News from Tartary: an ethnopharmacological approach to drug and therapeutic discovery

Abstract

Ethnopharmacology aims to identify new therapeutic agents based on their traditional use. It begins by the identification of disease states, and of the traditional therapies for these, most commonly herbals. Herbals of interest are selected from ethnopharmacological surveys, and tested on experimental models of the diseases of interest. Once the activity of the traditional remedy is demonstrated, including dose‐dependence, if possible comparatively to reference medications, the active ingredients can be explored, if possible using bioguided extraction. Identified molecules can then be further developed as medicinal products or pharmaceutical medicines (e.g., artemisine), or the herbal product can be developed as such (e.g. St John's wort). We provide examples of various study programmes, concerning the antiplatelet and antithrombotic effects of Armagnac extracts from Southwest France; antithrombotic and antihypertensive effects of extracts of Ocimum basilicum L; antithrombotic, antihypertensive and antihyperlipidemic effects of Cydonia oblonga; Antiproliferative and antithrombotic effects of Abnorma Savda Munziq of traditional Uyghur medicine; and the antidiabetic and hepatoprotective effects of Centaurium erythraea Rafn, Artemisia herba‐alba Asso and Trigonella foenum‐graecum L., all in collaboration between University of Bordeaux, France, Xinjiang Medical University in Urumqi, China and University Mentouri in Constantine, Algeria.

Plants contain very large numbers of molecules, most with biological activities. Many of the drugs in common therapeutic use are directly or indirectly derived from plants. In many regions of the world, especially where pharmaceutical drugs are expensive, plants and plant derivatives are commonly used for the primary care of patients. They may also be used in parallel to pharmaceutical medicines, depending on the local medical systems.

Medical systems can be divided into biologically based (also called Western or modern medicine) and non‐biological medicines. Biological medicine is based on physiology and evidence‐based medicine. Physiology is the same the world over and genetic differences do not change the basic validity of biological medicine. Biological medicine is most commonly associated with pharmaceutical (industrial) medicines. Differences in social systems, and especially diets may, however, influence the effect of medicines.

Non‐biological medical systems are those that are not based on biological systems, but on a cultural interpretation of events or states. This leads to different explanations and/or taxonomy for these diseases, and of their treatments. Non‐biological medicines include, for instance, Ayurveda, traditional Chinese medicine, Unani medicine, or homeopathy. That there is no biological substrate to the disease system does not exclude potential activity of the treatments of the disease states: it was long thought that Zeus, Jupiter, Baal, Lei Gong, Tlaloc, Apotaquetil or Thor were responsible for thunder and lightning. We all know now that the reason for lightning and thunder is elephants bowling in the clouds. These gods probably do not exist, but their nonexistence does not negate the existence of thunder and lightning. The empirical use of medicines, often herbal, in non‐biological medicine is based on observation, trial and error over long periods of time. A non‐biological explanation does not exclude biological activity.

Ethnopharmacology aims to identify what herbal or other components are used to treat patients in the biological or non‐biological disease environment. The local disease description needs to be understood and mapped to a biologically‐based disease. The traditional medicinal product used to treat it can then be tested on biologically determined experimental models to demonstrate pharmacological activity and dose dependence. Once this is established for crude extracts, or for plant mixtures as used traditionally, then the identification process for active ingredients can start.

The first stage of this process is to determine the target and/or a simple experimental model that can be used for bioguided extraction. In this strategy, the herbal preparation is extracted with various solvents and tested on a simple model. The most active fraction(s) is chosen, and further refined until there is no further gain in activity. The composition of the final extract is then determined using modern pharmacognosy and chemical analytical methods. The molecules thus identified can then be tested and validated on disease‐specific biological targets (receptors, enzymes). Target‐binding extraction could also be used to identify molecules active on defined bio‐targets.

If the initial product happens to have multiple actions, as may often be the case with herbal preparations, the bioguided extraction can be repeated for each of the suggested experimental models and targets, and probably result in different molecules involved in the different activities. On the other hand, if during successive extraction processes the activity is lost, it was probably the result of the combined effects of several molecules that segregate in different fractions.

