Volume 80, Issue 4
  • ISSN: 0002-9637
  • E-ISSN: 1476-1645


We evaluated the causal prophylactic antimalarial activity of a single oral dose of pafuramidine (DB289), an experimental prodrug of active metabolite DB75, in a randomized, double-blind, placebo-controlled, outpatient study. Sixteen healthy volunteers were dosed and challenged in a single cohort. Subjects were randomly assigned to one of three treatment arms: 100 mg pafuramidine eight days before challenge, 100 mg pafuramidine the day before challenge, or placebo. Challenge was by the bites of infected Malaria developed in 15 persons but did not develop in one person in the day −8 pafuramidine treatment arm. Plasma levels of DB75 were lower than expected, and as intended were too low to provide suppressive prophylaxis at the earliest appearance of erythrocytic parasites. We conclude that a single dose of 100 mg pafuramidine does not adequately protect non-immune individuals against and shows no clinically or statistically significant evidence of causal prophylactic activity.


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  1. Leder K, Black J, O’Brien D, Greenwood Z, Kain KC, Schwartz E, Brown G, Torresi J, 2004. Malaria in travelers: a review of the GeoSentinel surveillance network. Clin Infect Dis 39 : 1104–1112.
  2. Werbovetz K, 2006. Diamidines as antitrypanosomal, antileishmanial and antimalarial agents. Curr Opin Investig Drugs 7 : 147–157.
  3. Yeates C, 2003. DB-289 Immtech International. IDrugs 6 : 1086–1093.
  4. Bell CA, Hall JE, Kyle DE, Grogl M, Ohemeng KA, Allen MA, Tidwell RR, 1990. Structure-activity relationships of analogs of pentamidine against Plasmodium falciparum and Leishmania mexicana amazonensis. Antimicrob Agents Chemother 34 : 1381–1386.
  5. Kocken CH, van der Wel A, Arbe-Barnes S, Brun R, Matile H, Scheurer C, Wittlin S, Thomas AW, 2006. Plasmodium vivax: in vitro susceptibility of blood stages to synthetic trioxolane compounds and the diamidine DB75. Exp Parasitol 113 : 197–200.
  6. Carter NS, Berger BJ, Fairlamb AH, 1995. Uptake of diamidine drugs by the P2 nucleoside transporter in melarsen-sensitive and -resistant Trypanosoma brucei brucei. J Biol Chem 270 : 28153–28157.
  7. Damper D, Patton CL, 1976. Pentamidine transport and sensitivity in brucei-group trypanosomes. J Protozool 23 : 349–356.
  8. Bell CA, Cory M, Fairley TA, Hall JE, Tidwell RR, 1991. Structure-activity relationships of pentamidine analogs against Giardia lamblia and correlation of antigiardial activity with DNA-binding affinity. Antimicrob Agents Chemother 35 : 1099–1107.
  9. Dykstra CC, Tidwell RR, 1991. Inhibition of topoisomerases from Pneumocystis carinii by aromatic dicationic molecules. J Protozool 38 : 78S–81S.
  10. Shapiro TA, Englund PT, 1990. Selective cleavage of kinetoplast DNA minicircles promoted by antitrypanosomal drugs. Proc Natl Acad Sci USA 87 : 950–954.
  11. Stead AM, Bray PG, Edwards IG, DeKoning HP, Elford BC, Stocks PA, Ward SA, 2001. Diamidine compounds: selective uptake and targeting in Plasmodium falciparum. Mol Pharmacol 59 : 1298–1306.
  12. Lanteri CA, Tidwell RR, Meshnick SR, 2008. The mitochondrion is a site of trypanocidal action of the aromatic diamidine DB75 in bloodstream forms of Trypanosoma brucei. Antimicrob Agents Chemother 52 : 875–882.
  13. Lanteri CA, Trumpower BL, Tidwell RR, Meshnick SR, 2004. DB75, a novel trypanocidal agent, disrupts mitochondrial function in Saccharomyces cerevisiae. Antimicrob Agents Chemother 48 : 3968–3974.
