Partners and International Organizations
(English)
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A, B, CZ, DK, F, D, NL, P, E, S, CH, GB
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Abstract
(English)
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In the year 2001 and the first 7 months of 2002 the in vitro and in vivo screening of new compounds from various European collaborators continued. Our screening procedure was further improved, especially our mouse models. The Trypanosoma b.rhodesiense model was modified by replacing the strain STIB 900 which proved hard to cure by the more susceptible STIB 795. More than 1000 new compounds and plant extracts were screened in vitro against 4 protozoan parasites (T.b.rhodesiense, T. cruzi, L. donovani and P. falciparum), and also tested for cytotoxicity. Active and not overt cytotoxic compounds were tested in our primary mouse models. The data on the antiparasitic activity could assist the chemists through SAR analysis to guide further synthesis of new compounds. Suppliers of compounds also included phytochemists, extracting and fractionating medicinal plants to isolate pure compounds which can act as leads for synthetic chemistry. With WSP 744 (I. Gilbert, Cardiff, UK) a new lead compound could be found. This compound showed good in vitro and in vivo activity against T. b. rhodesiense. The available drugs against African sleeping sickness are old, expensive and toxic. The rate of treatment failures with melarsoprol, the most important drug, was observed to have increased to over 20% in some areas of Africa. One strategy to treat relapses is treatment with a combination of standard drugs, preferably with a synergistic mode of action. Using in vitro culture techniques, we studied the various combinations for synergistic or additive effects. Combination of melarsoprol with suramin, diminazene, nifurtimox, DB 75 and CPG 40215 (two experimental compounds) with fixed IC50 ratios (1+0, 2+1, 1+2, 0+1) were tested in vitro and the fractional inhibitory concentrations (FIC) were calculated. For analysis, the FICs were plotted as isobolograms. The preliminary result that the combination melarsoprol-suramin has a potential for synergism, could not be confirmed. All combinations so far tested showed only additive or even antagonistic effects. The elucidation of the reasons for relapses after melarsoprol treatment is still a major objective. Since it was so far not possible to isolate drug resistant trypanosomes from relapse patients nor to demonstrate that relapsing patients have insufficient drug levels in their bodies, the reasons for these treatment failures are still obscure. There is a great need for trypanosome populations from relapsing patients, however, the isolation of Trypanosoma b. gambiense is extremely difficult. In an attempt to improve the isolation of these parasites, we started to improve the cryopreservation, cultivation and in vivo propagation of T.b.gambiense. Two new animal models were evaluated, the Central African tree rat Grammomys surdaster and immunodeficient SCID mice. A breeding colony of Grammomys could be established at our institute. The handling of these animals iproved to be too problematic. With SCID mice a susceptible host could be found with the drawback of being expensive.
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