This activity‐guided strategy is different from the ‘brute force’ approach where plant are analysed and libraries of molecules are established and tested on all known targets, using high‐throughput screening. This approach does not take into account the preparation of the herbals before ingestion (most are boiled or used as teas), or the mixing of various plants, which could result in composites that are not found in individual plants. Some ingredients might also act on as yet unknown targets, and would not be identified in systematic screens. However, it is certain that secondary screening of active extracts for selected targets derived from a pharmacological approach would be a clear advantage.

Over the years, we have had the opportunity to work on a number of products. Some were based on observations of traditional use in local populations, with no specific reference to a medical system or theory; others were used according to a local medicinal system. These products come from North Africa, Central Asia and Southwest France.

The aim of the present paper is to present briefly the different studies, how they were developed, and with which conclusions.

Armagnac from Southwest France

Southwest France is the region in Europe with the lowest cardiovascular morbidity and mortality 1. It is a country of good food and good wine, with a diet that includes elements of the Mediterranean diet, but also fatted duck and its derivatives, foie gras and confit 2, 3, 4, 5, 6 It is also home to Armagnac, a spirit that is distilled using a process different from that of most other spirits (counter‐current continuous‐flow distillation) and is aged in oak barrels for a number of years. Along with Cognac and American Bourbon whiskey, it is the richest in polyphenols 7, 8. These are extracted from the wood, and do not include the resveratrol found in red wine 9, 10. We tested the effects of alcohol‐free extracts of Armagnac on platelet adhesion (closure time) and aggregation induced by ADP or collagen in vitro, on arterio‐venous shunt thrombosis in vivo, and in healthy human volunteers ex vivo. We found that there was a concentration and duration‐dependent inhibition of ADP‐induced platelet aggregation, with no effect on adhesion or on collagen‐induced aggregation 11. The extracts, given orally to rats, dose‐dependently inhibited arterio‐venous shunt thrombosis. This effect was more notable with younger rather than older Armagnac, and was the same for different provenances 12. In healthy volunteers, Armagnac inhibited ADP‐induced aggregation by 31%, more so than vodka with the same alcoholic strength, without the rebound effect found with vodka 13, 14. This effect does not seem to be mediated by polyphenols or ellagic acid derivative tannins, but by smaller phenolic compounds 15. The final active antiplatelet agent in Armagnac has not yet been identified, but it seems to act in the same way as non‐aspirin antiplatelet agents such as clopidogrel or ticagrelor, suggesting that Armagnac may indeed play a role in the low cardiovascular event rates in the user population.

Antidiabetic herbals from Algeria

An ethnobotanical survey among patients treated for diabetes and among pharmacies led to the selection of three candidate herbs, Centaurium erythraea Rafn, Artemisia herba‐alba Asso and Trigonella foenum‐graecum L. They were tested in C57BL/6J mice fed a high‐fat diet until diabetes was established. The herbal extracts were given either at the same time as the diet, to test their preventive effects on the development of diabetes 16, or once the diabetes was established while pursuing the high‐fat diet, to test a curative effect 17, 18. All three plants could oppose or decrease the effects of a high‐fat diet on diabetes, but only Centaurium erythraea Rafn had an effect on lipid accumulation in the liver 19.

Plants and treatments from Central Asia

These are used within traditional Uyghur medicine in the areas of Western China that are on the traditional silk road of Central Asia, whence the title of this review 20. Individual plants and plant preparations were tested and reported upon. Traditional Uyghur medicine is part of Unani or Greco‐Arabic medicine, derived from Hippocratic medicine and much influenced by the works of Ibn Sina (Avicenna), who came from this region (in fact Uzbekistan), and left a considerable medical literature.

Ocimum Basilicum L.

Ocimum basilicum L. (Sweet basil) is widely used in the Mediterranean diet. In Xinjiang (China) it is used for the prevention and treatment of cardiovascular disease. We showed it had antiplatelet and antithrombotic effects 21, which seem related to an effect on cyclooxygenase, with increased production of prostacyclin and reduced production of thromboxane 22. In addition, Ocimum extracts dose‐dependently reduced blood pressure in renovascular hypertensive rats to a lesser degree than captopril, but reduced cardiac hypertrophy and remodelling more 23, with an effect resembling that of endothelin converting enzyme inhibition 24. These results would support the use of the plant to treat or prevent cardiovascular and metabolic disorders, as is traditional locally, and might contribute to the effects of the Mediterranean diet.

Cydonia oblonga Mill.

