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Biologically active substances

Biologically active substances. Dietary Supplements Foods or Drugs?. Dietary Supplements. Alternative therapies and natural remedies (Wholistic Medicine Dietary supplements = 6.5 billion / Prescription Drug sales = 85 billion Increased consumer dissatisfaction with conventional health care

cade-mcfadden
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Biologically active substances

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  1. Biologically active substances

  2. Dietary SupplementsFoods or Drugs?

  3. Dietary Supplements • Alternative therapies and natural remedies • (Wholistic Medicine • Dietary supplements = 6.5 billion / Prescription Drug sales = 85 billion • Increased consumer dissatisfaction with conventional health care • ½ of US population use Dietary Supplements

  4. History of Dietary Supplements • 1938 Act established standards of identity for vitamins and minerals • Proxmire Amendments extended FDA jurisdiction to advertising of Vits and mins • Prohibited FDA from setting max limits on potency • Forbade FDA from classifying supplements as drugs

  5. History of Dietary Supplements • 1990 Nutritional Labeling and Education Act • Permitted use of therapeutic claims made about vits/mins • 1994 President Clinton signed Dietary Supplement, Health and Education Act (DSHEA) into law • Defined D/Sas “separate regulatory category of food”

  6. What is a Dietary Supplement? • Definition: • A product (other than tobacco) intended to supplement the diet that bears or contains one or more of the following dietary ingredients • Vitamins • Minerals • Herbs or other botanicals • Amino acids • Concentrate, metabolite, constituent, extract or combination of above listed ingredients

  7. Dietary Supplements • Traditionally defined as products made of one or more essential nutrients such as vitamins, minerals, and proteins, but… • DSHEA broadened definition to include almost any product intended for ingestion as a supplement to the diet • Must be identified on label as a D/S

  8. Dietary Supplements • Distinguished from Drugs: • Drug = article intended to diagnose, cure, mitigate, treat, or prevent disease • Both intended to affect structure and function of body • Drug must undergo FDA approval after clinical studies to determine effectiveness and safety • D/S = no pre-market testing

  9. Dietary Supplements • Distinguished from Foods: • Foods not intended to affect structure and function • D/S intended only to supplement diet • Not represented for use as conventional food • Not intended as sole item of a meal or the diet”

  10. Dietary Supplements • No premarket approval • Manufacturer responsible for safety evaluation • If D/S contains a new ingredient: • Manufacturer must submit information that ingredient “can reasonably be expected to be safe” within 75 days of marketing • Safe = no significant risk of illness

  11. Nutraceuticals / Functional Foods • Nutraceuticals / Designer foods / Phytochemicals / Functional Foods • “any food or food ingredient considered to provide medical or health benefits, including prevention and treatment of disease

  12. Terminology • Nutraceuticals • Nutrient rich productswith limited health claims • Functional Foods • Any modified food or ingredient that may provide a benefit beyond the traditional nutrients it contains • Phytochemicals • Such foods that are derived from naturally occurring ingredients

  13. Some Examples: • Benecol • “Plant stanol esters” • Glucosamine • New Approved Health Claims • Flavonoids (Teas) and heart disease

  14. Supplements, here, now. • Sales DS about $13 billion in 2000, growing  5% yr • Mayo Clinics 5/99: 61% pts said had used DS • FDA 1995 survey data > 55% adults • 5/00 Texas HMO survey: 40% • Use  elderly, females, white, obesity, EtOH • Most used per friend,relative, did not ask MD, Pharm • Most felt herbals “safe” and “no side effects”. • 6/99 JFP: most said “MD’s closed minded, don’t know about DS”

  15. Supplement regulation • 1906: FDA to eradicate “misbranding and adulteration” • 1938: FDA requires testing prior to marketing after health elixir kills 105– but allows traditional herbs • 1958 – 1993: GRAS list  250 trad. HS • 1962: Thalidomide. Kefauver-Harris laws require proof safety, efficacy, burden of proof on manufacturers.

