herbal toxins grand rounds feb 2014
TRANSCRIPT
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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.
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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.
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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
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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:
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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.
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1937
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Sulfanilamide, used to treat streptococcal infections
1937Salesmen for the S.E. Massengill Co. report demand for a liquid formulation
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Chief chemist and pharmacist, Harold Cole Watkins discovered he could dissolve sulfonamide in diethylene glycol.
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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
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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
by September 1937, Massengill had distributed 268 gallons of the liquid, called Elixir Sulfanilamide, across the country
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1937
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June
1937
Sales person reports demand
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June July Aug Sept
1937
Sales person reports demand 268 gallons shipped nationally
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June July Aug Sept Oct
1937
Sales person reports demand 268 gallons shipped nationally
American Medical Association received reports from Tulsa, OK, that an unfamiliar sulfanilamide compound was responsible for 6 deaths
Oct 11
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June July Aug Sept Oct
1937
Sales person reports demand 268 gallons shipped nationally
American Medical Association received reports from Tulsa, OK, that an unfamiliar sulfanilamide compound was responsible for 6 deaths
NY physician alerts the FDAAn inspector in the Kansas City Station confirms 9 deaths Oct 14
Oct 11
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June July Aug Sept Oct
1937
Sales person reports demand 268 gallons shipped nationally
American Medical Association received reports from Tulsa, OK, that an unfamiliar sulfanilamide compound was responsible for 6 deaths
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
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diethylene glycol is two ethylene glycol molecule bound by an ether bond
HO CH2 O CH2 OHCH2 CH2
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diethylene glycol is two ethylene glycol molecule bound by an ether bond
HO CH2 O CH2 OHCH2 CH2
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diethylene glycol is two ethylene glycol molecule bound by an ether bond
HO CH2 O CH2 OHCH2 CH2
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diethylene glycol is two ethylene glycol molecule bound by an ether bond
HO CH2 O CH2 OHCH2 CH2
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diethylene glycol is two ethylene glycol molecule bound by an ether bond
HO CH2 O CH2 OHCH2 CH2
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diethylene glycol is two ethylene glycol molecule bound by an ether bond
HO CH2 O CH2 OHCH2 CH2
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diethylene glycol is two ethylene glycol molecule bound by an ether bond
HO CH2 O CH2 OHCH2 CH2
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diethylene glycol is two ethylene glycol molecule bound by an ether bond
HO CH2 O CH2 OHCH2 CH2
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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
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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.
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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.
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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
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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
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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
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In 1937 the law did not prohibit the sale of dangerous, untested, or poisonous drugs.
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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.
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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.
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
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Final score
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Final score267 gallons confiscated268 gallons shipped
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Final score267 gallons confiscated
1 gallon consumed
268 gallons shipped
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Final score267 gallons confiscated
1 gallon consumed
105 dead, including 34 children
268 gallons shipped
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June July Aug Sept
1937
Sales person reports demand 268 gallons shipped nationally
Oct
National Tragedy
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June July Aug Sept
1937
Sales person reports demand 268 gallons shipped nationally
1938
Oct Nov Dec
Jan Feb Mar Apr May
National Tragedy
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June July Aug Sept
1937
Sales person reports demand 268 gallons shipped nationally
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
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Drugs have to be safe (1938) to be approved for sale in the United States
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Frances O. Kelsey receiving the President's Award for Distinguished Federal Civilian Service
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The Drug Amendment of 1962 was approved unanimously after Dr. Kelsey, an FDA officer, refused approval of Thalidomide.
Frances O. Kelsey receiving the President's Award for Distinguished Federal Civilian Service
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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.
