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 searchPhytochemical studiesIn vivo and in vitro studiesClinical studiesWhich is easier to get: a marketing license for an herbal products or a conventional medicine?herbal drugconventional medicineIt 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 licensingNone of above

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 evidences6-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 Al-

Albab", 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 “Evidence

Based Medicine”

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 4-hydroxycoumarins which act by antagonizing the effects of vitamin K.

Plants used in herbal medicine which contain coumarin derivatives and possess anti-

vitamin 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 familyImportant 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 veno-occlusive 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 anti-inflammatory 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 (meta-

analysis) 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 poor-

quality 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 shelf-

life 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.

Standardizationsee 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.