Increased Efficacy of Oral Fixed-Dose Combination of Amphotericin B and AHCC® Natural Adjuvant against Aspergillosis.

Alba Pérez-Cantero,Javier Capilla,Dolores R Serrano,Juan J Torrado,Patricia Navarro-Rodríguez,Ijeoma F Uchegbu,Andreas G Schätzlein

doi:10.3390/pharmaceutics11090456

Abstract

Invasive pulmonary aspergillosis represents one of the most serious fungal infections among immunocompromised patients. In this study, we aimed to analyze the in vivo efficacy of prophylactic oral amphotericin B (AMB) encapsulated in modified chitosan-nanoparticles (Nanomerics’ Molecular Envelope Technology (MET)) supplemented with a standardized extract of cultured Lentinula edodes mycelia (AHCC®) in a murine model of pulmonary aspergillosis. We determined fungal burden and survival of mice and additionally, we carried out a cytokine analysis in an attempt to understand the immunomodulation of the extract. Our results evidenced equivalent efficacy between orally administered AMB-MET and the intravenous liposomal AMB marketed formulation. Addition of the AHCC® supplement significantly improved efficacy in terms of burden reduction and survival increase of both oral and intravenous AMB therapies compared to the untreated control group. Moreover, a protective effect of the extract was observed in terms of weight loss. Regarding the cytokine profiles, the Th1 immune response was stimulated in treated animals when compared to the control group. This response was marked by an enhancement in the MCP-1, GM-CSF, VEGF, RANTES and IL-17 levels and a decrease in the IL-6, a biomarker related to the severity of the infection.

Highlights

Invasive aspergillosis (IA) is a life-threatening condition that mostly affects immunocompromised patients, including those following stem cell or solid organ transplantation, patients with hematological malignancies, granulomatous disease, and neutropenia, or those under chemotherapy or corticosteroid treatment [1,2]
Other recommended therapies include intravenous liposomal amphotericin B (LAMB), echinocandins or isavuconazole [5,6,7,8], yet other options are being studied in order to achieve better therapeutic outcomes and provide expanded alternatives of treatment
Different Amphotericin B (AMB) formulations are currently available for their parenteral use, including LAMB, AMB lipid complex (ABLC) or AMB colloidal dispersion (ABCD), all of them with reduced toxic effects when compared to the conventional micellar deoxycolate AMB formulation

Summary

Introduction

Invasive aspergillosis (IA) is a life-threatening condition that mostly affects immunocompromised patients, including those following stem cell or solid organ transplantation, patients with hematological malignancies, granulomatous disease, and neutropenia, or those under chemotherapy or corticosteroid treatment [1,2]. Other recommended therapies include intravenous liposomal amphotericin B (LAMB), echinocandins or isavuconazole [5,6,7,8], yet other options are being studied in order to achieve better therapeutic outcomes and provide expanded alternatives of treatment This has resulted in antifungal combinations [9,10], the development of new antifungal agents or improved formulations of the preexisting ones [11]. Amphotericin B (AMB) represented the first-line treatment for IA for many years due to its higher efficacy in treating aspergillosis It is well-known that it can display great nephrotoxicity and cause a broad variety of side effects [12]. Even though these lipidic formulations have improved the efficacy-safety profile of the drug, they still require parenteral administration and, in addition, there are no oral formulations commercially available nowadays, which hampers amphotericin’s use in developing countries [16]

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