Herbal toxins grand rounds feb 2014

Nobody but Almighty God and I can know what I have been through these past few days. I have been familiar with death in the years since I received my M.D. from Tulane University School of Medicine with the rest of my class of 1911.

Covington County has been my home. I have practiced here for years. Any doctor who has practiced more than a quarter of a century has seen his share of death.

But to realize that six human beings, all of them my patients, one of them my best friend, are dead because they took medicine that I prescribed for them innocently, and to realize that that medicine which I had used for years in such cases suddenly had become a deadly poison in its newest and most modern form, as recommended by a great and reputable pharmaceutical firm in Tennessee: well, that realization has given me such days and nights of mental and spiritual agony as I did not believe a human being could undergo and survive. I have known hours when death for me would be a welcome relief from this agony.

Letter by Dr. A.S. Calhoun, October 22, 1937

But to realize that six human beings, all of them my patients, one of them my best friend, are dead because they took medicine that I prescribed for them innocently, and to realize that that medicine which I had used for years in such cases suddenly had become a deadly poison in its newest and most modern form, as recommended by a great and reputable pharmaceutical firm in Tennessee:

well, that realization has given me such days and nights of mental and spiritual agony as I did not believe a human being could undergo and survive. I have known hours when death for me would be a welcome relief from this agony.

Sulfanilamide, used to treat streptococcal infections

1937Salesmen for the S.E. Massengill Co. report demand for a liquid formulation

Chief chemist and pharmacist, Harold Cole Watkins discovered he could dissolve sulfonamide in diethylene glycol.


Watkins tested the solution for flavor, appearance, and fragrance and found it satisfactory


Watkins tested the solution for flavor, appearance, and fragrance and found it satisfactory

by September 1937, Massengill had distributed 268 gallons of the liquid, called Elixir Sulfanilamide, across the country

June

1937

Sales person reports demand

June July Aug Sept

1937

Sales person reports demand 268 gallons shipped nationally

June July Aug Sept Oct

1937


American Medical Association received reports from Tulsa, OK, that an unfamiliar sulfanilamide compound was responsible for 6 deaths

Oct 11


1937



NY physician alerts the FDAAn inspector in the Kansas City Station confirms 9 deaths Oct 14

Oct 11


1937



NY physician alerts the FDAAn inspector in the Kansas City Station confirms 9 deaths Oct 14

Oct 17AMA, FDA Inspectors and the chemists at Messingil all concur, the elixir contains diethylene glycol.

Oct 11

diethylene glycol is two ethylene glycol molecule bound by an ether bond

HO CH2 O CH2 OHCH2 CH2

In order to recover all of the medicine, the entire field force of the FDA, 239 inspectors and chemists were told to stop their current projects and focus on sulfonilamide

One physician postponed his wedding to help an FDA chemist search for a 3-year-old boy whose family had moved into mountain country after obtaining a prescription.

Another inspector was investigating a pharmacy and was told that only 6 ounces had been dispensed. That patient had suffered no ill effects. But when the inspector examined shipping receipts, he found 12 ounces had been dispensed. After some questioning and poking through the local gossip he learned that two others had bought the elixir. Both died.

The first time I ever had occa-sion to call in a doctor for Joan and she was given Elixir of Sulf-anilamide. All that is left to us is the caring for her little grave.

letter to FDR

The first time I ever had occa-sion to call in a doctor for Joan and she was given Elixir of Sulf-anilamide. All that is left to us is the caring for her little grave.Even the memory of her is mixed with sorrow for we can see her little body tossing to and fro and hear that little voice screaming with pain and it seems as though it would drive me insane.

letter to FDR

The first time I ever had occa-sion to call in a doctor for Joan and she was given Elixir of Sulf-anilamide. All that is left to us is the caring for her little grave.Even the memory of her is mixed with sorrow for we can see her little body tossing to and fro and hear that little voice screaming with pain and it seems as though it would drive me insane.It is my plea that you will take steps to prevent such sales of drugs that will take little lives and leave such suffering behind and such a bleak outlook on the future as I have tonight. letter to FDR

In 1937 the law did not prohibit the sale of dangerous, untested, or poisonous drugs.


25 seizures were made under federal law. The charge was misbranding. "Elixir," FDA said, implied the product was an alcoholic solution.


25 seizures were made under federal law. The charge was misbranding. "Elixir," FDA said, implied the product was an alcoholic solution.

If the product had been called a "solution" no charge of violating the law could have been made. FDA would have had no legal authority to seize the drug

Final score

Final score267 gallons confiscated268 gallons shipped

Final score267 gallons confiscated

1 gallon consumed

268 gallons shipped

Final score267 gallons confiscated

1 gallon consumed

105 dead, including 34 children

268 gallons shipped

June July Aug Sept

1937


Oct

National Tragedy

June July Aug Sept

1937


1938

Oct Nov Dec

Jan Feb Mar Apr May

National Tragedy

June July Aug Sept

1937


June

1938

Passed the house June 1Passed the Senate June 2

Signed into law June 25

Food, Drug, and Cosmetic ActThe law required manufacturers to submit evidence of a drug's safety before it could go on the market.

Oct Nov Dec

Jan Feb Mar Apr May

National Tragedy

Drugs have to be safe (1938) to be approved for sale in the United States

Frances O. Kelsey receiving the President's Award for Distinguished Federal Civilian Service

The Drug Amendment of 1962 was approved unanimously after Dr. Kelsey, an FDA officer, refused approval of Thalidomide.


The Drug Amendment of 1962 was approved unanimously after Dr. Kelsey, an FDA officer, refused approval of Thalidomide.

The amendment added a requirement for effectiveness for drug approval.


