Dear Jyoti,

The following publications cover the answer to your question:

1-Pharmacogn Rev. 2014 Jul-Dec; 8(16): 73–80.

doi:  10.4103/0973-7847.134229

PMCID: PMC4127824

Polyherbal formulation: Concept of ayurveda

Subramani Parasuraman, Gan Siaw Thing, and Sokkalingam Arumugam Dhanaraj1

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Abstract

Ayurveda is one of the traditional medicinal systems of Indian. The philosophy behind Ayurveda is preventing unnecessary suffering and living a long healthy life. Ayurveda involves the use of natural elements to eliminate the root cause of the disease by restoring balance, at the same time create a healthy life-style to prevent the recurrence of imbalance. Herbal medicines have existed world-wide with long recorded history and they were used in ancient Chinese, Greek, Egyptian and Indian medicine for various therapies purposes. World Health Organization estimated that 80% of the word's inhabitants still rely mainly on traditional medicines for their health care. The subcontinent of India is well-known to be one of the major biodiversity centers with about 45,000 plant species. In India, about 15,000 medicinal plants have been recorded, in which the communities used 7,000-7,500 plants for curing different diseases. In Ayurveda, single or multiple herbs (polyherbal) are used for the treatment. The Ayurvedic literature Sarangdhar Samhita’ highlighted the concept of polyherbalism to achieve greater therapeutic efficacy. The active phytochemical constituents of individual plants are insufficient to achieve the desirable therapeutic effects. When combining the multiple herbs in a particular ratio, it will give a better therapeutic effect and reduce the toxicity. This review mainly focuses on important of the polyherbalism and its clinical significance.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4127824/

Single herbal versus polyherbal formulation

Drug formulation in Ayurveda is based on two principles: Use as a single drug and use of more than one drugs, in which the latter is known as PHF. This key traditional therapeutic herbal strategy exploits the combining of several medicinal herbs to achieve extra therapeutic effectiveness, usually known as polypharmacy or polyherbalism.

Historically, the Ayurvedic literature “Sarangdhar Samhita” dated centuries ago in 1300 A. D. has highlighted the concept of polyherbalism in this ancient medicinal system.[21] In the traditional system of Indian medicine, plant formulations and combined extracts of plants are chosen rather than individual ones. It is known that Ayurvedic herbals are prepared in a number of dosage forms, in which mostly all of them are PHF.[22,23]

Even though the active phytochemical constituents of individual plants have been well established, they usually present in minute amount and always, they are insufficient to achieve the desirable therapeutic effects. For this, scientific studies have revealed that these plants of varying potency when combined may theoretically produce a greater result, as compared to individual use of the plant and also the sum of their individual effect. This phenomenon of positive herb-herb interaction is known as synergism. Certain pharmacological actions of active constituents of herbals are significant only when potentiated by that of other plants, but not evident when used alone.

There are a few Ayurvedic herbs combinations to be cited here: Combination of ginger with black pepper and long pepper enhances their heating and mucous-reducing effects; bitter and cold herbs are combined with warmer herbs (combination of neem and ginger) to positively offset any extreme effects. Cumin, black pepper and asafoetida are used together traditionally to reduce bloating due to weak digestion; whereas guduchi and turmeric combination booster one's immunity.[24,25,26]

Based on the nature of the interaction, there are two mechanisms on how synergism acts (i.e., pharmacodynamics and pharmacokinetic).[27] In terms of pharmacokinetic synergism, the ability of herb to facilitate the absorption, distribution, metabolism and elimination of the other herbs is focused. Pharmacodynamic synergism on the other hand, studies the synergistic effect when active constituents with similar therapeutic activity are targeted to a similar receptor or physiological system. Other than that, it is believed that multiplicity of factors and complications cause diseases in most of the cases, leading to both visible and invisible symptoms. Here, combination of herbals may act on multiple targets at the same time to provide a thorough relief.[28]

Due to synergism, polyherbalism confers some benefits not available in single herbal formulation. It is evident that better therapeutic effect can be reached with a single multi-constituent formulation. For this, a lower dose of the herbal preparation would be needed to achieve desirable pharmacological action, thus reducing the risk of deleterious side-effects. Besides, PHFs bring to improved convenience for patients by eliminating the need of taking more than one different single herbal formulation at a time, which indirectly leads to better compliance and therapeutic effect. All these benefits have resulted in the popularity of PHF in the market when compared to single herbal formulation.

Many of the PHF have been pharmacologically and clinically proven to possess therapeutic activities as desired. Examples of some of the PHF are shown in Table 2.

Table 2

Examples of marketed PHFs

In the formulation of polyherbal preparations, it is crucial to note that herbs are sometimes considered to be incompatible (viruddha) and thus should not be taken together. Such incompatibility may be due to quantitative incompatibility, energetic incompatibility or functional incompatibility. For instances, ghee should not be taken in same proportions with honey by weight due to conflicting tastes and temperatures; whereas laxative and astringents brings to antagonistic action in which they negate each other's activities.[24] To ensure compatibility of multiple herbs in the formulation of PHF, there are needs of well-designed clinical trials prior to marketing.

