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Medical Students:
An Introduction
MacGerald V. Cueto
Department of Pharmacology & Therapeutics
Manila Theological College-College of
Medicine
Medical Case
A 53-year-old woman with a history of knee
osteoarthritis, high cholesterol, type 2 diabetes, and
hypertension presents with new onset of hot flashes and a
question about a dietary supplement. She is obese (body mass
index [BMI] 33), does not exercise, and spends a good portion
of her work day in a seated position. She eats a low-sugar diet
and regularly eats packaged frozen meals for dinner because
she doesn’t have time to cook regularly. Her most recent
laboratory values include a low-density lipoprotein (LDL)
cholesterol that is above goal at 160 mg/dL (goal < 100 mg/dL)
and a hemoglobin A1c that is well controlled at 6%. Her blood
pressure is high at 160/100 mm Hg.
Medical Case
Her prescription medications include
simvastatin, metformin, and benazepril. She also
takes over-the-counter ibuprofen for occasional knee
pain and a multivitamin supplement once daily. She
has heard good things about natural products and
asks you if taking a garlic supplement daily could help
to bring her blood pressure and cholesterol under
control. She’s also very interested in St. John’s wort
after a friend told her that it helped alleviate her hot
flashes and could also help improve mood. How
should you advise her? Are there any supplements
that could increase bleeding risk if taken with
ibuprofen?
Introduction
• In recent decades, spectrum of disease has shifted and
the complex chronic diseases have become prevalent.
The effect of Western medicine treatment is not
satisfactory and problems of the adverse drug reaction
are also very prominent.
• About 80% of people worldwide rely on herbal
medicines for some aspects of their primary health care
• It has been estimated that 25% of modern medicines
are made from plants first used traditionally, such as
aspirin, artemisinin, ephedrine, and paclitaxel.
• there is limited scientific evidence to establish the
safety and efficacy of most herbal products.
Introduction
• The medical use of plants in their natural and unprocessed
form undoubtedly began when the first intelligent animals
noticed that certain food plants altered particular body
functions.
• While there is a great deal of historical information about
the use of plant-based supplements, there is also much
unreliable information as a result of unknown or poor-
quality natural product formulations, poorly designed
clinical studies that do not account for randomization errors,
confounders, and—most importantly—a placebo effect that
can contribute 30–50% of the observed response.
• Since the literature surrounding dietary supplements is
evolving, reputable evidence-based resources should be
used to evaluate claims and guide treatment decisions.
“If Its all Natural, it is safe for
everyday use?”
• Many consumers have embraced the use of dietary
supplements as a “natural” approach to their health
care. Unfortunately, misconceptions regarding safety
and efficacy of the agents are common, and the fact
that a substance can be called “natural” does not of
course guarantee its safety.
• In fact, botanicals may be inherently inert or toxic at
high doses. If a manufacturer does not follow GMP, this
can also result in intentional or unintentional plant
species substitutions (eg, misidentification),
adulteration with pharmaceuticals, or contamination
Safety Issues of Herbal
Medicines
Safety Issues of Herbal Medicine
1. Herbal Medicine Is Drug, Not Food.
• Herbal medicine originated from nature and belongs to
“green” therapy and has no toxin or adverse effect and
people can take it in the long term or as often as one
wishes.
• Herbal medicinal products are widely considered to be of
lower risk compared with synthetic drugs but are not
completely free from the possibility of toxicity or adverse
effects.
• Exaggerated propaganda and giving up using synthetic
medicines for adverse events are prejudice against herbal
medicine
• To ensure the safety use of herbal medicinal products,
herbal medicine should be managed as drug
Safety Issues of Herbal Medicine
2. The Relative Property of Herbal Medicine Safety.
• As the Chinese proverb says “all medicines have
their own side effects”; that is, medicine is a
double-edge sword: it can cure disease or maintain
health, while it may also cause damage to human
body.
• Herbal medicine should be adopted by appropriate
dosage and course of treatment and for adapted
syndrome, rather than unrestricted abusing.