Drugs have to be safe (1938) and effective (1962) to be approved for sale in the United States

October 1994

Dietary Supplement Health and Education Act (DSHEA)

October 1994


FoodDrug

October 1994


FoodDrug Supplement

October 1994


Food

DrugSupplement

• Before 1994, herbal products were considered food additives

• Manufacturers required to show proof of safety before sales

before DSHEA

• Dietary supplements are presumed to be safe

• No FDA approval for marketing claim

• No FDA requirement for purity or manufacturing standards

• No FDA review of claims of efficacy

under DSHEA


Supplements do not have to be safe or effective to be approved for sale in the United States (1994)



This deregulation has worked just like Milton Friedman and Ralph Nader suspected



This deregulation has worked just like Milton Friedman and Ralph Nader suspected

$0

$7,500

$15,000

$22,500

$30,000

1994 2010

26000

700

Sals

es (

mill

ions

)

NIH$30,860,913,000

NIH$30,860,913,000

National Center of Complementary and Alternative

Medicine (NCCAM)

$128,057,000

NIH$30,860,913,000


Medicine (NCCAM)

$128,057,000

NCI$5,072,183,000

NIH$30,860,913,000


Medicine (NCCAM)

$128,057,000

Office of Cancer Complementary and Alternative

Medicine (OCCAM)

$105,341,737

NCI$5,072,183,000

• Who? What? Why?

• interaction and accumulation

• FDA inability to restrict unsafe drugs

• Adulteration

• Contamination

• Untoward side-effects

herbal dangers

2 out of 5 adults

1 out of 9 children

43%

57%

Caucasians

Use Don’t Use

supplement use

64%

36%

African Americans

69%

31%

Hispanics

Grubbs V, Plantinga LC, et al. AJKD 2013; 61(5):739-47.

65%

36%

less than high school

Use Don’t Use

supplement use

54%46%

high school

40%

60%

college


50%50%

Poverty Index ratio <1

Use Don’t Use

supplement use

35%

65%

Poverty Index ratio 1-3

31%

69%

Poverty Index ratio >3


• people that use supplements are not casual users

• they are committed, overwhelmingly they take them everyday

<7 7-20 21+

70%

18%10%


• people that use supplements are not casual users

• they are committed, they take them for years

< 6 m

onth

s

6-12

mon

ths

1-3 y

ears

>3 ye

ars

30%20%22%27%


No CKD CKD 1, 2 CKD 3, 4

65.1%50.2%48.9%

• supplement use in CKD

• the worse the CKD the more supplements

• same phenomenon in cancer


63%

37%

No FDA approval

Clueless Clued

physician knowledge

65%

35%

No requirement for efficacy

60%

40%

No FDA quality assurance

Ashar BH, Rice TN, Sisson SD. Arch Intern Med. 2007;167(9):966-9.

41%

59%

FDA approval

Required Not Required

patient knowledge

45%

55%

Evidence of efficacy

32%

68%

Labels list side effects & risks

Harris Interactive Pole 1,010 phone interviews. October 2002

• Who? What? Why?



• Contamination

• Adulteration


herbal dangers

silicate stones

• they are dog and sheep kidney stones

• about 1% of all stones evaluated in dogs are more than 70% silicate

• fewer than 50 cases have ever been reported in humans

• 38 yr old presents with episodic left flank pain and urinary gravel-like sediment

• after an initial work-up was unremarkable she recovered two small stones from her urine Stones were 100% silicate

Stones were 100% silicate

• Vitamin C

• calcium

• glutamine

• natural gelatin

• chinese herbal “neck formula”

• FlexProtex

• Digestive Advantage

• Uncaria tomentosa

Stones were 100% silicate

• all the supplements were less than 2% silica

• yet over two years she had ingested over 35 kg of silica and developed stones

Flank pain

Flank pain

Told to stop the pills

She stops the pills

Pain goes away

She resumes the pills

Pain returns

St John’s Wart

• Induces intestinal P-glycoprotein MDRP1

• moves drug from the blood to the intestinal lumen

• Induces hepatic cytochrome P-450

• 3A4

• Cyp2E1

• Cyp2C19

decreases bioavailability

reduced bioavailability• Calcineurin inhibitors

• protease inhibitors

• NNRTI

• lipid lowering agents

• thyroid hormone

• oral contraceptives

• digoxin

• theophylline

• warfarin

• SSRI

• Tyrosine kinase inhibitors

St John’s Wort Grapefruit Juice

Drug levels

increased P450 means drug levels fall

decreased P450 means drug levels rise

Orange Juice

Tomato juice

Pineapple juice

Noni Juice

Potassium Content

Orange Juice

Tomato juice 58

mEq/L

Pineapple juice

Noni Juice

Potassium Content

Orange Juice

Tomato juice 58

mEq/L

Pineapple juice

Noni Juice 56

mEq/L

Potassium Content

Orange Juice 51

mEq/L

Tomato juice 58

mEq/L

Pineapple juice

Noni Juice 56

mEq/L

Potassium Content

Orange Juice 51

mEq/L

Tomato juice 58

mEq/L

Pineapple juice 34

mEq/L

Noni Juice 56

mEq/L

Potassium Content

Orange Juice 51

mEq/L

Tomato juice 58

mEq/L

Pineapple juice 34

mEq/L

Noni Juice 56

mEq/L

Potassium Content

• dandelion• alfalfa• nettle• horsetail

Orange Juice 51

mEq/L

Tomato juice 58

mEq/L

Pineapple juice 34

mEq/L

Noni Juice 56

mEq/L

Potassium Content

• dandelion• alfalfa• nettle• horsetail

inhibit Na-K-ATP• milkweed• lily of the valley• hawthorne berries• siberian ginseng

• Who? What? Why?



• Adulteration

• Contamination


herbal dangers

Under DSHEA the FDA bears the burden of showing that a supplement is unsafe or mislabeled before it can restrict or ban the product’s use.

ephedra is a naturally occurring stimulant, alpha adrenergic found in the herb Ma Huang

It was marketed as a weight loss agent under many names, the most famous being Metabolife 356

And Metabolife International, the privately held

company that produces the stuff, says its sales will

approach $1 billion this year--a figure that places

Metabolife in the same league as such blockbuster

pharmaceuticals as Prozac and Viagra.Newsweek 10/3/99

It had predictable cardiovascular side effects, psychosis and radiolucent kidney stonesby 1996 15 deaths and >400 adverse reactions

In 1996 The FDA began proceedings to ban ephedra

In 1998 and 1999, Ellis and Metabolife sent letters to the FDA "...never received a notice from a consumer that any serious adverse health event has occurred because of the ingestion."


