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K R I S T O P H E R H U N T , M D

S T. V I N C E N T E M E R G E N C Y P H Y S I C I A N S

AT H L E T E , C H U R C H O F I R O N

There is No Substitute for Hard Work:The Unregulated Supplement Industry

K R I S T O P H E R H U N T , M D

S T. V I N C E N T E M E R G E N C Y P H Y S I C I A N S

AT H L E T E , C H U R C H O F I R O N

Supplements: Not Good

Outline

Words on the supplement industry

Supplements vs. FOOD

The “Natural” myth, and the mask it provides for steroids

The ephedra fiasco

Data regarding study on Creatine Monohydrate v. Creatine Ethyl Ester

Supplements

In 1994, the Dietary Supplement Health and Education Act of 1994 (DSHEA) defined a supplement as: A product intended to supplement the diet, containing:

Vitamins

Minerals

Herbs or other botanicals

Amino Acids

A concentrate, metabolite, etc. of any of the above

It also must be: Ingested in pill, capsule, tablet, powder, or liquid form

Not represented as food or as the sole item for diet

Labeled as a “supplement”

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How something becomes a medicine

Summary of Differences to get Approval

Medicine Pre-Clinical

Clinical

NDA

Post-Marketing

Supplement …Just label it as a

supplement, and say this:

THESE STATEMENTS HAVE NOT BEEN EVALUATED BY THE FOOD AND DRUG ADMINISTRATION. THIS PRODUCT IS NOT INTENDED TO DIAGNOSE, TREAT, CURE, OR PREVENT ANY DISEASE.

Sen. Orrin Hatch

Major lobbyist in D.C to launch the supplement industry

Has taken the supplement industry to become the most profitable venture in his home state

The DSHEA[1]

This was the effort of lobbyists to end restrictions by the FDA to exert authority over supplements The justification: manufacturers had to make no claims about

treating, preventing, or curing disease

The supp. manufacturer is left with proving the product is safe, with minimal regulation, and they are NOT required to prove efficacy in any way

The FDA monitors safety using a supplement “adverse event reporting system”, which captures only 1 to 10 percent of all adverse events[2]

1. "US Dietary Supplement Health and Education Act of 1994". Fda.gov. 2008-10-15. http://www.fda.gov/opacom/laws/dshea.html. Retrieved 2013-1-28.

2. Heinrich, J. (2000), Adverse drug events substantial problem but magnitude uncertain: Testimony before the committee on Health, Education, Labor, and Pensions, U.S. Senate

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Supplements Vs. FOOD

Supplements are not a food substitute.

They cannot replicate all of the nutrients and benefits of whole foods.

Whole foods offer greater nutrition

Vit C. Supplement

An orange provides vitamin C plus beta carotine, calcium, and fiber

Essential fiber

Whole foods such as grains, fruits, vegetables and beans provide this as well as essential nutrients

Has a beneficial glycemic index

Provide protective substances

Fruits, vegetables have phytochemicals, which protect against several diseases

Have antioxidants, which protect against cell and tissue damage

Meat Source V. Supplement Protein

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The “Natural” Myth

What does natural mean?

There is no universal definition for this wastebasket term

Consumers think natural = pure and unprocessed

Most are anything but Heavy metals

Pesticides

Bacteria

Prescription drugs

Mother nature packs a punch, too (poison ivy, hemlock)

"Nutritional Supplements: Your Questions Answered". Consumer Reports. 2006-06-14. http://www.consumerreports.org/mg/free-highlights/manage-your-health/supplements_questions.htm. Retrieved 2013-01-31.

Theobromine

“Natural” component of chocolate

Similar to caffeine, less CNS stimulation, more heart stimulation

Used as a supplement because theoretically causes stimulation more directly to muscle tissue as well

Kills dogs

Human toxicity Case from NYC poison control center

THEOBROMINE from the Hazardous Substances Data Bank, http://toxnet.nlm.nih.gov/cgi-bin/sis/search/r?dbs+hsdb:@term+@DOCNO+7332, accessed 2013-1-31

Hidden Steroids?

The hormones DHEA (a steroid) and pregnenolone (also a steroid) are marketed as supplements in the U.S. considered legal and AVAILABLE OTC

Barriers to ban are that these substances: Have a history of use as a food or food ingredient

A constituent of a “dietary substance”, such as an animal organ

A constituent of a plant or other botanical

A metabolite of a substance that is a dietary ingredient

“Body Building Products and Hidden Steroids: Enforcement Barriers”. Fda.gov. 2009-9-30. http://www.fda.gov/NewsEvents/Testimony/ucm184497.htm retrieved 2013-1-31

Hidden Steroids?

