PHG 415
Evidence-based herbal
medicine
Dr. Ghada Fawzy
How to find/generate evidences to evaluate the effect and efficacy of
an herbal drug?
Literature search
Phytochemical studies
In vivo and in vitro studies
Clinical studies
Which is easier to get: a marketing license for an herbal products or a
conventional medicine?
herbal drug
conventional medicine
It depends on whether herbal product will be marketed as dietary
supplement or as drug.
Both should obey the same official regulations required for license.
Why herbal products (e.g. extracts) intended for therapy should be
standardized?
To ensure the same efficacy.
To validate the clinical studies on these products.
A step of GMP required for product licensing
Objectives of Unit One (Introduction)
Objectives of lecture no. 1
By the end of the lecture, the student will be able to:
1-Realise the importance of natural remedies.
2-Define “evidence-based medicine”.
3-Recognize the need for scientific evidence to use herbs safely.
4-Recognize the need for clinical trials on herbs.
5-Evaluate herbal medications on the basis of clinical evidences
6-Differentiate between rational phytotherapy and herbalism.
7-Search in the different databases for articles on clinical studies of herbs.
Natural products are being increasingly
recognized as potential sources of new drug
leads. The use of plant remedies in the
prevention and treatment of illness has a
history as long as that of mankind. The
demand for herbal medicines has continued to
grow since 1980s.
• Patients are taking charge of their own health
and exploring treatment alternatives. They
have easy access to online health information,
which increases frequency of the use of herbal
medicines.
Herbal medication started with trial and error or experience with
the disease and possible treatment. This period included:
1-Ancient Egyptians
The ancient Egyptians 3000 B.C. were experts in using drugs for
curing diseases. Crude drugs of vegetable origin used included
Aloes, Gum, Myrrh, Poppy, Pomegranate, Colocynth, Linseed,
Squill, Coriander, Onion, Anise, Melon, Castor, etc.
2- The Babylonians
The Babylonian medicine was known (Laws of Hamorabi 772
B.C.).The drugs used include 250 materials of plant, and 180
materials of animal source.
3- Old Indian medicine
The "Riveda" and Ayurveda (Acoko 2000 B.C.), contained the sacred medicinal
plants. The most celebrated Indian drugs were; Sandal wood, Clove, Pepper,
Cardamom, Caraway, Ginger, Benzoin, Cannabis, Castor oil, Sesame oil,
Aloes, etc.
4- The old Chinese medicine
Beside the famous acupuncture, the Chinese medicine is very acknowledged for the
herbal medicine. The Pen Ts'ao Kang Moa 1000 B.C. contained an incredible
number of medicinal plants and drugs of animal origin. Their book includes many
recipes for every disease. Among the plants and minerals highly esteemed for its
magic health were; Ginseng, Rhubarb, Ephedra, Star Anise, Pomegranate,
Aconite.
5- The Greek and Romans
Pythagoras (560 B.C.) used drugs as Mustard and Squill, etc.
Hippocrates (466 B.C.) was familiar with numerous drugs, and wrote
"Corpus Hipocraticum 460 B.C.".The Greek Empire was followed by
that of the Romans Dioscorides who was a Greek by birth, he was the
first to describe drugs and his work "Greek Herbal of Dioscorides"
included 5000 medicinal plants in addition to animal and mineral
drugs.
6- Islamic Contribution
Abu Al Hosayn Ibn-Sina (980-1037 A.C.) whose name was Latinized
to Avicenna. He was one of the most eminent and gifted Arabian
physicians. His "Canoon If Elteb" has been described as the most
famous medical text ever written and as having dominated the medical
schools of Europe and Asia and served as the chief source of medical
knowledge for 5 centuries, till the 15th century.
Ibn Al-Baitar (1197-1248 A.C.) was the best Arabian pharmacognosist
and botanist and ranked with Dioscorides in that respect. His book
"Jame-ul-Muffradat" contains description of 2000 drugs.
Sheikh Dawood El-Antaki wrote a book named "Tazkaret Uli AlAlbab", now known as "Tazkaret Dawood Alantaki" which describes
several hundred herbs besides drugs of animal and mineral origin.
Since then many research studies were done over the years to try and
investigate the phytochemical and biological properties of the various
medicinal herbs. To end with the evidence-based herbal medicine
which is considered the ideal study of herbal medicines.
Activity could be presentation on the
main and important herbs mentioned
in this historical period
The question is where to find
evidence on herbs?
1-Traditional herb medicinal books used to find evidence or can be
utilized as starting points to do research in order to generate evidence,
such as:
-The Canon of Medicine (al-Qānūn if al-Ṭibb) is an encyclopedia of
medicine in five books compiled by Ibn Sīnā (Avicenna). It presents a clear
and organized summary of all the medical knowledge of the time.
-Ayurveda Herbal Medicine books.
-KAMPO, or the Japanese traditional medicine book ( is the study and
further development of Chinese Herbal Medicine in Japan).
2-Journals dealing with the results of different phytochemical and
preclinical (in vivo & in vitro) studies (e.g. phytochemistry, planta
medica, Phytotherapy research, J natural products, J
Ethnopharmacology, .etc.)
