Pharmacology and Toxicology

Pierre Duez (Chair) and Hongxi Xu (Co-Chair)

INTRODUCTION

Herbal medicines are nowadays used throughout the world, either as a primary care resource or as complementary or alternative medicines (WHO, 2019) Given the large number of herbal products used, and the relatively low budgets available for research to date, pharmacological and safety assessments have been carried out on relatively few herbs (Shaw et al., 2012; Zhang et al., 2012a).

Whereas pre-clinical pharmacology and toxicology studies are now an absolute pre-requisite before administration of drugs to human beings, the situation remains quite different for herbal medicines, for which often long-standing uses are generally considered a plausible indication of efficacy and safety (Committee on Herbal Medicinal Products (HMPC), 2008).

Nevertheless, the reasoned development of safe and efficacious herbal drugs requires integrated studies of quality, pharmacology and toxicology (Figure 1). Indeed pharmacology and toxicology are intimately linked to (i) the quality of herbal material and manufacturing; (ii) the clinical studies of safety and efficacy; and (iii) the regulatory aspects of drug development. The PTIG then develops its own objective and clear focus while closely cooperating with the other GP-TCM RA Interest Groups.

Figure 1-A. Pharmacology and toxicology and their relations with other aspects of herbal studies. Classical drug registration procedures (Pelkonen, 2017).

Figure 1-B. Pharmacology and toxicology and their relations with other aspects of herbal studies. Traditional drug registration procedures (Pelkonen, 2017).

THE NEED FOR AN INTEGRATED APPROACH

An integrated approach is required as, quite often:

• studies on toxicology and pharmacology are published without providing data on authentication and quality control of the studied herbal preparations, compromising their reproducibility and scientific value;
• studies of pharmacology are not combined to observation of toxicity, leading to the illusion that the studied “natural” drugs were free of adverse activities;
• studies of toxicology are often not linked to clinical relevant doses, processing methods and pharmacologic activities, as if the studied drugs were “poisons” only.

(Ouedraogo et al., 2012; Zhang et al., 2012a).

To overcome these problems, the GP-TCM RA has been founded to develop good practice guidelines for traditional Chinese medicine (TCM) research (Uzuner et al., 2012) and the GP-TCM RA PTIG is dedicated to integrated pharmacology and toxicology.

 

PHARMACOLOGY

The therapeutic value of traditional medicines is undeniable; although quite imperfect, often lacking in quality control and established procedures, traditional medicines cover the primary health care needs for 80 % of the world population (WHO, 2013). This is especially the case in China where the long-documented use of TCMs funds a solid corpus of knowledge (Tang et al., 2008; Xu et al., 2013). The situation nevertheless appears quite complex. Traditional medicines encompass a diversity of natural-origin drugs and practices, including spiritual therapies and dietetic and physical interventions; such holistic approaches complicate the ascription of observed therapeutic effects (Okpako, 1999; Kahumba et al., 2014). Moreover multi-component herbals are often administered in processed forms or as multi-herbal mixtures (Xu et al., 2013).

And so, despite indications from long-standing use, the efficacy of medicinal herbs and mechanisms of action are rarely explainable or formally demonstrated and often remain subject to caution. Promoting and conducting relevant scientific research on medicinal plants in collaboration with traditional health practitioners remains nowadays a major challenge to provide scientific-based evidence and validate claims of efficacy. Herbal remedies have yielded important drugs that are or have been cornerstones of modern medicine; their scientific study appears as an attractive venue to discover new therapies and/or active compounds with novel mechanisms of action that will open new perspectives in the management of diseases (Wall, 1998; Rasamiravaka et al., 2013). The wide and largely untapped field of traditional medicines still remains a unique source for the discovery of bioactive compounds (Chen et al., 2008; Kahumba et al., 2014).

The classical search for active compounds in a Western-type reductionist approach however does not consider the multi-component facets of complex preparations and may be inadequate in elucidating the bases for some pharmacological activities, especially in difficult-to-treat diseases. Beyond the success in isolating new chemical entities amenable to drugs, such as artemisinin, emerging evidence suggests that multiple compounds from herbals might demonstrate synergism (Xu et al., 2013).

