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2 Basic Principles
1. All substances can, under certain circumstances
be toxic (including chemicals in botanicals)
(as to dose or intrinsic chemical activity)
2. all dietary supplements and all therapies
promoted as health-enhancing should meet the
same standards of efficacy and safety as
conventional drugs and medical therapies
Good Evidence Good Medicine
Examples of Modern Medicines Derived from Plant Sources
Medicine
Common name Scientific name Indication
of plant
of plant
Aspirin
Bark of the
white willow
Salix alba
Oseltamivir
Atropine
Star anise
Belladonna
Tiotropium
bromide
Belladonna
Illicium verum
Atropa
belladona
Atropa
belladona
Digoxin
Purple foxglove
Digitalis
purpurea
Mechanism of action
Decreases production of prostaglandins and TXA2 due to
its irreversible inactivation of the cyclooxygenase
enzyme
Inhibits neuraminidase
Inhibits muscarinic actions of acetylcholine on structures
innervated by postganglionic cholinergic nerves
Inhibits muscarinic actions of acetylcholine on structures
innervated by postganglionic cholinergic nerves
Inhibits Na+/K+ pump in cardiac myocytes
Medicine
Common name of
plant
Scientific name
of plant
Indication
Mechanism of action
Warfarin
Melilotus
Artemisinin
Qinghaosu
Paclitaxel
Pacific yew
Artemisia
Treatment of chloroquine-resistant
annua
falciparum malaria
Taxus brevifolia Treatment of breast cancer
Vincristine
Periwinkle
Vinca rosea
Quinine
Cinchona bark
Cinchona
officinalis
Alternative treatment of severe malaria in Inhibits hemozoin biocrystallization in heme detoxification pathway,
combination with other antimalarials
which facilitates the aggregation of cytotoxic heme
Metformin
French lilac
Galega
officinalis
Treatment of type 2 diabetes mellitus and Reduction of hepatic glucose production and renal glucogenesis
polycystic ovary syndrome
Introduction
Dietary supplements - include botanical and herbal medications; available without
prescription; considered as nutritional supplements
-marketed without premarketing review of efficacy or safety and little
government oversight of purity, variations in potency, or adverse effects
Purified nonherbal nutritional supplements ex. dehydroepiandrosterone (DHEA)
and melatonin; used widely as alternative medicine
*Evidence from controlled clinical studies for their medical effectiveness is incomplete or
nonexistent.
Pharmaceuticals versus Dietary Supplements
Pharmaceuticals
Dietary Supplements
Chemical can be natural or synthetically
Chemical is derived from foods or animal
derived
tissues
FDA regulates as drugs
Generally, natural chemicals
Requires regulatory (FDA) pre- market
FDA regulates as foods (not drugs)
assessment of risk, efficacy
Pre-market assessment of risk (by FDA) is
Post-marketing surveillance (for
limited
adverse reactions)
No assessment of efficacy
System is not perfect
System is not perfect
Some risks not identified until after
Some risks not identified until after
marketing
marketing
Some risks differ from
pharmaceuticals
Common Intended Uses of Some Botanical or Nutritional Supplements
Botanical or Nutritional
Common Intended Use
Supplement
Echinacea
Decrease duration and intensity of cold symptoms
Ephedra (ma huang)
Treatment of respiratory ailments such as bronchitis
and asthma, and as a CNS stimulant
Garlic
For cholesterol lowering and atherosclerosis
Ginkgo
Treatment of intermittent claudication, and cerebral
insufficiency and dementia
Ginseng
Improvement of physical and mental performance
Milk thistle
Limitation of hepatic injury and as an antidote to
Amanita mushroom poisoning
Saw palmetto
Improvement in symptoms of benign prostatic
hyperplasia
St. Johns wort
Treatment of mild to moderate depression
Coenzyme Q10
Improvement of ischemic heart disease and for
Parkinsons disease
Glucosamine
Reduction of pain associated with osteoarthritis
Melatonin
Decrease jet lag symptoms and as a sleep aid
BOTANICAL SUBSTANCES
Synergism in Herbal Medicines