Frances O. Kelsey receiving the President's Award for Distinguished Federal Civilian Service
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Drugs have to be safe (1938) and effective (1962) to be approved for sale in the United States
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Drugs have to be safe (1938) and effective (1962) to be approved for sale in the United States
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October 1994
Dietary Supplement Health and Education Act (DSHEA)
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October 1994
Dietary Supplement Health and Education Act (DSHEA)
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October 1994
Dietary Supplement Health and Education Act (DSHEA)
FoodDrug
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October 1994
Dietary Supplement Health and Education Act (DSHEA)
FoodDrug Supplement
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October 1994
Dietary Supplement Health and Education Act (DSHEA)
Food
DrugSupplement
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• Before 1994, herbal products were considered food additives
• Manufacturers required to show proof of safety before sales
before DSHEA
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• 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
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Drugs have to be safe (1938) and effective (1962) to be approved for sale in the United States
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Drugs have to be safe (1938) and effective (1962) to be approved for sale in the United States
Supplements do not have to be safe or effective to be approved for sale in the United States (1994)
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Drugs have to be safe (1938) and effective (1962) to be approved for sale in the United States
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
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Drugs have to be safe (1938) and effective (1962) to be approved for sale in the United States
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
$0
$7,500
$15,000
$22,500
$30,000
1994 2010
26000
700
Sals
es (
mill
ions
)
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NIH$30,860,913,000
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NIH$30,860,913,000
National Center of Complementary and Alternative
Medicine (NCCAM)
$128,057,000
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NIH$30,860,913,000
National Center of Complementary and Alternative
Medicine (NCCAM)
$128,057,000
NCI$5,072,183,000
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NIH$30,860,913,000
National Center of Complementary and Alternative
Medicine (NCCAM)
$128,057,000
Office of Cancer Complementary and Alternative
Medicine (OCCAM)
$105,341,737
NCI$5,072,183,000
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• Who? What? Why?
• interaction and accumulation
• FDA inability to restrict unsafe drugs
• Adulteration
• Contamination
• Untoward side-effects
herbal dangers
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• Who? What? Why?
• interaction and accumulation
• FDA inability to restrict unsafe drugs
• Adulteration
• Contamination
• Untoward side-effects
herbal dangers
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2 out of 5 adults
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1 out of 9 children
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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.
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65%
36%
less than high school
Use Don’t Use
supplement use
54%46%
high school
40%
60%
college
Grubbs V, Plantinga LC, et al. AJKD 2013; 61(5):739-47.
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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
Grubbs V, Plantinga LC, et al. AJKD 2013; 61(5):739-47.
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• people that use supplements are not casual users
• they are committed, overwhelmingly they take them everyday
<7 7-20 21+
70%
18%10%
Grubbs V, Plantinga LC, et al. AJKD 2013; 61(5):739-47.
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• 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%
Grubbs V, Plantinga LC, et al. AJKD 2013; 61(5):739-47.
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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
Grubbs V, Plantinga LC, et al. AJKD 2013; 61(5):739-47.
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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.
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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
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• Who? What? Why?
• interaction and accumulation
• FDA inability to restrict unsafe drugs
• Contamination
• Adulteration
• Untoward side-effects
herbal dangers
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• Who? What? Why?
• interaction and accumulation
• FDA inability to restrict unsafe drugs
• Contamination
• Adulteration
• Untoward side-effects
herbal dangers
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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
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• 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
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Stones were 100% silicate
• Vitamin C
• calcium
• glutamine
• natural gelatin
• chinese herbal “neck formula”
• FlexProtex
• Digestive Advantage
• Uncaria tomentosa
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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
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Flank pain
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Flank pain
Told to stop the pills
She stops the pills
Pain goes away
She resumes the pills
Pain returns
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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
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reduced bioavailability• Calcineurin inhibitors
• protease inhibitors
• NNRTI
• lipid lowering agents
• thyroid hormone
• oral contraceptives
• digoxin
• theophylline
• warfarin
• SSRI
• Tyrosine kinase inhibitors
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St John’s Wort Grapefruit Juice
Drug levels
increased P450 means drug levels fall
decreased P450 means drug levels rise
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Orange Juice
Tomato juice
Pineapple juice
Noni Juice
Potassium Content
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Orange Juice
Tomato juice 58
mEq/L
Pineapple juice
Noni Juice
Potassium Content
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Orange Juice
Tomato juice 58
mEq/L
Pineapple juice
Noni Juice 56
mEq/L
Potassium Content
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Orange Juice 51
mEq/L
Tomato juice 58
mEq/L
Pineapple juice
Noni Juice 56
mEq/L
Potassium Content
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Orange Juice 51
mEq/L
Tomato juice 58
mEq/L
Pineapple juice 34
mEq/L
Noni Juice 56
mEq/L
Potassium Content
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Orange Juice 51
mEq/L
Tomato juice 58
mEq/L
Pineapple juice 34
mEq/L
Noni Juice 56
mEq/L
Potassium Content
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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
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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
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• Who? What? Why?
• interaction and accumulation
• FDA inability to restrict unsafe drugs
• Adulteration
• Contamination
• Untoward side-effects
herbal dangers
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• Who? What? Why?
• interaction and accumulation
• FDA inability to restrict unsafe drugs
• Adulteration
• Contamination
• Untoward side-effects
herbal dangers
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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.