3-Peer reviewed journals dealing with the results of clinical studies (e.g.
eCAM, Alternative medicine review,. etc.)
4-Data bases and monographs (Natural medicines, ESCOP
monographs, PDR herbal medicine, etc.)
Online data bases e.g.:
http://www.ncbi.nlm.nih.gov/pubmed (PubMed®).
http://nccam.nih.gov/research/camonpubmed
http://www.herbmed.org
http://www.ars-grin.gov/duke/
http://www.anmp.org/
http://toxnet.nlm.nih.gov/
http://clinicaltrials.gov/
http://www.cochrane.org/cochrane-reviews (for unpublished clinical trials data)
****Do you know the difference in role of the community
pharmacist and the clinical pharmacist?
• The community pharmacist has a role mainly in preparing
and dispensing prescriptions. He can also give more advice on
the treatment of minor ailments and the provision of a private
consultation area within the pharmacy. While The role of
clinical pharmacists in the care of hospitalized patients has
evolved over time, with increased emphasis on collaborative
care and patient interaction. Studies have shown that the
addition of clinical pharmacist services in the care of
inpatients generally resulted in improved care, with no
evidence of harm. Interacting with the health care team on
patient rounds, interviewing patients, reconciling
medications, and providing patient discharge counseling and
follow-up all resulted in improved outcomes.
**** People can easily get online information on the benefits of herbs,
but is this sufficient?
• It is true that ancient medicine and traditional uses of herbs still serve as the
framework for modern medicine and guide us in our research work, but it is
a much safer to carry out detailed clinical studies before approving such
herbs.
• Watch this video and answer the question on the next step
• Comment on the information given in this video and to what extent has it
changed your opinion on herbal medicine?
However, Natural does not always mean safe!!!
Watch video (1) and comment on it.
The practice of medicine based on medical efficacy
proven by clinical trials is known as
Based Medicine”
“Evidence
Evidence-based decision making
Evidence-based clinical decision making
requires consideration of the best available
clinical research evidence, the experience of
the clinician and the patients values and
preferences.
Clinical trials
Many of the medicinally used herbs have very little, if any,
published clinical data. However, since 1996, there has been
a significant increase in the publication of randomized
clinical trials on herbs, such as echinacea, garlic, ginkgo and
St John's wort.
There is scope for further research between clinicians and
scientists to produce new medicines for all mankind.
Randomized Controlled Trial (RCT) is considered the gold
standard in evidence-based herbal medicine.
What is RCT?
Why is it considered as
gold standard?
• A randomized controlled trial (RCT) is - a form of clinical trial - most
commonly used in testing the safety (or more specifically, information
about adverse drug reactions and adverse effects of other treatments)
and efficacy or effectiveness of healthcare services.
• The key distinguishing feature of the usual RCT is that study subjects are
randomly allocated to receive one or other of the alternative treatments
under study.
• After randomization, the two (or more) groups of subjects are followed
up in exactly the same way, and the only differences should be those
intrinsic to the treatments being compared.
• The most important advantage of proper randomization is that it
minimizes allocation bias.
• The terms "RCT" and randomized trial are often used synonymously, but
some authors distinguish between "RCTs" which compare treatment
groups with control groups not receiving treatment and "randomized
trials" which can compare multiple treatment groups with each other.
• RCTs are sometimes known as randomized control trials. RCTs are also
called randomized clinical trials or randomized controlled clinical
trials when they concern clinical research.
Blinding is a specific issue in clinical trials of
herbal products. This is because of the strong
convictions held by the public and health
care providers about herbal products and
the subjectivity in rating clinical symptoms.
• However, some herbalists argue that RCT is too
narrow a methodology for herbal medicine
research.
• RCT may be effective when assessing a single
medication for a single disease, but it is difficult
to apply this methodology to herbal medicine
practice in which prescriptions vary from person
to person. Also, each herb contains several active
chemicals rather than just one.
• We have to seek proper evidence on herbs before
using or recommending them.
• Important link on clinical trials on Ginkgo biloba
Review: donepezil, metrifonate, rivastigmine, and
Ginkgo biloba are more effective than placebo in
Alzheimer's disease
Evidence-based practice
• Herbal product evaluation involves special
considerations that distinguish it from the
assessment of conventional pharmaceutical
products.
• For pharmaceuticals, the active ingredient is
always known. This is not the case with herbal
products. There is uncertainty about the amount
of active ingredient in every non-standardized
batch of herbal product.
Why are quality control and standardization
crucial procedures in herbal preparations?
• Timing of harvest, drying and storage conditions
can affect herb potency.
• Differences in product formulation and dosage
preparation (e.g. teas, tinctures, extracts,
capsules) can affect the activity of the product.
Watch the second video on safety and efficacy
of herbs as homework.
Phytotherapy and
herbalism
Phytotherapy is a rational and science-based
approach to the use of medicinal plants in the
treatment and prevention of disease.
How about herbalism?
Watch the video and find out the possible risks
involved in it!