The truth was they received 14,000


Six months federal penitentiary

February 2003

February 2003

Ephedra was banned by

the FDA in April 2004

banning ephedra did nothing to ban similar

alpha agonists


alpha agonists

• bitter orange

• seville orange

• citrus aurantium

OHN

Ephedra

OHN

Ephedra

OHN

HOSynephrine


alpha agonists

• blue cohosh

• sympathomimetic alkaloids

• an ephedra derivative


alpha agonists

OH

Ephedra

N

OH

Ephedra

N

DMAAN

1948: Eli Lilly introduces 1,3 dimethylamylamine as a nasal inhaler for rhinitis.

• Physiology studies of the compound in the 1940s and 1950s

• sympathomimetic physiological effects that mimic the action of epinephrine

• increases in blood pressure

• increased heart rate

• increased blood sugar levels

ephedrine amphetamineDMAA

Council of Pharmacy and Chemistry of the American Medical Association described the toxicity of DMAA to be:

In 1983 Eli Lilly voluntarily removed it from the market sighting safety concerns

DMAA exerted a pressor effect 3.5 times that of epinephrine. J Pharmacol Exp Ther 1946; 88(1):10-3

20

06

• Under the DSHEA of 1994 in order for a supplement to be an ingredient it must be naturally naturally occurring and in use prior to 1994.

• DMAA was clearly used prior to 1994

• Naturally occurring is a bit slippery

In 1996 Ping et al. isolated DMAA from geranium oil

The journal is now defunct

Published in the Journal of the Guizhou Institute of Technology

• Others have failed to find DMAA in geraniums

• Prasad et al. 2008

• Jalali-Heravi et al. 2006

• Peterson et al. 2006

• Babu and Kaul 2005

• Vernin et al. 2004

• Rajeswara Rao et al. 2002

• Jain et al. 2001

105.5 105.0

7573

Renal failure

Severe metabolic acidosis

rhabdomyolysis

hyperkalemia

Department of defense report found 40 soldiers affected by DMAA

4 fatalities

5 heat injury/rhabdo

4 seizures syncope

4 tachycardia or palpitations

4 hypertensive crisis or cerebrovascular events

3 parasthesia

2 hepatic failure

2 renal failure

Department of defense report found 40 soldiers affected by DMAA

4 fatalities

5 heat injury/rhabdo

4 seizures syncope

4 tachycardia or palpitations

4 hypertensive crisis or cerebrovascular events

3 parasthesia

2 hepatic failure

2 renal failure

DMAA was banned from

base commissaries

1944: Eli Lilly patents and begins selling DMAA as a nasal decongestant. Trade name Florthane


1983: Eli Lilly removes DMAA from the market due to safety concerns



1994: DSHEA signed into law




1996: Sloppy, flawed and unreproducible research finds DMAA in geraniums





2006: DMAA is reintroduced without FDA approval by combining the DSHEA with geranium data





2006: DMAA is reintroduced without FDA approval by combining the DSHEA with geranium data

2012: FDA challenges use of DMAA sighting safety concerns from 42 adverse events. 11 companies are sent warning letters. 10 complied, but USPlabs challenged the order in court.

General Mills, Inc. 5/5/09

Department of Health and Human Services

Public Health ServiceFood and Drug Administration

Minneapolis District OfficeCentral Region250 Marquette Avenue, Suite 600Minneapolis, MN 55401Telephone: (612) 758-7114FAX: (612) 3344142

May 5,2009

WARNING LETTER

CERTIFIED MAILRETURN RECEIPT REQUESTED

Refer to MIN 09 -18

Ken PowellChairman of the Board and CEOGeneral MillsOne General Mills BoulevardMinneapolis, Minnesota 55426

Dear Mr. Powell:

The Food and Drug Administration (FDA) has reviewed the label and labeling of your Cheerios® ToastedWhole Grain Oat Cereal. FDA's review found serious violations of the Federal Food, Drug, and Cosmetic Act(the Act) and the applicable regulations in Title 21, Code of Federal Regulations (21 CFR). You can findcopies of the Act and these regulations through links in FDA's home page at http://www.fda.gov.1

Unapproved New Drug

Based on claims made on your product's label, we have determined that your Cheerios® Toasted WholeGrain Oat Cereal is promoted for conditions that cause it to be a drug because the product is intended foruse in the prevention, mitigation, and treatment of disease. Specifically, your Cheerios® product bears thefollowing claims ort its label:• "you can Lower Your Cholesterol 4% in 6 weeks" "• "Did you know that in just 6 weeks Cheerios can reduce bad cholesterol by an average of 4 percent?Cheerios is ... clinically proven to lower cholesterol. A clinical study showed that eating two 1 1/2 cupservings daily of Cheerios cereal reduced bad cholesterol when eaten as part of a diet low in saturated fatand cholesterol."These claims indicate that Cheerios® is intended for use in lowering cholesterol, and therefore inpreventing, mitigating, and treating the disease hypercholesterolemia. Additionally, the claims indicate thatCheerios® is intended for use in the treatment, mitigation, and prevention of coronary heart diseasethrough, lowering total and "bad" (LDL) cholesterol. Elevated levels of total and LDL cholesterol are a riskfactor for coronary heart disease and can be a sign of coronary heart disease. Because of these intendeduses, the product is a drug within the meaning of section 201(g)(1)(B) of the Act [21 U.S.C. § 321 (g)P)(B)]. The product is also a new drug under section 201(p) of the Act [21 U.S.C. § 321(p)] because it is notgenerally recognized as safe and effective for use in preventing or treating hypercholesterolemia orcoronary heart disease. Therefore,under section 505(a) of the Act [21 U.S.C. § 355(a)], it may not belegally marketed with the above claims in the United States without an approved new drug application.