Traditional pharmacology relies on measuring adequate end-points in enzyme-, receptor-, cell- and animals-based models. By contrast, an emerging omics-based pharmacology aims at simultaneously measuring multiple endpoints, at genomic, proteomic and metabolomic levels (Buriani et al., 2012). Platforms [e.g. the Chinese “Herbalome Project”(Stone, 2008; Zhang et al., 2012b), the Indian “Phytochemica” (Pathania et al., 2015), the German “SCON” (Koch et al., 2005)] and initiatives  (Atanasov et al., 2021) are being developed to clarify the chemical composition, structure and function of commonly used herbs and formulae, to establish standard resource libraries, to interpret the synergistic and complementary mechanisms of multiple components on multiple targets  and to revitalize the drug discovery process.

TOXICOLOGY

The FP7 GP-TCM project has defined the notion of toxicity for a herbal medicine as a “possible harmful reaction to the body which is not related to therapeutic effect”. Toxicity can then be classified into (i) side effects (covered by pharmacodynamics and often predictable); (ii) reactions occuring as a result of overdose, overduration, tolerance, dependence-addiction (covered either by pharmacodynamics and pharmacovigilance); (iii) hypersensitivity, allergic and idiosyncratic reaction (covered by pharmacovigilance); and (iv) mid-term and long-term toxic effects (liver, renal, genotoxicity, teratogenecity, neurotoxicity, cardiotoxicity,…).

Despite indications from long-standing use, the toxicity of many herbs has been identified only via serendipity or unfortunate clinical findings and point (iv) certainly appears as the most important field for predictive toxicology (Ouedraogo et al., 2012). Given the widespread use of herbal medicines, the study of herb-drug interactions is also an important part of the safety evaluation (Fugh-Berman, 2000).

Combining toxicogenomics (genomics, metabonomics, proteomics) together with appropriate pharmacological and toxicological data presents not only distinct advantages but also challenges and problems that were reviewed by the GP-TCM project (Ouedraogo et al., 2012):

• Among the advantages are the possibilities to study the effect at the whole model level by evaluating multiple endpoints;
• The challenges and problems reside in:
  • Extrapolation of data from high doses (acute) to low doses;
  • Relevance/ significance of gene activation profile;
  • Sensitivity of the current methods (oversensitive or not sensitive enough?)
  • Influence of metabolism on the outcome;
  • Effect of individual genetic background;
  • Relevance of transposition to humans of data from surrogate animal species.

A recent book has further developed the toxicological problems associated with herbal medicines (Pelkonen et al., 2017).

OBJECTIVES OF THE GP-TCM RA PHARMACOLOGY AND TOXICOLOGY INTEREST GROUP

The GP-TCM RA PTIG has the following objectives:

• To develop and maintain a competent collaborating network of TCM pharmacologists and toxicologists;
• To catalog and disseminate available pharmacological and toxicological data for selected herbal medicines, their extracts and phytochemicals;
• To organize and conduct research projects that integrate both classical and omic pharmacology;
• To identify relevant end-points for major toxicities and reliable methods to measure them;
• To refine good practice guidelines for in vitro, in vivo and omic pharmacological and toxicological tests (Chan et al., 2012; Uzuner et al., 2012);
• To organize forum for ongoing discussion and improvements in pharmacological and toxicological research of herbal medicines;
• To train young scientists in these highly multidisciplinary fields;
• To promote integration of pharmacology and toxicology, as well as pharmacology, toxicology and other aspects of herbal medicine studies.

ACTIVITIES FOR THE GP-TCM RA PHARMACOLOGY AND TOXICOLOGY INTEREST GROUP

• to plan future PTIG Workshops, e.g. the 10th GP-TCM RA On-line Meeting in 2022;
• to further develop PTIG webpage;
• to identify grant opportunities and coordinate application with interested members;
• to update members on the progress of the HMPC work and coordinate proposals for monograph amendment;
• to monitor the literature for key pharmacological and toxicological papers (original methods, new targets,…);
• to monitor the literature for papers on adverse events and unexpected toxicological findings;
• to produce in-depth reviews/perspectives, and/or monographs on pharmacology and toxicology.

