title: Antifungal activity of HWA-138 and amphotericin B in experimental systemic candidiasis.
abstract: HWA-138, a pentoxifylline analog, has been shown to increase yeast urinary clearance and to reduce yeast counts in the kidneys of rats infected with Candida albicans. Furthermore, HWA-138 has also been shown to prevent amphotericin B-induced acute renal failure in rats. We report here on the effects of HWA-138 alone and in combination with amphotericin B in the treatment of systemic candidiasis in mice. When single doses of HWA-138 were administered intravenously (10, 25, or 50 mg/kg of body weight) into infected mice, no significant improvement in survival was observed. In infected mice treated intravenously with multiple doses of HWA-138 (10, 25, or 50 mg/kg once daily for 5 consecutive days), a significant increase in survival time was seen only in animals also receiving 25 mg of HWA-138 per kg (14 +/- 3 days test versus 9 +/- 1 days control; P less than 0.05). The coadministration of subtherapeutic doses of amphotericin B and HWA-138 resulted in increased survival time. Combination therapy with amphotericin B (0.1-mg/kg single dose) and HWA-138 (10-, 25-, or 50-mg/kg multiple doses) resulted in a significant increase in survival time over controls (19 +/- 4, 19 +/- 5, and 21 +/- 9 days, respectively, versus 9 +/- 3 days; P less than 0.05). Combination therapy with amphotericin B (0.2-mg/kg single dose) and HWA-138 (10-, 25-, or 50-mg/kg multiple doses) also resulted in a significant increase in survival time over controls (24 +/- 6, 24 +/- 6, and 24 +/- 6, respectively, versus 9 +/- 3 days; P less than 0.05). Combination therapy with amphotericin B (0.2-mg/kg single dose) and HWA-138 (10-, 25-, or 50-mg/kg multiple doses) also resulted in a significant increase in survival time over controls (24 +/- 6, 24 +/- 6, and 24 +/- 6, respectively, versus 9 +/- 3 days; P < 0.05). Variance analysis of these findings indicate synergistic activity between amphotericin B and HWA-138 in the treatment of experimental candidiasis in mice.
authors.affiliation: Department of Pharmaceutics, University of Houston, Texas Medical Center, Houston 77030.
authors.forename: K M
authors.initials: KM
authors.lastname: Wasan
authors.forename: K
authors.initials: K
authors.lastname: Vadiei
authors.forename: D R
authors.initials: DR
authors.lastname: Luke
authors.forename: A
authors.initials: A
authors.lastname: Keyhani
authors.forename: R A
authors.initials: RA
authors.lastname: White
authors.forename: T J
authors.initials: TJ
authors.lastname: McQueen
authors.forename: R
authors.initials: R
authors.lastname: Mehta
authors.forename: G
authors.initials: G
authors.lastname: Lopez-Berestein
mesh_terms: D000666:Amphotericin B / Q000627:therapeutic use*; D000818:Animals; D000935:Antifungal Agents / Q000627:therapeutic use*; D002177:Candidiasis / Q000188:drug therapy*; D004357:Drug Synergism; D051379:Mice; D008813:Mice, Inbred ICR; D010431:Pentoxifylline / Q000031:analogs & derivatives* / Q000627:therapeutic use
chemical_list: D000935:Antifungal Agents; C062028:1-(5-hydroxy-5-methylhexyl)-3-methylxanthine; D000666:Amphotericin B; D010431:Pentoxifylline