A Novel Cryptococcal Meningitis Therapy: The Combination of Amphotericin B and Posaconazole Promotes the Distribution of Amphotericin B in the Brain Tissue.
The deficient brain tissue distribution of amphotericin B (AMPB) seriously restricts its treatment for the clinical efficacy of cryptococcus neoformans meningitis (CNM). We strive to develop a tactic to increase its concentration in brain tissue. We aimed to investigate whether the combination of AM...
| Publicado en: | BioMed Research International pp. 1 - 12 |
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| Autores principales: | , , , , , , , , |
| Formato: | pictorial research tables/charts Journal Article |
| Publicado: |
Wiley-Blackwell
11/29/2020
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| Acceso en línea: | Ver este registro en EBSCOhost |
| fields | @attributes: recordID: 1 pdfLink: plink: https://search.ebscohost.com/login.aspx?direct=true&db=ccm&AN=147265251&site=ehost-live header: @attributes: shortDbName: ccm uiTerm: 147265251 longDbName: CINAHL Complete uiTag: AN controlInfo: bkinfo: dissinfo: jinfo: jid: 23146133 FT2T jtl: BioMed Research International issn: 23146133 maglogo: N pubinfo: dt: 11/29/2020 pid: 480 pub: Wiley-Blackwell place: Malden, Massachusetts artinfo: ui: 147265251 147265251 147265251 10.1155/2020/8878158 147265251 ppf: 1 ppct: 11 formats: fmt: – @attributes: type: T – @attributes: type: P tig: atl: A Novel Cryptococcal Meningitis Therapy: The Combination of Amphotericin B and Posaconazole Promotes the Distribution of Amphotericin B in the Brain Tissue. aug: au: Yang, Ming Cheng, Lin Dai, Qing Yang, Bo Yuan, Qian Yu, MingJie Feng, Wei Sun, Fengjun Xia, Peiyuan affil: Department of Pharmacy, The First Affiliated Hospital of Third Military Medical University (Army Medical University), Chongqing 400038, China sug: subj: Meningitis, Cryptococcal Drug Therapy Amphotericin B Pharmacokinetics Antibiotics, Antifungal Pharmacokinetics Antibiotics, Combined Pharmacodynamics Treatment Outcomes Evaluation Animal Studies Mice In Vitro Studies Chromatography, High Pressure Liquid Amphotericin B Blood Brain Drug Effects Molecular Docking Simulation Ultrafiltration Albumins Blood Antibiotics, Antifungal Blood Staining and Labeling Methods Bacterial Colonization Drug Effects Microbial Culture and Sensitivity Tests Antibiotics, Antifungal Administration and Dosage Dose-Response Relationship, Drug Neurons Proteins Cell Proliferation ab: The deficient brain tissue distribution of amphotericin B (AMPB) seriously restricts its treatment for the clinical efficacy of cryptococcus neoformans meningitis (CNM). We strive to develop a tactic to increase its concentration in brain tissue. We aimed to investigate whether the combination of AMPB and posaconazole (POS) could be more effective in the treatment of CNM and to elucidate its potential mechanisms. HPLC analysis was used to analyze the concentration of AMPB in mouse serum, brain tissue, and BCECs cells. Schrodinger molecular docking, in vitro plasma balance dialysis, and ultrafiltration analysis were performed to evaluate the combinative effect of AMPB and POS with serum albumin and POS on AMPB plasma protein binding. H&E staining and colonization culture experiment of CN were employed to assess the effect of POS on the efficacy of AMPB. POS + AMPB significantly reduced the concentration of plasma total AMPB and increased its concentration in the brain tissue. However, the P-gp inhibitor zosuquidar, BCRP inhibitor Ko143, and a common inhibitor of both, elacridar, had no significant effect on its concentration. Molecular docking, balance dialysis, and ultrafiltration analysis showed that AMPB and POS had potential binding properties to serum albumin. Meanwhile, 4 and 8 μg/mL POS could significantly increase the concentration of free AMPB in plasma. POS and three inhibitors all had no significant effect on the uptake of AMPB by BCECs, but serum albumin had. The therapeutic effect of CNM in mice was confirmed that AMPB and AMPB+POS could restrain the infiltration of neutrophils and lymphocytes in cortical neurons and improve the bleeding and markedly inhibit the proliferation of CN. Collectively, we propose that POS competitively binds to the plasma protein sites of AMPB, thereby increasing its level in the brain tissue. Meanwhile, POS could enhance the efficacy of AMPB in the treatment of CNM, which may be independent of P-gp and BCRP proteins. pubtype: Academic Journal doctype: pictorial research tables/charts Journal Article ougenre: Article language: English refInfo: holdings: @attributes: islocal: N |
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