Importance of phytomedicines

Medicinal Plants and Phytomedicines. Linking Plant Biochemistry and

Physiology to Human Health
1. Donald P. Briskin *

doi: http://dx.doi.org/10.1104/pp.124.2.507

Plant Physiology October 1, 2000 vol. 124 no. 2 507-514

The past decade has witnessed a tremendous resurgence in the interest and use of medicinal plant products,
especially in North America. Surveys of plant medicinal usage by the American public have shown an increase from just
about 3% of the population in 1991 to over 37% in 1998 (Brevoort, 1998). The North American market for sales of
plant medicinals has climbed to about $3 billion/year (Glaser, 1999). Once the domain of health-food and specialty
stores, phytomedicines have clearly re-emerged into the mainstream as evidenced by their availability for sale at a
wide range of retail outlets, the extent of their advertisement in the popular media, and the recent entrance of several
major pharmaceutical companies into the business of producing phytomedicinal products (Brevoort, 1998; Glaser,
1999). No doubt a major contributing factor to this great increase in phytomedicinal use in the United States has been
the passing of federal legislation in 1994 (Dietary Supplement Health and Education Act or DSHEA) that facilitated
the production and marketing of phytomedicinal products (Brevoort, 1998).

PHYTOMEDICINAL ACTIONS OFTEN RESULT FROM SECONDARY PRODUCTS INVOLVED IN

PLANT ECOPHYSIOLOGY

The beneficial medicinal effects of plant materials typically result from the combinations of secondary
products present in the plant. That the medicinal actions of plants are unique to particular plant species or
groups is consistent with this concept as the combinations of secondary products in a particular plant are often
taxonomically distinct (Wink, 1999). This is in contrast to primary products, such as carbohydrates, lipids,
proteins, heme, chlorophyll, and nucleic acids, which are common to all plants and are involved in the primary
metabolic processes of building and maintaining plant cells (Kaufman et al., 1999; Wink, 1999). Although
plant secondary products have historically been defined as chemicals that do not appear to have a vital
biochemical role in the process of building and maintaining plant cells, recent research has shown a pivotal
role of these chemicals in the ecophysiology of plants. Accordingly, secondary products have both a defensive
role against herbivory, pathogen attack, and inter-plant competition and an attractant role toward beneficial
organisms such as pollinators or symbionts (Kaufman et al., 1999; Wink and Schimmer, 1999). Plant
secondary products also have protective actions in relation to abiotic stresses such as those associated with
changes in temperature, water status, light levels, UV exposure, and mineral nutrients (Kaufman et al., 1999).
Furthermore, recent work has indicated potential roles of secondary products at the cellular level as plant
growth regulators, modulators of gene expression, and in signal transduction (Kaufman et al., 1999).

Although secondary products can have a variety of functions in plants, it is likely that their ecological function
may have some bearing on potential medicinal effects for humans. For example, secondary products involved
in plant defense through cytotoxicity toward microbial pathogens could prove useful as antimicrobial
medicines in humans, if not too toxic. Likewise, secondary products involved in defense against herbivores
through neurotoxin activity could have beneficial effects in humans (i.e. as antidepressants, sedatives, muscle
relaxants, or anesthetics) through their action on the central nervous system. To promote the ecological
survival of plants, structures of secondary products have evolved to interact with molecular targets affecting
the cells, tissues, and physiological functions in competing microorganisms, plants, and animals (for
discussion, see Wink and Schimmer, 1999). In this respect, some plant secondary products may exert their
action by resembling endogenous metabolites, ligands, hormones, signal transduction molecules, or
neurotransmitters and thus have beneficial medicinal effects on humans due to similarities in their potential
target sites (e.g. central nervous system, endocrine system, etc.) (Kaufman et al., 1999). As noted by Wink
(1999), the development of structural similarity between plant secondary products and the endogenous
substances of other organisms could be termed evolutionary molecular modeling.

THE BENEFITS OF PHYTOMEDICINES OFTEN RESULT FROM SYNERGISTIC ACTIONS OF

MULTIPLE ACTIVE CHEMICALS

In contrast to synthetic pharmaceuticals based upon single chemicals, many phytomedicines exert their
beneficial effects through the additive or synergistic action of several chemical compounds acting at single or
multiple target sites associated with a physiological process. As pointed out by Tyler (1999), this synergistic
or additive pharmacological effect can be beneficial by eliminating the problematic side effects associated
with the predominance of a single xenobiotic compound in the body. In this respect, Kaufman et al.
(1999)extensively documented how synergistic interactions underlie the effectiveness of a number of
phytomedicines. This theme of multiple chemicals acting in an additive or synergistic manner likely has its
origin in the functional role of secondary products in promoting plant survival. For example, in the role of
secondary products as defense chemicals, a mixture of chemicals having additive or synergistic effects at
multiple target sites would not only ensure effectiveness against a wide range of herbivores or pathogens but
would also decrease the chances of these organisms developing resistance or adaptive responses (Kaufman et
al., 1999; Wink, 1999).