Comparison of herbalism with rational
phytotherapy
• Herbalism contrasts with rational phytotherapy in
several ways:
Herbalism
Rational phytotherapy
Assumes that synergy or additive
effects occur between herbal
constituents or between herbs
Seeks evidence that synergy
occurs between herbal
constituents or herbs
Preparations mainly formulated
as tinctures
Preparations mainly formulated
as tablets and capsules
Mainly uses combinations of
herbs
Single herb products used mainly
Some opposition towards
standardization of preparations
Aims at using standardized
extracts of plants or plant parts
Not scientifically evaluated
Science-based approach
• Herbalist's approach has not been evaluated in
controlled clinical trials, whereas there are
numerous controlled trials of specific
phytotherapeutic preparations.
Aromatherapy
(Example of herbalism)
The foundation of aromatherapy is attributed
to Rene-Maurice, a French perfumer chemist,
who first used the term aromatherapy in 1928.
He burnt his hand in a lab and found that
lavender oil healed the burn quickly with little
scarring.
Aromatherpy is the therapeutic use of aromatic
substances extracted from plants.
Aromatherapists believe that essential oils treat
and prevent diseases by their effects on mood,
emotion and well-being in addition to their direct
effect.
They believe that constituents of essential oils
work synergistically.
• On a first appointment and before treating a client,
an aromatherapist will take a case history,
including clients medical history, lifestyle, diet and
mood/emotions.
• Then, he will select the appropriate essential oil.
• Mostly applied by massage, where drops of the
essential oils are diluted in vegetable carrier oil
such as wheatgerm oil, or sesame oil.
Essential oils used should be referred to
by the latin binomial name of the
plant species, the plant part used.
Efficacy and safety
Essential oils are believed to act both by exerting
pharmacological effects following absorption into
the circulation and via the effects of their odor on
the olfactory system.
There is little good-quality clinical research
investigating the effects of essential oils and
aromatherapy as practiced by aromatherapists.
Data regarding safety of essential oils are
limited. Few adverse effects associated with
aromatherapy treatment have been reported
and include:
-contact dermatitis, drowsiness, headache and
nausea.
-The use of oils should be avoided during
pregnancy, particularly during the first trimester.
-The use of certain essential oils should be
avoided by patients with epilepsy.
• Search on clinical studies which
investigate the effects of essential oils and
aromatherapy as practiced by
aromatherapists.
Objectives of lecture no. 2
1-Identify natural products that act on the heart and
blood.
2-Identify natural products which affect the CNS.
2-Identify natural products used for treatment of
GIT diseases.
3-Identify herbs which act on the urinary system.
5-Identify natural products used to treat cancer.
Pharmacological aspects of herbal medicine
The study of medicinal plants and their products can be
based on pharmacological action.
One of the major pharmacological groupings involves
drugs which act on the different body systems.
However, there has to be active research between
scientists and clinicians on each traditionally used
herb to help elucidate the chemical nature of its active
constituents together with their pharmacological
properties.
Drugs acting on the heart,
circulation and blood
 This includes drugs that possess
antiarrhythmic, antihypertensive,
antihyperlipidaemic, blood
anticoagulant and platelet
aggregation activities.
 In a review, Ghisalberti et al.,
have listed 447 species from 109
families having cardiovascular
activity, together with a
compilation of over 700 secondary
plant metabolites having such
activity.
Cardioactive glycosides
• A number of plants contain C23 or C24 steroidal
glycosides which exert a slowing and strengthening effect
on the failing heart.
•
In Western medicine, it is the glycosides of various
Digitalis species that are extensively employed. The
inherent activity resides in the aglycones, but the sugars
render the compounds more soluble and increase the
power of fixation of the glycosides to the heart muscle.
• Other plant genera that contain cardioactive glycosides
are; Strophanthus, Convallaria, Nerium and Thevetia.
•
Watch digitalis video.
Oral anticoagulants
These compounds inhibit the clotting mechanism
of the blood and are of value in arterial
thrombosis.
One group of active drugs constitutes the 4hydroxycoumarins which act by antagonizing
the effects of vitamin K.
Plants used in herbal medicine which contain
coumarin derivatives and possess antivitamin K activity include
Melilotus officinalis and lavandula officinalis.
-Get clinical data on these plants to support
their use.
Hypolipidaemic drugs
 Much prominence has been given to the association of high levels
of blood cholesterol and plasma triglycerides with atherosclerosis
and ischaemic heart disease.
 Some of the herbs which are still under investigation for lowering
serum total cholesterol and improving lipid profile are
 garlic (Allium sativum),
 fenugreek (Trigonella foenum-graecum)
 globe artichoke (Cynara cardunculus var. Scolymus).
The nervous system
The nervous system coordinates and regulates the
various voluntary and involuntary activities of the
body. It is divided into central and autonomic
nervous systems.
Natural Drugs affecting mental activity
These include:
 Cannabis: hallucinogenic, active constituents are in
the resin of Cannabis sativa.
 Purine bases:e.g. caffeine, theophylline and
theobromine, present in tea, coffee and cocoa.
 Ginkgo biloba:improves short term memory.
