John D Cleary1, Stanley W Chapman, Edwin Swiatlo, Robert Kramer. 1. Schools of Pharmacy and Medicine, University of Mississippi Medical Center, 2500 North State Street, Jackson, MS 39216-4500, USA. jcleary@medicine.umsmed.edu
Abstract
OBJECTIVES: Amphotericin B (AmB) is a drug of choice for treatment of disseminated fungal infections, but its use is often associated with severe adverse effects. Our observation that generic formulations of AmB contain multiple polyene components led us to propose that removal of other polyenes would yield a high purity AmB (AmBHP) with an improved therapeutic index. METHODS: To test that premise, AmBHP was first isolated from generic AmB by semi-preparative reverse phase high-pressure liquid chromatography and then its effects were compared in vitro and in vivo with those of commercial AmB formulations. RESULTS: AmBHP proved to be as active as generic AmB against Candida albicans in vitro and as efficacious as both generic and lipid-complexed AmB in a Candida-infected mouse model. AmBHP appeared to be less toxic to human THP-1 monocytic cells than was generic AmB at low concentrations (<2 microM), as indicated by exclusion of Trypan Blue and incorporation of [(3)H]thymidine. At higher concentrations, effects of AmBHP and generic AmB (Pharma-Tek AmB, PTAmB) on thymidine incorporation and cytosolic calcium concentration were similar. General toxicity to AmBHP in vivo, as indicated by its apparent LD(50) and survival of Candida-infected mice, was roughly twofold less than that to generic or lipid-complexed AmB. Likewise, AmBHP decreased mean glomerular filtration rate about half as much as did a 10-fold lower dose of PTAmB. CONCLUSIONS: Taken together, these data indicate that AmBHP may represent a refinement of currently marketed AmB formulations, offering equal, if not better, efficacy with less toxicity.
OBJECTIVES:Amphotericin B (AmB) is a drug of choice for treatment of disseminated fungal infections, but its use is often associated with severe adverse effects. Our observation that generic formulations of AmB contain multiple polyene components led us to propose that removal of other polyenes would yield a high purity AmB (AmBHP) with an improved therapeutic index. METHODS: To test that premise, AmBHP was first isolated from generic AmB by semi-preparative reverse phase high-pressure liquid chromatography and then its effects were compared in vitro and in vivo with those of commercial AmB formulations. RESULTS:AmBHP proved to be as active as generic AmB against Candida albicans in vitro and as efficacious as both generic and lipid-complexed AmB in a Candida-infectedmouse model. AmBHP appeared to be less toxic to humanTHP-1 monocytic cells than was generic AmB at low concentrations (<2 microM), as indicated by exclusion of Trypan Blue and incorporation of [(3)H]thymidine. At higher concentrations, effects of AmBHP and generic AmB (Pharma-Tek AmB, PTAmB) on thymidine incorporation and cytosolic calcium concentration were similar. General toxicity to AmBHP in vivo, as indicated by its apparent LD(50) and survival of Candida-infectedmice, was roughly twofold less than that to generic or lipid-complexed AmB. Likewise, AmBHP decreased mean glomerular filtration rate about half as much as did a 10-fold lower dose of PTAmB. CONCLUSIONS: Taken together, these data indicate that AmBHP may represent a refinement of currently marketed AmB formulations, offering equal, if not better, efficacy with less toxicity.
Authors: R Lu; C Hollingsworth; J Qiu; A Wang; E Hughes; X Xin; K M Konrath; W Elsegeiny; Yoon-Dong Park; L Atakulu; J C Craft; E C Tramont; R Mannino; P R Williamson Journal: mBio Date: 2019-05-28 Impact factor: 7.867