2. 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.
3. 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.
4. 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
5. 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:
6. 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.
8. 1937
Sulfanilamide, used to treat
streptococcal infections
Salesmen for the S.E.
Massengill Co. report
demand for a liquid
formulation
9. Chief chemist and pharmacist, Harold
Cole Watkins discovered he could
dissolve sulfonamide in diethylene
glycol.
10. 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
11. 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
15. 1937
June
July
Aug
Sales person reports demand
Oct 11
Sept
Oct
268 gallons shipped nationally
American Medical Association received reports from Tulsa,
OK, that an unfamiliar sulfanilamide compound was
responsible for 6 deaths
16. 1937
June
July
Aug
Sales person reports demand
Oct 11
Oct 14
Sept
Oct
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 FDA
An inspector in the Kansas City Station confirms 9 deaths
17. 1937
June
July
Aug
Sales person reports demand
Oct 11
Sept
Oct
268 gallons shipped nationally
American Medical Association received reports from Tulsa,
OK, that an unfamiliar sulfanilamide compound was
responsible for 6 deaths
Oct 14
NY physician alerts the FDA
An inspector in the Kansas City Station confirms 9 deaths
Oct 17
AMA, FDA Inspectors and the chemists at Messingil all concur, the
elixir contains diethylene glycol.
18. diethylene glycol is two ethylene glycol
molecule bound by an ether bond
HO CH2 CH2 O CH2 CH2 OH
19. diethylene glycol is two ethylene glycol
molecule bound by an ether bond
HO CH2 CH2 O CH2 CH2 OH
20. diethylene glycol is two ethylene glycol
molecule bound by an ether bond
HO CH2 CH2 O CH2 CH2 OH
21. diethylene glycol is two ethylene glycol
molecule bound by an ether bond
HO CH2 CH2 O CH2 CH2 OH
22. diethylene glycol is two ethylene glycol
molecule bound by an ether bond
HO CH2 CH2 O CH2 CH2 OH
23. diethylene glycol is two ethylene glycol
molecule bound by an ether bond
HO CH2 CH2 O CH2 CH2 OH
24. diethylene glycol is two ethylene glycol
molecule bound by an ether bond
HO CH2 CH2 O CH2 CH2 OH
25. diethylene glycol is two ethylene glycol
molecule bound by an ether bond
HO CH2 CH2 O CH2 CH2 OH
26. 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
27. 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.
28. 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.
29. The first time I ever had occasion to call in a doctor for Joan
and she was given Elixir of Sulfanilamide. All that is left to us is
the caring for her little grave.
letter to FDR
30. The first time I ever had occasion to call in a doctor for Joan
and she was given Elixir of Sulfanilamide. 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
31. The first time I ever had occasion to call in a doctor for Joan
and she was given Elixir of Sulfanilamide. 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
32. In 1937 the law did not prohibit the sale of
dangerous, untested, or poisonous drugs.
33. 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.
34. 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
41. 1937
June
July
Aug
Sales person reports demand
1938
Jan
Feb
Mar
Sept
Oct
Nov
Dec
268 gallons shipped nationally
National Tragedy
Apr
May
June
Passed the house June 1
Passed the Senate June 2
Signed into law June 25
Food, Drug, and Cosmetic Act
The law required manufacturers to submit evidence
of a drug's safety before it could go on the market.
42. Drugs have to be safe (1938) to be approved for
sale in the United States
43. Frances O. Kelsey receiving the President's Award
for Distinguished Federal Civilian Service
44. 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.
45. Frances O. Kelsey receiving the President's Award
for Distinguished Federal Civilian Service
The Drug Amendment of 1962 The amendment added a
requirement for effectiveness
was approved unanimously
for drug approval.
after Dr. Kelsey, an FDA
officer, refused approval of
Thalidomide.
