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Antifungal activity of HWA-138 and amphotericin B in experimental systemic candidiasis
K M Wasan1, K Vadiei, D R Luke
1Department of Pharmaceutics, University of Houston, Texas Medical Center, Houston 77030.
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.
Insights
HWA-138, a pentoxifylline analog, shows synergistic effects with amphotericin B in treating systemic candidiasis in mice. Combination therapy significantly improves survival rates in experimental fungal infections.
Area of Science:
- Mycology
- Pharmacology
- Infectious Diseases
Background:
- Systemic candidiasis poses a significant health threat.
- Amphotericin B is a primary antifungal agent but has limitations.
- HWA-138, a pentoxifylline analog, has shown promise in preclinical models.
Purpose of the Study:
- To evaluate the efficacy of HWA-138 alone and in combination with amphotericin B for treating systemic candidiasis in mice.
- To determine if HWA-138 enhances the antifungal activity of amphotericin B.
Main Methods:
- Murine model of systemic candidiasis induced by Candida albicans.
- Intravenous administration of HWA-138 (single and multiple doses).
- Combination therapy with subtherapeutic doses of amphotericin B and HWA-138.
- Survival rates and time to survival were monitored.
Main Results:
- Single doses of HWA-138 did not improve survival.
- Multiple doses of HWA-138 (25 mg/kg) showed a modest increase in survival time.
- Combination therapy with subtherapeutic amphotericin B and HWA-138 significantly increased survival time.
- Synergistic antifungal activity was observed between HWA-138 and amphotericin B.
Conclusions:
- HWA-138 demonstrates synergistic activity with amphotericin B against systemic candidiasis in mice.
- Combination therapy offers a promising strategy for treating invasive fungal infections.
- Further research into HWA-138 as an adjunct antifungal agent is warranted.