FDA has issued a regulation authorizing a health claim associating soluble fiber from whole grain oats witha reduced risk of coronary heart disease (21 CFR 101.81). Like FDA's other regulations authorizing healthClaims about a food substance and reduced risk of coronary heart disease, this regulation provides for theclaim to include an optional statement, as part of the health claim, that the substance reduces the risk ofcoronary heart disease through the intermediate link of lowering blood total and LDL cholesterol. See 21CFR 101.81(d)(2),-(3). Although the lower left corner of the Cheerios® front label contains a solublefiber/coronary heart disease health claim authorized under 21 CFR 101.81, the two claims about loweringcholesterol are not made as part of that claim but rather are presented as separate, stand-alone claimsthrough their location on the package and other label design features. The cholesterol claim that mentionsthe clinical study is on the back of the Cheerios® box, completely separate from the health claim on thefront label. Although the other cholesterol claim is on the same panel as the authorized health claim, itsprominent placement on a banner in the center of the front label, together with its much larger font size,different background, and other text effects, clearly distinguish it from the health claim in the lower leftcorner.

Additionally, even if the cholesterol-lowering claims were part of an otherwise permissible claim, under 21CFR 101.81, the resulting claim language still would not qualify for the use of the soluble fiber healthclaim. To use the soluble fiber health claim, a product must comply with the claim specific requirements in21 CFR 101.81, including the requirement that the claim not attribute any degree of risk reduction forcoronary heart disease to diets that include foods eligible to bear the claim. See 21 CFR 101.81(c)(2)(E).However, the label of your Cheerios® cereal claims a degree of risk reduction for coronary heart diseaseby stating that Cheerios® can lower cholesterol by four percent in six weeks. High blood total and LDLcholesterol levels are a surrogate endpoint for coronary heart disease;; therefore, the cholesterol-loweringclaims on the Cheerios® label attribute a degree of risk reduction for coronary heart disease because iftotal and LDL cholesterol levels decline, the risk of coronary heart disease declines as well.

Misbranded Food:

Your Cheerios ® product is misbranded within the meaning of section 403(r)(1)(B) of the Act [21 U.S.C. §343(r)(1)(B)] because it bears unauthorized health claims in its labeling. We have determined that yourwebsite www.wholegrainnation.com is labeling for your Cheerios® product under section 201(m) of the Act[21 U.S.C. § 321 (m)] because the website address appears on the product label. This website bears thefollowing unauthorized health claims:

"Heart-healthy diets rich in whole grain foods, can reduce the risk of heart disease."

This health claims misbrands your product because it has not been authorized either by regulation [seesection 343(r)(3)(A)-(B) of the Act [21 U.S.C. § 343(r)(3)(A)(B)]] or under authority of the health claimnotificati6n provision of the Act [see section'343(r)(3)(C) of the Act [21 U.S.C. § 343(r)(3)(G)]]. AlthoughFDA has issued a regulation authorizing a health claim associating fiber-containing grain products with areduced risk of coronary heart disease (21 CFR 101.77), the claim on your website does not meet therequirements for this claim. For example, under section 101.77(c)(2), the claim must state that diets lowin saturated fat and cholesterol and high in fiber-containing fruit, vegetable, and grain products mayreduce the risk of heart disease. The claim on your website leaves out any reference to fruits andvegetables, to fiber content, and to keeping the levels of saturated fat and cholesterol in the diet low.Therefore, your claim does not convey that all these factors together help to reduce the risk of heartdisease and does not enable the public to understand the significance of the claim in the context of thetotal daily diet (see section 343(r)(3)(B)(iii) of the Act [21 U.S.C.§ 343(r)(3)(B)(iiill].

In addition to the health claim authorized by regulation in 21 CFR 101.77, other health claims linking theconsumption of whole grain foods to a reduced risk of heart disease have been authorized through thenotification procedure in section 403(r)(3)(C) of the Act. Of those authorized claims, the one closest to theclaim on your website states: "Diets rich in whole grain foods and other plant foods, and low in saturatedfat and cholesterol, may help reduce the risk of heart disease.1" Although the claim on your website alsoconcerns whole grains and reduced risk of heart disease, it is different from the authorized claim insignificant ways. To meet the requirements of the authorized claim, the claim must state that diets thatare (1) rich in Whole grains and other plant foods, and (2) low in saturated fat and cholesterol will helpreduce the risk of heart disease) Instead, the claim on your website only states that diets rich in wholegrains can reduce the risk of heart disease, with no mention of other plant foods or of low saturated fatand cholesterol.

"Including whole grain as part of a healthy diet may ... [h]elp reduce the risk of certain types ofcancers. Regular consumption of whole grains as part of, a low-fat diet reduces the risk for somecancers, especially cancers of the stomach and colon."

This health claim misbrands your product because it has not been authorized either by regulation [seesection 343(r)(3)(A)-(B) of the Act [21 U.S.C. § 343(r)(3)(A)(B)]] or under authority of the health claimnotification provision of the Act [see section 343(r)(3)(C) of the Act [21 U.S.C. § 343(r)(3)(C)]]. AlthoughFDA has issued a regulation authorizing a health claim associating fiber-containing grain products with areduced risk of cancer (21 CFR 101.76), the claim on your website does not meet the requirements for theauthorized claim.For example, under section 101.76(c)(2) the claim must state that diets high in fiber-containing grain products, fruits, and vegetables may reduce the risk of some cancers. The claim on yourwebsite leaves out any reference to fruits, vegetables, and fiber content. Therefore, your claim does notconvey that all these factors together help to reduce the risk of heart disease and does not enable thepublic to understand the significance of the claim in the context of the total daily diet [see section 343(r)(3)(B)(iii) of the Act [21 U.S.C. § 343(r)(3)(B)(iii)]].

In addition to the health claim authorized by regulation in 21 CFR 101.76, a health claim linking theconsumption of whole grain foods to a reduced risk of certain cancers has been authorized through thenotification procedure in section 403(r)(3)(C) of the Act. The authorized claim is: "Diets rich in whole grainfoods and other plant foods ... may help reduce the risk of... certain cancers."2 Although the claim on yourwebsite also concerns whole grains and reduced risk of some cancers, it is different from the authorizedclaim in significant ways. For example, the authorized claim states that diets rich in whole grain foods and"other plant foods" may help reduce the risk for certain cancers. However,the claim on your website doesnot mention "other plant foods." Also, by using the language "especially cancers of the stomach and colon"the claim on your website emphasizes the relationship between whole grain foods and stomach and coloncancers as compared to other cancers, suggesting a greater degree of risk reduction or stronger evidencefor the relationship between whole grain foods and risk of those two cancers. The claim authorized throughthe notification procedure does not emphasize the relationship between whole grain foods and stomach andcolon cancer as compared to other cancers.

