Suppression of Leishmania donovani by oral administration of a bis(benzyl)polyamine analog

Abstract

We reported previously that intraperitoneal administration of a bis(benzyl)polyamine analog, MDL 27,695, suppressed both pentavalent antimony (Sbv)-susceptible and -resistant Leishmania donovani in vivo. The present studies were performed to optimize parasite suppression by parenteral administration and to evaluate the efficacy of oral treatment with MDL 27,695. L. donovani infections in BALB/c mice were suppressed >99% after intraperitoneal dosing for 20 days with a total dose of 150 mg of MDL 27,695 per kg of body weight or 560 mg of SbV per kg. Suppression was not increased by a total dose of 400 mg of MDL 27,695 per kg given for 20 days. In mice treated for 2, 4, or 7 days with either MDL 27,695 or Sb" (total doses of 60, 120, and 210 mg/kg, respectively), more liver parasites were killed with MDL 27,695 than with Sb". Assessment of livers posttreatment showed that parasite killing continued for at least 3 days in MDL 27,695-treated mice but not for longer than 1 day in SbW-treated mice. Intramuscular administration of drugs resulted in 92% parasite suppression by MDL 27,695 (15 mg/kg three times per day for 5 days) and 64% suppression by Sbv (60 mg/kg once per day for 5 days). Dosing of mice by oral gavage with 100 mg of MDL 27,695 per kg twice per day for 14 days resulted in 99.7% parasite suppression, and the 50% effective dose was approximately 11 mg of MDL 27,695 per kg. MDL 27,695 represents an effective new drug potentially useful for oral or parenteral treatment of visceral leishmaniasis.

The putrescine analogue 1,4-diamino-2-butanone affects polyamine synthesis, transport, ultrastructure and intracellular survival in Leishmania amazonensis

“…PA synthesis inhibitors have been shown to have antiparasitic (Bacchi & Yarlett, 2002) and particularly antileishmanial activities (Baumann et al, 1991;Balaña-Fouce et al, 1991;Mukhopadhyay & Madhubala, 1995). The putrescine analogue DAB has been tested in different micro-organisms (Calvo-Méndez et al, 1993;ArteagaNieto et al, 1996;Reis et al, 1999;Garcia et al, 2005;Menezes et al, 2006) and was effective against DFMOresistant parasites (Calvo-Méndez et al, 1993;Reis et al, 1999).…”

Inhibition of host cell invasion and intracellular replication of Trypanosoma cruzi by N,N'-bis(benzyl)-substituted polyamine analogs

“…N,N'-Di-substituted tetraamines with the general formula RNH(CH2)XNH (CH2)YNH(CH2)NINHR have been reported to suppress the growth of several pathogenic protozoans (e.g., Leishmania donovani, Plasmodium falciparum, and Plasmodium berghei) in vitro and in infected animals (2)(3)(4) and could be suitable for exploring the role that polyamines and polyamine biosynthesis plays in T. cnuzi infection. In this work, we used two N,N'-bis(benzyl)-substituted polyamine analogs and studied their effects on T. cnuzi infectivity and replication using an in vitro model system of mammalian host cell infection.…”

In vitro and in vivo Activities of Three Acridine Thioethers against <i>Leishmania donovani</i>

“…More recently, investigators have sought for new molecules active against visceral leishmaniasis. Baumann et al [4] have studied the role of a polyamine analogue (alpha-difluoromethylornithine) against L. donovani; Marr [5] has demonstrated the therapeutic effectiveness of purine analogues against visceral leishmaniasis. Metal complexes, originally used for their antitumor activity, have also shown trypanocidal activity [6].…”