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What Is CAM?

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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  1. 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

  2. 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

  3. CAM’s Popularity: Growth of Visits to CAM Practitioners

  4. 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

  5. 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”

  6. CAM: The Evidence • Efficacy • Abundant anecdotes and tradition • Small studies Safety • Displacing/interfering with proven therapies • Inherent toxicity of CAM products

  7. NCCAM’s Mission • Conduct rigorous research on CAM practices • Educate and train CAM researchers • Inform consumers and health professionals

  8. 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

  9. 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

  10. NCCAM Research Support FY 2001 Clinical Basic

  11. Status of Phase III Randomized Controlled Trials

  12. Status of Phase III Randomized Controlled Trials

  13. 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

  14. 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

  15. 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

  16. NIH Multicenter Trial of SJW in Major Depression • 8-week acute efficacy phase • 18-week maintenance phase • Active drug and placebo control arms

  17. Study Outcome Primary Endpoints • Change in HAM-D score • Rate of complete response (CGI-I  2 and HAM-D  8)

  18. It’s All “Natural”…! “People can be induced to swallow anything, provided it is sufficiently seasoned with praise.” Jean Moliere

  19. St. John’s Wort Lowers Blood Levels of HIV Protease Inhibitor Indinavir HIV Inhibition threshold Piscitelli et al.

  20. Botanical/Drug Interactions

  21. Inhaled Absorbed Ingested Synthesized monooxygenases conjugation enzymes transporters Liver Intestine Chemoprotection: Defense Against Toxins • Xenobiotics = foreign chemicals • Endobiotics = chemicals produced by body

  22. 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.

  23. 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.

  24. 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.

  25. PXR Binds to CYP3A Promoter TGAACT caaagg AGGTCA <----- -----> CYP3A4 XRE CYP3A XRE - + + + - + PXR RXR Kliewer et al.

  26. 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.

  27. 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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