Transcript UIC

Life Sciences Research Office
“Evaluating Adverse Event Reporting
Systems for Dietary Supplements”
Bethesda, MD January 30-31, 2003
Considerations for
botanical supplements and
an overview of ephedra
Steven Dentali, Ph.D.
VP for Scientific and Technical Affairs
American Herbal Products Association
Today’s Talk

An Overview of Ephedra
– What it is, Does, and Regulatory Review
– Scientific Reviews and Studies
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Review of DSHEA
– Prior to and Findings of
Special Case of Botanicals
– Identification and Characterization
– Extracts and Standardization
American Herbal Products Association
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American Herbal
Products Association
The National Trade Association and
Voice of the Herbal Products Industry
 The American Herbal Products
Association exists to serve its
members by promoting the responsible
commerce of products which contain
herbs and which are used to enhance
health and quality of life.

American Herbal Products Association
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American Herbal
Products Association
Founded in 1983, the American Herbal
Products Association represents the
manufacturers, growers, suppliers and
retailers of herbal supplement products
 AHPA published Herbs of Commerce
and wrote Botanical Safety Handbook
 HerbMed® searchable database.
 www.ahpa.org.

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What ephedra is
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… a generic name with forty species.
...standardized common name for ma huang
(pharmacopeial term designating the dried
stem of Tsao-ma-huang, Mu-tsei-ma-huang,
San-ma-huang, and Chung-ma-huang or
Ephedra sinica Stapf, E. equisetina Bunge,
E. distachya L., and E. intermedia Schrenk
& Meyer, respectively (Hsu et al. 1986).
… the original source of the alkaloid
ephedrine reportedly first isolated from E.
equisetina in 1887 by Nagi.
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What ephedra is
One of the oldest herbs in Chinese
medicine, used extensively > 5,000 yrs
 Chen & Schmidt described
pharmacodynamic characteristics of
ephedrine in 1924. Value as a
circulatory stimulant in surgical shock
and bronchodilator in asthma.
 Traditional dosages of 3-9 g per day,
equivalent to as much as 75-225 mg
per day of ephedrine alkaloids.
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What ephedra is
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Products generally contain 8-24 mg
ephedrine alkaloids per dose. Formulated
using extracts containing 6% or 8%
ephedrine alkaloids.
Methods of quantification of ephedrine
alkaloids: (primarily the first two) ephedrine,
pseudoephedrine, norephedrine,
norpseudoephedrine, methylephedrine, and
methylpseudoephedrine are being validated.
PPA not present (racemic mixture)
Ephedrine usually predominates.
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What it does
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Indirect sympathomimetic adrenergics.
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Orally active causing bronchial dilation.
CNS stimulant & vasopressor effects.
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Anorectic and thermogenic effects.
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Regulatory Review

