Effect of cyclosporin A and some derivatives in Litomosoides carinii-infected Mastomys natalensis

Abstract

Litomosoides carinii-infected Mastomys natalensis were treated 85 days post infection with cyclosporin A (CyA) or 8 derivatives with different immunosuppressive capacities. CyA (oral doses of 5x25 mg/kg. 5x50 mg/kg, 5x80 mg/kg on consecutive days) reduced parasitaemia levels in a dose dependent way, beginning 3 weeks after first drug administration. Using 5x50 and 5x80 mg/kg animals were free from circulating microfilariae on the day of necropsy (day 56). Derivatives were administered in 5 daily oral doses of 50 mg/kg. Compounds B–5–49 and G–7–53 had similar effects as CyA. Compounds A–4–16 and E–6–44 caused mean microfilaraemia reductions of about 80% until day 56. Compounds C–5–34, D–6–45, F–7–62 and H–7–94 were only marginally effective (10–40%). None of the drugs affected the number or the motility of adult worms. However, in the case of efficacious compounds the number of intrauterine microfilariae was considerably reduced and most of the intrauterine stages were pathologically altered. The efficacy of the various derivatives was independent of their immunosuppressive activity in vivo and in vitro, their anti-inflammatory activity and their activity against Plasmodium berghei. Effects on intrauterine stages were first detectable 7 days after treatment with 5x80 mg CyA/kg when the number of intrauterine microfilariae had decreased and the proportion of pathologically altered stages had increased. Alterations increased with time after treatment. Additionally, the uteri contained relatively large amounts of highly active microfilariae which were still included in an ovoid sheath. These stages seemed to try unsuccessfully to stretch their stiff sheath, and also degenerated by 35 days.