• Overdosage and course of treatment are bound to
safety problems
• Toxic dose of Radix Bupleuri Chinensis (192 g/60 kg)
versus clinical common dose (9 g/60 kg). However, high-
dose and long-term use may also cause adverse events
Safety Issues of Herbal Medicine
3. The Complexity of Safety of Herbal
Medicine. (direct and indirect causes)
• Intrinsic Toxicity. Direct reason is the intrinsic
toxicity of some herb at normal therapeutic
dosage or in overdose.
• Ephedra, Aristolochia, and Aconitum are
considered to be toxic and are given in
controlled doses in TCM Herbology.
Safety Issues of Herbal Medicine
4. External Toxicity. Adverse effects associated
with herbal medicines may result from
contamination of products with toxic metals,
adulteration, misidentification or substitution of
herbal ingredients, or improperly processed or
prepared products
• For example, Caulis Akebiae replaced by Caulis
Aristolochiae Manshuriensis and Stephania
tetrandra replaced by Aristolochia fangchi have
led to the serious problem of “aristolochic acid
nephropathy” in the elderly in Japan.
Safety Issues of Herbal Medicine
5. Wrong Indication.
• Inappropriate use of herbal medicines can cause
negative or dangerous effects
• For instance, the herb “Ma Huang” (Ephedra) is
traditionally used in China to treat respiratory
congestion, while it was marketed as dietary
supplements formulated for weight reduction in
US.
• Over dosage use led to at least a dozen deaths,
heart attacks, and strokes
Safety Issues of Herbal Medicine
6. Herb-Drug Interaction.
• All herbal medicines are complex mixtures of
more than one active ingredient. Multitude of
active ingredients will increase the possibilities
of interactions between herbal medicines and
conventional drugs.
• Many users of medicinal herbs are usually
suffering from chronic conditions for which they
are likely to take prescribed drugs
concomitantly. This, in turn, further increases
the potential of herb-drug interaction
Safety Issues of Herbal Medicine
7. Weak Basic Research in Safety of Herbal Medicine.
• The toxicity classification is lack of scientific standard
and objective experimental data.
• Chinese Pharmacopoeia 2010, there are 83 types of
Chinese materia medica officially recorded and defined
as toxic and they were classified into three categories:
high toxicity, medium toxicity, and low toxicity. Efficacy
and toxicity of the majority of them are mostly based on
traditional knowledge and clinical experience
• There is no adequate data about toxic herbs, toxic
target organs, safe dose range, safety window of
effective dose, and minimum toxic dose
Safety Issues of Herbal Medicine
Current researches of Herbal Medicines.
• Based on the current situation, worldwide
research on herbal medicine safety is still not
broad or deep enough.
• Although, there are a limited number of
published scientific papers, the contents are
extensive, covering the safety evaluation
method, herb-drug interaction, safety
evaluation of skin-applied herbal medicine,
and the influence of herbal ingredients to
cytochrome P450 system
Safety Issues of Herbal Medicine
Next Steps
• Researches needed on the toxicity and
the herb-drug interaction of commonly
used herb medicines
• For clinical safety monitoring,
spontaneous reporting system or active
pharmacovigilance is effective in
identifying therapeutically relevant
safety issues.
Safety Issues of Herbal Medicine
• World Health Organization, WHO Traditional
Medicine Strategy 2014-2023
• devotes more attention than its predecessor to
prioritizing health services and systems,
including traditional and complementary
medicine products, practices and practitioners.
• proposes global unified planning, which includes
global management standards and quality
standards, radical source of herbs, seed and
seedling breeding, planting, harvesting and
storage, rational proceeding, manufacture, and
quality standards.
Safety Issues of Herbal Medicine
• A regulatory framework for herbal
medicines can provide greater
assurance to consumers.
• Herbal medicines managed as food
supplement, functional food, health
products, or drugs, caused differential
standards and chaotic market
• Establishment of a Safety guarantee
system comprised rational clinical
practice and risk monitoring
Botanical Substance with
Preliminary Clinical
Efficacy and Safety Data
ECHINACEA (ECHINACEA
PURPUREA)
• The three most widely used species of
Echinacea are Echinacea purpurea, E
pallida, and E angustifolia.
