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Herbal Medicine Development inTaiwan and the Research for
WYC-01 and WYC-02
Yang-Chang Wu
Graduate Institute of Natural ProductsKaohsiung Medical University
Kaohsiung, Taiwan
1ICSB, University of Mississippi, May 3, 2007
WHA No. 56.31 Resolution
• WHA No. 56.31 resolution urges membercountries to adjust, adopt and implement the“WHO traditional medicine strategy”.
• As the basis of national planning, there are fourmain 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
2ICSB, University of Mississippi, May 3, 2007
ICSB, University of Mississippi, May 3, 20073
The Global Trend of Traditional MedicineWHO 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, 20074
The Developing Dynamics and Trend ofTraditional Medicine (TM) in the World
–TM/CAM integrated into national healthcare systems where appropriate
–Safety, efficacy, and quality of TM/CAMenhanced
–Availability and affordability of TM/CAMenhanced
–Rational use of TM/CAM by providersand consumers promoted
•WHO Medicines strategy 2004-2007
ICSB, University of Mississippi, May 3, 20075
Recognition of WHO on Traditional Medicine Development(Current Traditional Medicine Conditions in Taiwan) (I)
• Statistics and data released by officialWHO organizations indicate that , so far,Taiwan, China, North Korea, Korea, andVietnam have established a completelyintegrated health care system with regardsto traditional medicine.
Recognition of WHO on Traditional Medicine Development(Current Traditional Medicine Conditions in Taiwan) (II)
• The National Medicinal Policy recognizestraditional medicine and its practitioners; itallows traditional medicinal products to becomeregister and regulated and, it also allowstraditional medicine to be practiced by hospitalsand public/private clinics.
• Traditional medicine is covered by healthinsurance and related researches andeducation will be made possible to all.
6ICSB, 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 policiesconcerning the development of traditionalmedicine
• Nearly 70 countries have stipulated lawsand regulation for the registration ofmedicinal herbal products.
7ICSB, University of Mississippi, May 3, 2007
Important Development and Achievement ofCommittee on Chinese Medicine and Pharmacy
(CCMP), Taiwan in Recent Years
8ICSB, University of Mississippi, May 3, 2007
The modernization and internalization of TCM
Provide a safe
development for TCM
environment of doctorconsultation and
medication for public
5-year plan: Establishment of anenvironment for safe use of TCM
Follow the global trendand accelerate the
The proposal to promote TCM modernization andinternationalization
Establish clinical teachingprogram for TCM
Integration of CMPmodernization and
internalization and Researchon Genome of TCM
9ICSB, University of Mississippi, May 3, 2007
ICSB, University of Mississippi, May 3, 200710
Important achievement in recent years (I)
• The Chinese medicine has been incorporatedinto the National Health Insurance.
• Complete standards and regulations of Chinesemedicine education, certification, preclinicaltraining, and accreditation are well established.
• Te overall practice of GMP in Chinese medicinehad been reached by Sep. 2005
Important achievement in recent years (II)
• The “unified formula” of Chinese medicine areannounced and implemented.
• Enhancing clinical teaching quality of Chinesemedicine
• Planning of appraisal of affiliated Chinesemedicine departments in Chinese medicinehospitals and regular hospitals
• Improving Chinese medicine personnel quality• 13 Clinical trial centers for Chinese medicine are
constructed.
11ICSB, University of Mississippi, May 3, 2007
Important achievement in recent years (III)
• Announcement of Pharmaceutical Affairsregulations
• Conducting supervision program on illegaladvertisement in print media with a total of 1379cases supervised and 222 cases in violation.
• Consigning a total of 73 research programs onChinese medicine and subsidizing 2 academicinterchange programs across the Strait in 2006
12ICSB, University of Mississippi, May 3, 2007
Important achievement in recent years (IV)
• Conducting Program of Chinese MedicineHealth Security Protection Network Technology
• Aggressively promoting academic Chinesemedicine and held 4 international symposiums
• Putting Chinese medicine evidence medicineresearch into practice.
13ICSB, University of Mississippi, May 3, 2007
Taiwan’s National Health Insurance (NHI)cover around 99% of population
1.33%
InsuredUninsured
98.67%
As of Dec. 2003, 22 million Taiwan people are covered in the NHI
14ICSB, University of Mississippi, May 3, 2007
The Chinese medicine doctor education system
• There are two Chinese Medical education systems – 8 year systemsand post Bachelor program (5 years)
College SchoolTotal
study year
7
8
RegistrationAnnual
enrollment
120
120
Accumulative no. ofStudents
1,804
219
No. ofgraduates
2,358
108
ChineseMedicine
ChinaMedical
University
ChangGung
university
ChinaMedical
University
1966-1995
1996~
ChineseMedicine
PostBachelorChineseMedicine
8 1998~ 50 0 0
8 1984 100 1.250 998
15ICSB, University of Mississippi, May 3, 2007
Promoting GMP in ConventionalTraditional Medicine Manufacturers
• The committee on Chinese Medicine andPharmacy has spared no efforts in the pastyears to promote the practice of GMP inconventional pharmaceutical manufacturers. It isconsidered imperative that these factoriespractice the GMP; and the overall practice ofGMP by manufacturers had been reach by 2005.
• 103 have passed the review of the GMP for thetime being.
• 5,000 licenses; 200 standard formula
16ICSB, University of Mississippi, May 3, 2007
Improve the quality and safety ofTraditional Medicine
• A total of 203 items ofTraditional Medicinalmaterials were compiled in a“TM Pharmacopoeia” andpublished on 2004.Theyprovide bases for the testingmethods and specificationsof raw materials.
17ICSB, University of Mississippi, May 3, 2007
Establishment of Traditional medicine clinicaltrials and legislative environment in Taiwan
• The clinical trials should keep the characteristicsof traditional medicine.
