What makes phytomedicines

unique ?

3
• Phytomedines have particular attributes, which are
not encounter when using synthetic drugs or single
compounds. Although many natural products have
been isolated and are used therapeutically as single
ingredients, for example most alkaloids (morphine
and hyoscine), cardiac glycosides (digoxine),
anticancer agents (paclitaxel, vincristine) and other
highly potent drugs. Many more are used in the
form of herbal remedies or phytomedicines. Either
the whole herb or an extract of the plant is prepared
, and may be combined with other herbs or extracts.
• Generally highly toxic drugs are used as a
single entities since the dose needs to be very
precise, but the natural mixture found in a
plant extract may have benefits conferred by
some form of interaction between the
components. Conversely, there may be toxic
ingredients present that do not contribute to
the therapeutic efficacy and which are,
therefore undesirable. If the toxic component
is also one of the active principles, than the
usual assessment of risk:benefit profile
applies.
• Phytomedicines often take a while to produce measurable
improvment and appear to have a cumulative effect, for this
reason, long-term therapy is routine. This is not a unique
property of natural products but it is also found in
conventional medicines (e.g. Antideppressants, where several
weeks of treatment may be necessary before a clinical
improvement is seen). The use of drug combinations is also
not confined to herbal products ; for example , cancer
chemotherapy and the treatment of HIV and hypertension
routinely use drug combinations. In addition, although many
phytomedicines may have been characterized
phytochemically, their mechanism of action is still unknown,
which makes isolation of one constituent impossible.
• PROPERTIES OF MIXTURES
• Herbal practitioners have always argued that the effects of
combinations of ingredients, such as those found in herbal
medicines, contribute the efficacy of phytomedicines, but until
recently there has been little evidence to demonstrate that this
is the case. In the absence of direct (i.e. clinical) evidence to
demonstrate that combination effects are taking place, indirect
evidence may be useful, for example, instances where it
appears that the dose of supposed active constituents,
calculated on the basis of the amount of a known constituent,
is too low to have an effect, but clinical and pharmacological
evidence has shown that the preparation is in fact effective.
This is the case with willow bark. In general, synergistic and
other interactions within the herbal mixtures are considered to
be positive , enabling lower doses of potent compounds to be
used and reducing the incidence and severity of side effects.
• SYNERGISTIC, MULTI-FACTORAL AND POLYVALENT EFFECTS
• Synergy and other forms of interaction between the
constituents of herbal extracts is expected, and widely
cited as fundamental tenet of phytotherapy, but it is still
poorly documented, despite a great deal of interest.
Interaction may result in enhancement of a therapeutic
effect, reduction of toxicity or preservation of stability.
Synergy is a specific type of interaction, and needs to be
proven experimentally; however, although it may take
place, it actually may not be the most important type of
interaction occuring in herbal mixtures. Not only may two
or more components of a mixture interact with each other,
but also single constituents may interact with different
pharmacological targets.
 The various interaction mechanisms involved in
the action of phytomedicines are now mainly
referred to as multi-factorial effects (also known as
polyvalent action) and may include the following:
• Several compounds affecting a single target, either
directly or indirectly: this may include synergy, the
metabolism of one active altered by the presence of
others in the extract, or the bioavailability of a
component change by the presence of another.
These are true interactions and may include
pharmacokinetic and pharmacodynamic interactions.
• A single compound affecting multiple targets:
This is not an interaction between components of a mixture of
course, but it helps to explain why a particular herbal medicine
(or any drug, for the matter) can be used for different purposes
• Multiple compounds affecting multiple related targets: these
are not necessarily interaction, but the results of a number of
constituents acting in different ways; however, interactions could
certainly also be taking place. There may be cases where the
effect of one compound cancels out the effect of another by
antoganism and this would not be known unless fraction of an
extract before testing had been carried out.
Several or all of these mechanisms may be taking place at the
same time, and the overall effects is, therefore, the results of a
complex interaction between different components of a mixture
and different targets which may all be relevant in the treatment
of a particular condition.
The various interaction mechanisms involved in
the action of phytomedicines are now mainly
referred to as multi-factorial effects (also
known as polyvalent action) and may include
the following:
• Several compounds affecting a single target,
either directly or indirectly
• A single compound affecting multiple targets:
• Multiple compounds affecting multiple
related targets
MULTIPLE PHARMACOLOGICAL EFFECTS IN A SINGLE PLANT
Ispaghula, Plantago ovata
Ispaghula, or psyllium husk is (paradoxically) effective in both
constipation and diarrhoea. The laxative effect is achieved
principally through its fiber content, but the reason why it is
more effective in chronic constipation than other types of fibre
may be due to the fact that the seed also contains constituents
with gut stimulatory properties, mediated partly through
cholinergic activation, which is likely to enhance the laxative
effect. Interestingly, it also contains gut inhibitory constituents,
which could provide a scientific explanation for the traditional
use of ispaghula in diarrhoea. In addition to gut stimulatory and
inhibitory constituents, ispaghula also contain anti-amoebic
constituents explaining its traditional use in amoebic dysentery,
thus demonstrating multiple effects , some supporting and
some opposing a particular activity in one medicinal plant.