 Ginseng:improves mental concentration especially in
the eldery.
• Watch video CNS (1).
Central depressants of motor function
These include:
Tropane alkaloids such as hyoscine and atropine
(present in Solanaceous plants)
Effective in alleviation of the symptoms of Parkinson’s
disease.
Some preparations occasionally used as antispasmodics.
Moreover, they are used in treatment of travel sickness
and delirium tremens.
Analgesics
These are effective for relief of severe pain and
include opium alkaloids such as morphine and
codeine (obtained from latex of poppy capsule).
Codeine, although less active than morphine, it is
a much safer drug for relief of pain and for use as
cough depressant.
How to overcome stress?
Watch panic video.
Drugs acting on the gastrointestinal tract
It is the upper and the lower portions of the
GIT that are most susceptible to disorder and
are consequently associated with the greatest
number of drugs for their treatment.
Watch video GIT (1)
Anticholinergic drugs
 Hyoscine and hyoscyamine (present in Datura
stramonium and Atropa belladonna), help
disturbances caused by gastric mobility and muscle
spasm particularly with some ulcer patients.
Antiemetics
Ginger has received scientific approval for the
prevention of the symptoms of travel sickness.
Cannabis affords sickness relief to patients
undergoing chemotherapy.
Check article:Efficacy of ginger for nausea and
vomiting: a systematic review of randomized
clinical trials
British journal of Anaethesia, 84(3): 367-71 (2000).
Carminatives
These aromatic plants include caraway, fennel,
peppermint, thyme and chamomile.
Ulcer therapy
 Derivatives of glycyrrhetinic acid ( a triterpenoid
of liquorice root) prove effective in the treatment
of peptic ulcer. Other antiulcer agents include
marshmallow and comfrey.
 Look up articles on clinical study of Althaea
officinalis (marshmallow).
Drugs acting on the urinary system
A number of herbs are to be included in this group
Do you know examples of
natural diuretics?
These include:

Xanthine derivatives (tea,
coffee). They act by promoting
dilation of the renal medullary
blood vessels
How about natural diuretics and urinary
antiseptics?
These include drugs used for the treatment of cystitis
and urethritis. Herbs with this activity include:
buchu, horsetail and juniper.
Get clinical articles on two of them.
Can herbs be used in treatment of
malignant diseases?
• Catharanthus roseus
• Taxus brevifolia
• Podophyllum peltatum
Check preparations in the market!!!
Plant families yielding important
phytopharmaceuticals
Asteraceae -the daisy family
Important medicinal plants from the family include:
Arnica montana L. used topically for bruises
Calendula officinalis L. used for some skin problems, heal
irritations and rashes.
Cynara scolymus L. (artichoke), used in
treatment of liver and gallbladder complaints.
Echniacea angustigolia , used as
immunostimulant
Family Fabaceae
Glycyrrhiza glabra L. (liquorice), used as
expectorant and for other purposes as well.
Family Fabaceae
Physostigma venenosum (calabar bean), contains the
cholinesterase inhibitor physostigmine, used as a
myotic in glaucoma and to counteract atropine
poisoning.
Hypericaceae
Hypericum perforatum L. (St Johns
wort) has clinically well-established
effects in mild forms of depression.
It has also been employed topically for
inflammatory conditions of the skin.
****Lamiaceae
Important medicinal plants from the family:
• Lavendula angustifloia (Lavender).
• Melissa officinalis (balm).
• Rosmarinus officinalis L. (rosemary)
• Salvia officinalis L. (sage).
• Thymus vulgaris L. (thyme)
Activity: investigate pharmacological activities
of such plants and make poster.
*****Zingiberaceae
Important medicinal plants from the family:
• Curcuma longa L. (turmeric).
• Elettaria cardamomum L. (cardamom).
• Zingiber officinale (ginger).
Activity, do and discuss and prepare poster.
• ****Photocopy p.45-52. of Trease and Evans,
on pharmacological activities of natural
products.
• P. 63-64, for drugs from traditional plants.
• P.68, for some uses.
• P.70, for effect of extraction on plant
constituents.
• P.72-73, for standardized herbal extracts
under clinical investigation.
Toxicity of herbal
constituents!!
Toxicity of herbal constituents
Most common herbal remedies are fairly safe
in clinical use, not because they are natural,
but because the long history of use has
uncovered some of the adverse effects.
There are a number of toxic constituents
which confer no apparent health benefit and
herbs containing them should be avoided.
Toxicity of herbal constituents
Most common herbal remedies are fairly safe in clinical use, not because
they are natural, but because the long history of use has uncovered some of
the adverse effects. There are a number of toxic constituents which confer no
apparent health benefit and herbs containing them should be avoided.
Herbs could be classified as:
• Food herbs: gentle action, very low toxicity, rarely cause an adverse
response and can be used in substantial quantities over long periods without
any toxicity. Examples: mentha, ginger, ginseng, garlic, chamomile.
• Medicinal herbs: strong action and should be used with greater knowledge
(dosage and rationale for use), for specific conditions (with a medical
diagnosis) for a limited period. They are not tonics and have a greater
potential for adverse reactions or drug interactions. Examples: cascara
sagrada, ephedra, senna, and uva-ursi.