October 11-12, 1995 Special Working Group of the
Food Advisory Committee of FDA on Foods
Containing Ephedrine Alkaloids was Convened.
– Considered significance and extent of serious adverse
events reported in a passive reporting system
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RECOMMENDATIONS
– Limit dosage of ephedrine alkaloids, per unit and per RDI
– List ephedrine and caffeine content
– List appropriate cautions and health risks, and statement
to discourage taking more than recommended dose
– Not for under 18, during pregnancy, long term use, or with
certain diseases or disorders, or with certain drugs
– Assure GMPs including identity and quantity of alkaloids
– Develop appropriate analytical methods to control content
– Conduct more laboratory and clinical research
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Regulatory Review
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August 27-28, 1996, Full Food Advisory
Committee Meeting
– Critical review of adverse event reports to
weed out non-applicables was not done
– Some adverse events apparent with short
term use or long term low doses use
– Approx. half of the panel recommended safe
dose for ephedrine in ds as zero
– Calls for the repeal of DSHEA were heard
– One ridiculed herbs, homeopathy, astrology
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Regulatory Review
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June 4, 1997 Dietary Supplements
Containing Ephedrine Alkaloids
Proposed Rule (62 FR 30677-30724)
– 8 mg per serving, 24 mg per day
– Prohibits use with stimulant ingredients and
claims requiring long term use (weight loss/body
building)
– Requires “Do not use this product for more than
7 days. ”If short term effects are promoted such
as increased energy, mental alertness, or well
being then the label shall state: “Taking more
than the recommenced serving may result in
heart attack, stroke, seizure or death.”
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Regulatory Review
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… and the following statement.
WARNING: If you are pregnant or nursing, or if you have heart
disease, thyroid disease, diabetes, high blood pressure,
depression or other psychiatric condition, glaucoma, difficulty
in urinating, prostate enlargement, or seizure disorder consult
a health care provider before using this product. Do not use if
you are using monoamine oxidase inhibitors (MAOI) or for 2
weeks after stopping a MAOI drug; certain drugs for
depression, psychiatric or emotional conditions; drugs for
Parkinson's disease; methyldopa; or any product containing
ephedrine, pseudoephedrine or phenylpropanolamine
(ingredients found in allergy, asthma, cough/cold and weight
control products). Stop use and call a health care professional
immediately if dizziness, severe headache, rapid and/or
irregular heart beat, chest pain, shortness of breath, nausea,
noticeable changes in behavior, or loss of consciousness
occur. Do not exceed recommended serving.
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AHPA Code of Ethics
March 1994 (revised March 2001)
 Ephedra Trade Recommendations
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– Warning statement
– Serving limits per dose and per day
– Use of standard common name (HOC)
– NO added synthetic alkaloids
– *List amounts of ephedrines and caffeine
– *NO legal high or “legal” illicit drug claims
– (*added since 1994)
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AHPA’s Cautionary
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WARNING. Not intended for use by anyone under the age of
18. Do not use this product if you are pregnant or nursing.
Consult a health care professional before using this product if
you have heart disease, thyroid disease, diabetes, high blood
pressure, depression or other psychiatric conditions,
glaucoma, difficulty in urinating, prostate enlargement, or
seizure disorder, if you inhibitor (MAOI) or any other
prescription drug, or you are using an over-the-counter drug
containing ephedrine, pseudoephedrine or
phenylpropanolamine (ingredients found in certain allergy,
asthma, cough/cold and weight control products).
Exceeding recommended serving will not improve results and
may cause serious adverse health effects.
Discontinue use and call a health care professional
immediately if you experience rapid heartbeat, dizziness,
severe headache, shortness of breath, or other similar
symptoms.
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GAO Report
House Committee on Science request
 August 4, 1999, Dietary Supplements:
Uncertainties in Analyses Underlying
FDA's PR on Ephedrine Alkaloids.
 Concerns about reported adverse
events in supporting proposed dosing
level and duration of use limit.
 April 3, 2000, withdrawal of Proposed
Rule limits on level and duration.
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More Info Needed
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August 8-9, 2000 Public Meeting
– Department of Health and Human
Services' Office on Women's Health
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December 2000 Cantox Report
– Formal risk assessment (nutrient based)
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St. Luke’s Hospital/Columbia Study
– Boozer CN et al. An herbal spl containing
Ma Huang-Guarana for weight loss: a
randomized, double-blind trial. Int J Obes
Relat Metab Disord 2001 25:316-24.
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More Info Needed
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Haller and Benowitz AER Review
– Adverse cardiovascular and central
nervous system events associated with
dietary supplements containing ephedra
alkaloids. N Engl J Med 2000 343:1833-8.
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Mayo Clinic AER Review
– Samenuk D et al. Adverse cardiovascular
events temporally associated with ma
huang, an herbal source of ephedrine.
Mayo Clin Proc 2002 77:12-6.
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More Info Needed
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Greenway Literature Review
– Greenway FL. The safety and efficacy of
pharmaceutical and herbal caffeine and
ephedrine use as a weight loss agent.
Obes Rev 2001 Aug;2(3):199-21.
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Harvard/Columbia Study
– Boozer CN et al. Herbal ephedra/caffeine
for weight loss: a 6-month randomized
safety and efficacy trial. International
Journal of Obesity (2002) 26:593–604
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More Info Needed
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Phenylpropanolamine Data Review
– Morgenstern LB et al. Use of Ephedracontaining products and risk for hemorrhagic
stroke. Neurology 2003 60:132-5
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RAND Corporation Report
– HHS funded comprehensive review of the
existing science on ephedrine alkaloids
– NIH to use information to guide expanded
research effort to better understand the
safety of ephedrine alkaloids.
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Prior to DSHEA
1972 FDA Proposed to Regulate
Vitamins and Minerals as Drugs
 1976 Rogers-Proxmire Amendment
Exempted Drug Status by Potency
 1990 Nutrition Labeling and
Education Act (NLEA)
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– Award winning nutrition facts box
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Food Additive Provisions Used to
Remove Dietary Supplements
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Prior to DSHEA
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June 18, 1993 ANPR-Dykstra Report