Products use code among the body building/strength community “anabolic”

“tren”

“blocks estrogen”

“minimizes gyno”

FDA retroactively found 8 products from American Cellular Labs to contain steroids

Travis Tygart, chief of US Anti-Doping Agency Estimates that 50 or more brands on the market that contain

steroids

“Supplements for Athletes Draw Alert from FDA.” 2009-7-28. http://www.nytimes.com/2009/07/29/health/nutrition/29drug.html?_r=0 Retreived 2013-1-31.

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Ephedra

“Natural” chemical occurring in the plant Ephedra sinica. “Natural” treatment in Chinese

medicine for asthma, hay fever, and the common cold

Has stimulant effects and thermogenic effects Contains ephedrine and pseudoephedrine

Increases heart rate, constricts blood vessels, and dilates bronchi

Is used as a precursor in the illicit manufacture of methamphetamine

Abourashed E, El-Alfy A, Khan I, Walker L (2003). "Ephedra in perspective--a current review". Phytother Res 17 (7): 703–12. doi:10.1002/ptr.1337. PMID 12916063

Ephedra

Mounting evidence became clear that SCD was occurring in young, healthy adults in labeled dosages Minnesota Vikings

lineman Korey Stringer, 2001

Baltimore Orioles pitcher Steve Bechler, 2003

Haller C, Benowitz N (2000). "Adverse cardiovascular and central nervous system events associated with dietary supplements containing ephedra alkaloids". N Engl J Med 343 (25): 1833–8. doi:10.1056/NEJM200012213432502. PMID 11117974

Ephedra Side effects

U.S. Dept. of Health and Human Svcs. conducted a meta-analysis of ephedra’s safety and efficacy

Found it promoted modest, short term weight loss No evidence that it was effective for long-term weight loss or

performance enhancement

Also, ephedra found to be 100-700 times more likely to cause significant adverse reactions than kava or Ginkgo biloba

1. Bent S, Tiedt T, Odden M, Shlipak M (2003). "The relative safety of ephedra compared with other herbal products". Ann Intern Med 138 (6): 468–71. PMID 126390792. Shekelle P, Hardy M, Morton S, Maglione M, Mojica W, Suttorp M, Rhodes S, Jungvig L, Gagné J (2003). "Efficacy and safety of ephedra and ephedrine for weight loss and athletic performance: a meta-analysis". JAMA 289 (12): 1537–45. doi:10.1001/jama.289.12.1537. PMID 12672771

The Legal Battle

On 4/12/2004, after proposing initial ban in 1997, ban was placed by FDA

Nutraceutical Corporation (based in, you guessed it, Utah) challenged the legality of the FDA’s ban Perceived as exceeding the DHSEA

Utah Fed. Dist. Judge ruled that the ban on the sale of ephedra should be lifted (2005)

Went to U.S. Court of Appeals, and in 2006 FDA’s ban was withheld FDA comprised a 133,000 page record on risk of ephedra

STILL appealed to supreme court, denied 20071. "Food and Drug Administration summary of actions regarding sale of ephedra supplements". http://www.fda.gov/oc/initiatives/ephedra/february2004/. Retrieved 2007-02-13.2. "FDA Statement on 10th Circuit Court's ruling to uphold ban of ephedra". U.S. Food and Drug Administration. http://www.fda.gov/bbs/topics/NEWS/2006/NEW01434.html.3. "Judge's Decision Lifts Ban On Sale of Ephedra in Utah", from the New York Times, published April 15, 2005. Accessed 7 February 2007.

What is in my daily intake?

Food

Hard work

Protein

Caffiene

Creatine Monohydrate

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Creatine

Non-essential AA formed by liver arginine and glycine

Average adult male has 120 gm of creatine phosphate in body

Also ingested from meat sources, esp. in beef Approx 1-2 grams obtained from normal diet

Acts as E buffer ADP -> ATP after first 2 sec. of excercise1

Serves as temporal E bridge

1. Lattavo A, Kopperud A, Rogers PD. Creatine and other supplements. Pediatr Clin N Am. 2007 Aug; 54(4):735-60, xi.

Re-summary of Creatine mechanism

Energy (ATP) obtained from 4 sources: Endogenous ATP

Creatine

Anaerobic gylcolysis

Aerobic glycolysis

Creatine serves to bridge energy stores in an oxygen depleted exercise environment

Supplementation increases skeletal muscle stores of creatine by ~20%

Steroid?

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Who cares?

Strength athletes!

