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Published on: November 2, 2016
High purity amphotericin B
John D Cleary1, Stanley W Chapman, Edwin Swiatlo
1Schools of Pharmacy and Medicine, University of Mississippi Medical Center, 2500 North State Street, Jackson, MS 39216-4500, USA. jcleary@medicine.umsmed.edu
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.
Insights
High purity Amphotericin B (AmBHP) shows equal or better efficacy than generic Amphotericin B (AmB) in treating fungal infections, with significantly reduced toxicity in both cell cultures and animal models.
Area of Science:
- Mycology
- Pharmacology
- Medicinal Chemistry
Background:
- Amphotericin B (AmB) is a primary treatment for disseminated fungal infections.
- Current AmB formulations are associated with severe adverse effects.
- Generic AmB contains multiple polyene components, suggesting potential for improved formulations.
Purpose of the Study:
- To develop and evaluate a high purity Amphotericin B (AmBHP) formulation.
- To compare the therapeutic index of AmBHP against existing AmB formulations.
- To assess the efficacy and toxicity of AmBHP in vitro and in vivo.
Main Methods:
- Isolation of AmBHP from generic AmB using semi-preparative reverse-phase high-pressure liquid chromatography.
- In vitro efficacy testing against Candida albicans.
- In vivo efficacy and toxicity studies in a Candida-infected mouse model, including assessment of LD(50) and glomerular filtration rate.
Main Results:
- AmBHP demonstrated comparable in vitro activity to generic AmB.
- AmBHP exhibited similar efficacy to generic and lipid-complexed AmB in a murine fungal infection model.
- AmBHP showed reduced toxicity to human monocytic cells at low concentrations and lower general in vivo toxicity compared to generic and lipid-complexed AmB.
- AmBHP caused approximately half the reduction in glomerular filtration rate compared to a significantly lower dose of generic AmB.
Conclusions:
- High purity Amphotericin B (AmBHP) formulation offers a potential improvement over current AmB products.
- AmBHP provides equivalent or enhanced antifungal efficacy with a reduced toxicity profile.
- These findings suggest AmBHP could represent a safer and more effective therapeutic option for disseminated fungal infections.