Herbal medicines composed of several molecules -> value comes from
synergy
Ex. Artemisia annua fresh extracts were 6 to 18 times more
efficacious against the plasmodium parasite than the same
amount of pure, synthesized artemisinin; 5 flavonoids:
-Artemetin, casticin, chrysoplenetin, cirsilineol,
chrysoplenol D
Mechanisms of synergy
Natural enzymes which promote transport of the active
substances across barriers
Inhibition of oxidative and reductive enzymes decreasing
metabolism
Naturally occurring multi-drug resistant proteins
BOTANICAL SUBSTANCES
Echinacea
flavonoids,
polyacetylenes
caffeoyl
conjugates
Ephedra
(Ma Huang)
major chemical
constituents -
ephedrine and
pseudoephedrine
Garlic
(Allium
sativum)
organic
thiosulfinates that
form allicin
(responsible for the
characteristic odor)
Ginkgo
(Ginkgo
biloba)
Leaves
flavone glycosides
and terpenoids
Toxicity GI effects,
scavenging effects and
neurotransmitters
anxiety, insomnia, headache;
increases nitric oxide formation
possible antiplatelet action
(CS)useful in intermittent claudication;
(caution if given with
pretreatment may reduce markers of oxidative stress
anticoagulants or
associated with CABG; mild benefit of ginkgo in patients
antiplatelets); may be
with cognitive impairment and dementia, but effects are
epileptogenic
unpredictable and unlikely to be significant.
Toxicity
unpleasant taste
GI effects, dizziness or
headache
Ginseng
genus Panax
Milk Thistle
flavonolignans
(silymarin)
Silybum
marianum
Fruit & seeds
oxicity - Estrogenic
effects (mastalgia, vaginal
bleeding); insomnia,
nervousness, hypertension;
use with caution in patients
receiving anticoagulant,
antihypertensive,
hypoglycemic, or psychiatric
medications
Toxicity loose stools; no
known drug interactions
Hypericin
hyperforin
(IV)decreased activity
of serotonergic
reuptake systems
(AS)downregulation of
adrenoceptors and
upregulation of 5-HT
receptors
Saw Palmetto
Serenoa repens or
Sabal serrulata
berries
phytosterols,
aliphatic
alcohols,
polyprenes, and
flavonoids
inhibits 5-reductase
and antagonizes
androgen receptors
abdominal pain, GI
distress, decreased libido,
headache, hypertension; no
effect on PSA
ADVERSE EFFECTS OF PLANT FOOD SUPPLEMENTS AND BOTANICAL
products and does not report their use if they are admitted to hospital or
PREPARATIONS: A systematic Review with Critical Evaluation of causality
emergency service;
CONCLUSIONS
as they use PFS (plant food supplements) at their own discretion,
14 plants were the most frequently cited; 2 were responsible for 32% of the adverse
consumers could avoid informing the family doctor, fearing a
effects reported
reprimand;
Glycine max (soybean) - considered in 95 papers; allergic reactions and
Data collected by poison centres are published only in a relatively few
hormone-like activity well known
cases.
Included in the list of major food allergens
Despite apparent reassuring ndings, it is important be aware of rare but severe
Hormonal activity is the reason that it is used in menopause
adverse effects from botanical preparations or ingredients of food supplements
Glycyrrhiza glabra (liquorice)
or traditional medicines; EXAMPLE:
Causes hypokalemia and hypertension due to glycyrrhetic acid
Camellia sinensis (green tea)
Severe hepatotoxixity was unknown before the product Exolise,
Cases of adverse effects of botanicals are numerous, in term of citations by
containing a hydroalcoholic extract responsible for a number
scientic literature or phytovigilance centres, but an assessment according to
of cases of acute hepatitis in France and Belgium
the WHO criteria indicates that the number of those with adequate evidence
Although very rare, the severity of these reactions needs
for a causal relationship is signicantly less.
information and vigilance.
Given the long period of time considered and the number of plants included in the
EXAMPLE:
review, the occurrence of adverse effects of botanical ingredients is relatively
Citrus aurantium (bitter orange)
low.
