Efficacy of Cochleated Amphotericin B in Mouse and Human Mucocutaneous Candidiasis.

Candida albicans causes debilitating, often azole-resistant, infections in patients with chronic mucocutaneous candidiasis (CMC). Amphotericin B (AMB) resistance is rare, but AMB use is limited by parenteral administration and nephrotoxicity. In this study, we evaluated cochleated AMB (CAMB), a new oral AMB formulation, in mouse models of oropharyngeal candidiasis (OPC) and vulvovaginal candidiasis (VVC) and in patients with azole-resistant CMC. OPC and VVC were modeled in Act1-/- mice, and mucosal tissue fungal burden was assessed after once-daily treatment with CAMB, vehicle, or AMB-deoxycholate (AMB-d). Four patients with azole-resistant CMC enrolled in a phase 2 CAMB dose-escalation study. The primary endpoint was clinical improvement at 2 weeks followed by optional extension for long-term CMC suppression to assess safety and efficacy. CAMB-treated mice had significantly reduced tongue and vaginal fungal burdens compared to vehicle-treated mice and exhibited comparable fungal burden reduction relative to AMB-d-treated mice. All CAMB-treated patients reached clinical efficacy by 2 weeks, three at 400 mg twice daily and one at 200 mg twice-daily dosing. All patients continued to the extension phase, with three having sustained clinical improvement of OPC and esophageal candidiasis (EC) for up to 60 months. One patient had a relapse of esophageal symptoms at week 24 and was withdrawn from further study. Clinical responses were not seen for onychomycosis or VVC. CAMB was safe and well-tolerated, without any evidence of nephrotoxicity. In summary, oral CAMB reduced tongue and vaginal fungal burdens during murine candidiasis. A proof-of-concept clinical trial in human CMC showed efficacy with good tolerability and safety. This study has been registered at ClinicalTrials.gov under identifier NCT02629419.

Potential Influence of Centrally Acting Herbal Drugs on Transporters at the Blood-Cerebrospinal Fluid Barrier and Blood-Brain Barrier.

Complementary and alternative medications (CAM) with known or suspected pharmacologic activity in the central nervous system (CNS) are common. These herbal preparations may cause clinically significant drug-drug interactions (DDIs) when coadministered with medications that act in the CNS. This can result in negative outcomes such as toxicity or loss of efficacy. Most drug interaction reports with CAM focus on cytochrome P450 (CYP) modulation. However, drug interactions between CAM and conventional medications may occur via mechanisms other than CYP inhibition or induction; in particular, modulation of drug transport proteins represents an important mechanism by which such interactions may occur. This article provides an updated review of transporter-mediated mechanisms by which herbal products may theoretically interact with centrally acting medications at the blood-brain barrier and blood-cerebrospinal fluid (CSF) barrier. Further research is required before the true clinical impact of interactions involving modulation of centrally located membrane transporters can be fully understood.