title: High-dose ascorbate with low-dose amphotericin B attenuates severity of disease in a model of the reappearance of candidemia during sepsis in the mouse.
abstract: Amphotericin B (Ampho B) isa fungicidal drug that causes cell wall injury. Pharmacological ascorbate induces the extracellular prooxidants, which might enter the Ampho B-induced cell wall porosity and act synergistically.W e tested low-dose Ampho B with a short course of pharmacological ascorbate using a mouse model of sepsis preconditioned with an injection of Candida albicans 6 h prior to cecal ligation and puncture (CLP). In this model, candidemia reappeared as early as 6 h after CLP with a predictably high mortality rate. This characteristic mimics sepsis in the phase of immunosuppression inpatients. Using the model, at 12- and 18-h post-CLP, we administered isotonic (pH neutralized) pharmacological ascorbate intravenously with low-dose Ampho B or sodium deoxycholate, vehicle-controlled, administered IP. The survival rate of low-dose Ampho B plus ascorbate was 53%, compared with < 11% for low-dose Ampho B or high-dose Ampho B alone. In addition, a beneficial effect was demonstrated in terms of kidney damage,liver injury, spleen histopathology, and serum markers at 24 h after CLP. Kidney injury was less severe in low-dose Ampho B plus ascorbate combination therapy due to less severe sepsis. Moreover, ascorbate enhanced the effectiveness of phagocytosis against C. albicans in human phagocytic cells. Taken together, the data indicate that the new mouse model simulates sepsis-induced immunosuppression and that the combination of pharmacological ascorbate with an antifungal drug is a potentially effective treatment that may reduce nephrotoxicity, and perhaps also increase fungicidal activity in patients with systemic candidiasis caused by Candida albicans.
authors.forename: Asada
authors.initials: A
authors.lastname: Leelahavanichkul
authors.forename: Poorichaya
authors.initials: P
authors.lastname: Somparn
authors.forename: Tanabodee
authors.initials: T
authors.lastname: Bootprapan
authors.forename: Hongbin
authors.initials: H
authors.lastname: Tu
authors.forename: Pattarin
authors.initials: P
authors.lastname: Tangtanatakul
authors.forename: Ratchanok
authors.initials: R
authors.lastname: Nuengjumnong
authors.forename: Navaporn
authors.initials: N
authors.lastname: Worasilchai
authors.forename: Khajohn
authors.initials: K
authors.lastname: Tiranathanagul
authors.forename: Somchai
authors.initials: S
authors.lastname: Eiam-ong
authors.forename: Mark
authors.initials: M
authors.lastname: Levine
authors.forename: Ariya
authors.initials: A
authors.lastname: Chinampon
authors.forename: Nattachai
authors.initials: N
authors.lastname: Srisawat
mesh_terms: D000666:Amphotericin B / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D001205:Ascorbic Acid / Q000008:administration & dosage / Q000494:pharmacology*; D058387:Candidemia / Q000150:complications / Q000188:drug therapy*; D004195:Disease Models, Animal; D004338:Drug Combinations; D007668:Kidney / Q000187:drug effects*; D008099:Liver / Q000187:drug effects; D008297:Male; D008807:Mice, Inbred BALB C; D018805:Sepsis / Q000188:drug therapy* / Q000209:etiology; D013154:Spleen / Q000187:drug effects
chemical_list: D004338:Drug Combinations; D000666:Amphotericin B; D001205:Ascorbic Acid