Enhancements in:2, 3, 4

lean-body mass

total Cr content in skeletal muscle

power development during exercise

rate of force-development

total work performed

muscle fiber

diameter2. Bird SP. Creatine Supplementation and Exercise Performance: A Brief Review. J Sports Sci Med 2003; 2: 123-1323. Buford TW, Krider RB, Stout JR, Greenwood M, Campbell B, Spano M, Ziegenfuss T, Lopez H, Landis J, Antonio J. International Society of Sports Nutrition position stand: creatine supplementation and exercise. J Int Soc Sports Nutr 2007; 4(6)4. Terjung RL, Clarkson P, Eichner R, Greenhaff PL, Hespel PJ, Israel RJ, Kraemer WJ, Meyer RA, Spiet LL, Tarnopolsky MA, Wagenmakers AJM, Williams MH. The physiological and health effects of oral creatine supplementation. Med Sci Sports Exerc 2000; 32: 706-717

Some stats on creatine…

From 1996 – 2001 sales went from $50m -> $400m

Reports between 25-78% among collegiate athletes5, 6, 7

Not doping among athletic governing bodies, including WADA8

5. Bamberger M. The Magic Potion. Sports Illustrated 1998; 88: 58-616. Calfee R, Fadale P. Popular Ergogenic Drugs and Supplements in Young Athletes. Pediatrics 2006; 117: 577-5897. Metz JD, Small E, Levine SR, Gershel JC. Creatine Use Among Young Athletes. Pediatrics 2001; 108: 421-4258. Williams MH, Branch JD. Creatine supplementation and exercise performance: an update. J Am Coll Nutr 1998; 17:216—34.

Creatine Monohydrate

Classic formulation creatine monohydrate

Monohydrate form poor cell membrane permeability9, 10,

11, 12

Can cause weight gain D/t glc and H2O cotransport

Insulin-mediated mechanism11

9. Dash AK, Miller DW, Huai-Yan H, Carnazzo J, Stout JR. Evaluation of creatine transport using Caco-2 monolayers as an in vitro

model for intenstinal absorption. J Pharm Sci 2001; 90: 1593-1598

10. Dash AK, Sawhney A. A simple LC method with UV detection for the analysis of creatine and creatinine and its application to several

creatine formulations. J Pharm Biomed Anal 2002; 29: 939-945

11. Green AL, Hultman E, MacDonald IA, et al. Carbohydrate feeding augments skeletal muscle creatine accumulation during creatine supplementation

in humans. Am J Physiol 1996;271:821—6.

12. Lattavo A, Kopperud A, Rogers PD. Creatine and other supplements. Pediatr Clin N Am. 2007 Aug; 54(4):735-60, xi.

13. Persky AM, Brazeau GA. Clinical Pharmacology of the Dietary Supplement Creatine Monohydrate. Pharmacol Rev 2001; 53: 161-176

Creatine Ester

2003, patent filed for “creatine ester pronutrients” alternative to monohydrate “ester group makes the molecule more lipophilic”16

Theoretically avoids excessive weight gain16

Ester form does not get past stomach? Stability of ester in HCL at 60 min of 62-73% and 120 min. of 11-72% monohydrate stability of 99% at 120 min.14

Even if it does, it probably gets broken down right away: When incubated in human plasma for 4 hours, only creatinine when creatine ester

added Large peak in NMR spectrum for creatine when monohydrate added15

14. Child R and Tallon MJ. Creatine ethyl ester rapidly degrades to creatinine in stomach acid. 4th Annual International Society of Sports Nutrition Conference (Las Vegas, USA).

15. Giese M and Lecher C. Qualitative in-vitro NMR analysis of creatine ethyl ester pronutrients in human plasma. In Print.16. Vennerstrom JL, Miller DW. Creatine Ester Pronutrient Compounds and Formulations. US 2003/0212136.

Methods

Two arm, double blind

25 total subjects

Ingestion of 10 mg CEE vs. 10 mg CrM

Subjects serve as own controls

Obtained hourly serum Crn X 5 hours

Also urine samples X 4 over that time

Obtained both 24 hour f/u urine and blood samples

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Discussion

CrM use in this group resulted in elevation of Crn dramatic enough to mimic AKI

CEE use elevated Crn enough to minic ARF

Interpretation of serum Crn in these patients may risk misinterpretation of AKI/ARF

Discussion

Urine Crn in this group demonstrated a significant increase after ingestion of CEE

Urine Crn in this group actually diminished after ingestion of CrM

This supports previous claim that users of CEE may break down and excrete it before it is active as an ergogenic substance

Conclusions

Be skeptical, be very skeptical Don’t throw the baby out with the bath water

Some supplements do work, including CrM, HMB, glutamine

FOOD is better than any supplement

“Natural”

There is no way for the FDA to prospectively govern supplements, only retroactively

Remember the CEE vs. CrM example

Documentary for ALL athletes

http://www.youtube.com/watch?v=ThdFqGLq4QU

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Questions?