REFERENCES

Atanasov, A. G., Zotchev, S. B., Dirsch, V. M., Orhan, I. E., Banach, M., Rollinger, J. M., Barreca, D., Weckwerth, W., Bauer, R., Bayer, E. A., Majeed, M., Bishayee, A., Bochkov, V., Bonn, G. K., Braidy, N., Bucar, F., Cifuentes, A., D’Onofrio, G., Bodkin, M., Diederich, M., Dinkova-Kostova, A. T., Efferth, T., El Bairi, K., Arkells, N., Fan, T.-P., Fiebich, B. L., Freissmuth, M., Georgiev, M. I., Gibbons, S., Godfrey, K. M., Gruber, C. W., Heer, J., Huber, L. A., Ibanez, E., Kijjoa, A., Kiss, A. K., Lu, A., Macias, F. A., Miller, M. J. S., Mocan, A., Müller, R., Nicoletti, F., Perry, G., Pittalà, V., Rastrelli, L., Ristow, M., Russo, G. L., Silva, A. S., Schuster, D., Sheridan, H., Skalicka-Woźniak, K., Skaltsounis, L., Sobarzo-Sánchez, E., Bredt, D. S., Stuppner, H., Sureda, A., Tzvetkov, N. T., Vacca, R. A., Aggarwal, B. B., Battino, M., Giampieri, F., Wink, M., Wolfender, J.-L., Xiao, J., Yeung, A. W. K., Lizard, G., Popp, M. A., Heinrich, M., Berindan-Neagoe, I., Stadler, M., Daglia, M., Verpoorte, R., Supuran, C. T. and the International Natural Product Sciences, T., 2021, Natural products in drug discovery: advances and opportunities, Nature Reviews Drug Discovery 20(3):200-216.

Buriani, A., Garcia-Bermejo, M. L., Bosisio, E., Xu, Q., Li, H., Dong, X., Simmonds, M. S., Carrara, M., Tejedor, N., Lucio-Cazana, J. and Hylands, P. J., 2012, Omic techniques in systems biology approaches to traditional Chinese medicine research: Present and future, J Ethnopharmacol 140:535-544.

Chan, K., Shaw, D., Simmonds, M. S., Leon, C. J., Xu, Q., Lu, A., Sutherland, I., Ignatova, S., Zhu, Y. P., Verpoorte, R., Williamson, E. M. and Duez, P., 2012, Good practice in reviewing and publishing studies on herbal medicine, with special emphasis on traditional Chinese medicine and Chinese materia medica, J Ethnopharmacol 140(3):469-475.

Chen, S. T., Dou, J., Temple, R., Agarwal, R., Wu, K. M. and Walker, S., 2008, New therapies from old medicines, Nat Biotechnol 26(10):1077-1083.

Committee on Herbal Medicinal Products (HMPC), 2008, Guideline on the assessment of genotoxicity of herbal substances/preparations, Doc. Ref. EMEA/HMPC/107079/2007, European Medicines Agency (EMEA), London, pp. 12.

Fugh-Berman, A., 2000, Herb-drug interactions, Lancet 355(9198):134-138.

Kahumba, J., Rasamiravaka, T., Okusa, P. N., Bakari, A., Bizumukama, L., Kalonji, J.-B., Kiendrebeogo, M., Rabemanantsoa, C., El Jaziri, M., Williamson, E. M. and Duez, P., 2014, Traditional African medicine: from ancestral knowledge to a modern integrated future?, Science Submitted for publication.

Koch, M. A., Schuffenhauer, A., Scheck, M., Wetzel, S., Casaulta, M., Odermatt, A., Ertl, P. and Waldmann, H., 2005, Charting biologically relevant chemical space: A structural classification of natural products (SCONP), Proceedings of the National Academy of Sciences 102(48):17272-17277.

Okpako, D. T., 1999, Traditional African medicine: theory and pharmacology explored, Trends Pharmacol Sci20(12):482-485.

Ouedraogo, M., Baudoux, T., Stevigny, C., Nortier, J., Colet, J. M., Efferth, T., Qu, F., Zhou, J., Chan, K., Shaw, D., Pelkonen, O. and Duez, P., 2012, Review of current and “omics” methods for assessing the toxicity (genotoxicity, teratogenicity and nephrotoxicity) of herbal medicines and mushrooms, J Ethnopharmacol 140(3):492-512.

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