  16. New law, New label • 1993: FDA proposal removal of HS from market if don’t meet rules. Congress deluged c protest, $$ ads • 1994 FDA (de) regulations: DSHEA • List ingredients, allowed nutrition claims on labels • Manufacturer responsible for safety • “This product has not been tested or approved by the FDA and makes no claim to diagnose, treat, cure or prevent any disease.” “This product has not been tested or approved by the FDA and makes no claim to diagnose, treat, cure or prevent any disease.”

  17. Hey what’s in that bottle? • Ingredient mixups harvest  bottle • Belgium: ARF: Fang-ji (Stephania tetandra) slimming herbal – consumed: Fang-chi (Aristolochia) • Contamination • 1990 L-tryptophan “E” 1000 eosinophilia, 38 deaths • Lead: “natural” Ca, 1994, 2000 -- Azarcon, Rueda • Kombucha “antioxidant, tonic” yeasts + soil bact (+ anthrax) • Adulteration • Unlisted ingredients–NSAIDs, steroids • 1995 aplastic anemia- Phenylbutazone “natural” cold Rx.

  18. More trouble • Interactions • Dong Quai, Tonka Beans– natural coumarins • Grapefruit Seed – Cyto P450 inhibitor • Overuse, “More is better” dosing (evidence in athletes) • Vit C– mega procarcinogen, calculi • Ginseng overdose syndrome– aggression, manias • Abuse • “Herbal Ecstasy” Ephedra, “Liquid ecstasy” GHB • Artemesia Absinthium (Oil of Wormwood)- thujone, neurotoxin

  19. Testing? • “Consumer Lab” testing 6/00: • Vit C (n=26): 15% failed. (<95% amt claimed) • Glucosamine/ Chondroitin (n=25): 30% failed • Gingko, Saw Palmetto, Methionine… similar. • Products “passed” see ConsumerLab website • Many calls for 3rd party review- FDA hearings, 2000 • NIH Office of Alternative Medicine– underfunded • 1997 Fed Commission on DS: “Rec scientific evidence”. • Meanwhile, we’re stuck • GRAS/ German Health Authority 1998 Comm. E publ, 300 HS

  20. URI • Echinacea (e. purpura, purple coneflower, 9 spp) • Biggest selling HS in US, as it was pre-abx. • RCT’s 1993, 94, show some  URI sx, proph. RCT’s 98, 99 Ø. • Animal Studies:  WBC,  cytokines. • No sig toxicity known. Usual dose 50 drops, or 400 mg tid. • Zinc Gluconate, “Cold Ease” • RCT x 2 1996, ‘98 conflicting. Nausea at effective doses (qid) • Licorice (Glychyrrhiza glabru)For cough. Avoid -  aldosterone • Ephedra / Ma Huang

  21. Ephedra / Ma Huang • Stimulant, weight loss, decongestant • Ephedrine: sympathomimetic, vasoconstrictive effects. • >3 billion products containing sold in US per yr • >1400 rpts to FDA 1999-2001 (HTN, CV, CVA, sz, ) • Poison Cntrl: 876 rpts 1997-99 (ASA 2000 qy) • 12/00 NEJM review 31% “probably” + 31% “possibly” caused • Interactions- MAO inhib’s: life threatening • Banned by the NFL, etc.

  22. Weight Loss • “Metabolife”, “Herbal Phen-Phen”… • Ephedra, St. John’s Wort, caffeine • Phenylpropanolamine- avoid • Use with caution per individual ingredients • “No effect” trials: Garcinia, Yohimbine, creatine, DHEA • Unknown effectiveness: Cola Acuminata, Dwarf Elder, Germander

  23. Sedatives / Hypnotics • Melatonin • Pineal hormone, normal trigger bright light • Irregular sleep cycles of blind pts improve c melatonin • Studies: Ø effect nl patients sleep latency, quality • Usually safe, if pure product. • Chamomile • Apigenin, binds benzo receptors, mice: mild sedative • Cross rxn’s ragweed allergy. • GRAS, no adverse rpts pregnancy, lactation. Tea prn.

  24. Still not sleepy? • Valerian (Valeriana Officialis root) • Effective per 2 small RDBCT. In-vitro binds GABA, like benzo’s • Some pts paradoxical effects. Not rec pregnancy. • GRAS, long hx use, no sig toxicity. 400 mg qhs. • Kava-Kava (Piper methysticum) • Some evidence better than placebo,  Oxazepam 15 mg • Very heavy use: reports of adverse sx. • Generally safe, intermittent use no known toxicity. • Mistletoe, Catnip, Gutu kola, Hops, Lavendar, Skullcap Passionflower… No evidence.