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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
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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
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It had predictable cardiovascular side effects, psychosis and radiolucent kidney stonesby 1996 15 deaths and >400 adverse reactions
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It had predictable cardiovascular side effects, psychosis and radiolucent kidney stonesby 1996 15 deaths and >400 adverse reactions
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In 1996 The FDA began proceedings to ban ephedra
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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."
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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
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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."
Six months federal penitentiary
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February 2003
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February 2003
Ephedra was banned by
the FDA in April 2004
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banning ephedra did nothing to ban similar
alpha agonists
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banning ephedra did nothing to ban similar
alpha agonists
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banning ephedra did nothing to ban similar
alpha agonists
• bitter orange
• seville orange
• citrus aurantium
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banning ephedra did nothing to ban similar
alpha agonists
• bitter orange
• seville orange
• citrus aurantium
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OHN
Ephedra
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OHN
Ephedra
OHN
HOSynephrine
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banning ephedra did nothing to ban similar
alpha agonists
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• blue cohosh
• sympathomimetic alkaloids
• an ephedra derivative
banning ephedra did nothing to ban similar
alpha agonists
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• blue cohosh
• sympathomimetic alkaloids
• an ephedra derivative
banning ephedra did nothing to ban similar
alpha agonists
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OH
Ephedra
N
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OH
Ephedra
N
DMAAN
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1948: Eli Lilly introduces 1,3 dimethylamylamine as a nasal inhaler for rhinitis.
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• 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
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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
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20
06
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• 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
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In 1996 Ping et al. isolated DMAA from geranium oil
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The journal is now defunct
Published in the Journal of the Guizhou Institute of Technology
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The journal is now defunct
Published in the Journal of the Guizhou Institute of Technology
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• 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
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• 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
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• 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
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105.5 105.0
7573
Renal failure
Severe metabolic acidosis
rhabdomyolysis
hyperkalemia
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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
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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
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1944: Eli Lilly patents and begins selling DMAA as a nasal decongestant. Trade name Florthane
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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
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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
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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
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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
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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
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.
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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
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.
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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.
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Home Inspections, Compliance, Enforcement, and Criminal Investigations Enforcement Actions Warning Letters
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This product is not intended to diagnose, treat, cure or prevent disease
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• Who? What? Why?
• interaction and accumulation
• FDA inability to restrict unsafe drugs
• Adulteration
• Contamination
• Untoward side-effects
herbal dangers
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• Who? What? Why?
• interaction and accumulation
• FDA inability to restrict unsafe drugs
• Adulteration
• Contamination
• Untoward side-effects
herbal dangers
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• adulteration: intensional addition of unlabeled ingredients
• contamination: accidental addition of unlabeled ingredients
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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.
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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.
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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.
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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
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Zotrex was a male sexual enhancement supplement manufactured by Nova pharmaceutical in Utah.
The primary active ingredient was Ophioglossum polyphyllous
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Zotrex was a male sexual enhancement supplement manufactured by Nova pharmaceutical in Utah.
The primary active ingredient was Ophioglossum polyphyllous
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Zotrex was a male sexual enhancement supplement manufactured by Nova pharmaceutical in Utah.
The primary active ingredient was Ophioglossum polyphyllous sulfoaildenafil
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Zotrex was a male sexual enhancement supplement manufactured by Nova pharmaceutical in Utah.
The primary active ingredient was Ophioglossum polyphyllous sulfoaildenafil
Nova sold over 14 million pills of suloaildenafil under various names, including:
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Zotrex was a male sexual enhancement supplement manufactured by Nova pharmaceutical in Utah.
The primary active ingredient was Ophioglossum polyphyllous sulfoaildenafil
Nova sold over 14 million pills of suloaildenafil under various names, including:
OMG
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Zotrex was a male sexual enhancement supplement manufactured by Nova pharmaceutical in Utah.
The primary active ingredient was Ophioglossum polyphyllous sulfoaildenafil
Nova sold over 14 million pills of suloaildenafil under various names, including:
OMG-45
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Zotrex was a male sexual enhancement supplement manufactured by Nova pharmaceutical in Utah.
The primary active ingredient was Ophioglossum polyphyllous sulfoaildenafil
Nova sold over 14 million pills of suloaildenafil under various names, including:
Maxyte
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Zotrex was a male sexual enhancement supplement manufactured by Nova pharmaceutical in Utah.
The primary active ingredient was Ophioglossum polyphyllous sulfoaildenafil
Modified form of sildenafil, modifying existing drugs is a sinister method to evade FDA detection.
Nova sold over 14 million pills of suloaildenafil under various names, including:
Maxyte
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herbal weight loss medications
Vaysse J. Food Additives Contaminants Part A: Chemical Analysis, Control, Exposure & Risk Assessment 2010; 27: 903-16.
