- Pharmacokinetic and Pharmacodynamic Comparison of Intravenous and Inhaled Caspofungin.
Pharmacokinetic and Pharmacodynamic Comparison of Intravenous and Inhaled Caspofungin.
J Aerosol Med Pulm Drug Deliv. 2020 Sep 24;:
Authors: Yu IG, O'Brien SE, Ryckman DM
Background: Aspergillosis is a serious fungal lung infection caused by Aspergillus spp. and is often fatal in immunocompromised patients. Current antifungal drug treatment and delivery results in modest efficacy in these patients may be due to low drug distribution to the lung. A comparison of intravenous (IV) caspofungin and lung-targeted inhaled caspofungin was conducted in rats. The goal was to determine the concentrations of drug at the site of infection and systemic distribution that leads to toxicity. This was performed to understand the difference in the in vitro activity of caspofungin and modest in vivo efficacy. Methods: Caspofungin was delivered to rats through IV injection and nose-only inhalation. Each cohort received a single 2 mg/kg dose of drug. Plasma and tissue samples were analyzed by high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS-MS) and drug levels were compared. Results: The lung drug level was above the minimum effective concentration for 168 hours in the inhaled group but <24 hours in the IV cohort. The lung Cmax and area under curve (AUC) in the inhaled group was 20 times higher than in the IV group. Lung-targeted delivery doubled lung drug half-life compared with IV delivery. Systemic distribution to the liver and kidney was 45% lower for the inhaled cohort than the IV group of animals. Conclusions: Based on pharmacokinetic and pharmacodynamic indices, lung-targeted inhaled caspofungin is likely to provide an improved therapeutic benefit without any increase in systemic toxicities. Furthermore, inhaled delivery supports a weekly dosing regimen instead of daily IV dosing.
PMID: 32985935 [PubMed - as supplied by publisher]
- Sodium New Houttuyfonate Inhibits Candida albicans Biofilm Formation by Inhibiting the Ras1-cAMP-Efg1 Pathway Revealed by RNA-seq.
Sodium New Houttuyfonate Inhibits Candida albicans Biofilm Formation by Inhibiting the Ras1-cAMP-Efg1 Pathway Revealed by RNA-seq.
Front Microbiol. 2020;11:2075
Authors: Wu J, Wu D, Zhao Y, Si Y, Mei L, Shao J, Wang T, Yan G, Wang C
Here, we aim to investigate the antifungal effect and mechanism of action of sodium new houttuyfonate (SNH) against Candida albicans. Microdilution analysis results showed that SNH possesses potent inhibitory activity against C. albicans SC5314, with a MIC80 of 256 μg/mL. Furthermore, we found that SNH can effectively inhibit the initial adhesion of C. albicans. Inverted microscopy, crystal violet staining, scanning electron microscopy and confocal laser scanning microscopy results showed that morphological changes during the transition from yeast to hypha and the biofilm formation of C. albicans are repressed by SNH treatment. We also found that SNH can effectively inhibit the biofilm formation of clinical C. albicans strains (Z103, Z3044, Z1402, and Z1407) and SNH in combination with fluconazole, berberine chloride, caspofungin and itraconazole antifungal agents can synergistically inhibit the biofilm formation of C. albicans. Eukaryotic transcriptome sequencing and qRT-PCR results showed that SNH treatment resulted in significantly down-regulated expression in several biofilm formation related genes in the Ras1-cAMP-Efg1 pathway (ALS1, ALA1, ALS3, EAP1, RAS1, EFG1, HWP1, and TEC1) and significantly up-regulated expression in yeast form-associated genes (YWP1 and RHD1). We also found that SNH can effectively reduce the production of key messenger cAMP in the Ras1-cAMP-Efg1 pathway. Furthermore, using Galleria mellonella as an in vivo model we found that SNH can effectively treat C. albicans infection in vivo. Our presented results suggest that SNH exhibits potential antibiofilm effects related to inhibiting the Ras1-cAMP-Efg1 pathway in the biofilm formation of C. albicans.
PMID: 32983053 [PubMed]