  14. Saulter JY, Kurian JR, Trepanier LA, Tidwell RR, Bridges AS, Boykin DW, Stephens CE, Anbazhagan M, Hall JE, 2005. Unusual dehydroxylation of antimicrobial amidoxime prodrugs by cytochrome b5 and NADH cytochrome b5 reductase. Drug Metab Dispos 33 : 1886–1893.
  15. Midgley I, Fitzpatrick K, Taylor LM, Houchen TL, Henderson SJ, Wright SJ, Cybulski ZR, John BA, McBurney A, Boykin DW, Trendler KL, 2007. Pharmacokinetics and metabolism of the prodrug DB289 (2,5-bis[4-(N-methoxyamidino)phenyl]furan monomaleate) in rat and monkey and its conversion to the anti-protozoal/antifungal drug DB75 (2,5-bis(4-guanylphenyl)furan dihydrochloride). Drug Metab Dispos 35 : 955–967.
  16. Yeramian P, Meshnick SR, Krudsood S, Chalermrut K, Silachamroon U, Tangpukdee N, Allen J, Brun R, Kwiek JJ, Tidwell R, Looareesuwan S, 2005. Efficacy of DB289 in Thai patients with Plasmodium vivax or acute, uncomplicated Plasmodium falciparum infections. J Infect Dis 192 : 319–322.
  17. Tidwell RR, Jones SK, Geratz JD, Ohemeng KA, Bell CA, Berger BJ, Hall JE, 1990. Development of pentamidine analogues as new agents for the treatment of Pneumocystis carinii pneumonia. Ann NY Acad Sci 616 : 421–441.
  18. Das BP, Boykin DW, 1977. Synthesis and antiprotozoal activity of 2,5-bis(4-guanylphenyl)furans. J Med Chem 20 : 531–536.
  19. Bell CA, Dykstra CC, Naiman NA, Cory M, Fairley TA, Tidwell RR, 1993. Structure-activity studies of dicationically substituted bis-benzimidazoles against Giardia lamblia: correlation of anti-giardial activity with DNA binding affinity and giardial topoisomerase II inhibition. Antimicrob Agents Chemother 37 : 2668–2673.
  20. Meis JF, Verhave JP, Meuwissen JH, Jap PH, Princen HM, Yap SH, 1984. Fine structure of Plasmodium berghei exoerythrocytic forms in cultured primary rat hepatocytes. Cell Biol Int Rep 8 : 755–765.
  21. Meis JF, Verhave JP, Wirtz P, Meuwissen JH, 1984. Histochemical observations on the exoerythrocytic malaria parasite Plasmodium berghei in rat liver. Histochemistry 81 : 417–425.
  22. Gutteridge WE, Dave D, Richards WH, 1979. Conversion of dihydroorotate to orotate in parasitic protozoa. Biochim Biophys Acta 582 : 390–401.
  23. Murphy JR, Baqar S, Davis JR, Herrington DA, Clyde DF, 1989. Evidence for a 6.5-day minimum exoerythrocytic cycle for Plasmodium falciparum in humans and confirmation that immunization with a synthetic peptide representative of a region of the circumsporozoite protein retards infection. J Clin Microbiol 27 : 1434–1437.
  24. Chappell WR, Mordenti J, 1991. Extrapolation of toxicological and pharmacological data from animals to humans. Testa B, ed. Advances in Drug Research. Volume 20. New York: Academic Press, 244–254.
  25. Gray H, 1973. Splanchnology. Warwick R, Williams PL, eds. Gray’s Anatomy. 35th edition. Edinburgh, UK: Longman Group Ltd., 1344–1363.
  26. Davis JR, 1994. Laboratory methods for the conduct of experimental malaria challenge of volunteers. Vaccine 12 : 321–327.
  27. Ponnudurai T, Leeuwenberg AD, Meuwissen JH, 1981. Chloroquine sensitivity of isolates of Plasmodium falciparum adapted to in vitro culture. Trop Geogr Med 33 : 50–54.
  28. Desjardins RE, Canfield CJ, Haynes JD, Chulay JD, 1979. Quantitative assessment of antimalarial activity in vitro by a semiautomated microdilution technique. Antimicrob Agents Chemother 16 : 710–718.
