Journal of Alternative Complementary & Integrative Medicine Category: Medicine Type: Review Article
Methodology for the Development of Evidence-based Herbal Tonics for Preventive Purposes
- LEUNG Ping-Chung1*
- 1 Institute Of Chinese Medicine, Jockey Club School Of Public Health Building, Prince Of Wales Hospital, Shatin, The Chinese University Of Hong Kong, NT, Hong Kong
*Corresponding Author:
LEUNG Ping-ChungInstitute Of Chinese Medicine, Jockey Club School Of Public Health Building, Prince Of Wales Hospital, Shatin, The Chinese University Of Hong Kong, NT, Hong Kong
Tel:+852 22528868,
Fax:+852 26325441
Email:pingcleung@cuhk.edu.hk
Received Date: Jun 23, 2015 Accepted Date: Aug 21, 2015 Published Date: Sep 04, 2015
Abstract
Unlike the production of chemical drugs which has little difficulty over uniformity and quality control, medicinal herbs are grown in small plots of cultivations which do not guarantee uniform production. Standard procedures of authentication, from gross appearances, histology to chemical profiling are all required to facilitate repetition of research and development of potential market products.
Full use of available biological tests, from cellular, to molecular and genomic studies should be utilized to work out the biological and pharmacological activities of the herbs under study. Animal experiments follow in-vitro platforms.
To give genuine proof of efficacy of the study herb or herbal formula, clinical trials following the standard recommendations advocated in the research production of pharmaceuticals, should be conducted.
The supplement thus developed would command an efficacy near to the requirements of a pharmaceutical, against a specially chosen health target. Development of a cardio-vascular protective tonic is chosen as an example.
The research development of a specific health supplement requires that the best available quality of herbs is used and their mechanism of action, not only limited to laboratory data, but also clinical evidences is worked out.
Keywords
INTRODUCTION
Disease prevention is particularly important for the elderlies. The Cardiovascular area is probably most suitable for an illustrative discussion. Pathologies related to the cardiovascular system remain the major causes of death in recent decades [3,4]. Active interventions to maintain the integrity of arteries have done great contributions while therapeutic agents to promote effective circulation have also deferred vascular accidents [5]. Yet in spite of the great promises, failure to totally revert progressive vascular occlusions has led to a never ending search for novel agents that could offer additional benefits to cardiovascular health [6,7].
Many herbal items described in Chinese Medicinal classics possess impressive records: either in the context of acute treatment, eg: angina relief, or in the maintenance of circulatory well-being. Given the trust that historical records do offer useful and possibly reliable information, in the present era of evidence-based medicine, one still needs to further prove the experience-based assumptions. A practical methodology has been developing in the Research Institute of Chinese Medicine in Hong Kong to testify the validity of innovative herbal medicine formulae, targeting against specific clinical problems. Such difficult areas that yet lack perfect treatment include viral infections and cancers, as well as common concerns of the elderly like cardiovascular health and dementia [8,9]. In this report, I shall be using the example of a cardiovascular tonic developed for the maintenance of cardiovascular health. In fact many other areas of common health concern that might need additional maintenance and preventive supplements apart from standard quality interventions exist and deserve equal attentions.
AN INTEGRATED METHODOLOGY
The Integrated Methodology consists of the following components [10]:
- The Clinical target
- An innovative solution using Traditional Chinese Medicine
- Procedures required to give evidence of efficacy
- Interpretation of results
- Recommendations
The clinical target
The available means in modern hospital practice to maintain blood circulation include mechanical dilatation (i.e., Stenting), prevention of lipid deposits and haemodilution to thin down the blood viscosity hence maintain an adequate flow. It has been known that the biological mechanisms behind the circulatory hazards and inefficient flow are multiple. The clinical role required of the selected Chinese herbal medicine in the plan of overcoming the aging pathological changes in the vascular tree would need to take multiple directions involving the luminal integrity, smooth muscle relaxation and circulatory flow [14-16].
An innovative solution using Traditional Chinese Medicine
In this search for a cardiovascular tonic, a simple formula with only two herbs and reasonable clinical records of efficacy was selected. The twin formula has the merit of very favorable clinical reports and the simplest requirements for a herbal formula authentication [19].
