Transcript Biologically Based Systems

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
CAM Domains
Biologically
Based Systems
Diets
Herbals
Energy
Therapies
Reiki
Magnets
Qi qong
Massage
Chiropractic
Common
CAM
Practices
Manipulative and
Body-Based
Systems
Yoga
Prayer
Meditation
Homeopathy
Naturopathy
Alternative Medical Systems
Mind-Body
Medicine
CAM’s Popularity: Growth of
Visits to CAM Practitioners
700
629
600
500
386
388
427
400
1990
1997
300
200
100
0
MDs
CAM
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
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”
CAM: The Evidence
Efficacy
Abundant anecdotes and tradition
Small studies
Safety
Displacing/interfering with proven therapies
Inherent toxicity of CAM products
NCCAM’s Mission
Conduct rigorous research on CAM practices
 Educate and train CAM researchers
 Inform consumers and health professionals
Setting Priorities
for 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
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
NCCAM Research Support
FY 2001
Clinical
Basic
Status of Phase III
Randomized Controlled Trials
St. John’s 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
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
CAM Domains
Biologically
Based Systems
Diets
Herbals
Energy
Therapies
Reiki
Magnets
Qi qong
Massage
Chiropractic
Common
CAM
Practices
Manipulative and
Body-Based
Systems
Yoga
Prayer
Meditation
Homeopathy
Naturopathy
Alternative Medical Systems
Mind-Body
Medicine
St. John’s Wort
 Medicinal herb
 Widely used
$6 billion European sales (1998)
$140 million U.S. sales (1998)
 Complex mixture of > 2 dozen compounds
 Antidepressant constituent = hyperforin
 Drug interactions
oral contraceptives
indinavir
cyclosporin
Systematic Review of SJW Studies
Shrader
Phillips
Laakmann
Bjerken
Witte
Volz
Shelton
Wiedey
Montgomery
1996-2001
Holoman
Quandt
Hoffmann
Hansgen
Schilch
Schmidt
Reh
Sommer
Huber
Lehrl
Osterhei
Konig
1996
0
Bars = one standard
deviation
10
20
Odds Ratio
30
40
NIH Multicenter Trial of SJW
in Major Depression
 8-week acute efficacy
phase
 18-week maintenance
phase
 Active drug and placebo
control arms
Study Outcome
Primary Endpoints
 Change in HAM-D
score
 Rate of complete
response
(CGI-I  2 and HAM-D  8)
It’s All “Natural”…!
“People can be
induced to swallow
anything, provided
it is sufficiently
seasoned with
praise.”
Jean Moliere
St. John’s Wort Lowers Blood
Levels of HIV Protease
Inhibitor Indinavir
Indinavir level (ug/ml)
0.6
0.5
0.4
0.3
0.2
HIV Inhibition threshold
0.1
0
Indinavir alone
Piscitelli et al.
Indinavir+SJW
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
Chemoprotection:
Defense Against Toxins
• Xenobiotics = foreign chemicals
• Endobiotics = chemicals produced by body
Inhaled
Absorbed
Ingested
Synthesized
monooxygenases
conjugation enzymes
transporters
Liver
Intestine
CYP3A Induction Causes
Drug Interactions
• Expressed in liver and intestine
• Bind to CYP3A promoter
• Activated by xenobiotics and endobiotics
Drug A
“Inducer”
?
XRE
Rifampicin
Dexamethasone
Troglitazone
Phenytoin
Taxol
St. John’s Wort?
Kliewer et al.
Drug B
“Substrate”
CYP3A
CYP3A
HO-Drug B
excreted
Indinavir
Ethinylestradiol
Atorvostatin
Cyclosporin
Warfarin
Tamoxifen
Doxorubicin
Nuclear Receptor Superfamily
N
DNA
Ligand
C
48 NRs in human genome
Classical Receptors
Glucocorticoid
Mineralocorticoid
Progesterone
Estrogen (a,b)
Androgen
Thyroid Hormone (a,b)
Vitamin D
all-trans Retinoic Acid (a,b,g)
Kliewer et al.
Orphan Receptors
CAR
PPAR (a,g,d)
COUP (a,b,g)
PXR
DAX
revErb (a,b)
ERR (a,b,g)
RXR (a,b,g)
FXR
ROR (a,b,g)
GCNF1
SF1 (a,b)
HNF4 (a,g)
SHP
LXR (a,b)
Tlx
NGFI-B (a,b,g)
TR2 (a,b)
PNR
Northern blot
Kliewer et al.
heart
brain
placenta
lung
liver
muscle
kidney
pancreas
spleen
thymus
prostate
testis
ovary
small intestine
colon
Human PXR
Expression Pattern
PXR Binds to CYP3A Promoter
TGAACT caaagg AGGTCA
<--------->
CYP3A4 XRE
PXR RXR
XRE
CYP3A
PXR
RXR
Kliewer et al.
- + +
+ - +
1
Kliewer et al.
5
..
sitosterol
HO
scopoletin
Cell-based
reporter assay
umbelliferone
hyperforin
hyperoside
rutin
amentoflavone
isoquercitrin
quercitrin
quercetin
myricetin
luteolin
kaempferol
pseudohypericin
Hypericin
extract 3
extract 2
extract 1
SR12813
rifampicin
Fold activation
St. John’s Wort Activates PXR
O
O
8
7
O
6
hyperforin
4
3
2
SJW Regulates Other PXR
Target Genes
1 human
hepatocytes
• Phase II enzymes (conjugation)
SULT1A1
• Transporters
MDR1
Kliewer et al.
solubilization
• Phase I enzymes (oxidation)
CYP3A4
CYP2B6
CYP2A4
ALDH1A4
excretion