This letter is not intended to be an all-inclusive review of your products and their labeling. It is yourresponsibility to ensure that all of your products are in compliance with the Act and its implementingregulations.

Failure to promptly correct the violations specified above may result in enforcement action without furthernotice. Enforcement action may include seizure of violative products and/or injunction against themanufacturers and distributors of violative products.

Please advise this office in writing 15 days from your receipt of this letter of the specific steps you havetaken to correct the violations noted above and to ensure that similar violations do not occur. Yourresponse should include any documentation necessary to show that correction has been achieved. If youcannot complete all corrections before you respond, state the reason for the delay and the date by whichyou will complete the corrections.

Please send your reply to the attention of Tyra S. Wisecup, Compliance Officer, at the address in theletterhead. If you have any questions regarding this letter, please contact Ms. Wisecup at (612) 758-7114.

Sincerely,

/s/

W. Charles BecoatDirectorMinneapolis District

TSW/cd

1 See "Health Claim Notification for Whole Grain Foods with Moderate Fat Content," December 9, 2003(http://www.cfsan.fda.gov/~dms/f1grain2.html).

2 See "Health Claim Notification for Whole Grain Foods," July 1999 (http://www.cfsan.fda.gov/-dms/flgrain2.html).

Page Last Updated: 06/18/2009 Note: If you need help accessing information in different file formats, see Instructions for DownloadingViewers and Players.

Accessibility Contact FDA Careers FDA Basics FOIA No Fear Act Site Map Transparency WebsitePolicies

U.S. Food and Drug Administration10903 New Hampshire Avenue Silver Spring, MD 20993 Ph. 1-888-INFO-FDA (1-888-463-6332)Email FDA

For Government For Press

Combination Products Advisory Committees Science & Research Regulatory Information SafetyEmergency Preparedness International Programs News & Events Training and Continuing EducationInspections/Compliance State & Local Officials Consumers Industry Health Professionals FDA Archive

Links on this page:

1. http://www.fda.gov.

Inspections, Compliance, Enforcement, and Criminal Investigations

Home Inspections, Compliance, Enforcement, and Criminal Investigations Enforcement Actions Warning Letters

This product is not intended to diagnose, treat, cure or prevent disease

• Who? What? Why?



• Adulteration

• Contamination


herbal dangers

• adulteration: intensional addition of unlabeled ingredients

• contamination: accidental addition of unlabeled ingredients

The U.S. FDA laboratory isolated two anabolic steroids:

• dimethazine

• methasterone (Class III controlled substance)

To date, 29 illnesses have been confirmed, but federal health officials say that number could rise.

From 35 to 50% of herbal erectile dysfunction treatments contain

PDE-5 inhibitors

Laing Q, J Pharm Biomed Anal. 2006; 40:305-11Gratz SR, J Pharm Biomed Anal. 2004; 36:525-33

Zotrex was a male sexual enhancement supplement manufactured by Nova pharmaceutical in Utah.

The primary active ingredient was Ophioglossum polyphyllous


The primary active ingredient was Ophioglossum polyphyllous sulfoaildenafil



Nova sold over 14 million pills of suloaildenafil under various names, including:




OMG




OMG-45




Maxyte



Modified form of sildenafil, modifying existing drugs is a sinister method to evade FDA detection.


Maxyte

herbal weight loss medications

Vaysse J. Food Additives Contaminants Part A: Chemical Analysis, Control, Exposure & Risk Assessment 2010; 27: 903-16.



Medical impact of obesity




Social impact of obesity





Few medications





Medication safety concerns

Few medications

2D diffusion ordered spectroscopy 1H-nuclear magnetic resonance spectroscopy

0

20

Sibutramine

phenolphth

aleinsynep

hrine caffeine

115

13

0

20

Sibutramine

phenolphth

aleinsynep

hrine caffeine

115

13CatharticCarcinogenic

Dunnick JK, Hailey JR. Phenolphthalein exposure causes multiple carcinogenic effects in experimental model systems. Cancer Res. 1996;56(21):4922-6.

Among the 20 formulations analysed, 2 were strictly herbal (formulations 17 and 18), and 4 had a composition corresponding to declared ingredients on the packaging or the leaflet (formulations 6, 16, 19, 20). The others were all adulterated.

adulterated14

declared4

Herbal2

sibutramine

must have a history of

randomized, double blind10 mg silbutramine or placebo

age 55+

BMI 25-27

CV disease DM + CV risk factorboth

• Nonfatal MI• Nonfatal CVA

• Cardiac arrest• CV death

0

10

20

30

40

1 2 3 4 5 7 8 9 10 11 13 14 15

141415

31

1112135

201623

413

mg/

pill

Sample number

licorice glycyrrhiza glabra50x sweeter than sucrose

often it is an undeclared ingredient, sweetener

11-beta steroid dehydrogenase

adulteration

7-30 ng/dLaldo

5-20 mcg/dLCortisol

Cortisol circulates at 1,000 times the aldosterone concentration

MR

Mineralcorticoid receptor

7-30 ng/dLaldo

MR 5-20 mcg/dLCortisol


Inside the principle cell

MR


7-30 ng/dLaldo


Na-K ATPaseENacK+ channelH+-ATPase






Inside the principle cell Na-K ATPaseENacK+ channelH+-ATPase




Inside the principle cell Na-K ATPaseENacK+ channelH+-ATPase

but does not have any mineral-ocorticoid activity. Why?

MR Cortisol

• 11ß-hydroxysteroid dehydrogenase converts cortisol to cortisone

• Prevents cortisol from having mineralocorticoid effect

MR Cortisol

11ß-hydroxysteroid dehydrogenase



MR Cortisol


Cortisone



MR Cortisol


Cortisone



cortisol cortisone11ß-hydroxysteroid

dehydrogenase

• Glycyrrhiza glabra is 11ß-hydroxysteroid dehydrogenase inhibitor

• Allows cortisol to have mineralocorticoid activity

MR Cortisol




MR Cortisol




MR Cortisol

Na-K ATPaseENacK+ channelH+-ATPase

1463.0 33

106 8

0.478165/96

• hypertension

• hypokalemia

• metabolic alkalosis

Consumer Health Informationwww.fda.gov/consumer

Black Licorice: Trick or Treat?As it turns out, you really can overdose on candy—

or, more precisely, black licorice.

