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Synergy in relation to the pharmacological action of phytomedicinals

What is synergy?
The term synergy comes from the Greek word syn-ergos, meaning "working together". Synergy refers to extra energy, power or success achieved by two or more components working together. Synergism is an effect larger than addition. Phytomedicinals: Phytomedicinals are the plant based medicinal formulations. They may be mono herbal (obtained from single plant) or polyherbal. Phytomedicinals consist of large number of pharmacologically active constituents that express their actions together and the overall action of the particular drug is the resultant of all the components, what we call the synergistic action. In herbal remedies, better therapeutic results are commonly obtained from whole plant extracts or poly herbal formulations because of synergistic effect of different chemical constituents. The synergistic interactions involve the potentiation of therapeutic effects and attenuation of toxicity or side effects.

 Mechanism of action of many phytomedicine is still unknown and there are several instance where total extract shows better activity than an equivalent dose of isolated compound Synergy in Traditional medicine In contrast to the modern pharmaceuticals, combination of herbs is the main philosophy of traditional medication systems like ayurveda, tibetan, chinese etc The therapeutic excellence of such traditional herbal formulations are practically approved for their historical use which is in fact due to the synergistic action of different ingredients present in a particular drug. For example: side effects caused by ephedrine are not found with the crude extract of ephedra. Synergy analysis is one of the major aspects for the standardization of herbal formulations. Some of the valuable and potential drugs like taxol (Taxus), digoxin (Digitalis), vincristine (Catharanthus) etc are though natural products, due to their high potency or toxicity, the source plants have less or almost no history of inclusion in any herbal preparations. In such conditions, synergy analysis is the best solution to find their way in t he herbal formulations.

 If synergy is occurring in any formulation, any change in the ratio of individual components can make the formulation unsuitable or results might be unpredictable. Thus, synergistic combination of herbals is essential to ensure quality standards and reproducibility. Measurement of synergy Synergy is measured in terms of efficiency of phytomedicines. It is quite complicated but essential task in the standardization of phytomedicinals. Synergy analysis of even a single herbal extract requires fractionation of the extract, testing each fraction, recombining and testing different combinations. When one of the agents is inactive and its combination with an active component produces higher effects than that observed for active component alone, the combination is synergistic and the degree of synergy is measured in terms of increment in the effectiveness.

 But complications arise when herbal formulation contains more than one (many) active components. There are various methods suggested for the measurement of synergy in phytomedicinals. Most important are:
Prediction of effect: Synergy is deemed present if the total effect of a combination is greater than would be predicted on the basis of expected additive effect of mixture. a)Dose response curve method

b) Summation of effects method This is the simple method for the determination of degree of synergy when the number of active components, because of which the real synergy occurs , is defined. In such combination, if the therapeutic effect of combination is greater then the sum of individual effect, synergy is said to be exist. In such case synergy of combination is the sum of the individual effects. It is mathematically expressed as: E (da, db) = E (da) + E (db) (synergy present) Where, E = observed effect, da and db are the doses of agent a and b Summation method is not appropriate for polyherbal formulations. The isobole method: The isobole method is an application of dose addition. Isobolographic method can detect whether the dose dependent effects of two or more compounds in a mixture are more or less effective than the expected effects based on tests of compounds individually. The advantage of isobolographic method: 1) Analyze wide variety of dose response data 2) It does not require an mechanism of synergy

If the agents do not interact, the isobole curve will be straight line, if synergy is occurring then small amounts are needed to produce the effect and the isobole will be concave up. If antagonism takes place, curve will be concave down.

Synergy and polyvalent action in phytomedicines

The terms synergy and polyvalence are often used to explain the effects of the many constituents found in herbal medicinal products and their extracts, particularly where it is difficult to distinguish the active ingredient. Polyvalence can be defined as the range of biological activities that an extract may exhibit which contribute to the overall effect observed clinically or in vivo. It is often confused with synergism but the distinction lies in the fact that synergism is strictly concerned with only one pharmacological function, rather than a range of activities resulting in an overall effect. Polyvalent action includes all the various effects of multiple active constituents acting in combination, in harmony and possibly in synergy. For example: triphala, chyawanprash etc. Polyvalence can be due to the following: 1) A variety of types of chemical compound is present, each type having a different biological effect.

2) Compounds of one particular chemical type are present which have more than one biological effect relevant to treating the disease and/or improving the health of the patient. 3) Compounds are present, which do not affect the cause or symptoms of the disease itself, but which modify the side-effects, absorption, distribution, metabolism and excretion of active constituents. Some reasons for not isolating individual compounds from plant extracts for herbal formulations are summarized as follows: Most of the extracts are known to contain a range of similar active components with well practiced and documented clinical activity: Aloe, Ginger, Valerian etc Unsure of active constituent(s) even if some chemistry known: Oats, Hypericum etc Actives known or suspected might be unstable: Garlic, Ginger, Valerian etc Synergy or antagonism known or suspected: Artemisia, Cannabis etc

Role of synergy
Synergy and synergy analysis plays a crucial role in quality enhancement and quality assurance. The major roles of synergy are (a) Enhancement of activity and (b) attenuation of toxicity which are essential for standardization of phytomedicinals. 1. Enhancement of activity a) Single herb extracts Ginkgo: Ginkgo biloba preparations contain ginkgolides, terpenoids and flavonoids. Although these all constituents have their own action, Ginkgo is used for two main indications: asthma and cerebral insufficiency. Ginkgolides antagonize the bronchioconstriction and allergic responses and Ginkgo flavones are also anti inflammatory. But the extract of Ginkgo acts as an antioxidant in nervine preparations. Here the anti oxidant activity is supposed to be due to the collective action (synergistic as well as polyvalent ) of different constituents Valerian Different constituents of valerian show sedative action. It has been found that Valeriana extract reduces the glucose consumption in rat brain however valtrate, valerinic acid and valeronone didnt have any such action. The reduction on glucose consumption might be due to synergistic action of different components.

Ginger Ginger fraction containing zingiberene, sesquiphellandrene, bisabolene and curcumene shows anti ulcer activity but the crude extract is expected to have about 66 times much activity than individual constituents. b) Multiple herb extracts Most of the ayurvedic formulations, traditional Chinese medicines, Tibetan medicines and other herbal preparations consist multiple herbs and such herbal remedies are renowned for their superior activities which actually due to the synergistic or more specifically due to the polyvalent action of all the ingredients present in the drug. 2. Attenuation of toxicity The better performance of herbal preparations may also be due to the decrease of toxic effects of one or more components by another components present in the drug. For example: Cannabis is generally used as relaxant or hallucinogenic agent. The main psychoactive compound present in cannabis is tetrahydrocannabinol (THC) and it has been found that if another compound cannabidol (CBD) is absent in the extract, THC alone induce anxiety. Thus CBD decrease the toxic effects caused by THC.

Thus, knowledge on the synergistic composition plays vital role in standardization of phytomedicines that assures the reproducibility of the drugs. Now days due to the synergistic excellence of the complex herbal formulations, new concept has been generated to treat the diseases like cancer, AIDS etc. by using cocktails of chemotherapeutic agents.