• Flavonoids, lipophilic constituents (eg,
alkamides, polyacetylenes), water-
soluble polysaccharides, and water-
soluble caffeoyl conjugates (eg,
echinacoside, cichoric acid, caffeic acid).
ECHINACEA (ECHINACEA PURPUREA)
• Immune modulation—increased phagocytosis, total circulating
monocytes, neutrophils, and natural killer cells, indicative of general
immune modulation. inhibited the rise in pro-inflammatory cytokines
and interleukins-6 and -8, and also inhibited mucin secretion caused by
exposure to rhinovirus type 1A in a 3D tissue model of human airway
epithelium
• Anti-inflammatory effects—Inhibition of cyclooxygenase, 5-
lipoxygenase, and hyaluronidase
• Antibacterial, antifungal, antiviral, and antioxidant effects—
demonstrated virucidal activity (MIC100 < 1 mcg/mL) against influenza
and herpes simplex viruses and bactericidal activity against
Streptococcus pyogenes, Haemophilus influenzae, and Legionella
pneumophila in human bronchial cells. In vitro, Echinaforce inactivated
both avian influenza virus (H5N1, H7N7) and swine-origin influenza
virus (H1N1) at doses consistent with recommended oral consumption.
• The extract blocked key steps (ie, viral hemagglutination activity and
neuraminidase activity in vitro) involved in early virus replication and
cellular entry. It was less effective against intracellular virus. Newer
ECHINACEA (ECHINACEA PURPUREA)
• Clinical Uses
• enhance immune function in individuals who have colds
and other respiratory tract infections as prophylaxis and
treatment.
• Preliminary studies were conducted to enhance
hematologic recovery following chemotherapy
• as an adjunct in the treatment of urinary tract and
vaginal fungal infections.
• Adverse effects with oral commercial formulations
are minimal and most often include unpleasant
taste, gastrointestinal upset, or allergic reactions (eg,
rash). No adverse pregnancy outcomes
GARLIC (ALLIUM SATIVUM)
• The pharmacologic activity of garlic
involves a variety of organosulfur
compounds
• Allicin is responsible for the
characteristic odor of garlic, and alliin is
its chemical precursor
GARLIC (ALLIUM SATIVUM)
• Cardiovascular effects—In vitro, allicin and related
compounds inhibit HMG-CoA reductase, which is
involved in cholesterol biosynthesis , and exhibit
antioxidant properties. Antiplatelet effects through
inhibition of thromboxane synthesis or stimulation
of nitric oxide synthesis and enhancement of
fibrinolytic activity
• Antimicrobial effects—Allicin has been reported to
have in vitro activity against some gram-positive
and gram-negative bacteria as well as fungi
(Candida albicans), and protozoa (Entamoeba
histolytica) via inhibition of thiol-containing
enzymes.
GARLIC (ALLIUM SATIVUM)
• Antineoplastic effects— in Animal Studies, garlic
inhibits procarcinogens for colon, esophageal, lung,
breast, and stomach cancer, possibly by
detoxification of carcinogens and reduced
carcinogen activation. Several epidemiologic case-
control studies demonstrate a reduced incidence of
stomach, esophageal, and colorectal cancers in
persons with high dietary garlic consumption.
• Endocrine effects—The effect of garlic on glucose
homeostasis does not appear to be significant in
persons with diabetes
GARLIC (ALLIUM SATIVUM)
• Adverse effects
• nausea (6%), hypotension (1.3%), allergy
(1.1%), and bleeding (rare).
• Herb-Drug Interaction
• warfarin, aspirin, ibuprofen, reduce the
bioavailability of saquinavir
GINKGO (GINKGO BILOBA)
•Active constituents in ginkgo are
flavone glycosides and terpenoids
including ginkgolides A, B, C, and J,
and bilobalide
GINKGO (GINKGO BILOBA)
• Cardiovascular effects—In animal models and some human
studies, ginkgo has been shown to increase blood flow,
reduce blood viscosity, and promote vasodilation, thus
enhancing tissue perfusion. Enhancement of endogenous
nitric oxide effects and antagonism of platelet-activating
factor have been observed in animal models.