Days before the biggest candy eat-ing holiday of the year, the Food and Drug Administration (FDA) encour-ages moderation if you enjoy snack-ing on the old fashioned favorite.

So, if you’re getting your stash ready for Halloween, here’s some advice from FDA:

If you’re 40 or older, eating 2 ounces of black licorice a day for at least two weeks could land you in the hospital with an irregular heart rhythm or arrhythmia.

FDA experts say black licorice con-tains the compound glycyrrhizin, which is the sweetening compound derived from licorice root. Glycyr-rhizin can cause potassium levels in the body to fall. When that happens, some people experience abnormal heart rhythms, as well as high blood

has a long history of use as a folk or traditional remedy (www.nlm.nih.gov/medline-plus/druginfo/natural/881.html) in both Eastern and Western medicine. It has been used as a treatment for heartburn, stomach ulcers, bron-chitis, sore throat, cough and some infections caused by viruses, such as hepatitis; how-ever, NIH says there are insufficient data available to determine if licorice is effective in treating any medical condition.

Licorice is also used as a flavoring in food. Many “licorice” or “licorice flavor” products manufactured in the United States do not contain any lic-

some medications, herbs and dietary supplements. Consult a health care professional if you have questions about possible interactions with a drug or

• Who? What? Why?



• Adulteration

• Contamination


herbal dangers

contaminationsloppy production practices can result in lead and cadmium contamination

contaminationsloppy production practices can result in lead and cadmium contamination

Ayurvedic medicationsHeavy metals are mixed with herbs for

therapeutic effect

• used by the majority of India’s 1.1 billion people

• Two varieties

• Herbal only

• Rasa Shastra deliberately combining herbs with metals (Hg, Pb, Fe, Zn), minerals, and gems.

Ayurvedic medications

Saper RB, Phillips RS, Sehgal A, et al. Lead, Mercury, and Arsenic in US- and Indian-Manufactured Ayurvedic Medicines Sold via the Internet. JAMA. 2008;300(8):915-923.

• randomly selected 230 ayurvedaic products that were top search results and available for sale over the Internet

• examined the samples by x-ray fluorescence

Of 230 products randomly selected for purchase, we received and analyzed 193 (84%) made by 37 different manufacturers. Reasons for failure to fill our orders included the following: 21 products were no longer available or out of stock; 1 supplier refused to fill our order of 14 products after recognizing that we were authors of a previous study of Ayurvedic medicines.

None153

Metals40

entire cohort

None137

Metals38

US Website or Distributor

None43

Metals3

Member of AHPAAmerican Herbal Products Association

None20

Metals5

Member of ADMAAyurvedic Drug Manufacturers Association

None121

Metals30

Claims GMP or metal testingAmerican Herbal Products Association

None19

Metals13

Rasa shastra medicine

None131

Metals27

Non Rasa shastra medicine

0.1 1.0 10 100 1,000 10,000 100,000

Safe

10 100 1,000 10,000 100,000

Safe

1.0 10 100 1,000

Safe

• NHANES

• examined use of herbal supplements found to have excess lead in previous studies:

• Ayuvedic medicine

• Traditional Chinese medicine

• St John Wort

• Ginko

• Ginseng

• 455 with exposure

• 12,352 with exposure

• Echinacea

• Kava*

• Velerian*

• Black kohosh*

• Bee polen*

• Nettle*

percent change in blood lead levels (BLL)

• Similar results in Taiwan among users of Traditional Chinese Medicine

• In China, higher lead levels were found in the breast milk of users of Chinese herbs

Ernst E. Risks of herbal medicinal products. Pharmacoepidemiol Drug Saf. 2004;13(11):767–771.

Chu NF, Liou SH, Wu TN, et al. Risk factors for high blood lead levels among the general population in Taiwan. Eur J Epidemiol. 1998;14:775–781.

Chien LC, Yeh CY, et al. Effect of the mother’s consumption of traditional Chinese herbs on estimated infant daily intake of lead from breast milk. Sci Total Environ. 2006;354 (2–3): 120–6.

CDC action threshold for BLL in children

0

15

30

45

60

1960’s 1970 1975 1985 1991 2011510

253040

60

mcg

/dL

CDC action threshold for BLL in children

• the kidney is on the front line for damage from heavy metals

tubular toxicitynephrotic syndrome

lead

cadmium

uranium

arsenic

mercury

• The renal tubules contain divalent cationic transporters:

• Zn2+ Fe 2+ Mg 2+ Cu2+

• Limited ability to discriminate among divalent cations so the tubules avidly reabsorb

• Cd2+ Pb2+ Pt2+ Ni2+ Hg2+

• Who? What? Why?



• Adulteration

• Contamination

• Unexpected side-effects

herbal dangers

• January 1992, 40 year old woman who complained of fatigue presented with a Cr 5. A kidney biopsy showed interstitial fibrosis and normal glomeruli.

• From May 1990-March 1991 she enrolled in a slimming clinic and taken herbal medications

• by March she was on chronic dialysis

• April 1992, 46 year old woman referred for an incidental finding of a Cr of 3.8. Renal biopsy showed tubular atrophy and interstitial fibrosis.

• 4 months later her Cr was 7.7.

• From May 1990 to November 1991 she was enrolled in the same slimming clinic and took the same herbal regimen.

