice. 13 ICSB, University of Mississippi, May 3, 2007

Taiwan’s National Health Insurance (NHI) cover around 99% of population 1.33% Insured Uninsured 98.67% As of Dec. 2003, 22 million Taiwan people are covered in the NHI 14 ICSB, University of Mississippi, May 3, 2007

The Chinese medicine doctor education system • There are two Chinese Medical education systems – 8 year systems and post Bachelor program (5 years) College School Total study year 7 8 Registration Annual enrollmen t 120 120 Accumulati ve no. of Students 1,804 219 No. of graduates 2,358 108 Chinese Medicine China Medical University Chang Gung university China Medical University 1966-1995 1996~ Chinese Medicine Post Bachelor Chinese Medicine 8 1998~ 50 0 0 8 1984 100 1.250 998 15 ICSB, University of Mississippi, May 3, 2007

Promoting GMP in Conventional Traditional Medicine Manufacturers • The committee on Chinese Medicine and Pharmacy has spared no efforts in the past years to promote the practice of GMP in conventional pharmaceutical manufacturers. It is considered imperative that these factories practice the GMP ; and the overall practice of GMP by manufacturers had been reach by 2005. • 103 have passed the review of the GMP for the time being. • 5,000 licenses ; 200 standard formula 16 ICSB, University of Mississippi, May 3, 2007

Improve the quality and safety of Traditional Medicine • A total of 203 items of Traditional Medicinal materials were compiled in a “ TM Pharmacopoeia ” and published on 2004.They provide bases for the testing methods and specifications of raw materials. 17 ICSB, University of Mississippi, May 3, 2007

Establishment of Traditional medicine clinical trials and legislative environment in Taiwan • The clinical trials should keep the characteristics of traditional medicine. • The department of Health announced its Advice on Herbal Medicine NDA Application on 1998 • The Application Guidelines on Herbal Medicinal Clinical Trials (IND) and guidelines on Herbal Medicine NDA Applications (NDA) are to be researched and drawn up. 18 ICSB, University of Mississippi, May 3, 2007

New traditional Medicine Clinical Trial Application case (2001-2004) • 22 cases (partial ones are center test) • 11 cases have been passed the examination and verification for clinical trail. • 6 cases under submitting another application and examination • 2 cases have been withdrawn • The first NDA approval in 2005 19 ICSB, University of Mississippi, May 3, 2007

Kaohsiung Medical University Kaohsiung, Taiwan 20 ICSB, University of Mississippi, May 3, 2007

Natural Products Chemistry and TCM Analysis • Discover of new lead compound from natural products • Total/partial synthesis of bioactive compounds • TCM fingerprint, qualitative & quantitative analysis 21 ICSB, University of Mississippi, May 3, 2007

Pharmacology and Bioactivity Anti-cancer, anti-platelet agents screening and mechanisms research 22 ICSB, University of Mississippi, May 3, 2007

The Characteristics of WYC01 23 ICSB, University of Mississippi, May 3, 2007

The structural features of Annonaceous acetogenins some oxygen-bearing moieties , such as zero to three tetrahydrofuran (THF) and/or tetrahydropyran (THP) rings and several hydroxyl groups the spacer moiety linking the two rings with hydroxyl groups a terminal γ -lactone ring a terminal aliphatic side chain Annonaceous acetogenins are unique second metabolites of Annonaceous plants containing C35-C37 , 0-3 THF rings , a γ -lactone ring , and a long aliphatic regions. Till now, more than 450 annonaceous acetogenins were isolated from this family. 24 ICSB, University of Mississippi, May 3, 2007

Biological activity against human cancer cells The IC 50 values of WYC-01 , Doxorubicin and Taxol against Various Human Cancer Cell Lines. Cell lines Hepatoma HepG2 Lung Calu-1 H23 H23/0.3 Colon MES-SA/Dx5 COLO205 Ovary SKOV3 Breast BT474 MDA-MB-453 MDA-MB-231 MCF-7 Prostate PC-3 LNCaP.FGC Gastric TSGH9201 27.42 37.89 0.3571 3.57 5.02 3.87 60.45 23.5 34.18 <0.01 18.0357 3.6866 27.7 5.94 0.48 54.86 1.14 0.82 1.37 0.82 1.03 1.04 0.5942 0.9587 0.7396 6.19 0.0775 0.0065 7.09 2.54 0.006 0.015 15.01 0.0102 0.002 - - - 0.0098 WYC-01( μ g/ml) 36.4 Doxorubicin ( μ M) 1.49 Taxol ( μ M) 11.7 25 ICSB, University of Mississippi, May 3, 2007