• Metabolic effects—Antioxidant and radical-scavenging
properties have been observed for the flavonoid fraction of
ginkgo as well as some of the terpene constituents.
superoxide dismutase-like activity and superoxide anion-
and hydroxyl radical-scavenging properties. antiapoptotic
properties
GINKGO (GINKGO BILOBA)
• CNS Receptor densities increased for muscarinic, α2, and 5-
HT1a receptors, and decreased for β adrenoceptors.
Increased serum levels of acetylcholine and norepinephrine
and enhanced synaptosomal reuptake of serotonin and
dopamine, inhibition of amyloid-beta fibril formation and
protective effects of Egb761 on hippocampal neurons
against cell death induced by beta-amyloid.
• Clinically used to treat cerebral insufficiency and dementia
of the Alzheimer type
• Promising results studied for its effects in schizophrenia,
tardive dyskinesia, allergic and asthmatic
bronchoconstriction, short-term memory in healthy,
nondemented adults, erectile dysfunction, tinnitus and
hearing loss, and macular degeneration
GINKGO (GINKGO BILOBA)
• Adverse effects
• nausea, headache, stomach upset, diarrhea,
allergy, anxiety, and insomnia. Noted bleeding
complications in the patients also using either
aspirin or warfarin.
• Herb Drug Interaction
• Efavirenz, (virologic falilure) ,trazodone
(sedation), Risperidone (priapism), valproic
acid and phenytoin ( Seizures).
• Uncooked ginkgo seeds are epileptogenic due to
the presence of ginkgotoxin
GINSENG
• Panax ginseng (Chinese or Korean
Variety) Panax quinquefolium,
Eleutherococcus senticosus (Siberian
ginseng) and Pfaffia paniculata
(Brazilian ginseng)
• The active principles are triterpenoid
saponin glycosides called ginsenosides
or panaxosides and eleutherosides
(Siberian ginseng)
GINSENG
• Modulation of immune function (induced mRNA expression
for interleukins-2 and -1α, interferon-γ, and granulocyte
macrophage colony-stimulating factor; activated B and T
cells, natural killer cells, and macrophages).
• Central nervous system effects included increased
proliferating ability of neural progenitors and increased
central levels of acetylcholine, serotonin, norepinephrine,
and dopamine in the cerebral cortex.
• Antioxidant activity; anti-inflammatory effects (inhibited
tumor necrosis factor-α, interleukin-1β, and vascular and
intracellular cell adhesion molecules)
GINSENG
• Anti-stress activity (ie, stimulated pituitary-adrenocortical
system, agonist at glucocorticoid receptor);
• analgesia (inhibited substance P); vasoregulatory effects
(increased endothelial nitric oxide, inhibited prostacyclin
production);
• cardioprotective activity (reduced ventricular remodeling
and cardiac hypertrophy in animal models of myocardial
ischemia); antiplatelet activity;
• improved glucose homeostasis (reduced cell death in
pancreatic beta cells; increased insulin release, number of
insulin receptors, and insulin sensitivity);
• anticancer properties (reduced tumor angiogenesis,
increased tumor cell apoptosis).
Ginseng
• Adverse Effects
• Vaginal bleeding and mastalgia (possible
estrogenic effects) Central nervous system
stimulation (eg, insomnia, nervousness) and
hypertension.
• Methylxanthines found in the ginseng plant
may contribute to this effect.
• Vasoregulatory effects have not been found to
be clinically significant
GINSENG
• Herb-Drug Interaction
• Phenelzine, lithium, neuroleptics (Irritability,
sleeplessness, and manic behavior) .
• Caution in patients taking any psychiatric,
estrogenic, or hypoglycemic medications. Ginseng
has antiplatelet properties
• Should not be used in combination with warfarin.