There must be two practical ways to select the herbal formula that will satisfy the need. One way is to follow the advice of traditional practitioners who emphasize on the syndrome presentation of the patient. Another way is to choose according to popular clinical reports and information already available for the choice of herbs. We are in favor of the latter principle which is more practical. We could have chosen other herbal formulae with more than two herbs. Nevertheless our chosen two herbs, viz., Danshen (Radix Salviae Miltiorrhizae) and Gegen (Radix Puerariae), have already attracted many bioscientists’ interests and many reports suggesting their cardiovascular protective effects are already available.
Procedures required to give evidence of efficacy
Quality control
In order to allow readers to gain solid knowledge about our practice to achieve the best possible quality assurance of the herbs through standardization processes in our evidence-based methodology development, the example of Danshen and Gegen can be quoted as follows:
- The dried herbs were purchased directly from the well-known places of production, viz., Sichuan for Danshen and Guangdong for Gegen. Large batches should be obtained for both experimental and clinical uses.
- Authentication of Danshen and Gegen included gross, histological and chemical (chromatography) examinations. Voucher specimens should be kept as described.
- Extractions should go through the standard procedures of using the right proportions of herbs in 10 fold water soaking for 1.5 hours, followed by extraction at 100 C for 1 hour. Two subsequent extractions in the similar way. After filtering and evaporation to dryness, powdered extracts would be obtained.
- Chemical analysis of the extracts using LC-DAD-MS instrumentation with set conditions. Subsequently, the chemical finger print of Danshen Gegen mixture would be established and registered [11,22].
Pharmacological Tests
For the simple herbal formula being developed as a cardiovascular tonic, the following tests are considered essential, basing on the prediction that the user could be suffering from vascular deficiencies in the major or cardiac vessels, hypertension and other concomitant pathologies [23,24].
Laboratory platforms aiming at the following biological mechanisms are included:
- Anti-inflammation and anti-oxidation
- Vascular protection, smooth muscle relaxations cardiac functions, myocardial viability
- Functional genomics to demonstrate the mechanistic pathways
- Herb-drug interactions to check whether the herb formula interfere with the concomitant medications.
Interpretation of results
Quality control
Standard aqueous extraction gave the standard Salvia and Puerariae (D&G) powder mixture which systematically went through the procedures of chemical analysis in the establishment of the chemical finger print.
Although the procedures described for the standardization and quality assurance of D&G are far inferior to those required of pharmaceuticals, in view of the complicated components of the herbs and that their combined use is not as a therapeutic agent of a pathological target, but instead, as a tonic to maintain the stability of cardiovascular health, what we are doing could be considered safe and qualified [27-29]. The fact is many health supplements and tonics claiming specific pharmacological merits do not have a system of practice procedures for the maintenance of a quality supply of ingredients used in their preparations. A system of standard procedures like ours could be the answer.
Pharmacological testsAnti-inflammation and anti-oxidation:D&G inhibited LPS via induced nitric oxide production [30] and inflammatory cytokines, iNOS COX2 and NFKB protein expressions [31] and foam cell formation [32].
Vascular protection, smooth muscle relaxation:D&G was found to dilate ex-vivo aortic rings of rat [30]; helped to repair balloon-injured arterial intima [17]; supported viability of myocardium [33]; lowered blood pressure in hypertensive rats [34] and maintained better survival of brain tissues under the adverse effects of middle-cerebral artery occlusion [35,36].
Cardiac functions, myocardial viability:D&G modulated neurotransmitter effects on the heart and heart rate [24].
Functional genomics to demonstrate the mechanistic pathways:5 categories of genes were found involved in the various pharmacological activities of D&G viz., cardio-vascular, apoptosis, cell proliferation, cytokine production and anti-inflammatory [37].
Herb-drug interaction with anticoagulant (mainly warfarin):D&G was found to induce additional effects with anticoagulants [38,39].