1989 1990 1991 1992

1 1

3

9

following these two cases the investigators did an analysis of woman starting dialysis prior to the age 50.

first 6 months

1989 1990 1991 1992

1 1

3

9


Nine had followed the same slimming regimen from the same clinic.

first 6 months

1989 1990 1991 1992

1 1

3

9



Eight had renal biopsies that showed interstitial nephritis

first 6 months

1989 1990 1991 1992

1 1

3

9



Eight had renal biopsies that showed interstitial nephritis

first 6 months

In mid 1990 they introduced pow-dered extracts of Stephania tetrandra and Magnolia officinalis

• Stephania tetrandra belongs to the same Feng-ji family as Aristolochia Fang-ji

• the Chinese characters for both plants are the same except for prefixing:

• Guang for Aristolochia

• Han for Stephania

Aristolochia

A Wrist Loki

Aristolochia

Vanhaelen MR, Vanhaelen-FastrePB, Jean-Louis Vanherweghem. 1994. The Lancet 343, (8890) (Jan 15): 174

Analysis of 12 different samples of Stephania

tetrandra delivered to Belgium from 1990 to 1992 showed only

two contained Stephania, eleven contained Aristolochia

Vanhaelen MR, Vanhaelen-FastrePB, Jean-Louis Vanherweghem. 1994. The Lancet 343, (8890) (Jan 15): 174

• Ultimately 100 women were found with varying degrees of renal failure

• 70 were on dialysis or pre-terminal phase of CKD

• 30 had stable creatinine less than 3 mg/dL

• Estimates of exposure by looking at import records point to 1,500-2,000 people

• Later the women developed urogenital cancer

• transitional cell carcinoma of the bladder in a 28 year old 12 months after her kidney transplant

• 42 year old woman developed papillary transitional cell carcinoma

• 49 year old woman developed multifocal transitional cell carcinoma of the ureter after transplant

• women on dialysis were offered prophylactic bilateral nephrectomy and ureterectomies

• this was highly effective

None6

Cancer4 None

21

Cancer18

Cosyns JP, Jadoul M, Squifflet JP, Wese FX, Van ypersele de strihou C. Urothelial lesions in Chinese-herb nephropathy. Am J Kidney Dis. 1999;33(6):1011-7.

Nortier JL, Martinez MC, Schmeiser HH, et al. Urothelial carcinoma associated with the use of a Chinese herb (Aristolochia fangchi). N Engl J Med. 2000;342(23):1686-92.

COOH

NO2

O

O

N

NN

N

H2N

O

OH

HO N

NN

NNH2

O

OH

HO

NH2

O

Aristocholic Acid

deoxyadenosine deoxyguanosine

COOH

NO2

O

O

N

OO

O

N

NN

N

H2N

O

OH

HO N

NN

NNH2

O

OH

HO

NH2

O

Aristocholic Acid Aristolactam nitrenium ion

metabolic activation


COOH

NO2

O

ON

OO

O

N

NN

N

H2N

O

OH

HO N

NN

NNH2

O

OH

HO

NH2

O

Aristocholic Acid Aristolactam nitrenium ion

metabolic activation


DNA Add

uct F

ormati

on

DNA Adducts are aristocholic acid’s fingerprints

DNA Adducts are aristocholic acid’s fingerprints

Moreover, Schmeiser et al. were able to detect DNA adducts formed by metabol i tes of ar istolochic ac id (aristolactams) in samples of kidneys removed from five patients with Chinese-herb nephropathy. These adducts are specific markers of exposure to aristolochic acids and are directly involved in tumorigenesis.

Nortier JL, et al. N Engl J Med. 2000; 342.

These DNA adducts cause adenine to thymine transversion mutations in the

tumor suppressor gene TP53

These DNA adducts cause adenine to thymine transversion mutations in the

tumor suppressor gene TP53

“It is now clear that p53 inactivation is essential for the formation of nearly all cancers...TP53 is more frequently mutated in human tumors than any other gene in the genome...”

Bert Vogelstein and Carol Prives

The FDA found Aristolochia in numerous herbal supplements in the U.S.

Rheumix PharmaBotanixx

BioSlim Doctor's Natural Weight Loss System Slim Tone Formula

Thane International

Prostatin Herbal Doctor Remedies

Fang Ji Stephania Lotus Herbs Inc

Mu Tong Clematis armandi Lotus Herbs Inc

Temple of Heaven Chinese Herbs Radix aristolochiae

Mayway Corporation

Jade Meridian Circulation: East Earth Herb Inc

Qualiherb Chinese Herbal Formulas Dianthus Formulas Ba Zheng San

QualiHerb (Division of Finemost)

Clematis & Carthamus Formula 21280

QualiHerb (Division of Finemost)

Virginia Snake Root, Cut Aristolochia serpentaria

Penn Herb Co.

Green Kingdom Akebia Extract Ava Health

Green Kingdom Stephania Extract Ava Health

Neo Concept Aller Relief BMK International, Inc.

Mu Tong Clematis armandi Botanicum.com

Fang Ji Stephania Botanicum.com

Stephania tetrandra, roots, whole Ethnobotanical

The FDA found Aristolochia in numerous herbal supplements in the U.S.

Balkan nephropathy, a disease of middle-aged Romanian farmers

• chronic interstitial nephritis

• affects people in the Danube River basin

• ages 30-60 with a latency of 15 years

• familial but not inherited pattern of distribution

Etiologies of ESRD

Etiologies of ESRD

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100% 19

80

1982

1984

1986

1988

1990

1992

1994

1996

1998

2000

2002

2004

2006

2008

Diabetes Hypertension Glomeruloneph Cystic kidney

Etiologies of ESRD

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100% 19

80

1982

1984

1986

1988

1990

1992

1994

1996

1998

2000

2002

2004

2006

2008

Diabetes Hypertension Glomeruloneph Cystic kidney

Balkan nephropathy is responsible for

70% of ESRD in some endemic areas

70%

“An important complicating feature is an apparently increased incidence in the development of transitional cell tumors of the renal pelvis, ureter, and bladder. These malignancies may be multiple and bilateral.”

The pathway of exposure to humans remained a mystery. So Grollman spoke with dialysis patients.

"I was sure they had been taking herbal medicines," Grollman says. "And then we interviewed them through a translator and that made clear they hadn't."

When shown pictures of the plant, the patients identified it as Wolf's Paw, a common weed. Grollman says he later walked around the farms outside the city and found the plant on the outer fringes of the fields. When they tramped the plowed rows, they found it entwined among the wheat stalks.

Mead JC. The Scientist Nov 1, 2007.

Taiwan

highest incidence of dialysis in the world

430 per million

Yang MH, Chen KK, Yen CC, et al. Unusually high incidence of upper urinary tract urothelial carcinoma in Taiwan. Urology. 2002;59(5):681-7.