• Caution with Immunocompromised individuals
and autoimmune disorders due to Cytokine
stimulation and natural killer cell activity
MILK THISTLE (SILYBUM
MARIANUM)
• Contain a lipophilic mixture of
flavonolignans known as silymarin.
• Three isomers: silybin (also known as
silybinin or silibinin; most potent),
silychristin (silichristin), and silydianin
(silidianin).
MILK THISTLE (SILYBUM MARIANUM)
• Liver disease—In animal models, milk thistle purportedly
limits hepatic injury associated with a variety of toxins,
including Amanita mushrooms, galactosamine, carbon
tetrachloride, acetaminophen, radiation, cold ischemia, and
ethanol.
• Noncompetitively inhibits lipoxygenase activity and reduces
leukotriene formation. Inhibition of leukocyte migration.
• Inhibits nuclear factor kappa B (NF-κB). increase in RNA
polymerase I activity in nonmalignant hepatocytes but not
in hepatoma or other malignant cell lines.
• It reduced collagen accumulation, and in an in vitro model it
reduced expression of the fibrogenic cytokine transforming
growth factor-β. Dose-dependent stimulatory effect on bile
flow that could be beneficial in cases of cholestasis
MILK THISTLE (SILYBUM
MARIANUM)
• Chemotherapeutic effects— In vitro and animals studies.
skin cancer, reduce tumor initiation and promotion.
• Induction of apoptosis in melanoma, prostate, colon,
leukemia cells, bladder transitional-cell papilloma cells,
cervical and hepatoma cells.
• Inhibition of cell growth and proliferation by inducing a G1
cell cycle arrest in cultured human breast and prostate
cancer
• Lactation—Historically, milk thistle has been used by
herbalists and midwives to induce lactation in pregnant or
postpartum Women for it increases prolactin production
MILK THISTLE (SILYBUM
MARIANUM)
• Adverse Events
• At high doses (>1500 mg), it can have a
laxative effect caused by stimulation of
bile flow and secretion
• Herb-Drug interaction
• posing no risk for drug interactions in
humans.
ST. JOHN’S WORT (HYPERICUM
PERFORATUM)
• Antidepressant action—The hypericin fraction was
initially reported to have MAO-A and -B inhibitor
properties.
• Inhibition of nerve terminal reuptake of serotonin,
norepinephrine, and dopamine.
• Significantly downregulate the expression of cortical
β adrenoceptors and up-regulate the expression of
serotonin receptors (5-HT2).
• Sigma receptor binding using the hypericin fraction
and GABA receptor. Reduced Interleukin-6
production.
ST. JOHN’S WORT (HYPERICUM
PERFORATUM)
• Adverse events
• Photosensitization-Consumers should be instructed to wear
sunscreen and eye protection while using this product when
exposed to the sun
• mild gastrointestinal symptoms, fatigue, sedation, restlessness,
dizziness, headache, and dry mouth. Hypomania, mania, and
autonomic arousal
• Herb-Drug Interaction
• risk of serotonin syndrome with antidepressants and
stimulantsrisk of serotonin syndrome
• Subtherapeutic levels of digoxin, birth control drugs (and
subsequent pregnancy), cyclosporine, HIV protease and
nonnucleoside reverse transcriptase inhibitors, warfarin,
irinotecan, theophylline, and anticonvulsants
SAW PALMETTO (SERENOA REPENS
OR
SABAL SERRULATA)
• Phytosterols (eg, β-sitosterol), aliphatic
alcohols, polyprenic compounds, and
flavonoids are all present.
• Saw palmetto is most often promoted
for the treatment of benign prostatic
hyperplasia (BPH).
SAW PALMETTO (SERENOA REPENS
OR
SABAL SERRULATA)
• Enzymatic conversion of testosterone to
dihydrotestosterone (DHT) by 5α-reductase
is inhibited by saw palmetto in vitro
• Noncompetitive inhibition of isoforms I and II of
5α-reductase enzyme,
• Inhibits the binding of DHT to androgen
receptors.
• inhibition of prostatic growth factors,
blockade of α adrenoceptors, and inhibition
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