  29. Posner G, Gonzalez L, Cumming J, Klinedinst D, Shapiro T, 1997. Synthesis and antimalarial activity of heteroatom-containing bicyclic endoperoxides. Tetrahedron 53 : 37–50.
  30. Cheng Q, Lawrence G, Reed C, Stowers A, Ranford-Cartwright L, Creasey A, Carter R, Saul A, 1997. Measurement of Plasmodium falciparum growth rates in vivo: a test of malaria vaccines. Am J Trop Med Hyg 57 : 495–500.
  31. Mount DL, Nahlen BL, Patchen LC, Churchill FC, 1989. Adaptations of the Saker-Solomons test: simple, reliable colorimetric field assays for chloroquine and its metabolites in urine. Bull World Health Organ 67 : 295–300.
  32. Anthony RL, Bangs MJ, Anthony JM, Purnomo, 1992. On-site diagnosis of Plasmodium falciparum, P. vivax, and P. malariae by using the quantitative buffy coat system. J Parasitol 78 : 994–998.
  33. Pinto MJ, Rodrigues SR, Desouza R, Verenkar MP, 2001. Usefulness of quantitative buffy coat blood parasite detection system in diagnosis of malaria. Indian J Med Microbiol 19 : 219–221.
  34. Rickman LS, Long GW, Oberst R, Cabanban A, Sangalang R, Smith JI, Chulay JD, Hoffman SL, 1989. Rapid diagnosis of malaria by acridine orange staining of centrifuged parasites. Lancet 1 : 68–71.
  35. Shapiro TA, Ranasinha CD, Kumar N, Barditch-Crovo P, 1999. Prophylactic activity of atovaquone against Plasmodium falciparum in humans. Am J Trop Med Hyg 60 : 831–836.
  36. Church LW, Le TP, Bryan JP, Gordon DM, Edelman R, Fries L, Davis JR, Herrington DA, Clyde DF, Shmuklarsky MJ, Schneider I, McGovern TW, Chulay JD, Ballou WR, Hoffman SL, 1997. Clinical manifestations of Plasmodium falciparum malaria experimentally induced by mosquito challenge. J Infect Dis 175 : 915–920.
  37. Epstein JE, Rao S, Williams F, Freilich D, Luke T, Sedegah M, de la Vega P, Sacci J, Richie TL, Hoffman SL, 2007. Safety and clinical outcome of experimental challenge of human volunteers with Plasmodium falciparum-infected mosquitoes: an update. J Infect Dis 196 : 145–154.
  38. Jenkins MM, Prachal JT, 1997. A high-frequency polymorphism of NADH-cytochrome b5 reductase in African-Americans. Hum Genet 99 : 248–250.
  39. Nakornchai S, Konthiang P, 2006. Potentiation of antimalarial drug action by chlorpheniramine against multidrug-resistant Plasmodium falciparum in vitro. Parasitol Int 55 : 195–199.
  40. Sowunmi A, Fehintola FA, Ogundahunsi OA, Oduola AM, 1998. Comparative efficacy of chloroquine plus chlorpheniramine and halofantrine in acute uncomplicated falciparum malaria in Nigerian children. Trans R Soc Trop Med Hyg 92 : 441–445.
  41. Chong CR, Chen X, Shi L, Liu JO, Sullivan DJ Jr, 2006. A clinical drug library screen identifies astemizole as an antimalarial agent. Nat Chem Biol 2 : 415–416.
  42. Chulay JD, Schneider I, Cosgriff TM, Hoffman SL, Ballou WR, Quakyi IA, Carter R, Trosper JH, Hockmeyer WT, 1986. Malaria transmitted to humans by mosquitoes infected from cultured Plasmodium falciparum. Am J Trop Med Hyg 35 : 66–68.
  43. Coatney G, Copper W, Young M, McLendon S, 1947. Studies in human malaria I. The protective action of sulfadiazine and sulfapyrazine against sporozoite-induced falciparum malaria. Am J Hyg 46 : 84–104.

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  • Received : 18 Aug 2008
  • Accepted : 09 Oct 2008

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