Perhaps the most important contribution herbal medicine can make in the whole field of neurology is in
strengthening and ''feeding'' the nervous system. In cases of shock, stress or nervous debility, the nervine
tonics strengthen and restore the tissues directly. On the other hand they can contribute to the healing of
damaged nervous tissue, whether this is due to a pathological process or physical trauma. This invaluable
group of remedies is best exemplified by oats (also referred to as oatstraw), which has neither a relaxant nor
stimulant effect. Ginkgo is an important tonic for the nervous system, but appears to work via its vasodilating
action on the blood vessels of the brain. This will increase oxygen availability to brain cells. Other nervine
tonics that have, in addition, a relaxing effect, include skullcap and St. John's wort. Of these relaxing nervine
tonics, skullcap is often the most effective, particularly for problems related to stress.

Natural products and drug discovery

Can thousands of years of ancient medical knowledge lead us to new and powerful drug
combinations
in the fight against cancer and dementia?
Hong-Fang Ji, Xue-Juan Li & Hong-Yu Zhang

EMBO reports VOL 10 | NO 3 | 2009

The co-evolution theory also explains other phenomena, including synergistic effects. Several years ago,
Lewis and co-workers showed that the high anti microbial potential of Berberis spp. (Pepperidge bush) is
caused not only by antimicrobial agents such as berberine, but also by multidrug-resistance (MDR) inhibitors
such as 5-methoxyhydnocarpin (Stermitz et al, 2000). The latter have no microbicidal activity of their own,
but seemingly potentiate the antibiotic effects of other molecules. This phenomenon could be explained in
terms of co-evolution and the classic arms race between host and pathogen. Plants that evolved
antimicrobials were able to defend themselves against pathogenic bacteria; pathogens that evolved
resistance mechanisms, such as MDR pumps, were able to break plant defences; in turn, plants that
developed MDR inhibitors had a significant evolutionary advantage (Li & Zhang, 2008).

We already know of some compounds that are more powerful in combination than alone: for example, the
combination of Realgar, Indigo naturalis, Radix salvia miltiorrhizae and Radix pseudo stellariae constitutes a
formula in TCM that has proven effective against human acute promyelocytic leukaemia (Huang et al, 1995).
Its synergistic effect was recently attributed to the direct anti-cancer properties of tetra-arsenic
tetrasulphide from Realgar and the complementary effects of indirubin and tanshinone IIA from Indigo
naturalis and Radix salvia miltiorrhizae, respectively, which enhance the transport of tetra-arsenic
tetrasulphide into target cells and thus potentiates its efficacy(Wang et al, 2008).

These formulae also contain important

clues about synergistic effects that could
provide new leads for the fight against
complex diseases such as cancer and
dementia. Most of these compounds are
available as pure chemicals and some
have already been used in the clinic for
many years. This accumulated experience
from TCM and other ancient medicinal
practices could allow modern researchers
to design and control synergistic effects far
better than was possible by blending crude
natural products.

TRENDS in Pharmacological Sciences 26, 178-182 (2005)

www.arxiv.org/q-bio.MN/0412045

The efficiency of multi-target drugs:

the network approach might help drug design
1*2
Pter Csermely and Sndor Pongor , Vilmos goston

Several highly efficient drugs, such as non-steroidal anti-inflammatory drugs (NSAIDs), salicylate, metformin or Gleevec, affect
many targets simultaneously. Furthermore, combinatorial therapy, which represents another form of multi-target drugs, is used
increasingly to treat many types of diseases, such as AIDS, cancer and atherosclerosis [3-5].

Snake and spider venoms are both multi-component systems and plants also employ batteries of various factors to fence off
pathogenic attack; thus the use of multiple molecules is apparently an evolutionary success story

Single hits are often insufficient

(single-hits) might not always affect complex systems in the desired way even if they completely change the behavior of their
immediate target. For example, single targets might have back-up systems that are sometimes different enough not to respond
to the same drug, and many cellular networks are robust and prevent major changes in their outputs despite dramatic changes in
their constituents [Agents that affect one target only
Multi-target drugs are often low-affinity binders
Development of a multi-target drug is likely to produce a drug that interacts with lower affinity than a single target drug because it
is unlikely that a small, drug-like molecule will bind to a variety of different targets with equally high affinity. However, low-affinity
drug binding is apparently not a disadvantage. For example, memantine (a drug used to treat Alzheimers disease) and other multi-
target non-competitive NMDA receptor antagonists show that low-affinity, multi-target drugs might have a lower prevalence and
a reduced range of side-effects than high-affinity, single-target drugs [9,10].

multiple targets might have a better chance of affecting the complex equilibrium of whole cellular networks than drugs that act on
a single target.

The idea of multi-target attacks is not new. Perhaps the first, formal advocate of the multi-target approach was the military
strategist Carl von Clausewitz who argued that instead of striving for successful single battles, strategy should simultaneously aim
at the enemy's forces, his resources, and his will to fight [36]. His complex approach proved to be an efficient antidote to
Napoleons rationally designed campaigns. Therefore, we think it is appropriate to conclude paraphrasing another dictum of
Clausewitz that multi-target drugs and the network approach might become useful as the continuation of drug design by other
means.