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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
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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
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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
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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
Medication safety concerns
Few medications
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2D diffusion ordered spectroscopy 1H-nuclear magnetic resonance spectroscopy
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0
20
Sibutramine
phenolphth
aleinsynep
hrine caffeine
115
13
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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.
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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
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sibutramine
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sibutramine
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must have a history of
randomized, double blind10 mg silbutramine or placebo
age 55+
BMI 25-27
CV disease DM + CV risk factorboth
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• Nonfatal MI• Nonfatal CVA
• Cardiac arrest• CV death
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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
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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
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licorice glycyrrhiza glabra50x sweeter than sucrose
often it is an undeclared ingredient, sweetener
11-beta steroid dehydrogenase
adulteration
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7-30 ng/dLaldo
5-20 mcg/dLCortisol
Cortisol circulates at 1,000 times the aldosterone concentration
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7-30 ng/dLaldo
5-20 mcg/dLCortisol
Cortisol circulates at 1,000 times the aldosterone concentration
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MR
Mineralcorticoid receptor
7-30 ng/dLaldo
MR 5-20 mcg/dLCortisol
Cortisol circulates at 1,000 times the aldosterone concentration
Inside the principle cell
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MR
Mineralcorticoid receptor
7-30 ng/dLaldo
MR 5-20 mcg/dLCortisol
Cortisol circulates at 1,000 times the aldosterone concentration
Inside the principle cell
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MR
Mineralcorticoid receptor
7-30 ng/dLaldo
MR 5-20 mcg/dLCortisol
Na-K ATPaseENacK+ channelH+-ATPase
Cortisol circulates at 1,000 times the aldosterone concentration
Inside the principle cell
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Mineralcorticoid receptor
MR 5-20 mcg/dLCortisol
Cortisol circulates at 1,000 times the aldosterone concentration
Inside the principle cell
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Mineralcorticoid receptor
MR 5-20 mcg/dLCortisol
Cortisol circulates at 1,000 times the aldosterone concentration
Inside the principle cell
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Mineralcorticoid receptor
MR 5-20 mcg/dLCortisol
Cortisol circulates at 1,000 times the aldosterone concentration
Inside the principle cell Na-K ATPaseENacK+ channelH+-ATPase
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Mineralcorticoid receptor
MR 5-20 mcg/dLCortisol
Cortisol circulates at 1,000 times the aldosterone concentration
Inside the principle cell Na-K ATPaseENacK+ channelH+-ATPase
but does not have any mineral-ocorticoid activity. Why?
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MR Cortisol
• 11ß-hydroxysteroid dehydrogenase converts cortisol to cortisone
• Prevents cortisol from having mineralocorticoid effect
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MR Cortisol
11ß-hydroxysteroid dehydrogenase
• 11ß-hydroxysteroid dehydrogenase converts cortisol to cortisone
• Prevents cortisol from having mineralocorticoid effect
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MR Cortisol
11ß-hydroxysteroid dehydrogenase
Cortisone
• 11ß-hydroxysteroid dehydrogenase converts cortisol to cortisone
• Prevents cortisol from having mineralocorticoid effect
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MR Cortisol
11ß-hydroxysteroid dehydrogenase
Cortisone
• 11ß-hydroxysteroid dehydrogenase converts cortisol to cortisone
• Prevents cortisol from having mineralocorticoid effect
cortisol cortisone11ß-hydroxysteroid
dehydrogenase
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• Glycyrrhiza glabra is 11ß-hydroxysteroid dehydrogenase inhibitor
• Allows cortisol to have mineralocorticoid activity
MR Cortisol
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11ß-hydroxysteroid dehydrogenase
• Glycyrrhiza glabra is 11ß-hydroxysteroid dehydrogenase inhibitor
• Allows cortisol to have mineralocorticoid activity
MR Cortisol
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11ß-hydroxysteroid dehydrogenase
• Glycyrrhiza glabra is 11ß-hydroxysteroid dehydrogenase inhibitor
• Allows cortisol to have mineralocorticoid activity
MR Cortisol
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11ß-hydroxysteroid dehydrogenase
• Glycyrrhiza glabra is 11ß-hydroxysteroid dehydrogenase inhibitor
• Allows cortisol to have mineralocorticoid activity
MR Cortisol
Na-K ATPaseENacK+ channelH+-ATPase
1463.0 33
106 8
0.478165/96
• hypertension
• hypokalemia
• metabolic alkalosis
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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
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• Who? What? Why?
