Traditional medicines are gifted candidates for traditional knowledge guided drug discovery and play a vital role in development of bioactive small organic compounds. The working hypothesis for ethnopharmacological research developed from anthropological field research. Thus, Ethnopharmacological research includes anthropological, ethnobiological and pharmacological investigations (Jurg, 2009).
However, 90% of new drug candidates fail in clinical trials after rigorous optimisation in preclinical studies. Among this 40-50% clinical failure due to lack of efficacy of new drugs. Although, pharmacological validation of new drug in targeted human ailment is a challenge due to pharmacological inconsistency in in-vitro, animal diseases models and human diseases. 30% clinical failure of new drugs is due to unmanageable toxicity and 10-15% clinical failure due to poor-drug-link properties, less commercial requirements and poor strategy. Therefore, delicate dose selection is essential for best selected drug candidates for better efficacy and lower toxicity for development of successful clinical drugs (Sun et al.,2022).
In case of traditional knowledge guided drug discovery crude extract of traditional medicine/plant/mixture of plant investigated on in-vitro and in-vivo animal disease models initially for justifying the traditional claim. In this process, generally acute toxicity study performed in order to determine the ALD50 cut off the dose under GHS 5 (safe dose), as per Globally Harmonised Classification System (GHS) for Chemical Substances and Mixtures described in OECD guideline 423/420/425. However, the majority of the traditional medicine/ edible plants candidates do not show toxicity in higher doses such as 2000 mg/kg body weight. But, for therapeutic purposes only 100 mg/kg (low) and 150 mg/kg (high) body weight doses should be selected for in-vivo animal diseases models and 50-100 µg/ml doses for ex-vivo and in-vitro studies. The published report suggested that ≥200 mg/kg body weight of extracts for in-vivo studies and ≥200 µg/ml of extract concentrations in in-vitro are likely to be artificial despite yielding reproducible effects. Even worse, such high concentrations may trigger non-physiological effects resulting in artifacts (Deb et al., 2012; Jurg, 2009).
The majority of published reports on preclinical studies showing efficacy of crude drugs at the doses of 400 -1000 mg/kg body weight per day. Which is not feasible and scientifically logical for further translation to the clinical doses for human diseases. Such misleading preclinical outputs may be responsible for 40-50% clinical failure due to lack of efficacy of new drugs.
References:
- Deb Lokesh, Dutta Amitsankar (2012). Evaluation of Mechanism for Antihypertensive Action of Clerodendrum Colebrookianum Walp., used by Folklore Healers in North-East India. Journal of Ethnopharmacology. 143; 207–212
- Jurg Gertsch (2009). How scientific is the science in ethnopharmacology? Historical perspectives and epistemological problems. Journal of Ethnopharmacology. 122, 177–183
- Sun Duxin, Gao Wei, Hu Hongxiang, Zhou Simon (2022). Why 90% of clinical drug development fails and how to improve it? Acta Pharmaceutica Sinica B. 12(7): 3049-3062.