– rules on safety levels for vitamins/minerals
– regulating amino acids as drugs
– food additive/drug status for some herbs
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Problems of the day included:
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no claims, dosage, cautions, warnings allowed
no third party literature
proof of safety-manufacturer’s burden
food or not food? If not food then what is it?
uncertain and inconsistent enforcement
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DSHEA: Findings
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Improving Citizen Health - Top National Priority
Preventative Health Measures (diet, lifestyle,
and use of supplements) Can Reduce Chronic
Disease and Health Care Costs
Consumers are Increasingly Relying on
Alternative Health Methods
Almost 50% of Americans Take Supplements
Consumers Should Be Empowered to Make
Choices Based on Data from Scientific Studies
of Health Benefits from Dietary Supplements
Federal Government Should Take Swift Action
Against Unsafe or Adulterated Products
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DSHEA: Findings
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Federal Gov Should Not Restrict or Slow the
Flow of Safe Products and Accurate Information
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DS are Safe Within a Broad Range of Intake
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Safety Problems with DS are Relatively Rare
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Legislative Action That Protects Consumer’s
Access to Safe Dietary Supplements is
Necessary to Promote Wellness
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Rational Federal Framework Must be
Established to Supersede the Current ad hoc,
Patchwork Regulatory Policy on DS
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Dietary Supplement
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A product (not tobacco) intended to
supplement the diet: vitamin, mineral,
herb or other botanical, amino acid, or
concentrate, metabolite, constituent,
extract, or combination of the above
…intended for ingestion in form…not
food or food replacement ….labeled as
a dietary supplement and is not
formerly a drug….
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DSHEA Enacted
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Food Additive Exclusion
Presumption of Safety
Statements of Nutritional Support
New Dietary Ingredients Unsafe
GMPs to be Modeled After Foods
(Feb 6, 1997 ANPR of Dietary Supplement cGMPs
from Industry Proposal submitted Nov 20, 1995)
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June 18, 1993 ANPR Withdrawn
Commission Labels Established
Office of DS Established (ODS/NIH)
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Special Case of
Botanicals (AERs)
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Closer to foods than most drugs
– Complex mixtures derived from plants
Regulated as foods + DSHEA
 Identification of material is critical (‘97)
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– digitalis with plantain from Europe
– germander not skullcap in Belgium
– aristolochia root for stephania root
– Periploca sepium for eleuthero
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The Hairy Baby Case
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Androgenized baby boy born to mother
taking “Siberian ginseng”
– toxicity attributed to “Siberian ginseng”
– silk vine (Periploca sepium) substituted for
eleuthero (Eleutherococcus senticosus)
– 'Ci Wu Jia' (eleuthero) frequently confused
with Southern 'Wu Jia Pi' and 'Xiang Jia Pi'
– Product actually labeled Panax ginseng root
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Misidentification or Adulterations
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Characterization for
Publication (or AERs)
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Study material needs explicit definition
– Proper identification, collection
– Plant part, method of extraction
– Solvent, ratio of solvent to herb
– Ratio of herb to finished extract
– Percent native extract in total extract
– Percent of identified markers
– Manufacturer, part and lot numbers
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Types of Extracts
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Wide spectrum extracts
– Exhaustive extracts, solvent nonspecific
 St.
John’s wort, black cohosh
 Multiple groups of chemical constituents
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Narrow spectrum extracts
– Selective, solvent specific or purifications
 Milk
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thistle, saw palmetto, green tea catechin
Intermediate extracts
 Ginkgo
– 30% flavonols/terpenes, 70% other
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Botanical Process Flow
Chart
C ru d e D rie d B o ta n ica l
S p e cifica tio n s
S im p le E xtra ct
(S e le ct S o lv e n t)
A c e to n e /W a te r
M a c e ra tio n
R e sid u e
(d is c a rd )
S o lu b le M a te ria l
(T o ta l C ru d e E x tra c t)
F in ish e d E x tra ct
H e x a n e E x tra c tio n
L ip id S o lu b le s
(d is c a rd )
W a te r S o luble C o ns titue nts
(E nric he d B io a c tiv ity)
A c id /B a s e E x tra c tio n
A c id s
N e utra ls
B a se s
F inis he d s e m i-purifie d E x tra c t
C he m ic a lly D e fine
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Semi-Purified Extracts
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Prepared for a Specific Purpose
– Not a whole plant extract
– Not a single isolated compound
Isolation of “Active” Fractions
 Ratio is Starting to Final (ex. 50:1)
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– Ginkgo, silymarin, green tea catechins
– Not a conc. of all possible extractables
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Guidance Documents
for the Manufacture and Sale of
Botanical Extracts
Retail Labeling – extract ratios/ranges
 Manufacture and Sale of Bulk Extracts
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– Extract types and approaches, QA/QC
Marker Compounds in Manufacturing
and Labeling of Botanical Products
 Standardization White Paper
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How to Standardize
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In order to produce a consistent
product, controls must be implemented
over both the raw material supply and
the manufacturing process.
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The ultimate purpose of each of these
controls is to reduce variability in the
composition of the raw material.
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What to Standardize
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Good Agricultural Practices (material)
– Seed, growing, harvesting (wild), drying
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Good Manufacturing Practices (process)
– Powdering, extraction, granulation
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Safe and Effective Products
– Adequate specifications (expertise)
– Validated methods of analysis
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Standardized Quality
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Standardization requires a thorough
description of the starting plant material
and of the whole extraction process…It is
more than the assay of an active
principle or marker. “Standardization
signifies the body of information and
controls that are necessary to guarantee
constancy of composition…”
– A. Bonati (1991) journal of ethnopharmacol., 32:195-197
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