Toxicity test The hepatic , renal functions , and hematological values of the tested mice by oral administration of WYC-01 for 14 and 28 days 20.0 19.0 18.0 17.0 16.0 15.0 14.0 13.0 12.0 11.0 10.0 9.0 8.0 0.8 0.6 0.4 0.2 0.0 0 1 2 250 GOT 200 BUN 150 25.0 24.0 23.0 22.0 21.0 20.0 19.0 18.0 17.0 16.0 15.0 14.0 13.0 12.0 11.0 10.0 9.0 8.0 0.8 0.6 0.4 0.2 0.0 0 1 350 GOT BUN 300 250 200 150 GPT 100 Creatinine 50 0 0 1 2 3 4 100 GPT Creatinine 50 0 0 1 2 3 4 3 4 2 3 4 300 250 200 150 100 HCT MCV 50 20 16 12 8 4 0 0 WBC RBC HGB MCH MCHC TestParameters PLT 85 80 75 70 65 60 55 50 45 40 35 30 25 20 15 5 4 3 2 1 0 0 Neturo-Seg TestParameters 550 500 450 400 350 300 250 200 Lymphocytes 150 100 50 20 16 12 8 4 0 0 1 2 3 4 5 6 7 8 9 TestParameters TestParameters Monocytes 90 85 80 75 70 65 60 55 50 45 40 35 30 25 20 15 5 4 3 2 1 0 0 1 TestParameters 1 2 3 4 5 6 7 8 9 10 1 2 TestParameters 3 4 10 2 TestParameters 3 4 TestParameters 14 days Normal Vesicle formulation AS 25mg/kg AS 20mg/kg AS 15mg/kg 28 days Normal Vesicle formulation AS 25mg/kg AS 20mg/kg AS 15mg/kg 1. The values of WYC01 are stable as that of control. 2. WYC01 is quite low toxicity to test mice. 26 ICSB, University of Mississippi, May 3, 2007

Toxicity test The 15th day The 29th day normal control 25 20 15 normal control 25 20 15 (mg/kg/10ml) No differences in mice organs, including liver, renal, heart, lung, and gastrointestinal between tested and control groups 27 ICSB, University of Mississippi, May 3, 2007

In Vivo test Some side effects on the skin of mice, such as skin rough, skin bits and erythma (red spots), were present after oral administrating WYC-01 for 21 days, but these phenomena disappeared after stopping drug administration for six days. 28 ICSB, University of Mississippi, May 3, 2007

Anti-angiogenesis activity 1.5 hr ~ 2hr -> 24hr human umbilical vascular endothelial cell (HUVEC) cord formation Cisplatin with a dose of 333 μ M cannot affect the formation of HUVEC Doxorubicin was reported to inhibit the anti-angiogenesis activity. 29 ICSB, University of Mississippi, May 3, 2007

Anti-angiogenesis activity (4 Hr) Anti-angiogenesis activity (24 Hr) WYC-01 2.5 µg/ml WYC-01 25 µg/ml WYC-01 2.5 µg/ml WYC-01 25 µg/ml Doxorubicin 17.7 µM Doxorubicin 177 µM Doxorubicin 17.2 µM Doxorubicin 172 µM Both, WYC-01 and Doxorubicin, show similar effects on anti-angiogenesis. 30 ICSB, University of Mississippi, May 3, 2007

Anti-Solid Lung Tumor Experiment Post-treatment model (Therapy) Procedures 1. Culture tumor cell 2. Implant tumor cell 3. Treat with drugs After induced tumor 4 days Nude mice 10 wks WYC-01 P.O route 7.5, 10, 12.5mg/kg ; qd x 30 31 ICSB, University of Mississippi, May 3, 2007

Drug resistant is a problem for cancer therapy Multi-Drug resistant solid lung tumor H23/0.3 test in nude mice model Post-treatment (therapeutic) model Pre-treatment (prevent) model 32 ICSB, University of Mississippi, May 3, 2007

Anti-Solid Lung Tumor Experiment Pre-treatment model (Prevention) Procedures Pre-treatment WYC-01 1. Treat with drugs 2. Culture tumor cell 3. Implant tumor cell 4. Treat with drugs again Nude mice 8 wks : WYC-01 P.O route 10mg/kg ; qd x 10 Nude mice 8 wks : Cisplatin I.V. route 10mg/kg ; q3d x 2 After induced tumor 5 days Nude mice 10 wks : WYC-01 P.O route 10mg/kg ; qd x 42 Nude mice 10 wks : Cisplatin I.V. route 10mg/kg ; q3d x 2 33 ICSB, University of Mississippi, May 3, 2007

Post-treatment model results 800 700 Control 7.5mg/kg 10mg/kg 12.5mg/kg 25 24 500 400 300 200 100 0 1d ay 3d ay 5d ay 9d ay 12 da y 16 da y 19 da y 22 da y 26 da y 30 da y 600 23 22 21 20 19 18 17 16 ay ay ay ay ay ay ay ay ay ay 1d 3d 5d 9 d 12 d 16 d 19 d 22 d 26 d 30 d Days after treatment 1. Tumor size is smaller than control 2. Optimization dose: 10 mg / kg Days after treatment Body weight is not obviously change 34 ICSB, University of Mississippi, May 3, 2007

Physiological observation • Activity observation - normal • During drug administration, nude mice observe hair growth in each group. 35 ICSB, University of Mississippi, May 3, 2007

Pre-treatment model results-I WYC-01 10mg/kg treatment group #3-1 10 days after stop treatment #4-3 10 days after stop treatment After stop treatment 10 days, the tumor is disappear #3-1 80 days after stop treatment #4-3 80 days after stop treatment After 80 days, the tumor is still not found in nude mice 36 ICSB, University of Mississippi, May 3, 2007

 

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