• Poisonous herbs: strong potential for acute or chronic toxicity and should
be used only by trained clinicians who clearly understand their toxicology
and appropriate use. Most of them are not available to the public in herb
stores. Examples: aconite, arnica, belladonna, bryonia, henbane, and
veratrum.
I-Pyrrolizidine alkaloids
These have been reported in families:
Boraginaceae, Asteraceae, Leguminosae,
Apocynaceae, Ranunculaceae and
Scrophulariaceae.
Not all pyrrolizidine alkaloids are toxic, only
those that are unsaturated at the 1,2-position,
e.g. Senecionine.
These are liver toxins and can produce venoocclusive disease of the hepatic vein as well as
being hepatocarcinogenic.
Several documented clinical examples can be
found in the literature (look them up as activity).
The total recommended maximum dose of
these alkaloids is less than 1 µg daily for less
than six weeks per year.
so the content must be estimated and if
necessary the alkaloids should be removed
before use.
Some herbal products that may contain
pyrrolizidine alkaloids
Butterbur
Coltsfoot
Butterbur is used for pain, upset stomach,
stomach ulcers, migraine and other headaches,
ongoing cough, chills, anxiety, fever, trouble
sleeping (insomnia).
Only butterbur products that are certified and
labeled “PA-free” should be used.
II-Aristolochic acid
They were formerly used as antiinflammatory agents and also as
contraceptives in India and have been
found in slimming formula.
They are banned from sale in Europe and
USA.
Aristolochic acid A is nephrotoxic and
causes renal failure as well as cancer.
III-Monoterpenes
Some of the mono- and sesquiterpenes found
in essential oils have been shown to be
carcinogenic, e.g. safrole (from Sassafras
bark).
Thujone present
in wormwood
(Artemisia
absinthium) is
toxic and
hallucinogenic.
A famous example of
toxic hallucinating
agent is myristicin (a
major phenylpropanoid
ether in nutmeg and
nutmeg oil).
Myristicin from nutmeg
•
Myristicin, or methoxysafrole, is the principal aromatic constituent of the volatile oil of nutmeg, the
dried ripe seed of Myristica fragrans. Myristicin is also found in several members of family
Umbelliferae (like parsley and dill). Several intoxications have been reported after an ingestion of
approximately 5 g of nutmeg, corresponding to 1-2 mg myristicin/kg body weight (b.w.). Although
these intoxications may be ascribed to the actions of myristicin, it is likely that other components of
nutmeg may also be involved.
•
Nutmeg has psychoactive properties at doses much higher than used in cooking. In case reports,
intoxications with nutmeg had effects that varied from person to person, but were often reported to
be an excited and confused state with headaches, nausea and dizziness, dry mouth, bloodshot eyes
and memory disturbances. Nutmeg was also reported to induce hallucinogenic effects, such as visual
distortions.
IV-Furanocoumarins
Some of these compounds ( e.g.
psoralen, xanthotoxin and
imperatorin), which are found in
umbelliferous plants and citrus peels are
phototoxic and produce
photodermatitis and rashes on contact.
-These compounds are known to form
adducts with DNA.
Regulation of herbal
medicines
Systemic review and metanalysis
With an ever-increasing plethora of studies being published in the health sciences, it is
challenging if not impossible for busy clinicians and researchers alike to keep up with the
literature. Reviews summarizing the outcomes of various intervention trials are therefore
an extremely efficient method for obtaining the “bottom line” about what works and what
doesn’t.
A systematic review is a literature review focused on a research question that tries
to identify, appraise, select and synthesize all high quality research evidence relevant
to that question.
Systematic reviews of high-quality randomized controlled trials are crucial to
evidence-based medicine. An understanding of systematic reviews and how to
implement them in practice is becoming mandatory for all professionals involved in
the delivery of health care.
Systematic reviews often, but not always, use statistical techniques (metaanalysis) to combine results of the eligible studies, or at least use scoring of the levels
of evidence depending on the methodology used.
Steps of systemic review:
1- Formulate a Question
2- Conduct a comprehensive literature search (?)
3- Refine (filter) the search by predetermined inclusion andexclusion criteria
4- Extract the appropriate data and assess its validity and quality(by applying
scoring tools e.g. Jadad& Chalmers scoring ).
5-Synthesizes, interprets, and reports data (as a summaryoutcomes or effect).
Steps of meta-analysis:
1-Define the Research Question
2-Perform the literature search (critical step, in MEDLINE, EMBASE, CINAHL,
and also in unpublished controlled clinical trials in Cochrane Central Register
of Controlled Trials ).
3-Select the studies
4-Extract the data
5-Analyze the data (Statistics)
6- Report the results
Common Questions addressed in meta-analysis are whether one treatment is more
effective than another or if exposure to a certain agent will result in disease or
toxicity.