• interaction and accumulation
• FDA inability to restrict unsafe drugs
• Adulteration
• Contamination
• Untoward side-effects
herbal dangers
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• Who? What? Why?
• interaction and accumulation
• FDA inability to restrict unsafe drugs
• Adulteration
• Contamination
• Untoward side-effects
herbal dangers
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contaminationsloppy production practices can result in lead and cadmium contamination
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contaminationsloppy production practices can result in lead and cadmium contamination
Ayurvedic medicationsHeavy metals are mixed with herbs for
therapeutic effect
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• 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
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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.
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• randomly selected 230 ayurvedaic products that were top search results and available for sale over the Internet
• examined the samples by x-ray fluorescence
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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.
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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.
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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.
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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.
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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.
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None153
Metals40
entire cohort
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None137
Metals38
US Website or Distributor
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None43
Metals3
Member of AHPAAmerican Herbal Products Association
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None20
Metals5
Member of ADMAAyurvedic Drug Manufacturers Association
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None121
Metals30
Claims GMP or metal testingAmerican Herbal Products Association
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None19
Metals13
Rasa shastra medicine
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None131
Metals27
Non Rasa shastra medicine
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0.1 1.0 10 100 1,000 10,000 100,000
Safe
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10 100 1,000 10,000 100,000
Safe
1.0 10 100 1,000
Safe
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• 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*
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• 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*
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percent change in blood lead levels (BLL)
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percent change in blood lead levels (BLL)
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percent change in blood lead levels (BLL)
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percent change in blood lead levels (BLL)
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percent change in blood lead levels (BLL)
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• 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.
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CDC action threshold for BLL in children
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0
15
30
45
60
1960’s 1970 1975 1985 1991 2011510
253040
60
mcg
/dL
CDC action threshold for BLL in children
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• the kidney is on the front line for damage from heavy metals
tubular toxicitynephrotic syndrome
lead
cadmium
uranium
arsenic
mercury
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• 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+
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• Who? What? Why?
• interaction and accumulation
• FDA inability to restrict unsafe drugs
• Adulteration
• Contamination
• Unexpected side-effects
herbal dangers
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• Who? What? Why?
• interaction and accumulation
• FDA inability to restrict unsafe drugs
• Adulteration
• Contamination
• Unexpected side-effects
herbal dangers
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• 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
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• 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.
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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
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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.
Nine had followed the same slimming regimen from the same clinic.
first 6 months
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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.
Nine had followed the same slimming regimen from the same clinic.
Eight had renal biopsies that showed interstitial nephritis
first 6 months
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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.
Nine had followed the same slimming regimen from the same clinic.
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
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• 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
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Aristolochia
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A Wrist Loki
Aristolochia
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Vanhaelen MR, Vanhaelen-FastrePB, Jean-Louis Vanherweghem. 1994. The Lancet 343, (8890) (Jan 15): 174
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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
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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
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• 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
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• 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
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• 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.
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COOH
NO2
O
O
N
NN
N
H2N
O
OH
HO N
NN
NNH2
O
OH
HO
NH2
O
Aristocholic Acid
deoxyadenosine deoxyguanosine
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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
deoxyadenosine deoxyguanosine
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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
deoxyadenosine deoxyguanosine
DNA Add
uct F
ormati
on
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DNA Adducts are aristocholic acid’s fingerprints
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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.
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These DNA adducts cause adenine to thymine transversion mutations in the
tumor suppressor gene TP53
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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
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The FDA found Aristolochia in numerous herbal supplements in the U.S.
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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.
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Balkan nephropathy, a disease of middle-aged Romanian farmers
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• 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
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Etiologies of ESRD
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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
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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%
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“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.”
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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.
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Taiwan
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highest incidence of dialysis in the world
430 per million
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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.
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• 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.
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• 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
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• 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
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• 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
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this represents nearly 1,200 people avoiding dialysis a year
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• 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
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The Taiwan experience shows
us the way. Government
action to restrict dan-
gerous herbals can
influence public
health.
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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.
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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
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2 out of 5 adults
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1 out of 9 children
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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.
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Senators John McCain (R-AZ) and Byron Dorgan (R-ND)
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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.
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Orin Hatch (R-UT)Chief author of DSHEA
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Orin Hatch (R-UT)Chief author of DSHEA
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Orin Hatch (R-UT)Chief author of DSHEA
Tom Harkin (D-IA)Co-author of DSHEARecieved money from Herbalife
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Orin Hatch (R-UT)Chief author of DSHEA
McCain droppped support for his own bill after talking with Hatch
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thank-you
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•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
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