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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.

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What Is CAM?

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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

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


CAM’s Popularity: Growth of Visits to CAM Practitioners


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


Status of Phase III Randomized Controlled Trials


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


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

Holoman

Quandt

Hoffmann

Hansgen

Schilch

Schmidt

Reh

Sommer

Huber

Lehrl

Osterhei

Konig

1996-2001

1996

0 10 20 30 40

Odds Ratio

Bars = one standard deviation


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

HIV Inhibition threshold

Piscitelli et al.


Botanical/Drug Interactions


Inhaled

Absorbed

Ingested

Synthesized

monooxygenases

conjugation enzymes

transporters

Liver

Intestine

Chemoprotection: Defense Against Toxins

• Xenobiotics = foreign chemicals

• Endobiotics = chemicals produced by body


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

Cyclosporin

Warfarin

Tamoxifen

Doxorubicin

Drug B

“Substrate”

CYP3A

XRE

CYP3A

Rifampicin

Dexamethasone

Troglitazone

Phenytoin

Taxol

St. John’s Wort?

HO-Drug B

excreted

Kliewer et al.


C

N

Classical Receptors

Orphan Receptors

Glucocorticoid

Mineralocorticoid

Progesterone

Estrogen (a,b)

Androgen

Thyroid Hormone (a,b)

Vitamin D

all-trans Retinoic Acid (a,b,g)

CAR

COUP (a,b,g)

DAX

ERR (a,b,g)

FXR

GCNF1

HNF4 (a,g)

LXR (a,b)

NGFI-B (a,b,g)

PNR

PPAR (a,g,d)

PXR

revErb (a,b)

RXR (a,b,g)

ROR (a,b,g)

SF1 (a,b)

SHP

Tlx

TR2 (a,b)

Nuclear Receptor Superfamily

DNA

Ligand

48 NRs in human genome

Kliewer et al.


Human PXR Expression Pattern

Northern blot

small intestine

pancreas

placenta

prostate

thymus

muscle

spleen

kidney

ovary

colon

testis

heart

brain

lung

PBL

liver

Kliewer et al.


PXR Binds to CYP3A Promoter

TGAACT caaagg AGGTCA

<----- ----->

CYP3A4 XRE

CYP3A

XRE

- + +

+ - +

PXR

RXR

Kliewer et al.


hyperforin

rutin

luteolin

Hypericin

extract 1

extract 2

extract 3

myricetin

sitosterol

quercetin

quercitrin

SR12813

rifampicin

hyperforin

scopoletin

hyperoside

kaempferol

isoquercitrin

umbelliferone

amentoflavone

pseudohypericin

St. John’s Wort Activates PXR

Cell-based

reporter assay

8

7

6

5

Fold activation

4

3

2

1

Kliewer et al.


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.


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