… medical and health care practices outside the realm of conventional medicine, which are yet to be validated using scientific methods

What Is CAM?

Complementary: together with conventional practices

Alternative: in place of conventional practices

Complementary: together with conventional practices

Alternative: in place of conventional practices

CAM Domains

Biologically Based Systems

Manipulative and Body-Based Systems

Mind-Body Medicine

Alternative Medical Systems

Energy Therapies

Diets Herbals

Homeopathy Naturopathy

Yoga Prayer

Meditation

Massage Chiropractic

Reiki Magnets Qi qong

CommonCAM

Practices

CAM’s Popularity: Growth of Visits to CAM Practitioners

388 386 427

629

0

100

200

300

400

500

600

700

MDs CAM

1990

1997

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 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

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

Manipulative and Body-Based Systems

Mind-Body Medicine

Alternative Medical Systems

Energy Therapies

Diets Herbals

Homeopathy Naturopathy

Yoga Prayer

Meditation

Massage Chiropractic

Reiki Magnets Qi qong

CommonCAM

Practices

St. John’s WortMedicinal 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

ShraderPhillips LaakmannBjerkenWitteVolzSheltonWiedeyMontgomery

HolomanQuandtHoffmannHansgenSchilchSchmidtRehSommerHuberLehrlOsterheiKonig

1996-2001

0 10 20 30 40

Odds RatioBars = one standard deviation

1996

Systematic Review of SJW Studies

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

Change in HAM-D score

Rate of complete response

(CGI-I 2 and HAM-D 8)

Primary Endpoints

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

0

0.1

0.2

0.3

0.4

0.5

0.6

Indinavir alone Indinavir+SJW

Indi

navi

r le

vel

(ug/

ml)

HIV Inhibition threshold

Piscitelli et al.

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

Inhaled

Ingested

• Xenobiotics = foreign chemicals

• Endobiotics = chemicals produced by body

Absorbed

Synthesized

LiverIntestine

monooxygenasesconjugation enzymes

transporters

CYP3A Induction Causes Drug Interactions

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

CYP3A

Drug A“Inducer”

XRE

CYP3ACYP3A

??Drug B

“Substrate”

HO-Drug B

excreted

IndinavirEthinylestradiol

AtorvostatinCyclosporin

WarfarinTamoxifen

Doxorubicin

RifampicinDexamethasone

TroglitazonePhenytoin

TaxolSt. John’s Wort?

Kliewer et al.

Nuclear Receptor Superfamily

CARCARCOUP (COUP ())DAXDAXERR (ERR ())FXRFXRGCNF1GCNF1HNF4 (HNF4 ())LXR (LXR ())NGFI-B (NGFI-B ())PNRPNR

PPAR (PPAR ())PXRrevErb (revErb () ) RXR (RXR ())ROR (ROR ())SF1 (SF1 ())SHPSHPTlxTlxTR2 (TR2 ())

GlucocorticoidGlucocorticoidMineralocorticoidMineralocorticoidProgesteroneProgesteroneEstrogen (Estrogen ())AndrogenAndrogenThyroid Hormone (Thyroid Hormone ())Vitamin DVitamin Dall-all-transtrans Retinoic Acid ( Retinoic Acid ())

Classical ReceptorsClassical Receptors Orphan ReceptorsOrphan Receptors

CCNN DNADNADNADNA LigandLigandLigandLigand

48 NRs in human genome

Kliewer et al.

Human PXR Expression Pattern

hear

t

brai

n

plac

enta

lung

liver

mus

cle

kidn

ey

panc

reas

sple

en

thym

us

pros

tate

test

is

ovar

y

smal

l int

estin

e

colo

n

PB

L

Northern blot

Kliewer et al.

PXR Binds to CYP3A Promoter

CYP3A

PXRPXR RXRRXR

TGAACT caaagg AGGTCA<----- ----->

CYP3A4 XRE

- + ++ - +

PXR

RXR

XRE

Kliewer et al.

pseu

dohy

peric

in

amen

tofla

vone

Hyp

eric

in

kaem

pfer

ol

lute

olin

myr

ice

tin

que

rce

tin

que

rcitr

in

isoq

uerc

itrin

rutin

hype

rosi

de

hype

rfor

in

umbe

llife

ron

e

scop

olet

in

sito

ster

ol

St. John’s Wort Activates PXR

extr

act

1

extr

act

2

extr

act

3

rifam

pici

n

SR

1281

3

Fo

ld a

ctiv

atio

n

1

2

3

4

5

6

7

8O

HO O

O

..

hyperforin

Cell-basedreporter assay

Kliewer et al.

SJW Regulates Other PXR Target Genes

• Phase I enzymes (oxidation)CYP3A4CYP2B6CYP2A4ALDH1A4

• Phase II enzymes (conjugation)SULT1A1

• TransportersMDR1 excretion

solubiliza

tion

1 humanhepatocytes

Kliewer et al.