Natural products in drug discovery
The discovery of drugs from nature is complex
and is depicted in the following scheme:
Biomass (plant, microbe, marine)
Extraction
Bioassay Screening
Structure elucidation
Large scale isolation
In vivo studies
Clinical trials
Drug
Food and drug administration required testing phases for
drug approval:
• FDA phase testing involves the use of animals for pre-clinical
testing before allowed in humans (3.5 years).
• If the new drug has proven to be non-toxic and has benefit, then
it can be awarded Investigational New Drug (IND) status, and
enter the three phases of clinical trials.
-Phase I: one year on 20-80 healthy volunteers to determine safety
and dosage.
-Phase II: two years, on 100-300 patient volunteers to evaluate
effectiveness and look for side effects.
-Phase III: three years, to verify effectiveness and monitor
adverse reactions from long-term use.
If the drug is successful in the three phases, it can receive a
New Drug Application (NDA) and likely approval for
marketing.
FDA continues evaluating the NDA for another 2.5 years,
resulting a total of 12 years for a successful drug approval.
• The process is very lengthy, it may take 12-15
years from the collection of the biomass to the
granting of a license for a new natural
product drug. And is a vey costly process too.
The regulation of herbal medicines in the UK (as
example)
Herbal products are available on the UK market
as:
• Licensed herbal medicines.
• Herbal medicines exempt from licensing (very
limited).
• Unlicensed herbal products, sold as food or
dietary supplements.
• Prescription-only medicines (hazardous plants).
• Pharmacy-only medicines; supplied by a
registered pharmacist.
Yet, the current regulatory framework for
herbal medicines does not always give
consumers adequate protection against poorquality and unsafe unlicensed herbal products.
• It also fails to reward manufacturers producing good
quality herbal products, since consumers may purchase
cheaper products unaware of the issues involved.
• A new regulatory European Union directive has been
proposed which aims to solve such problems.
• It will set up a simplified registration procedure, based
on quality and safety and relying on evidence of
traditional herbal medicinal products, which could not
otherwise fulfill medicines licensing criteria.
Manufacturers will be required to provide:
-Evidence that the herb has been used traditionally for at least 30
years
-Bibliographic data on safety with an expert report.
-A quality dossier demonstrating manufacture according to
principles of good manufacturing practice.
This directive does not apply to licensing for prescription –only
medicine, nor to traditional herbal medicines that could be
licensed by the conventional route.
Drug Interactions
Classification of drug interactions:
Drug interactions that occur in vivo are generally
classified as pharmacokinetic or pharmacodynamic
interactions.
1-Pharmacokinetic or biopharmaceutical interactions
occur when the absorption, distribution or elimination
of the drug is affected by another drug, food or
chemical.
2-Pharmacodynamic interactions occur when
the biochemical, physiological effects of drugs
and the mechanisms by which they produce
such effects are altered by another drug,
chemical or food element, producing an
antagonistic, synergistic or additive effect.
Drug-herbal interactions can occur as
pharmacokinetic or pharmacodynamic interactions.
• See table 18-7, p.424 of Comprehensive Pharmacy
Review.
Example: Ginger, garlic and feverfew increase
bleeding in patients taking warfarin by directly
inhibiting platelets and cause increased risk of
bleeding.
• Wheat grass contains high levels of vitamin
K, which directly antagonizes warfarin,
causing inadequate anticoagulation and
therapeutic failure.
Herb-drug interactions
Medicinal herbs exert clinical effects and so, may
interact with pharmaceutical medicines.
Ex. St John wort not to be used with
contraceptive pills, digoxin, HIV protease
inhibitors and selective serotonin reuptake
inhibitors, theophylline and warfarin.
Quality control
Standards applicable to crude drugs
• There are a number of standards which can be
applied to the evaluation of crude drugs either
in the whole or the powdered condition
In case of whole drugs, the macroscopical, microscopical and sensory
characters are usually sufficient for drug identification. Certain important
items to examine include:
•
color of leaves, if leaves are baled before being propperly dried, much
discolored material may be found in the middle of the bale. While over drying
makes leaves brittle and easily broken.
•
Drugs with high mucilage content (e.g. psyllium, linseed and squill) may show
moulds if stored under moist conditions.
•
Size and color are to be checked in certain drugs such as ginger, senna pods
and chamomile flowers.
•
Evidence of insect attack must also be looked for.
Pharmacopoeias contain statements as to the
percentage of other parts of the plant or of
other organic matter which may be permitted.
This may be checked by the help of
quantitative microscopy.
What is quantitative microscopy?
Important pharmacopoeial parameters include:
i-Extractive value
Significances
Useful for the evaluation especially when the constituents of the drugs can not
be readily estimated by any other means. It also helps to indicate the nature
of chemical constituents present in the drug. Also helps in the identification of
adulterants.
Types
1.Water soluble extractive values
2.Alcohal soluble extractive values
3.Ether soluble extractive values
Extractive value
1.Water soluble extractive value is applied for the drugs which contain water
soluble constituents such as tannins, sugars, plant acids and mucilage.
2.Alcohol soluble extractive value is applied for the drugs which contain
alcohol soluble constituents such as tannins, resins and alkaloids
Official method for the assay of myrrh & asafoetida
3.Ether soluble extractive value is applied for the extraction of volatile oils,
fixed oils and resins.