  25. • St. John’s Wort (Hypericum perforatum) • 2nd most popular HS. Effective per 1996 meta-analysis. • MAO (-) ?, SSRI. Interactions, photosensitivity • Avoid pregnancy-  ctx. Case reports thrombocytopenia. • 300 mg tid  TCA’s, amytriptilene 75mg qd • NIH currently studying vs. fluoxetine. • Gingko ( G. biloba) • Dementia, memory. Some evidence  intracerebral circulation • Gingkolides: (-) PAF, bleeding rpts. • Germany: (Egb 761), US trials: similar to tacrine, donezepil. • Gingko seed: neurotoxin. Egb 761 (leaf extract) 80 mg bid

  26. Athletics I • Creatine: Big sales, Big stars • Precursor to creatine phosphate, ADPATP • Small  wt bodybuilders (? H20). ? Weight lifters, sprinters. • Ø effect rowers, swimmers, cyclers, runners • Elderly Ø effect. Serum creatinine can . • Caffeine blocks ( - phosphocreatine resynthesis) • Probably safe : 20g qd x 1 wk, then 5g qd. (Diet  1-2 g qd) • Chromium • Øevidence efficacy. • Anemia concern: binds transferrin • > 600 g qd  RF. Not rec. but probably safe < 200 g qd

  27. Athletics II • Androstenedione, DHEA • Testosterone precursors,  oxytestosterone. Estrone may • Studies: Ø effect performance or muscle mass but  HDL ~ 5. • GHB (gammahydroxybutyrate) • “Growth hormone releaser” No evidence effective. • “GHB intoxication” syndrome: MS , coma,13% intubated • Banned FDA for OTC, but still available internet • GBL (gammabutyrolactone) available, similar toxicity • Amino acids, muscle tonics: Øevidence. Carbo load better.

  28. Anti-inflammatories • Glucosamine/ Chondroitin • Meta-analysis (flawed) studies : moderate  sx OA. • Less SE’s than NSAIDS • Some RCTs show  progression OA (unlike NSAIDs) • Feverfew (Tanacetum parthenium) • Arthritis: Ø effect in studies. Conflicting evidence for HA’s. • Parthenolide (-) arachadonic acid, serotonin. • Rebound HA, nausea common. Avoid in preganancy,  ctx. • Commercial prep’s weak, “placebos”. • Not recommended

  29. Anti-inflammatories to avoid • Chaparral / Creosote Bush/ Greasewood • (-) cyclooxygenase, lipoxygenase • Chronic use assoc hepatitis/ hepatic vein occlusions • Aconitum • Opens cardiac, neuronal Na channels • SE’s similar to cardiac glycosides, vent Dysrhthmias, neuro • Arnica • Long traditional use but not rec. due reports hepatitis, myalgias • Homeopathic preps probably safe, low concentration

  30. Antioxidants / Cancer • Selenium • Intracellular metalloid assoc with glutathione peroxidase • Selenosis in overdose amounts- similar to arsenic • No evidence effectiveness. • Vitamin A • Frequent toxicity reports • Megadose levels > 25,000 IU/kg  ICP, hepatotoxic • Chronic use > 4,000 IU/kg neuro, hepatic, derm sx • Beta-carotene: Slow absorbtion, no Vit A toxicity • Skin discoloration • Avoid in smokers

  31. Antioxidants / Cancer • Vitamin E • No evidence anticancer effectiveness. • CHD: Large trials (HOPE, GISSI) now show no benefit CAD pts. • Physician’s Study 2001, Vit E  CV death rate. • Extreme doses– anti-coagulation, but wide safety margin. • Vit C: • Studied more than any other DS but no proof definitive benefit • Procarcinogenic, nephrolithiasis in some studies hi doses • MANY-- Green Tea, Glutathione, Gingko, Grape Seed, n-acetylcysteine, Melatonin, Bilberry, curcumin, Laetrile...