2- Problems associated with clinical trials of Ayurvedic medicines

 Problemas associados com ensaios clínicos de medicamentos Ayurvédicos

 Ashish K Sharma*,I; Rajesh KumarII; Anurag MishraIII; Rajiv GuptaIII

ABSTRACT

Herbal drugs have been used since ancient times as medicines for the treatment of various diseases. Especially in countries like India many of herbal drugs and formulations are used in different practices of treatment like Ayurveda, Siddha and Unani. It is estimated that about 25% of all modern medicines are directly or indirectly derived from plants sources. The contribution of developing countries in global herbal business is very poor due to lack of quality control and standardization measures. There is lack of common standards and appropriate methods for evaluating Traditional Medicine to ensure the safety, efficacy and quality control. This indicates the importance and necessity to develop a standard operational procedure for the standardization of herbal drugs and formulations. Benchmarking the evaluation protocols including both quality control and quality assurance of herbal drugs would play a major role in providing highly reliable and effective herbals drugs and to attract international trade, thus generating revenue. The article highlights various problems being faced by developing countries and suggests a unique approach for the preparation of SOP/guidelines for the standardization of all herbal based formulations, also there is a need for systematic clinical trials of traditional plant based medicines to enhance global acceptance.

MAJOR PROBLEMS WITH CLINICAL TRIALS OF AYURVEDIC MEDICINES

• Ayurvedic HMPs (Herbal Medicinal Products) are marketed as dietary supplements, they are regulated under the Dietary Supplement Health and Education Act (DSHEA), which does not require proof of safety or efficacy and hence bypasses the stringent quality tests of Drugs and Cosmetics Act 1940. Recently with use of Ayurvedic HMPs Lead toxicity has been reported, which might result in conditions like status epilepticus, fatal infant encephalopathy, congenital paralysis, sensoryneural deafness, and foetal developmental delay. Since 1978, at least 65 cases of heavy metal intoxication associated with Ayurvedic HMPs in adults and children have been reported in the United States and abroad (Eisenburg et al., 1998; Robert et al., 2004).

• Conducting clinical trials on traditional/herbal medicines is quite challenging due to lot of reasons, for instance, it is very difficult, impracticable or sometimes impossible to have active and control groups with identical color, smell and taste. Also, the use of placebo involves similar difficulties as the herbal study drug may exhibit its strong aroma, a specific distinguished taste and hence these cannot be exactly imitated while manufacturing a placebo. The comparative placebo use in evaluation of herbal drugs also raises ethical issues as it is unethical to assign unaware patients a placebo instead of using an available therapy effective in treating their condition (Rothman & Michels, 1994).

• Quite often the problems are multiplied when working with formulations containing more than one plant extracts. Special attention must also be paid on standardization of the compounds using bioactive markers.

• There are difficulties in estimation of "active" molecules in body fluids in the pharmacokinetic studies in phase I of drug development especially in Ayurvedic formulation (Bhattaram et al., 2002).

• Storage conditions can also alter the bioavailability of herbal medicines, which may lead to loss of activity, fungal or bacterial contamination resulting into batch to batch variation, are the bane of large clinical trials with medicinal plants (Thatte, 2005).

• Importance of Good Manufacturing Practices are generally not given due consideration while manufacturing Ayurvedic products hence, while working with marketed formulation, it is necessary to keep a check on adulteration and substitution.

• Selection of dosage regimen may also pose problems. Dose must be calculated on the basis that whether crude drug or extract is used, and the dose of the extract has to be calculated on the basis of extractive value (Thatte, 2005).

• The system of herbal medicine advocates the choice of herbs, compounding or mixtures, dosage and duration so that it suits the particular psychosomatic constitution (Prakriti) of the patient. It is well known in Ayurveda that the "Prakriti" determines the effectiveness of particular herbal medicines which influences response to drugs and also a major factor to consider as an inclusion/exclusion criterion in clinical studies. This approach, since ancient times, helps in enhancing the therapeutic effect as well as reduces the unwanted effects of the drug. Therefore, administration of a study drug to a subject population of various constitutions may not yield uniform outcomes (Dahanukar & Thatte, 1997).

• Many a times the medicine system advocates other procedures along with oral therapy which again may or may not be standardized. Also, there is no standard single benchmark formulation, especially if a single drug therapy is concerned for various therapeutic areas, as they are present in modern medical science.

• Another reason is that the crude raw herb material has number of variations as per geographical locations, climatic conditions, environmental hazards, harvesting methods, collection protocols, etc which makes it a difficult task to standardize the end product for a reproducible quality (Bauer & Tittel, 1996).

• Other reasons include the fact that integrated approach of many herbal systems does not differentiate the disease from the patient. This approach creates difficulties for the inclusion and exclusion criteria in clinical trial.

• Also, Ayurveda proposes different interventions at different stages of disease in the same patient providing another difficult to control variable in a clinical trial.

• Diet component may also affect the treatment outcome in clinical trial.