46. Drugs have to be safe (1938) and effective (1962)
to be approved for sale in the United States
47. Drugs have to be safe (1938) and effective (1962)
to be approved for sale in the United States
53. before DSHEA
• Before 1994, herbal products were
considered food additives
• Manufacturers required to show proof of
safety before sales
54. under 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
55. Drugs have to be safe (1938) and effective (1962)
to be approved for sale in the United States
56. 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)
57. 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
58. 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
Salses (millions)
$30,000
26000
$22,500
$15,000
$7,500
$0
700
1994
2010
69. Grubbs V, Plantinga LC, et al. AJKD 2013; 61(5):739-47.
supplement use
Hispanics
African Americans
31%
Caucasians
36%
43%
64%
69%
Use
Don’t Use
57%
70. Grubbs V, Plantinga LC, et al. AJKD 2013; 61(5):739-47.
supplement use
less than high school
high school
college
36%
46%
40%
54%
65%
Use
Don’t Use
60%
71. Grubbs V, Plantinga LC, et al. AJKD 2013; 61(5):739-47.
supplement use
50%
Poverty Index ratio 1-3
Poverty Index ratio >3
35%
Poverty Index ratio <1
31%
50%
65%
Use
69%
Don’t Use
72. Grubbs V, Plantinga LC, et al. AJKD 2013; 61(5):739-47.
•
•
people that use supplements are not casual users
they are committed, overwhelmingly they take them
everyday
70%
10%
<7
18%
7-20
21+
73. Grubbs V, Plantinga LC, et al. AJKD 2013; 61(5):739-47.
people that use supplements are not casual users
they are committed, they take them for years
ye
ar
s
30%
>3
ye
ar
s
3
hs
m
on
t
12
6-
on
t
m
6
20%
1-
22%
hs
27%
<
•
•
74. Grubbs V, Plantinga LC, et al. AJKD 2013; 61(5):739-47.
•
•
•
supplement use in CKD
the worse the CKD the more supplements
same phenomenon in cancer
48.9%
50.2%
No CKD
CKD 1, 2
65.1%
CKD 3, 4
75. Ashar BH, Rice TN, Sisson SD. Arch Intern Med. 2007;167(9):966-9.
physician knowledge
No FDA approval
No requirement for efficacy
35%
37%
63%
40%
65%
Clueless
No FDA quality assurance
Clued
60%
76. Harris Interactive Pole 1,010 phone interviews. October 2002
patient knowledge
Evidence of efficacy
FDA approval
Labels list side effects & risks
32%
41%
59%
45%
55%
68%
Required
Not Required
77. herbal dangers
• Who? What? Why?
• interaction and accumulation
• FDA inability to restrict unsafe drugs
• Contamination
• Adulteration
• Untoward side-effects
78. herbal dangers
• Who? What? Why?
• interaction and accumulation
• FDA inability to restrict unsafe drugs
• Contamination
• Adulteration
• Untoward side-effects
79. 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
80.
81. • 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
83. • all the supplements were less
than 2% silica
• yet over two years she had
ingested over 35 kg of silica and
developed stones
Stones were 100% silicate
102. Potassium Content
Noni Juice
56
mEq/L
inhibit Na-K-ATP
• milkweedJuice 51
Orange
• lily of the valley mEq/L
• hawthorne berries
Tomato juice
• siberian ginseng 58
mEq/L
Pineapple juice
34
mEq/L
•
•
•
•
dandelion
alfalfa
nettle
horsetail
103. herbal dangers
• Who? What? Why?
• interaction and accumulation
• FDA inability to restrict unsafe drugs
• Adulteration
• Contamination
• Untoward side-effects
104. herbal dangers
• Who? What? Why?
• interaction and accumulation
• FDA inability to restrict unsafe drugs
• Adulteration
• Contamination
• Untoward side-effects
105. 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.
106. 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
107.
108. ld
ivately he ll
r
nal, the p its sales wi
Internatio stuff, says
fe
Metaboli oduces the
An d
at places
h
that pr
-a figure t ckbuster
company 1 billion this year- s such blo
a
$
approach in the same league Viagra.
3/99
life
sweek 10/
and
New
Metabo
as Prozac
aceuticals
phar m
109. It had predictable cardiovascular side effects,
psychosis and radiolucent kidney stones
by 1996 15 deaths and >400 adverse reactions
110. It had predictable cardiovascular side effects,
psychosis and radiolucent kidney stones
by 1996 15 deaths and >400 adverse reactions
111. In 1996 The FDA began
proceedings to ban ephedra
112. 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."
