1
(No Transcript)
2
What Is CAM?
medical and health care practices outside the
realm of conventional medicine, which are yet to
be validated using scientific methods
Complementary together with conventional
practices Alternative in place of conventional
practices
3
CAM Domains
Manipulative and Body-Based Systems
Biologically Based Systems
Massage Chiropractic
Diets Herbals
Common CAM Practices
Yoga Prayer Meditation
Reiki Magnets Qi qong
Mind-Body Medicine
Energy Therapies
Homeopathy Naturopathy
Alternative Medical Systems
4
CAMs Popularity Growth of Visits to CAM
Practitioners
5
Conventional Medicine Push Factors

• Failure to yield cures
• Adverse effects of orthodox regimens
• Lack of practitioner time
• Dissatisfaction with the technical approach
• Fragmentation of care by specialists

6
CAM Therapies Pull Factors

• Media reports of dramatic results
• Belief that CAM treatments are natural
• Patient empowerment
• Focus on spiritual and emotional well-being
• Therapist providing touch, talk, time

7
CAM The Evidence

• Efficacy
• Abundant anecdotes and tradition
• Small studies

• Safety
• Displacing/interfering with proven therapies
• Inherent toxicity of CAM products

8
NCCAMs Mission

• Conduct rigorous research on CAM practices
• Educate and train CAM researchers
• Inform consumers and health professionals

9
Setting Prioritiesfor NIH Research

• Burden of disease
• Use by U.S. public
• Opportunity to reveal new principles
• Data from preliminary studies encouraging
• Studies are ethical, feasible
• Private investment in research is low, lacking

10
Investment Priorities

• Extramural Program
• Phase I-III studies of many CAM approaches
• Pre-clinical and translational research
• Research training

• Intramural Program
• Clinical and translational studies of CAM
  approaches to age-related stressors
• Research training

11
NCCAM Research Support FY 2001
Clinical
Basic
12
Status of Phase III Randomized Controlled Trials

St. Johns Wort for major depression In press
Shark cartilage for lung cancer In progress
Ginkgo biloba to prevent dementia In progress
Acupuncture for osteoarthritis pain In progress
13
Status of Phase III Randomized Controlled Trials

Glucosamine/chondroitin for osteoarthritis In progress
Vitamin E/selenium for prostate cancer In progress
EDTA chelation therapy for CAD Award pending
Saw palmetto/P. africanum for BPH Announced
14
CAM Domains
Manipulative and Body-Based Systems
Biologically Based Systems
Massage Chiropractic
Diets Herbals
Common CAM Practices
Yoga Prayer Meditation
Reiki Magnets Qi qong
Mind-Body Medicine
Energy Therapies
Homeopathy Naturopathy
Alternative Medical Systems
15
St. Johns Wort

• Medicinal herb
• Widely used
• 6 billion European sales (1998)
• 140 million U.S. sales (1998)
• Complex mixture of gt 2 dozen compounds
• Antidepressant constituent hyperforin
• Drug interactions
• oral contraceptives
• indinavir
• cyclosporin

16
Systematic Review of SJW Studies
Shrader Phillips
Laakmann Bjerken Witte Volz Shelton Wiedey Montgo
mery Holoman Quandt Hoffmann Hansgen Schilch Schm
idt Reh Sommer Huber Lehrl Osterhei Konig
1996-2001
1996
0 10
20
30 40 Odds
Ratio
Bars one standard deviation
17
NIH Multicenter Trial of SJW in Major Depression

• 8-week acute efficacy phase
• 18-week maintenance phase
• Active drug and placebo control arms

18
Study Outcome
Primary Endpoints

• Change in HAM-D score
• Rate of complete response
• (CGI-I ? 2 and HAM-D ? 8)

19
Its All Natural!
People can be induced to swallow anything,
provided it is sufficiently seasoned with praise.
Jean Moliere
20
(No Transcript)
21
St. Johns Wort Lowers Blood Levels of HIV
Protease Inhibitor Indinavir
HIV Inhibition threshold
Piscitelli et al.
22
Botanical/Drug Interactions
Goal Increase knowledge of botanicals and their interaction with other drugs
Current Use Est. 18 of prescription drug users also use herbals, high-dose vitamin products, or both (1998)
Designs Pre-clinical, Phase I and II trials
23
Chemoprotection Defense Against Toxins
Xenobiotics foreign chemicals
Endobiotics chemicals produced by body
24
CYP3A Induction Causes Drug Interactions

• Expressed in liver and intestine
• Bind to CYP3A promoter
• Activated by xenobiotics and endobiotics

Drug A Inducer
?
Indinavir Ethinylestradiol Atorvostatin Cyclospori
n Warfarin Tamoxifen Doxorubicin
Drug B Substrate
CYP3A
XRE
CYP3A
Rifampicin Dexamethasone Troglitazone Phenytoin Ta
xol St. Johns Wort?
HO-Drug B
excreted
Kliewer et al.
25
Nuclear Receptor Superfamily
DNA
Ligand
48 NRs in human genome
Kliewer et al.
26
Human PXR Expression Pattern
Northern blot
small intestine
pancreas
placenta
prostate
thymus
muscle
kidney
spleen
ovary
testis
colon
heart
brain
lung
PBL
liver
Kliewer et al.
27
PXR Binds to CYP3A Promoter
TGAACT caaagg AGGTCA lt----- -----gt
CYP3A4 XRE
CYP3A
XRE
- -
PXR
RXR
Kliewer et al.
28
St. Johns Wort Activates PXR
Cell-based reporter assay
8
7
6
5
Fold activation
4
3
2
1
Kliewer et al.
29
SJW Regulates Other PXR Target Genes
1? human hepatocytes

• Phase I enzymes (oxidation)
• CYP3A4
• CYP2B6
• CYP2A4
• ALDH1A4
• Phase II enzymes (conjugation)
• SULT1A1
• Transporters
• MDR1

solubilization
excretion
Kliewer et al.