Contains adrenergic amines
The number of severe clinical reactions is very limited, but some fatal cases have
must be considered a potential risk both for athletes and for the
been described.
general population
It is important to recognize that an underestimation is also possible, for the
possible abuse as a substitute for the products containing
following reasons:
Ephedra
the consumer usually considers botanicals as safe
PURIFIED NUTRITIONAL SUBSTANCES
Coenzyme Q10
Ubiquinone
; cofactor in the mitochondrial
antioxidant; predominant form after
Toxicity well tolerated; GI disturbances -
electron transport chain; reduced
ingestion
most common adverse effect; Rare
form (ubiquinol)
small degree of efficacy in reducing BP
effects - include rash, thrombocytopenia,
and treating CAD and chronic stable
irritability, dizziness, and headache;
angina; not useful as adjunct in HF (?);
structural similarity to vitamin K
some efficacy in statin- related
decreases effects of warfarin
myopathy
Glucosamine
amino sugar
precursor of nitrogen-containing
sugars (glycosaminoglycans)
major constituent of connective
tissue (cartilage in joints)
Melatonin
serotonin
derivative
DRUG-HERB
INTERACTIONS
Ginkgo biloba
- inhibits platelet
aggregation
Echinacea
- contain alkaloids that
may deplete hepatic
glutathione stores
St. John's wort
syndrome
may increase affects of
antidepressants
decrease effectiveness of
SSRIs -
Kava
Ma-huang and
ephedra
cyclosporine,
idinavir, oral
contraceptives,
and warfarin
anticoagulant or
increase risk of bleeding
antiplatelet drugs
sedative-hypnotics additive CNS depression
(including alcohol
sympathomimetics additive
Cogon
Akapulco
Malunggay
Herba buena
Luyang dilaw
Oregano
Kataka-taka
Lubigan
Makabuhay
Ampalaya
Mayana
Tanglad
Abutra
Kalamansi
Dita
Psidium quajava L.
Jatropha curcas L.
Cough
Diarrhea
Fractures, sprains
and dislocated
joints
Kidney trouble
Preparati
on
Decoction
Decoction
Decoction
Decoction
Poultice
Roots
Decoction
Skin diseases
Wounds
Stomach ache
Stomach ache
Cough
Boils, swelling
Leaves
Poultice
Poultice
Decoction
Poultice
Juice drink
Poultice
Stomach ache
Malaria
Cough, colds
Boils
High BP
Rhizomes
Vines
Leaves
Rhizomes
Leaves
Roots
Irregular mens
Cough, colds
Alstonia scholaris (L.) R. Br. Malaria
Decoction
Decoction
Decoction
Decoction
Decoction
Decoction
Fruits
Bark
Juice
Decoction
Akapulko
(Cassia alata)
Ampalaya
(Momordica
charantia)
Bawang (Allium
sativum)
Bayabas (Psidium
guajava)
guava";
Lagundi (Vitex
negundo)
Niyog-niyogan
(Quisqualis indica L.)
"5-leaved chaste
tree"
"Chinese honey
suckle";
Sambong (Blumea
balsamifera)-
Tsaang Gubat
(Ehretia microphylla
Lam.)
Ulasimang
Bato/Pansit-Pansitan
(Peperomia
pellucida)
Yerba Buena
(Clinopodium
douglasii)
Blumea camphora
Peppermint
used as an analgesic
Local name
Scientific
name
Other names
Sambong
Blumea
balsamifera (L)
DC
Vitex negundo
(L)
Bukadkad
Subsob
Blumea Camphor
Five leaf chaste tree
Chinese chaste tree
Lagundi
Akapulco
Pharmacologic
Action
Diuresis
Chemolysis of urinary tract stones
Bronchial smooth muscle
relaxation
Antihistamine
Anti-leukotriene
Anti-inflammatory
Fungicide
Sonting
Antifungal
Leaf/lotion
Kasitas
Candlebush
Ringworm bush
NOTE: Herbal medicines are composed not only of a single compound but of several molecules. The value of medicines from plant compounds come from the synergy of
several compounds into one herbal drug product
SUMMARY
Dietary Supplements: Observations and Challenges
Botanicals and Nutritional Supplements
Components of dietary supplements can have pharmacological,
Concepts
toxicological effects on healthy individuals
Botanicals and nutritional supplements are marketed without FDA
What about individuals with disease?
review of efficacy
Role of chemical interactions?