113. 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
114. 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
129. 1948: Eli Lilly introduces 1,3 dimethylamylamine as a nasal
inhaler for rhinitis.
130. • 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
131. Council of Pharmacy and Chemistry of the American Medical
Association described the toxicity of DMAA to be:
ephedrine
DMAA
amphetamine
DMAA exerted a pressor effect 3.5 times that of epinephrine.
J Pharmacol Exp Ther 1946; 88(1):10-3
In 1983 Eli Lilly voluntarily removed it from
the market sighting safety concerns
133. • 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
134. In 1996 Ping et al. isolated
DMAA from geranium oil
135. Published in the Journal of the Guizhou Institute of Technology
The journal is now defunct
136. Published in the Journal of the Guizhou Institute of Technology
The journal is now defunct
137. • 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
138. • 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
139. • 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
144. 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
145. Department of defense report found 40
soldiers affected by DMAA
4 fatalities
4 hypertensive crisis or
cerebrovascular events
rom
ed f
n
anparasthesiaes
as b 3 sari
w
AA syncope mmis
4 seizures
DM
e co 2 hepatic failure
bas or
4 tachycardia
5 heat injury/rhabdo
palpitations
2 renal failure
146.
147. 1944: Eli Lilly patents and begins selling DMAA as a
nasal decongestant. Trade name Florthane
148. 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
149. 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
150. 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
151. 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
152. 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.
153. 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.
171. This product is not intended to
diagnose, treat, cure or prevent disease
172. herbal dangers
• Who? What? Why?
• interaction and accumulation
• FDA inability to restrict unsafe drugs
• Adulteration
• Contamination
• Untoward side-effects
173. herbal dangers
• Who? What? Why?
• interaction and accumulation
• FDA inability to restrict unsafe drugs
• Adulteration
• Contamination
• Untoward side-effects
174. • adulteration: intensional addition of
unlabeled ingredients
• contamination: accidental addition of
unlabeled ingredients
175. 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.
176. 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.
177. 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.
178.
179.
180. Laing Q, J Pharm Biomed Anal. 2006; 40:305-11
Gratz SR, J Pharm Biomed Anal. 2004; 36:525-33
From 35 to 50% of herbal erectile
dysfunction treatments contain
PDE-5 inhibitors
181. Zotrex was a male sexual
enhancement supplement
manufactured by Nova
pharmaceutical in Utah.
The primary active ingredient was
Ophioglossum polyphyllous
182. Zotrex was a male sexual
enhancement supplement
manufactured by Nova
pharmaceutical in Utah.
The primary active ingredient was
Ophioglossum polyphyllous
183. Zotrex was a male sexual
enhancement supplement
manufactured by Nova
pharmaceutical in Utah.
The primary active ingredient was
Ophioglossum polyphyllous sulfoaildenafil
184. 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:
185. 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
186. 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
187. 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
188. 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
Modified form of sildenafil, modifying existing drugs
is a sinister method to evade FDA detection.
189. herbal weight loss medications
Vaysse J. Food Additives Contaminants Part A: Chemical Analysis, Control, Exposure & Risk
Assessment 2010; 27: 903-16.
190. herbal weight loss medications
Medical impact of obesity
Vaysse J. Food Additives Contaminants Part A: Chemical Analysis, Control, Exposure & Risk
Assessment 2010; 27: 903-16.
191. herbal weight loss medications
Medical impact of obesity
Social impact of obesity
Vaysse J. Food Additives Contaminants Part A: Chemical Analysis, Control, Exposure & Risk
Assessment 2010; 27: 903-16.
192. herbal weight loss medications
Medical impact of obesity
Social impact of obesity
Few medications
Vaysse J. Food Additives Contaminants Part A: Chemical Analysis, Control, Exposure & Risk
Assessment 2010; 27: 903-16.
193. herbal weight loss medications
Medical impact of obesity
Social impact of obesity
Few medications
Medication safety concerns
Vaysse J. Food Additives Contaminants Part A: Chemical Analysis, Control, Exposure & Risk
Assessment 2010; 27: 903-16.
