BIOLOGICALLY ACTIVE SUBSTANCES

DIETARY SUPPLEMENTSFOODS OR DRUGS?

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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

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

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/S as “separate regulatory category of food”

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

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

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

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”

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

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

TERMINOLOGY

Nutraceuticals

Nutrient rich products with 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

SOME EXAMPLES:

Benecol “Plant stanol esters”

Glucosamine New Approved Health Claims

Flavonoids (Teas) and heart disease

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”

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.

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.”

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.

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

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

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

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.

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

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.

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.

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

Athletics I

Creatine: Big sales, Big stars Precursor to creatine phosphate, ADPATP 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 Ø evidence efficacy. Anemia concern: binds transferrin > 600 g qd RF. Not rec. but probably safe < 200 g qd

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: Ø evidence. Carbo load better.

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

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

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

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...

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”

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

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

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

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.

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.

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)

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

Kids

Avoid all but the safest DS

Fluoride – Effective preventer tooth decay. Public Health Service Rec [.7-1.2 mg/ L]. Seattle 2001 [1mg/L] Supplementation Recs per AAP if H20 < .6 ppm. No evidence current levels carcinogen, etc.

Flouride Overdosing? Poisonings: 1992 Alaska, ‘93 Hawaii, ’98 Miss. All 200 mg/L Fluorosis: Usually small opaque areas tooth, can be brown

Avoid excess flouride/ toothpast in kids- rice sized glob enough