Clinical trialsThe clinical trials to be conducted for this cardiovascular tonic were aiming at the maintenance of flow integrity of the arteries at large. The well-accepted surrogate markers were the intimal thickness of the common carotid artery and the extensibility of the brachial artery as would be revealed from high resolution ultrasonic studies [40-42]. Target groups with different clinical backgrounds were selected, varying from risky patients with proven coronary occlusions, to vulnerable patients with hypertension and diabetes mellitus, to perimenopausal women with border-line hypercholesterolemia. Thus the indications for the use of the cardiovascular tonic ranged from quasi-treatment considerations to preventive needs.
Trial 1.Patients with coronary arterial occlusions:Two hundred patients were randomized into two equal groups of treatment and control. D&G was taken by the treatment group for 24 weeks. Carotid Intima Thickness (IMT) and Brachial Flow-Medicated Dilation (FMD) were measured using ultrasonic technology. Results showed significant improvements in D&G group (p<0.05). D&G was well tolerated; no significant adverse effects were encountered [18,29].
Trial 2.Patients with hypertension and/or diabetes mellitus:Ninety patients were given D&G in high or low doses and were compared with no treatment controls. The same surrogate markers were measured after 12 months of treatment and both IMT and FMD were found to have improved compared with the placebo group, with either the low dose or high dose administration [25].
Trial 3.Patients with border-line hypercholesterolemia:One hundred and sixty five post-menopausal women with early hypercholesterolemia were randomized to take D&G or placebo daily for 12 months. The same surrogate markers and blood lipid profiles were taken. The herbal formula D&G improved the carotid intimal thickness, lowered low density lipid and total cholesterol [43].
Recommendations
The pharmacological effects of D&G were further proved through clinical trials on patients with different backgrounds and needs. When patients suffering from coronary occlusions were benefiting from D&G, the indications may extend to post-stenting patients in the prevention against restenosis. Hypertension and diabetics were at risk patients threatened with progressive vascular deteriorations, notably in the cerebral or cardiac regions. D&G may be a good choice to provide reasonable prevention. As D&G was found to lower LDL and total cholesterol, it should be an alternative to statins when hypercholesterolemia is developing or getting out of control.
So far D&G has laboratory indications of positive, multi-directional effects on cardio-vascular protection, and clinical proofs of intimal thickness control and vascular relaxation. Whether the circulatory support would also be provided in other common vascular conditions, eg: peripheral vascular diseases or multiple cerebral vascular occlusions would need further investigations [44]. Through-out the clinical trials involving various clinical groups, no adverse effects resembling those of statins viz., muscle weaknesses, were encountered. So far the evidences collected were related to large arteries and blood lipids, whether D&G would also be suitable for peripheral and small arteries will need to be further studied.
DISCUSSION AND CONCLUSION
Apparently safety is not an issue, since the two herbs are frequently used in household cooking and clinical trials completed did not report serious adverse events. However, patients put on D&G might well be maintained on other cardiac medications, including anti-coagulants. Hence, pharmacodynamic and pharmacokinetic studies need to be more thoroughly explored before its wide applications [27].
The methodology developed is unique for the development of evidence-based health supplements with specific aims. The concept follows closely that of new drug development adopted by the pharmaceutical production. However since the target is one of maintenance and prevention, the design of the methodology will not be as strict and stringent. Nevertheless, conventional supplement provider on the contrary, might find the methodology over-demanding. In this era of evidence-based demand, there might be no other way to give assurance to the general consumers [45].
The story of D&G serves as a comprehensive illustration on the methodology of developing an effective specific health supplement from an old herbal formula along the evidence-based pathway. The methodology has allowed the old classical herbal formula is converted into a trustworthy supplement or proprietary drug, targeting specifically on the maintenance of cardio-vascular integrity. Other herbal combinations with special indications recorded in classical literatures could be identified and put on similar systematic research platforms to be developed as multi-target botanical items for specific health maintenance purposes [8]. We have indeed completed explorations on specific supplements for osteoporosis, allergic skin conditions and wound healing just to mention a few areas [46-48].
ACKNOWLEDGEMENT
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Citation:Leung PC (2015) Methodology for the Development of Evidence-based Herbal Tonics for Preventive Purposes. J Alten Complement Integr Med 1: 004.
Copyright: © 2015 LEUNG Ping-Chung, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.