Ash values
The residue remaining after incineration is the ash content of the drug.(
inorganic salts of carbonates, phosphates, silicates of sodium, potassium,
calcium and magnesium) is known as ash content.
•
Ash value is a criterion to judge the identity OR purity of the crude drug
TYPES OF ASH VALUES
1.Total ash value
2.Acid insoluble ash value
3.Sulphated ash value
4. Water soluble ash value
Assays
A crude drug may be assayed for a group of constituents (e.g. glycosides of digitalis), or it may be
necessary to evaluate specific components in extracts as will be indicated under standardization
methods.
Also, biological assays remain important for screening plant materials and their fractionated
extracts in the search for new drugs.
•
In view of the large number of plant species potentially available for study, it is essential to have
efficient systems available for the rapid chemical and biological screening of the plant extracts selected
for investigation.
BIOLOGICAL SCREENING
•
Screening programmes for biologically active natural products require the right bioassays.
•
Detection of compounds with the desired activity in complex plant extracts depends on the reliability and
sensitivity of the test systems used. Bioassays are also essential for monitoring the required effects
throughout activity-guided fractionation: all fractions are tested and those continuing to exhibit activity
are carried through further isolation and purification until the active pure constituents are obtained.
Types of pharmacological screening
1-Blind screening
The aim is to see if a new compound has any useful pharmacological
activity.
2- Simple screening
The aim is to find a substance having a particular property e.g. A
single test for the conc. of sugar in blood may be used to screen
compounds for hypoglycemic activity.
3- Programmed screening
In this type of screening the most important pharmacological action of
the new compound is fully investigated.
Biological assays
Antimicrobial Screening of Natural Products
The Screening methods for the detection of antimicrobial activity of
natural products fall into three groups, including:
-Bioautographic
-Dilution methods (turbidimetric assay).
-Agar diffusion (plate assay)
Examples of herbs known for their antimicrobila activity include
-Thymus vulgaris
(Thymol)
-Lavendula officinalis
(Linalool)
Anticancer screening of natural products
There are currently four structural classes of plant derived anticancer agents on the market, which are:
•
The vinca alkaloids (vinblastine, vincristine): were isolated from Catharanthus roseus and are used for
the treatment of a wide variety of cancers, including leukemia, bladder cancer and testicular cancer.
•
The taxanes (paclitaxel and taxol): were isolated from Taxus brevifolia and are used for the treatment of
a wide variety of cancer including Ovarian, Lung, Gastric, Cervical, Prostate & Colon cancer
•
The camptothecin derivatives (topotecan and irinotecan), Uses: Ovarian cancers, Colorectal cancer.
Cytotoxicity assays
In vitro antitumor evaluation
•
Several methods for determining cellular viability and/or growth and metabolic activity, following in
vitro exposure to compounds have been reported.
These methods use well know dyes that develop a color, allowing a colorimetric measurement, such as
MTT assay which measures mitochondrial activity and Crystal violet staining method (CVS), that
measures cell viability.
Quality control
Q.C. of pure compounds is covered by standard
pharmaceutical procedures.
-Q.C. for plant extracts and unprocessed plants, is a
multistep process that covers all stages from the
growing of the botanical material to the final control of
the finished product and evaluation of its stability and
quality over time.
Many factors can influence the quality of the finished
product, e.g.Quality of the botanical material used, which
is affected by:
-infection with microorganisms
-climatic factors
-contamination with heavy metals, pesticides, herbicides.
-Adequate processing of the fresh material, including drying,
transportation, storage.
Quality of the botanical material used, which is
affected by:
-The use of appropriate and reproducible
extraction techniques.
-Storage under appropriate conditions (generally
dry, cool, in the dark).
-Use of material only within the accepted shelflife of the botanical drug.
How is quality control of herbs
more difficult than single
compounds?
Q.C. needs to assure:
• The correct botanical identity of the drug (i.e. the correct species and plant
part) in an appropriate quality (time of collection, age).
• The purity of the material used (i.e. that other botanical drugs are only
present in minimal amounts).
• Contaminants such as insects, mites, bacteria, fungi, heavy metals,
herbicides, fungicides, pesticides and any other toxins are below the legal
threshold (e.g. Eur. Ph.).
• That the required level of active compounds or a defined level of biological
activity is reached.
The above requirements are defined in a monograph in a legally binding
pharmacopoeia.
Typically a monograph includes the following:
-Title (English name, Latin name used in international
trade).
-Definition of the drug.
-Characteristics: organoleptic properties (smell, color).
-Identification (macroscopic, microscopic description, and
in some cases thin-layer chromatographic
characteristics.)
-Tests for purity (providing data on maximum
amounts of foreign matter, loss on drying, ash
values, extractive values, crude fibre.
-Required level of biologically active or lead
compounds.
-Storage (general information about required
forms of storage).
List items of a typical
monograph.
There are several methods which help to assure a
reproducible quality of the botanical material by help
in correct identification.
I-Botanical methods
It is easy to establish botanical identity and quality
using the microscope.
