The major aims of our research are

  • rationalization and development of phytomedicines
  • discovery of biologically active (plant-derived) lead compounds for further development of drugs in areas of unmet medical need
To arrive at these objectives, we have developed a strategy which comprises
  • a survey of information on the use of particular plants in traditional medicine (i.e. field studies and studies of classical texts, e.g. Ayurvedic manuscripts)
  • a literature survey of modern scientific facts concerning the plants under investigation
  • experimental research which is projected on the basis of data collected during the previous two stages.
In the experimental stage, single active plant constituents are obtained through (in vitro) activity-guided fractionation and isolation procedures and their structures are elucidated. Subsequently, these compounds are subjected to mechanistic studies and in vivo experiments. By the approach described we have obtained several interesting plant constituents, e.g. acetophenones, triterpenoids, cyclic peptides or polysaccharides. Phytomedicines and plant preparations used as therapeutics may vary in their composition. Therefore, discovery and identification of their active principles as outlined above is needed for the standardization and quality control of these products. In addition, we aim at the pharmaceutical-technological improvement of phytomedicines by developing new formulations and new production and extraction procedures.

Active compounds with new molecular structures or known compounds with new activities can be applied in pharmacotherapy as such or can serve as lead compounds in the development of drugs with improved qualities. Since we have a broad overview of the occurrence of plant constituents and their distribution we are able to find look-a-like compounds elsewhere in the plant kingdom. Besides that, lead compounds themselves can be chemically modified in cooperation with the organic synthesis unit of the Department of Medicinal Chemistry(Prof. dr. R.M.J. Liskamp; Universiteit Utrecht) to obtain chemical entities with improved qualities.

Our research is focused on the immune system, (phyto)estrogens and plants which prevent carcinogenesis. Most of our In vitro assays for activity represent key processes in inflammatory reactions, such as activation of human complement, induction of the respiratory burst in human polymorphonuclear neutrophils (granulocytes), proliferation of T-cells, or production of cytokines by mononuclear cells (e.g. TNF-α, IL-1-ß IL-6, IL-10, IL-4, IL-8, IFN-g). In addition, we are able to selectively determine ER-a or ER-?agonistic activity. We are particularly interested in compounds and/or plant preparations that can be applied
(1) against rheumatoid arthritis, colitis ulcerosa, Crohn's disease, asthma, and septic shock, preventing the induction of genetic damage
(2) in menopausal disorders
 

Example

A nice example of our research is apocynin, a relatively simple molecule (4'-hydroxy-3'-methoxyacetophenone) obtained from the roots of Picrorhiza kurrooa (Scrophulariacea).

P. kurrooa is a small perennial herb common in the alpine Himalayas. Its rhizomes have been used in Oriental traditional medicine for thousands of years.In ancient books of Ayurveda, P. kurrooa (Kutki, Katuki) is described to be particularly effective in liver and lung diseases, but in contemporary Asian folk medicine its list of applications also includes rheumatic disease.

Already in the late eighties apocynin was isolated at our laboratory by bio assay-guided procedures and we were the first who discovered its most pronounced inhibitory effect on the production of reactive oxygen species by granulocytes. Since then many investigators have chosen apocynin as item of their research.

R.P. Labadie, J.M. van der Nat, J.M. Simons, B.H. Kroes, S. Kosasi, A.J.J. van den Berg, L.A. 't Hart, W.G. van der Sluis, A. Abeysekera, A. Bamunuarachchi, and K.T.D. de Silva (1989) An ethnopharmacognostic approach to the search for immunomodulators of plant origin. Planta medica 55, 339-348.

L.A. 't Hart, J.M. Simons, S. Knaan-Shanzer, N.P.M. Bakker, and R.P. Labadie (1990) Antiarthritic activity of the newly developed neutrophil oxidative burst antagonist apocynin. Free Radical Biology & Medicine 9, 127-131.

M.J.H.J. Palmen, C.J. Beukelman, R.G.M. Mooij, S.G.M. Meeuwissen, and E.P. van Rees (1995) Beneficial effect of apocynin, a plant-derived NADPH oxidase antagonist, in TNBS-induced experimental colitis. Gasteroenterology 108, A889.

C.J. Beukelman, A.J.J. van den Berg, B.H. Kroes, R.P. Labadie, E.E. Mattsson, and H. van Dijk (1995) Plant-derived metabolites with synergistic antioxidant activity. Immunology Today 16, 108.

F.B.J.G. Lafeber, C.J. Beukelman, E. van den Worm, J.L.A.M. van Roy, M.E. Vianen, J.A.G. van Roon, H. van Dijk, and J.W.J. Bijlsma (1999) Apocynin, a plant-derived, cartilage-saving drug, might be useful in the treatment of rheumatoid arthritis. Rheumatology 38, 1088-1093