201. 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.
Herbal
2
declared
4
adulterated
14
213. Inside the principle cell
aldo
MR
7-30 ng/dL
Mineralcorticoid receptor
MR
Cortisol
5-20 mcg/dL
Cortisol circulates at 1,000 times
the aldosterone concentration
214. Inside the principle cell
MR
7-30 ng/dL
aldo
Mineralcorticoid receptor
MR
Cortisol
5-20 mcg/dL
Cortisol circulates at 1,000 times
the aldosterone concentration
215. Inside the principle cell
MR
Na-K ATPase
ENac
K+ channel
H+-ATPase
7-30 ng/dL
aldo
Mineralcorticoid receptor
MR
Cortisol
5-20 mcg/dL
Cortisol circulates at 1,000 times
the aldosterone concentration
216. Inside the principle cell
Mineralcorticoid receptor
MR
Cortisol
5-20 mcg/dL
Cortisol circulates at 1,000 times
the aldosterone concentration
217. Inside the principle cell
Mineralcorticoid receptor
MR
Cortisol
5-20 mcg/dL
Cortisol circulates at 1,000 times
the aldosterone concentration
218. Inside the principle cell
Na-K ATPase
ENac
K+ channel
H+-ATPase
Mineralcorticoid receptor
MR
Cortisol
5-20 mcg/dL
Cortisol circulates at 1,000 times
the aldosterone concentration
219. Inside the principle cell
Na-K ATPase
ENac
K+ channel
H+-ATPase
Mineralcorticoid receptor
MR
Cortisol
5-20 mcg/dL
Cortisol circulates at 1,000 times
the aldosterone concentration
but does not have any mineralocorticoid activity. Why?
228. Consumer Health Information
www.fda.gov/consumer
Black Licorice:
Trick or Treat?
A
s it turns out, you really can overdose on candy—
or, more precisely, black licorice.
Days before the biggest candy eating holiday of the year, the Food and
Drug Administration (FDA) encourages moderation if you enjoy snacking 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 contains the compound glycyrrhizin,
which is the sweetening compound
derived from licorice root. Glycyrrhizin 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/medlineplus/druginfo/natural/881.
html) in both Eastern
and Western medicine.
It has been used as a
treatment for heartburn,
stomach ulcers, bronchitis, sore throat, cough
and some infections caused
by viruses, such as hepatitis; however, 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
229. herbal dangers
• Who? What? Why?
• interaction and accumulation
• FDA inability to restrict unsafe drugs
• Adulteration
• Contamination
• Untoward side-effects
230. herbal dangers
• Who? What? Why?
• interaction and accumulation
• FDA inability to restrict unsafe drugs
• Adulteration
• Contamination
• Untoward side-effects
232. contamination
sloppy production practices can result
in lead and cadmium contamination
Ayurvedic medications
Heavy metals are mixed with herbs for
therapeutic effect
233.
234. Ayurvedic medications
• 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.
235. Saper RB, Phillips RS, Sehgal A, et al. Lead, Mercury, and Arsenic in US- and IndianManufactured Ayurvedic Medicines Sold via the Internet. JAMA. 2008;300(8):915-923.
236. • randomly selected 230 ayurvedaic products
that were top search results and available
for sale over the Internet
• examined the samples by x-ray
fluorescence
237. 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.
238. 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.
239. 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.
240. 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.
241. 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.
252. • 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*
253. • 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*
259. 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.
• 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
261. CDC action threshold
for BLL in children
60
mcg/dL
45
30
60
40
15
30
25
10
0
s
60’
19
1970
1975
1985
1991
5
2011
262. • the kidney is on the front line for damage
from heavy metals
tubular toxicity
lead
✔︎
cadmium
✔︎
uranium
✔︎
arsenic
✔︎
mercury
✔︎
nephrotic
syndrome
✔︎
263. • 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+
264. herbal dangers
• Who? What? Why?
• interaction and accumulation
• FDA inability to restrict unsafe drugs
• Adulteration
• Contamination
• Unexpected side-effects
265. herbal dangers
• Who? What? Why?
