Action of cyclosporins against hymenolepid tapeworms
Hymenolepis microstoma and H.diminuta were explored as models to elucidate further the mechanism and target of cyclosporin A (CsA) action in helminths. It was established that the mode of action against H.microstoma was direct and not mediated via the host immune response. Supporting evidence includes: (1) the weakly immunosuppressive derivative of CsA, B-5-49 showed similar anthelmintic action to that of CsA against H.microstoma in vivo. When administered around the time of infection, B-5-49 was marginally more effective than CsA in reducing the survival of juvenile worms, reversibly inhibiting worm growth and delaying the anterior migration of the worms to the bile duct. B-5-49 showed activity equal to that of CsA when administered to adult (19 day-old) H.microstoma reducing the numbers and weights of worms in a dose-dependent manner, causing destrobilation and ceasing worm oncosphere production. When administered subcutaneously prior to infection with H.microstoma, B-5-49 reduced worm weight although to a lesser extent than CsA. These reductions were dependent on dose and on route of administration; drug activity was considerably diminished when delivered orally rather than subcutaneously or intraperitoneally; (2) physiologically attainable concentrations of both CsA and B-5-49 were active against H.microstoma in vitro in a dose-dependent manner. Juvenile worms were more susceptible to drug action than adults; and (3) in vivo administration of B-5-49 resulted in morphological damage to the surface of H.microstoma identical to that caused by CsA. Similar morphological changes were also demonstrated when worms were exposed to either drug in vitro. Damage was both dose- and age-dependent and was characterised by proglottis swelling accompanied by apparent fluid accumulation and the formation of protuberances extending from the worm surface.