A Reverse Pharmacology approach for evaluating traditional medicines in the Republic of Palau to improve the management of obesity-linked diabetes Joëlle Houriet1, Christopher Kitalong2, Renata Campos Nogueira3, Carla Rudigier4, Jeanne Benichou5, Victor Yano2, Vanessa Espangel2, Pearl L. Marumoto2, Josepha Tiobech2, Christian Wolfrum4, Jean-Luc Wolfender1, Bertrand Graz2, 3 1 School of Pharmaceutical Sciences, University of Geneva, University of Lausanne, Rue Michel-Servet 1, 1206 Geneva, Switzerland 2 Pacific Academic Institute for Research, 822 Ernguul Rd., Koror, Palau 3Antenna Foundation, Avenue de la Grenade 24, 1207 Geneva, Switzerland 4 Institute of Food, Nutrition and Health, ETH Zurich, Schorenstrasse 16, CH-8603 Schwerzenbach, Switzerland. 5 ENSAT-National Institute of Agronomy and Environment of Toulouse, Avenue de l’Agrobiopole, BP 32607 Auzeville-Tolosane, France Contact Joëlle Houriet joelle.houriet@unige.ch Aim Republic of Palau (Micronesia, Pacific ocean) An important recommendation of the World Health Organization is the evaluation of traditional medicines. Reverse Pharmacology is an ethnopharmacological methodology which aims precisely to evaluate traditional practices [1]. It includes three main stages: Selection of medicinal herbs Clinical evaluation Laboratory studies A reverse pharmacology approach was implemented in the Republic of Palau to improve the management of Non-Communicable Diseases. Prevalence of overweight and obese adults of around 80 %, according to WHO data. State of Emergency Declaration of State of Emergency on Non-Communicable Diseases in 2011 (obesity-linked diseases, i.e. diabetes and hypertension). 1. Selection of medicinal herbs Selection method Selected herb Selection by a Retrospective Treatment Outcome (RTO) method. RTO statistically identified the remedies correlating with the best clinical outcomes [2]. The drink of the leaves of Phaleria nisidai (thymelaeaceae) positively correlated with the lower blood sugar criterion. This drink is also called by the Palauan population Delal A Kar, the Mother of medicine [3]. 2. Clinical evaluation Study design Key results This first clinical study ever organized in Palau was designed as a pilot randomized, double-blind, crossover clinical study. The drink of Phaleria nisidai was evaluated as an an adjuvant therapy for patients with insufficient diabetes control [4]. Patients with insufficient diabetes control improved their glycemia during the clinical study (reduction of HbA1C). Decreased blood pressure and weight reduction were also observed [4]. 3. Laboratory studies Material Transfer Agreement Bioactivity Phytochemistry A Material Transfer Agreement (MTA) was established between the Pacific Academic Institute of Research (PAIR) and both universities. Mice fed a high fat diet with the freeze-dried drink showed: Greater sensitivity to insulin Improved glucose tolerance Higher insulin secretion The freeze-dried drink is characterized by a high amount of the C-glycoside xanthone mangiferin and other minor related xanthones [5]. Future steps Advantages of the Reverse Pharmacology This study succeeded in identifying a promising herbal medicine to improve diabetes control. Valorization of traditional medicine made by the population. Prioritization of the clinical evaluation of the selected medicinal herb at the beginning of the drug development process [1]. Highly valuable post-clinical laboratory studies thanks to the preliminary clinical evaluation. Low cost compared to the classic drug development approach [1]. Clinical study on non-treated diabetic patients, compared to the standard first-line treatment. Identification of the bioactive components to select markers for standardization and quality control. References Acknowledgments Willcox M., et al., A "reverse pharmacology" approach for developing an anti-malarial phytomedicine. Malar J, 2011. 10 Suppl 1: p. S8. Graz B., et al., Screening of traditional herbal medicine: First, do a retrospective study, with correlation between diverse treatments used and reported patient outcome. J Ethnopharmacol, 2005. 101(1–3): p. 338-339. Graz B., et al., Traditional local medicines in the republic of Palau and non-communicable diseases (NCD), signs of effectiveness. J Ethnopharmacol, 2015. 161: p. 233-7. Kitalong C., et al., "DAK", a traditional decoction in Palau, as adjuvant for patients with insufficient control of diabetes mellitus type II. J Ethnopharmacol, 2017. 205: p. 116-122. Kitalong C., et al., Phenolics from Phaleria nisidai with Estrogenic Activity. Records of Natural Products, 2012. 6(3): p. 296-300. Icons from Noun Project: Gan Khoon Lay (overweight humans), Corpus delicti (Choose pharmacy), Eucalyp (diabetes), Wilson Joseph (population), Juan Manueal Corredor (human), Dinosoft Labs (agreement), Alina Oleynik (mouse), Juraj Sedlka (molecule), Meaghan Hendricks (future), Gan Khoon Lay (advantages).