  32. General Tonics • Garlic (Allium sativum) • HTN: maybe  5%, cholesterol: probably Ø • Allicin degraded by crushing, heat, acid. • GRAS, rec dose: 1 clove qd. Commercial tabs 93% Ø allicin. • Comfrey tea • “Wound healing” no evid. but may be carcinogenic, hepatotoxic • Esp. avoid pregnancy (DNA damage in vitro), lactation. • Ginseng (Panax ginseng)  “Siberian g” (E. Senticosis) • Mild stimulant, no other proven. • Ginsenosides: wide variation of content • GRAS, rare mastalgia, PMP bleed. “Ginseng abuse syndrome”

  33. GI • Hepatitis: Milk Thistle (St. Mary’s Thistle, Holy Thistle) • Sylmarin: some evid.  LFT’s, esp in EtOH cirrhosis • Europe uses IV,  mortality 50%, mushroom poisoning cases • GRAS: Long used safely as food in Mideast • Diarrhea: Goldenseal (Hydrastis canadensis) • Berberine: intraluminal antidiarrheal (E. Coli, Vibrio studies) • Drug screens: doesn’t mask. • Contraindicated: pregnancy, lactation, anti-coagulation, sz. • See also pregnancy, below

  34. CAD: Is Merlot a Vitamin? • EtOH and cardiac dz: • 490,000 pts: 1 qd  21% overall mortality, 30-40% CHD. • Evidence 2-6 drinks qw  34-53% CHD mortality, overall  28%. • But: heavier drinkers  51% overall mortality. • Other agents • Omega-3  CVA, MI in post-MI pts. (GISSI prevention trial) (850mg eicos + 750 mg decos qd) • Folate, Vit B6  homocysteine, unk. effect on CHD. • Diet works: low Na, DASH and Ornish…& exercise

  35. Female • Pennyroyal (Hedoma pulegioides) • Birth control,  ctx. Hepatoxicity, neurotoxic, deaths. Teratogen. • Pulegone – effects similar acetomin toxicity, TD 10ml. Avoid. • Blue / Black Cohosh • Midwives: cervical ripening, labor,menopause. Does seem ctx. • Possible teratogenic effects, in-vitro coronary artery constrict. • Soy / isoflavones (Many formulations, inconsistent dosing) • Ob/Gyn 2000 review: Some  menopause sx, prob safe. • Evening Primrose Oil- Some evidence breast sx relief, GRAS

  36. Pregnancy • UCSF 1999-00 150 pts, 13% used, 75% reported • Similar stats: 2000 N. Carolina midwives study • Echinacea 9%, • Not rec. By German Commmission E > 8 weeks • Recent study 5-7 d, 206 women all trimesters: no malformations • Pregnancy Tea 9% • Spearmint, raspberry, strawberry, nettle, rosehip, lemon verbena, alfalfa “uterine toner”. No data x use.

  37. Nausea/ pregnancy • Ginger (Zinziber officinale) 7% • Nausea: data mixed, but results similar to Reglan. • 70% vs. 15% placebo (n=27), other RCDBT also good results. • Contraindicated in bleeding disorders. (- Thrombox synth) • GRAS, rec. dose ¼ to 1 g powder qid. • B6 / pyridoxine 2% • Nausea/ hyperemesis: some evidence helpful • No known toxicity, 50mg po tid rec.

  38. Male • Saw Palmetto (Serenoa Repens) • BPH some evidence  sx, (flow, nocturia) • In-vitro 5- R (-), similar to finasteride, not effective as 1(-) • Few side effects (HA, GI). Usual dose 160 mg bid. • Yohimbine (Pausinystalia yohimbe bark)- • ED: central adrenergic feedback inhib– HTN, emesis • Ch’an Su (Bufo toad) • Bufalin aphrodisiac- sx similar to dig toxicity (Digibind)

  39. Elderly • “Aggressive marketing tactics” • Atrophic Gastritis • Affects 1/3 elder adults -- past h.pylori usually •  Absorbtion Fe, Folate, Ca, Vit K, Vit B-12 • Intolerance of lactose/dairy further  Ca. • Overall small intestine, pancreatic fxn stays intact • Nutritional health most affected mobility, diet, $ • RDA’s need further study for elders per recent FDA rpts

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