• Taiwan had a high rate of urothelial cancer, especially upper tract disease which ordinarily is unusual

• this was thought to be due to arsenic poisoning, blackfoot disease

• epidemiological studies showed high rates in areas not endemic for arsenic

• High rates of women, young people and elevated creatinine

Yang MH, Chen KK, Yen CC, et al. Unusually high incidence of upper urinary tract urothelial carcinoma in Taiwan. Urology. 2002;59(5):681-7.

• Following the publication of the Belgian slimming clinic other cities began reporting series of Chinese herb nephropathy

• Taiwan published an early case series of 12 people with the syndrome

Yang CS, Lin CH, Chang SH, Hsu HC. Am J Kid Dis Feb 2000 vol 35;2: 313-8

• Cohort of 200,000

• Prescription data from the National Health Insurance

• 39.3% of the Taiwanese population treated Chinese herbal medicine with aristocholic acid January 1997 and November 2003

• Cumulative dose exceeded 100g per person

• Cohort of 200,000

• Prescription data from the National Health Insurance

• 39.3% of the Taiwanese population treated Chinese herbal medicine with aristocholic acid January 1997 and November 2003

• Cumulative dose exceeded 100g per person

Aristolochia was banned

in November 2003

this represents nearly 1,200 people avoiding dialysis a year

• Jean-Louis Vanherweghem

• Michel F. Depierreux

• Michel Jadoul

• Renee Vanhaelen-Fastre

• Maurice Vanhaelen

• Discovered the nephropathy

• Tracked down the cause

• Decided to offer prophylactic nephrectomy

• Inspired the solution to Balkan nephropathy

• Key to the discovery of the cause of Taiwanese ESRD

The Taiwan experience shows

us the way. Government

action to restrict dan-

gerous herbals can

influence public

health.

2011: 584 dietary supplement users over the age 18

None75%

Stop25% only 25.4% would stop

using a supplement if public health authorities stated it was ineffective

Blendon RJ, Benson JM, Botta MD, Weldon KJ. Users' Views of Dietary Supplements. JAMA Intern Med. 2013;173(1):74-76.

2011: 584 dietary supplement users over the age 18

None64%

discussed36%

only 25.4% would stop using a supplement if public health authorities stated it was ineffective

Blendon RJ, Benson JM, Botta MD, Weldon KJ. Users' Views of Dietary Supplements. JAMA Intern Med. 2013;173(1):74-76.

only 35.9% had told their doctor about their use of supplements

2 out of 5 adults

1 out of 9 children

In America we expect all foods, medicines, supplements, vitamins, and health foods to be safe and uncontaminated.

We give these medicines to our children. They have to be safe and pure.

Senators John McCain (R-AZ) and Byron Dorgan (R-ND)

2010: Dietary Supplement Safety ActReplaced the existing new dietary ingredient provisions of the Food, Drug and Cosmetic Act (FDCA) with a list of accepted dietary ingredients to be created by the FDA

Created potential civil liability for retailers that fail to obtain certification from their suppliers that the products they sell have met all upstream regulatory requirements

Required companies to report all adverse events to FDA.

Orin Hatch (R-UT)Chief author of DSHEA


Tom Harkin (D-IA)Co-author of DSHEARecieved money from Herbalife


McCain droppped support for his own bill after talking with Hatch

thank-you

•http://argunalbayrak.files.wordpress.com/2010/06/

chicago_cemetary_1989_bw.jpg

•cemetary pic

•http://www.shorpy.com/node/10051?size=_original

•steam boat

•http://commons.wikimedia.org/wiki/

File:Tulane_U_Gibson_Hall_from_Audubon_Park_New_Orleans_1900.jpg

•tulane

•bottle

•https://www.etsy.com/listing/98628805/foley-co-4-apothecary-bottle-

chicago-usa?ref=related-1, and i bought the bottle

•http://commons.wikimedia.org/wiki/

File:StateLibQld_1_140295_Portrait_of_a_wedding_party,_1930-1940.jpg

•wedding

•http://www.defense.gov/DODCMSShare/NewsStoryPhoto/2011-05/

hrs_110503-D-9999G-001.JPG

•badge

•http://sydney.edu.au/senate/images/pharmacy/a417001.jpg

•pharmacy (http://sydney.edu.au/senate/

students_early1_gallery_pharmacy.shtml)

•http://www.huffingtonpost.co.uk/2012/04/18/queen-mother-lady-colin-

campbell-french-cook-_n_1433853.html#s881105

•lady writing, queen mother

•Image credit: <a href='http://www.123rf.com/photo_10500918_herbs-with-

alternative-medicine-herbal-supplements-and-pills.html'>elenathewise / 123RF

Stock Photo</a>

•http://jama.jamanetwork.com/article.aspx?articleid=187430#REF-JED80023-12

•FDR

•http://www.thenation.com/sites/default/files/fdr_ap.jpg

School girls

http://www.stjohns-es.org/page.cfm?

p=1792&nmonth=any&nyear=any&ncat=6%2C2&pageStart=121

NIH Budget

http://officeofbudget.od.nih.gov/pdfs/FY12/Approp.%20History%20by%20IC)2012.pdf

OCCAM budget from annual report on complementary and alternative medicine

2011

1940 eli lilly

http://www.friendsofwillis.hampshire.org.uk/elylilly.jpg

geraniums

http://www.coldclimategardening.com/2009/06/16/garden-bloggers-bloom-day-

june-2009/

Muscle guys

http://farm5.staticflickr.com/4124/5064711595_b968ac2589_o.jpg

http://farm4.staticflickr.com/3093/2651904068_ccaa17a5f8_o.jpg

picture of meat

http://youronestophalalshop.com/meat.html

picture of chicken

http://www.fresh-poultry.com/poultry-menu/

Picture of eggs

http://www.imcpl.org/kids/blog/?p=8917

Dialysis patient

http://upload.wikimedia.org/wikipedia/commons/c/c2/

Patient_receiving_dialysis_03.jpg

Herbal toxins grand rounds feb 2014

Documents

Transcript of Herbal toxins grand rounds feb 2014