Examples:
i- Species of family Solanaceae can be identified
according to type of calcium oxalate crystal seen in the
powdered plant.
Cluster crystals and prisms of calcium oxalate
Solanaceae plants include:
• Atropa belladona, Datura stramonium,
Hyoscyamus niger.
• They contain high concs. of atropine, which is
used as spasmolytic in cases of gastrointestinal
cramps and ashma and as a diagnostic aid in
ophthalmology.
I-Botanical methods (contd.)
ii- The glandular and non-glandular hairs can be
used in plant identification.
Examples of glandular and non-glandular hairs
in plants of family Lamiaceae, Asteraceae,
Solanaceae
Demonstrate how microscopy
may be used in quality control
of herbs?
II-The bitterness value (Eur. Ph. 2002, chapter
2.8.15)
This is used for solutions of drugs that are used
for their bitter effect (appetite stimulating). It is
determined organoleptically (by taste) by
comparison with quinine as standard.
It is important for centaury herb, gentian root.
 The centaury herb, mainly prepared as tea,
beneficial for patients with gastric and liver
diseases. It is also a powerful antioxidant.
 The active ingredients of the centaury are
mainly phenolic acids as ferulic and sinapic
acids
III-The swelling index (Eur. Ph. 2002, chapter 2.8.4)
This index is an indicator for the amount of
polysaccharides present in a certain drug.
It is defined as the volume (in ml) occupied by 1 g of a
drug, after it has swollen in an aqueous liquid for 4 h.
The required minimal swelling indices for a variety of
botanical drugs are given in pharmacopoeias.
If these values are not reached, it may be an
indication that the botanical drug is contaminated
or that it is not of adequate quality.
Examples:
Foenugreek, linseed.
Microbial contamination
The BP requires a number of drugs (e.g. acacia, agar,
tragacanth, powdered digitalis), to be free of E.coli in
the quantity of material stated.
-Others are tested for absence of Salmonella.
-Generally, manufacturers will ensure that for crude drugs to
be taken internally, the limits for bacterial and mould
contamination as applied to foodstuffs are adhered to.
Toxic residues
These may arise in crude drugs as a result of
pesticide application during cultivation of the
drug or from fumigation of the stored product.
-In certain instances it may be necessary to test for
aflatoxins and radioactive impurities.
-TLC and GC methods are used for determination of
organochlorine and urea derivatives.
Heavy metal accumulation
Herbal drugs, like foods, should comply with the
WHO guidelines and the Pharmacopoeial
monograph, with respect to heavy metal content.
-The level of some metals such as lead, cadmium,
copper and mercury can increase due to the soil
and atmospheric pollution.
Limitations for particular metals are placed on
some products that have been chemically
manipulated, e.g.
• nickel in hydrogenated soya, and arachis oils.
• Cadmium in linseed oil.
Determination is by atomic adsorption
spectroscopy.
Assays
A crude drug may be assayed for a particular
group of constituents e.g. the total alkaloids
in belladonna or total glycosides in digitalis.
-Alternatively, it may be necessary to evaluate
specific components, e.g. the reserpine
content of Rauwolfia spp.
The key to modern industrial Q.C. are the phytochemical methods
for the identification of active ingredients and their quantification.
The most commonly used analytical techniques are:
-Tandem mass spectroscopy (MS-MS).
-HPLC, used in quantification and fingerprinting of extracts.
-GC and GC/MS, used mostly for essential oils.
-TLC, cheap and easy. It is good for identification of drugs and for
detecting contaminants.
DNA- fingerprinting techniques are also being used recently, as sensitive
tools for analysing quality of botanical materials.
•
Good manufacturing practices (GMP) refer to guidelines laid down by agencies which control
authorization and licensing for manufacture and sale of food, drug products , and active
pharmaceutical products. These guidelines are laid down with the intention of providing
minimum requirements that a pharmaceutical or a food product manufacturer must meet while
manufacturing drugs or food products ,which then assures that the products
manufactured/produced are of high quality and do not pose any risk to the consumer or public.
•
Good manufacturing practice guidelines provides guidance for manufacturing, testing, and quality
assurance in order to ensure that drug product is safe for human consumption. Many countries have
legislated that pharmaceutical and medical device manufacturer must follow GMP procedures, and have
created their own GMP guidelines that correspond with their legislation. Basic concepts of all of these
guidelines remain more or less similar to the ultimate goals of safeguarding the health of patient as well
as producing good quality medicine, medical devices or active pharmaceutical products.
•
In the U.S.A a drug may be deemed adulterated even though it has passed all of the specifications
tests and it is found to be manufactured in a facility or condition which violates or do not comply with
current good manufacturing guideline. Therefore complying with GMP is a mandatory aspect in
pharmaceutical manufacturing.
Standardization
see lecture no 6 in Final digital 2
It is essential to provide the patient with high-quality
botanical product. It applies only to extracts.
It can be defined as:
The establishment of reproducible pharmaceutical
quality by comparing a product with established
reference substances and by defining minimum
amounts of one or several compounds or groups of
compounds.