Präklinische Evaluation neuer Testsubstanzen und Studien der Wirkungsweise und der Resistenzentwicklung

• Research unit: COST
• Project number: C97.0069

Key words (English)

CHEMOTHERAPY; PARASITIC DISEASES; DRUG SCREENING; DRUG RESISTANCE; SWISS TROPICAL INSTITUTE

Research programs (English)

COST-Action B9 - Protozoal infections

Short description (English)

See abstract

Partners and International Organizations (English)

A, B, CZ, DK, F, D, NL, P, E, S, CH, UK

Abstract (English)

Drug discovery. The in vitro and in vivo screening of synthetic compounds and natural products for antiparasitic activity and cytotoxicity continued. Series of compounds were received from partners in the COST B9 action and from other groups. Specific in vitro activity against P. falciparum and T.b.rhodesiense was followed in the corresponding mouse model. Compounds with pronounced activity against one or the other parasite could be found, but none reached the status of a lead compound. Over 340 compounds from over 10 suppliers were investigated in our integrated in vitro screening against 4 protozoan parasites. Evaluation of active compounds in rodent models focussed on the African trypanosomes and malaria. For African trypanosomes we use an acute T.b.rhodesiense model, an acute T.b.gambiense rodent model and a chronic (CNS) T.b.brucei model, and for malaria the P.berghei mouse model. Nanoparticles. Nanoparticles were evaluated as carriers of active compounds which do not pass the blood-brain barrier (BBB). In collaboration with the Free University of Berlin solid lipid particles made from stearic acid were used as carriers and in collaboration with the University of Frankfurt polybutylcyanoacrylate nano-particles. Both types of particles are supposed to either pass or bind to the BBB and facilitate penetration of the drug into the CNS. So far the results were disappointing, the mouse CNS model could not be cured. A basic discussion with all groups involved will have to decide on further steps or termination. Treatment failure. The phenomenon of treatment failure in sleeping sickness patients after melarsoprol treatment was studied using various approaches. Drug levels in patients and drug sensitivity of the parasites were investigated . For patients in north-western Uganda it was found that serum and cerebrospinal fluid levels were comparable in relapse and in curable patients. T.b.gambiense isolates from relapse patients had the same melarsoprol sensitivity as isolates from curable patients. A study of old T.b.rhodesiense isolates from East Africa from the 1960's from patients who did not respond to melarsoprol treatment revealed a 10-fold reduced in vitro sensitivity and complete refractoriness in the mouse model. This was the first demonstration of melarsoprol resistant human African trypanosomes causing treatment failure.

References in databases (English)

Swiss Database: COST-DB of the State Secretariat for Education and Research Hallwylstrasse 4 CH-3003 Berne, Switzerland Tel. [phone] Swiss Project-Number: C97.0069