• interaction and accumulation
• FDA inability to restrict unsafe drugs
• Adulteration
• Contamination
• Unexpected side-effects
266.
267.
268.
269. • 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
270. • 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.
271. following these two cases the investigators
did an analysis of woman starting dialysis
prior to the age 50.
9
3
1
1
1989
1990
1991
1992
first 6 months
272. 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.
9
3
1
1
1989
1990
1991
1992
first 6 months
273. 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.
9
Eight had renal biopsies that
showed interstitial nephritis
3
1
1
1989
1990
1991
1992
first 6 months
274. prior to the age 50.
Nine had followed the same slimming
regimen from the same clinic.
Eight had renal biopsies that
showed interstitial nephritis
9
In mid 1990 they introduced powdered extracts of Stephania
tetrandra and Magnolia
3
officinalis
1
1
1989
1990
1991
1992
first 6 months
275. •
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
279. 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
280. 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
281. • 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
282. • 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
283. 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.
• women on dialysis were offered prophylactic
bilateral nephrectomy and ureterectomies
• this was highly effective
Cancer
4
None
6
Cancer
18
None
21
286. Aristocholic Acid
O
Aristolactam nitrenium ion
COOH
O
NO2
N
A
Ad
du
c
tF
or
m
at
io
n
metabolic activation
D
H2N
O
N
N
O
OH
deoxyadenosine
HO
O
N
N
O
N
N
O
N
O
HO
N
N
OH
NH2
deoxyguanosine
NH2
288. DNA Adducts are aristocholic acid’s fingerprints
Moreover, Schmeiser et al. were able to
detect DNA adducts formed by
metabolites of aristolochic acid
(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.
289. These DNA adducts cause adenine to
thymine transversion mutations in the
tumor suppressor gene TP53
290. 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
291. The FDA found Aristolochia in numerous herbal
supplements in the U.S.
292. Radix aristolochiae
Jade
Meridian Circulation: East Earth Herb
Inc
The FDA found Aristolochia in numerous herbal
Qualiherb ChinesesupplementsQualiHerb (Division of Finemost)
Herbal Formulas
in the U.S.
Dianthus Formulas Ba Zheng San
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
297. • 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
300. Etiologies of ESRD
100%
90%
80%
70%
Balkan nephropathy
is responsible for
70% of ESRD in
some endemic areas
40%
30%
20%
70%
2000
50%
1986
60%
10%
Diabetes
Hypertension
Glomeruloneph
Cystic kidney
2008
2006
2004
2002
1998
1996
1994
1992
1990
1988
1984
1982
1980
0%
301. “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.”
302. 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.
307. 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.
308. 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
309. Yang CS, Lin CH, Chang SH, Hsu HC.
Am J Kid Dis Feb 2000 vol 35;2: 313-8
• 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
310.
311.
312. • 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
313. • Cohort of 200,000
• Prescription data from the National Health
Insurance
ned
ban
39.3% of the Taiwanesewas
•
hia population treated
oloc medicineer 2003
ist herbal emb with aristocholic
r Chinese 1997 and November 2003
A acid Januaryov
in N
• Cumulative dose exceeded 100g per
person
317. •
•
•
•
•
Jean-Louis Vanherweghem
Michel F. Depierreux
Michel Jadoul
Renee Vanhaelen-Fastre
Maurice Vanhaelen
•
•
•
Discovered the nephropathy
•
Inspired the solution to
Balkan nephropathy
•
Key to the discovery of the
cause of Taiwanese ESRD
Tracked down the cause
Decided to offer
prophylactic nephrectomy
318.
319. The Taiwan experience shows
us the way. Government
action to restrict dangerous herbals can
influence public
health.
320. 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
Stop
25%
only 25.4% would stop
using a supplement if
public health authorities
stated it was ineffective
None
75%
321. 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
discussed
36%
None
64%
only 25.4% would stop
using a supplement if
public health authorities
stated it was ineffective
only 35.9% had told their
doctor about their use of
supplements
325. 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.
328. 2010: Dietary Supplement Safety Act
Replaced 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.