• The department of Health announced its Adviceon Herbal Medicine NDA Application on 1998
• The Application Guidelines on Herbal MedicinalClinical Trials (IND) and guidelines on HerbalMedicine NDA Applications (NDA) are to beresearched and drawn up.
18ICSB, University of Mississippi, May 3, 2007
New traditional Medicine Clinical TrialApplication case (2001-2004)
• 22 cases (partial ones are center test)
• 11 cases have been passed theexamination and verification for clinicaltrail.
• 6 cases under submitting anotherapplication and examination
• 2 cases have been withdrawn
• The first NDA approval in 2005
19ICSB, University of Mississippi, May 3, 2007
Kaohsiung Medical UniversityKaohsiung, Taiwan
20ICSB, 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
21ICSB, University of Mississippi, May 3, 2007
Pharmacology and BioactivityAnti-cancer, anti-platelet agents
screening and mechanisms research
22ICSB, University of Mississippi, May 3, 2007
The Characteristics of
WYC01
23ICSB, University of Mississippi, May 3, 2007
The structural features ofAnnonaceous acetogenins
some oxygen-bearing moieties, such aszero 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 plantscontaining 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.
24ICSB, University of Mississippi, May 3, 2007
Biological activity against human cancer cellsThe IC50 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(μg/ml)
36.4
Doxorubicin (μM)
1.49
Taxol (μM)
11.7
25ICSB, University of Mississippi, May 3, 2007
Toxicity test
The hepatic, renal functions, and hematological values ofthe tested mice by oral administration of WYC-01 for 14 and 28 days
20.019.0
18.017.016.015.0
14.013.012.0
11.010.09.0
8.00.80.60.40.20.0
0 1 2
250GOT
200
BUN
150
25.024.023.022.021.020.019.018.017.016.015.014.013.012.011.010.09.08.00.80.60.40.20.0
0 1
350GOT
BUN300
250
200
150
GPT100
Creatinine 50
00 1 2 3 4
100
GPT
Creatinine50
00 1 2 3 43 4 2 3 4
300
250
200
150
100HCT MCV
50
201612840
0
WBC RBCHGB
MCHMCHC
TestParametersPLT
858075706560555045403530252015543210
0
Neturo-Seg
TestParameters
550
500
450
400
350
300
250
200Lymphocytes 150
100
50201612840
0 1 2 3 4 5 6 7 8 9
TestParameters
TestParameters
Monocytes
90858075706560555045403530252015543210
0 1
TestParameters
1 2 3 4 5 6 7 8 9 10 1 2
TestParameters
3 410 2
TestParameters
3 4
TestParameters
14 days Normal
Vesicle formulation
AS 25mg/kg
AS 20mg/kg
AS 15mg/kg
28 daysNormal
Vesicle formulation
AS 25mg/kg
AS 20mg/kgAS 15mg/kg
1. The values of WYC01 are stable as that of control.2. WYC01 is quite low toxicity to test mice.
26ICSB, 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
27ICSB, 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, butthese phenomena disappeared after stopping drug administration for six days.
28ICSB, University of Mississippi, May 3, 2007
Anti-angiogenesis activity
1.5 hr ~ 2hr → 24hrhuman umbilical vascular endothelial cell (HUVEC) cord formation
Cisplatin with a dose of 333μM cannot affect the formation of HUVECDoxorubicin was reported to inhibit the anti-angiogenesis activity.
29ICSB, University of Mississippi, May 3, 2007
Anti-angiogenesisactivity (4 Hr)
Anti-angiogenesisactivity (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 µMDoxorubicin 177 µMDoxorubicin 17.2 µM Doxorubicin 172 µM
Both, WYC-01 and Doxorubicin, show similar effects on anti-angiogenesis.
30ICSB, University of Mississippi, May 3, 2007
Anti-Solid Lung Tumor Experiment
Post-treatment model (Therapy)
Procedures1. Culture tumor cell2. Implant tumor cell3. Treat with drugs
After induced tumor 4 days
Nude mice 10 wksWYC-01 P.O route
7.5, 10, 12.5mg/kg ; qd x 30
31ICSB, University of Mississippi, May 3, 2007
Drug resistantis a problemfor cancer
therapyMulti-Drug resistant solid lung tumor
H23/0.3 test in nude mice model
Post-treatment (therapeutic) model
Pre-treatment (prevent) model
32ICSB, University of Mississippi, May 3, 2007
Anti-Solid Lung Tumor ExperimentPre-treatment model (Prevention)
Procedures
Pre-treatment WYC-01
1. Treat with drugs2. Culture tumor cell3. Implant tumor cell4. Treat with drugs again
Nude mice 8 wks :WYC-01 P.O route10mg/kg ; qd x 10
Nude mice 8 wks :Cisplatin I.V. route10mg/kg ; q3d x 2
After induced tumor 5 days
Nude mice 10 wks :WYC-01 P.O route10mg/kg ; qd x 42
Nude mice 10 wks :Cisplatin I.V. route10mg/kg ; q3d x 2
33ICSB, University of Mississippi, May 3, 2007
Post-treatment model results
800
700Control
7.5mg/kg
10mg/kg
12.5mg/kg
25
24
500
400
300
200
100
0
1day
3day
5day
9day
12da
y
16da
y
19da
y
22da
y
26da
y
30da
y
600 23
22
21
20
19
18
17
16ay ayay ay ayay 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
34ICSB, University of Mississippi, May 3, 2007
Physiological observation
• Activity observation - normal
• During drug administration, nude miceobserve hair growth in each group.
35ICSB, University of Mississippi, May 3, 2007
Pre-treatment model results-IWYC-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 mice36
ICSB, University of Mississippi, May 3, 2007