 There may be unwanted interactions in or
between phytomedicines, such as the
presence of high levels of tannins in a herbal
drug, which may complex with and inhibit the
absorption of proteins and alkaloids.
 MECHANISMS OF INTERACTIONS
Interactions can also be classified as:
• Pharmacodynamic: where the effects of one drug are
altered or added to by the prence of another at the
site of action (so-called ‘pharmacological’ interactions)
• Pharmacokinetic: process involving absorption,
distribution, metabolism and excretion.
Pepper (Piper longum) contains the alkaloid
piperine, which has many useful pharmacological
activities (anti-inflammatory, anti-allergic, digestive),
which add to the desired effects of the other
ingredients in the formula.
 Liquorice, Glycyrrhiza glabra
In traditional Chinese Medicine (TCM), liquorice is added
to many formulae as a synergistic agent, to enhance
activity and detoxify, and it demonstrates a number of
instances of synergism not only with its own constituents,
but also with other herbs. For example, blood levels of
glycyrrhizine are lower, due to the reduced absorbtion, if
it is taken as part of an extract or mixture rather than as
an isolated compound. Whole extract of liquorice inhibit
angiogenesis, granuloma formation and fluid exudation in
inflammation, as does isoliquiritin, whereas glycyrrhizine
and glycyrrhetic acid tend to promote angiogenesis.
 CLINICAL EXAMPLES OF SYNERGY AND POLYVALENT
ACTIVITY
Ginkgo, Ginkgo biloba
The ginkgolides are known to be platelet-activating factor
(PAF) antagonist, a mechanism of anti-inflammatory activity,
and a synergistic interaction between ginkgolides A and B has
been shown using an in vitro platelet aggregation test. A
positive interaction was shown by an isobole curve using a
50% mixture of the two. Furthermore, the presence of other
ginkgolides and the ginkgoflavones also had an effect on
overall activity: the mixture of ginkgolides A, B and C at a
dose of 100-240 mg, generated a PAF-antagonizing effect in
humans which was equivalent to to a dose of 120 mg of a
standardized ginkgo extract containing only 6-7 mg of
ginkgolides, together with bilabolide and flavonol glycosides.
• However, ginkgo flavones are also anti-
inflammatory, the combination being considered
additive and possibly synergistic in effect as
well as increasing blood circulation to the brain,
and a total ginkgo extract acts as an anti-oxidant
activity in brain preparations. Clinical studies
have shown ginkgo to be effective in improving
cognitive function as well as the early stages of
demantia; the preparation used being a total
extract not just the flavonoids. This suggests
polyvalent as well as synergistic activity.
 Ginkgo, taken in combination with other
herbs, also shows synergistic-like interactions:
a double-blind, cross-over trial using 20
young, healty volunteers tested ginsenk with
ginkgo extract and found it to be more
effective in improving cognitive function than
either alone.
 Cannabis, Cannabis sativa
Cannabis has potential as a therapeutic agent in chronic
conditions such as rheumatoid arthritis, HIV infection and
multiple sclerosis. Documented reports of interactions
within the herb include tha fact that levels of
tetrahydrocannabinol (THC) in the brain can be elevated
by cannabidiol, and it is known that THC taken alone can
induce anxiety, which can be attenuated by the presence
of cannabidiol in the herb. There is additional evidence to
show that the effect of the herb is both qualitatively and
quantitatively different to that of isolated THC. The herb
extract is a better antispastic agent than THC alone, as
measured in an immunogenic model of multiple sclerosis.
• Willow bark, Salix alba
A randomized, placebo-controlled trial of the extract of the
efficacy of a standardized effect of willow bark, for
osteoarthritis of the hip and knee, was carried out recently
mainly in elderly patients. The level of pain is assessed by both
the patient and physician and efficacy was confirmed. However,
the results also suggested the involment of some form of
synergy. Firstly, the gastrointestinal side effects commonly
encountered with non-steroidal anti-inflammatory drugs,
including aspirin, were not seen at the doses used, although it
is usually assumed that willow bark is effective due to its salicin
(and therefore salicylic acid) content. Furthermore, when the
amount of salicin in the study preparation was taken into
account, the dose used (equivalent to 240 mg of salicin daily)
was insufficient to explain the activity. Investigation were than
carried out to see if another mechanism might be operating.
The effect on COX-1 (a cyclooxygenase isoenzyme) was
examined and no involment found (despite the fact
that COX-1 is inhibited by aspirin). COX-1 is responsible
for many side effects, especially those on the digestive
system. However, COX-1 and lipoxygenase, which are
also involved in pain and inflammation, were both
inhibited. This shows that the phytomedicines do not
necessarily in the same way as isolated constituents,
and indicated that interactions were taking place in the
willow bark preparations, but further clinical studies are
needed for confirmation.