Cydonia oblonga Mill. is commonly known as quince. Its fruit is widely used in food preparations and is included in many traditional recipes in Xinjiang. Its leaves and seeds are also traditionally used for treatment and prevention of cardiovascular diseases. Uyghur people have lower blood pressure and greater longevity than other central Asian people. In a renovascular rat model, Cydonia extracts dose‐dependently reduced blood pressure and improved rheology. The most effective were the leaf extracts 25. Leaf extracts had similar effects to captopril on hypertension and related biomarkers in renovascular rats 26. Cydonia leaf extracts also had effects on haemostasis in mice and on arterio‐venous shunt thrombosis in rats, with effects comparable to those of aspirin 27. Finally Cydonia also has an effect on blood lipids and on oxidative processes 28, 29. The cumulative effect of these different activities: antihypertensive, antithrombotic and antihyperlipidaemic make Cydonia leaf extract a kind of natural ‘polypill’ 30, 31, 32.

Abnormal Savda Munziq

The previous products were based on traditional use, but were single‐plant products not directly embedded in traditional Uyghur medicinal theory. Traditional Uyghur medicine is a Unani, Greco‐Arabic, or Hippocratic medicine, whereby the liver produces humours, which, when unbalanced, result in disease. The treatment aims to restore this balance. There are four humours: blood, black bile (melancholia), phlegm (or yellow bile) and lymph, resulting in sanguine, melancholic or bilious, phlegmatic and lymphatic characters. These are Savda, Saprah, Belghem and Khan in Uyghur medicine. Excess black bile (Savda) is associated with a number of diseases such as cancer of the colon, coronary heart disease, chronic obstructive pulmonary disease or type 2 diabetes. The relationship between these diseases is immediate. They share common risk factors, occur in the same patient phenotypes (often called the ‘metabolic syndrome’), and are associated with excess oxidative states 33. The treatment of abnormal Savda syndrome is traditionally to give two compounds, Munziq and Mushil of abnormal Savda. These are multi‐plant preparations that follow strict recipes, are prepared by hospital pharmacies and sold as standard medicines, in tablets, solutions or decoctions. We tested abnormal Savda Munziq, a mixture of 14 plants, in a series of experiments to confirm its activities on the disease entities covered by the abnormal Savda syndrome. This included a study of its effect on oxidative stress‐induced mitochondrial damage 34, and in cancer cells, using HepG2 lines 35, 36 and Caco lines 37, as well as in in vivo chemically induced colon cancer in rats 38, and implanted S180 sarcoma in mice 39, 40. Additionally, it was tested on platelet aggregation and shunt thrombosis 41. In all these models it has shown dose‐dependence and an effect similar to that of standard pharmaceutical drugs.

There are many other studies and publications on abnormal Savda syndrome and on abnormal Savda Munziq, including development of animal models of abnormal Savda syndrome 42, 43, effects on cardiac ischemia and remodelling 44, 45 or chronic obstructive pulmonary disease 46, and more formal metabolomics studies in the various disease states 46, 47, 48, 49.

Other studies have looked at traditional Uyghur treatment of hyperuricaemia 41, or experimental asthma 50. Further studies are ongoing, and the yearly number of publications mentioning traditional Uyghur medicine and its various therapeutic instruments is growing in the peer‐reviewed scientific media.

Conclusion

Traditional herbal‐based medicines, based on observational evidence, clearly have strong therapeutic potential. That they may be based on non‐biological medical systems does not detract from their potential interest nor from the need to explore potential new therapeutic options and new chemical and pharmaceutical entities. Some might also lead to insights into novel therapeutic mechanisms.

Competing Interests

All authors have completed the Unified Competing Interest form at www.icmje.org/coi_disclosure.pdf (available on request from the corresponding author) and declare no support from any organization for the submitted work; no financial relationships with any organizations that might have an interest in the submitted work in the previous 3 years; no other relationships or activities that could appear to have influenced the submitted work.

The authors wish to thank all their co‐workers over the years, who have participated in the different studies cited in this paper.

Moore, N. , Hamza, N. , Berke, B. , and Umar, A. (2017) News from Tartary: an ethnopharmacological approach to drug and therapeutic discovery. Br J Clin Pharmacol, 83: 33–37. doi: 10.1111/bcp.13042.