The parasite surface as a target for novel chemotherapy
Three independent studies investigated the parasite surface as a potential drug-target for chemotherapy. The first study was based on an observation that a 'range of 5-HT active compounds were anthelmintic' (Schering Agrochemicals Ltd). The potency of these compounds to inhibit 5-HT stimulated glucose uptake and glycogen breakdown was investigated using the tapeworms Hymenolepis microstoma and Hymenolepis diminuta. However, although some of these drugs were shown to effect 5-HT induced components of carbohydrate metabolism this could not be conclusively attributed to their 5-HT activities. A ligand binding study found a single 5-HT receptor on brush border membranes of H. diminuta with a Kd of 0.17 μM and Bmax of 8.93 x 10-9 moles. mg protein-1. Although 5-HT1 antagonists were most potent at displacing labelled 5-HT from H. diminuta brush-border preparations the affinity of these antagonists and 5-HT for the receptor was low. The second study investigated the activity of two novel antiparasitics to disrupt the surface of a range of model parasites. In vivo these drugs were potent against Heligmosomoides polygyrus and H. microstoma, but not Schistosoma mansoni and H. diminuta. In contrast to H. polygyrus, where activity of the drug decreased with worm age in vivo, only adult H. microstoma were susceptible. In vitro, all worms were susceptible to these drugs which showed similar potency to salicylanilide, a proposed uncoupler of oxidative phosphorylation in the liver fluke. Surface damage to the platyhelminths, but not H. polygyrus, was rapidly induced by the novel antiparasitic drugs and salicylanilide. Microscope examination demonstrated that ultrastructural changes to the surface were similar. Few mitochondria were observed in the syncytium of the trematodes and tapeworms and importance of oxidative phosphorylation is therefore questioned. CsA was potent against the liver fluke, Fasciola hepatica. Metabolites of CsA were less potent than the present drug in vitro and the drug was most potent against newly-hatched worms both in vivo and in vitro.