IMPLICATIONS OF SYNERGY
Bioassay-led isolation of activities
Scientists often investigate and extract medicinal plants with
a view to finding the single chemical entity responsible for
the effect, but this may lead to inconclusive results. If a
combination of substances is needed for the effect, then the
bioassay-led method of investigation, narrowing activity first
to a fraction and eventually to a compound, is doomed to
failure, and tih has led to the suggestion that some videly
used plants are in fact devoid activity. An example, would be
the investigation into the ‘sausage tree’ (Kigelia pinnata),
where fractionation destroyed the previously noted cytotoxic
effect. The possibilty of polyvalent action should, therefore,
be taken into account, and, if activity appears to be lost
during purification, interaction should be suspected and a
search for synergy could be instigated.
• ESTABLISHING THE ACTIVE PHARMACEUTICAL INGREDIENT (API)
OF A PRODUCT
There are many examples of multifactorial effects in a single
plant due to the several constituents acting at multiple targets,
and consequently many herbal medicines can be used for
several different disorders. This present an opportunity for
developing specific extracts, or combinations for particular
purposes, based on the same plant (and perhaps in different
combinations with other herbs), for different therapeutic
indications. Once the optimum composition of a product has
been determined by pre-clinical and clinical studies, this specific
extract should be considered ‘the active pharmaceutical
ingredient’ (API). For a manufacturer, this provides an
opportunity for patent protection. It also means that all extracts
are not necessarily equivalent in therapeutic effect, or
bioavailability.
 OTHER REASONS FOR NOT ISOLATING INDIVIDUAL
CONSTITUENTS
• The most important reason for not isolating an individual
component is the presence of multifactorial or polyvalent
effects in a mixture, and the enhanced therapeutic benefit that
such effects are expected to produce. However, there are issues
of cost, and also the following should be taken into account:
• Unstable constituents: Sometimes the presence of all
components isolated from the plant material, which may
include antioxidants for example, may ‘protect’ the actives from
decomposition. Examples of herbs in which is thought to take
place include valerian (Valeriana spp.), garlic (Allium sativum),
ginger (Zingiber officinalis) and hops (Humulus lupulus).
• OTHER REASONS FOR NOT ISOLATING INDIVIDUAL
CONSTITUENTS (cont.)
• Unknown active constituents: For some herbs, even
those which are widely used, the actives may not have
been completely identified. This is in fact very common,
and can be seen from the example of liquorice, and,
even for a herb with a very long history, new effects for
old compounds are continually being discovered.
• A range of activities identified: It is unusuall for a plant
to contain only one active constituent. Even for cannabis,
where there is only one significant psychoactive
ingredient, tetrahydrocannabinol, other constituents of
the herb may enhance its activity.
• METABOLOMICS AND THE FUTURE OF RESEARCH ON
PHTOMEDICINES
Since the early 1990s hyphenated techniques have allowed
scientists to identify many of the metabolites in an extract
in a relatively short period of time. A range of novel
approaches, and the most importantly, metabolomics, now
offer unique opportunities for understanding such complex
mixtures, and their effects. Metabolomics, has been
defined as ‘both the qualitative and quantitatice analysis of
all metabolites in an organism’, or : the metabolome
represents the collection of all metabolites in a biological
organism, which are the end products of its gene expression
(Daviss 2005).*

*Daviss,B.,2005.Growing pains for metabolomics.The Scientist 19. 25-28.

 Traditional System of Herbal
Medicines
• All modern medicine is derived from ancient herbal traditions.
These have evolved to produce the conventional medicine
known in the West, which uses both synthetic drugs and
isolated natural compounds. Plant extracts are now rarely used
by physicians or in hospitals, although herbal remedies are
popular with the public and improvements in their formulation
have resulted in a new generation of phytomedicines that are
more potent than before and also chemically standardized.
There is, however, a resurgance of interest in the older
Oriental systems; this is due partly to dissatisfaction with
conventional treatments and partly to the constantly growing
interest in all things natural , environmentally friendly and
biodegradable.
• These older types of medicine are philosophically based,
and are holistic in that they treat the patient as a whole
rather than as the ‘owner’ of a disease or multifunctioning
organ. They also have much in common with traditional
medical herbalism as it was, and still is, practised in
Europe and America. Whether or not pharmacists, doctors
and and other healthcare professionals accept the validity
of these older medical systems, it is necessary for them to
know about their basic principles for two main reasons.
First, to be in a position to advise patients who may wish
to consult and alternative practitioner and second ,
because traditional use is a common starting point in the
ongoing search for new drugs.
• It is necessary to consider the cultural environment
in which traditional medicines are being used to
make our expectations more reasonable, put these
treatments in the context of Western thinking and
widen the criteria of selection of remedies for our
own use within modern medicine.
• Three types of traditional medicine have been
chosen as follows:
* Traditional Chinese Medicine (TCM)
* Ayurveda
* Traditional African Medical systems (TAMS)
 Traditional Medicine can be defined as:
Medical practice that includes diagnosis,
prevention and treatment, relying on
practical experience and observations
handed down from generations to
generations, whether verbally or writing.