• As most herbal medicines used in traditional systems are used in the humans without any toxicity studies, their embryotoxic, foetotoxic, and carcinogenic effects are likely to remain unrecognized in traditional practice. Recently the embryotoxic effects of 'Pippalyadi vati' (traditional contraceptives consisting of Embelia ribes,Piper longumand Borax) have been reported (Chaudhary et al., 2001, Chan, 2003).

• Other reasons include the fact that integrated approach of many herbal systems does not differentiate the disease from the patient. This approach creates difficulties for the inclusion and exclusion criteria in clinical trial.

• With Ayurvedic medicines, it is difficult to plan double-blind randomized clinical trials. For clinical evidence of safety and efficacy the placebo-controlled, double blind randomized trial may be considered as gold standard, even for herbal medicine. However, randomized clinical trials on herbal medicine may be quite difficult to conduct because it needs large volunteer groups, is of long duration and requires expensive healthcare services. Moreover, one major problem that exists is that the funds for such trials, is usually not readily available (Shukla et al.,, 1991; Armstrong & Ernst, 1999).

• One key issue in planning clinical trials is that some herbs have been reported to be poisonous (Moore & Adler, 2000).

• The problem with the use of herbal medicines is the fact that it is not always clear whether interactions exist between herbal medicine and other medicinal products or substances like alcohol, caffeine, tobacco or nicotine or with diet. Some of the common herb-drug interactions includes: a) Bleeding- when warfarin is combined withGinkgo biloba, garlic, dong quai or danshen; b) Serotonin syndrome- when St. Johns' wort is combined with serotonin- reuptake inhibitors; and c) Induction of mania in depressed patients - when antidepressants are mixed with Panax ginseng(Fugh-Berman, 2000).

• The issues associated with safety and quality of herbal medicines include toxic herbs, contamination with heavy metals, microbial organisms, and other contaminants (such as pesticides) as well as deliberate combination (adulteration) with pharmaceutical products.

• Another problem with research on alternative medicine is the fact that complementary health practitioners often question the suitability of randomized clinical trials in relation to complementary medicine because of the holistic approach (i.e. treating mind, body and soul at the same time) that is required and the fact that the alternative medicine is normally tailored specifically for each individual. Practitioners suggest it is inappropriate to test only one treatment in isolation and to give it to all participants in the same manner and amount, as occurs in randomized clinical trials (Kristofferson, 1996).

As a function of such difficulties, few herbal drugs have been studied adequately but well-controlled double-blind clinical trials to prove their safety and efficacy have been lacking. e.g. Although the clinical trials including the extract of Ginkgo biloba(used for the treatment of CNS and cardiovascular disorders) and Hypericum perforatum(St. John's wort, used as an antidepressant) (Ernst et al., 1998) have shown that these two herbal drugs are quite safe and devoid of serious side effects, their clinical efficacy still requires well-controlled randomized double-blind studies. Other botanical drugs such as Panax ginseng(ginseng) herbs used as a tonic, Tanacetun parthenium (feverfew) used to treat migraine headache, Allium sativum (garlic) used to lower serum low-density protein, cholesterol level and some cardiovascular disturbances, Matricaria chamomilla (chamomile) recommended as a carminative, anti-inflammatory and antispasmodic, Silybium marianun(milk thistle) used for normalizing liver function including cirrhosis, Valeriana officinalis(valerian), used as a sedative and sleeping aid,Piper methysticum(Kava kava) used as an anxiolytic, Aesculus hippocastanum(horse chestnut) used for the treatment of chronic venous insufficiency, Cassia acutfolia(Senna) and Rhamnus purshiana(cascara sagrada) which are used as laxatives, Echinacea purpura(Echinacea) used as an anti-inflammatory and immunostimulant,Arnica montana(arnica) used to treat post-traumatic and postoperative conditions, and Serenoa repens (saw palmetto) used for the treatment of benign prostatic hyperplasia are all herbal medicines with the largest worldwide market, and although they have been evaluated in different clinical trials, additional well-controlled and appropriate randomized clinical trials are still needed in order to prove their efficacy (Bauer & Tittel, 1996; Harrer et al. 1999; Armstrong & Ernst, 1999).

To view the full publication, please use the following link:

http://www.scielo.br/scielo.php?script=sci_arttext&pid=S0102-695X2010000200023

Hoping this will be helpful,

Rafik

Dear Jyoti 

Please go through the following link wherein the need for pharmacokinetic studies for herbal drugs has been discussed. 

https://www.researchgate.net/post/Should_pharmacokinetic_studies_be_performed_for_herbal_crude_extracts_or_bioactive_fractions_obtained_from_them

Dear Jyoti

Although I was follower of this question. I review the link  sent by Ashok Nahata and discussion on it. As  we know plant is cosmos of chemicals and even till date we are not sure how many chemicals remain undiscovered in particular medicinal plant, how can we put particular palnt for pharmaccokinetics? Turmeric and Neem are thoroughly investigated. There are evidence that curcumin negative fraction also have activity as well as Azadirachtin negative fraction also have antimicrobial activity. I think Ayurvedic Principles are more subtle and simply can not explain on the basis of present chemistry.