Must follow GMP and be registered
Dietary supplements with pharmaceutical drugs
Must show studies that it is safe
Does the regulatory risk assessment process for dietary
In many cases, evidence for medical effectiveness is incomplete or
supplements take these factors in consideration?
non-existent
POSSIBLE CLINICAL USES AND COMMON TOXICITIES
Agent
Echinacea
Clinical/Intended Uses
Common cold
Toxicities
GIT distress, dizziness, headache
Ephedra
As for ephedrine
CNS and cardiovascular stimulation; arrhythmias, stroke, and seizures at high doses
Feverfew
Migraine
Garlic
Chronic anxiety
Gingko
Ginseng
Kava
Agent
Milk thistle
Saw palmetto
St. Johns wort
Coenzyme Q10
Clinical/Intended Uses
Viral hepatitis
Benign prostatic hyperplasia
Mild-moderate depression
Ischemic heart disease and Parkinsons
disease
Toxicities
Loose stools
GIT distress, decreased libido, hypertension
GIT distress, phototoxicity, serotonin syndrome with SSRIs; induces cytochrome P450 enzymes
GIT distress, can decrease effects of warfarin (structurally similar to vitamin K
Glucosamine
Dehydroepiandrosterone
Osteoarthritis
Symptomatic improvement in females
with SLE or AIDS
Melatonin
Jet lag, insomnia
Sedation, suppresses mid-cycle LH, hypoprolactinemia
Chaparral
Anti-infective, antioxidant
Ephedra
Extracts from the genus Ephedra (ma-huang) contain ephedrine and
Coltsfoot
Anti-infective
pseudoephedrine
Prior to FDA regulations, ephedra products were commonly used for asthma
Germander Dietary and digestive aid
and bronchitis, as nasal congestants, and as aids to weight reduction
Agent
Intended Uses
Chinese medicine - relieve cold and flu symptoms, for diuresis, and for bone
Jimsonweed Respiratory tract diseases
and joint pain
CARDIOTOXICITY major problem in overdose
Pennyroyal Abortifacient, induces
Contraindications: same as for ephedrine anxiety states, cardiac arrhythmias,
menses, digestive aid
diabetes, heart failure, hyperthyroidism, pregnancy
Pokeweed
Root extracts for emesis
CLAIMED USES AND IMPORTANT TOXICITIES OF SELECTED BOTANICALS
and rheumatism
Royal jelly
Immune potentiation,
Agent
Intended Uses
Toxicities
tonic, hyperlipidemias
Aconite
Analgesic (topical and
Cardiac and CNS toxicity with oral
Sassafras
Anticoagulant, urinary
oral)
use
tract disorders; oil used
Borage
Anti-inflammatory,
GIT distress and hepatic dysfunction
as antiseptic
diuretic
with oral use
REVIEW QUESTIONS
Does the United States Food and Drug Administration (FDA)
regulate herbal medications? No
Are herbal medications considered drugs by FDA standards?
No, considered nutritional supplements
What herbal medication is used for migraine and fever?
Feverfew
What herbal medication is used for jet lag?
Melatonin
What herbal medication is used for depression?
St. Johns wort
What herbal medication is used for benign prostate hyperplasia
(BPH)? Saw palmetto
What herbal medication is used for anxiety? Kava kava
What herbal medication is used for Alzheimer disease?
Gingko biloba
What herbal medication is used for hypercholesterolemia? Garlic
What herbal medication is used for the common cold?
Echinacea
What herbal medication is used for hepatitis? Milk thistle
What herbal medication is used to treat hot flushes in
menopause? Black cohosh
Is St. Johns wort a metabolic enzyme inducer or inhibitor?
Inducer
What herbal supplements should one use with caution when
using warfarin concomitantly?
The G4 supplements: garlic, ginger, gingko, and ginseng. These
substances may interact with warfarin, and some, especially
gingko which has antiplatelet effects, may increase bleeding
risk. Ginseng may decrease warfarins effects.
diane