scholarly journals High-dose ascorbate with low-dose amphotericin B attenuates severity of disease in a model of the reappearance of candidemia during sepsis in the mouse

2015 ◽  
Vol 309 (3) ◽  
pp. R223-R234 ◽  
Author(s):  
Asada Leelahavanichkul ◽  
Poorichaya Somparn ◽  
Tanabodee Bootprapan ◽  
Hongbin Tu ◽  
Pattarin Tangtanatakul ◽  
...  
Keyword(s):  
Cell Wall ◽  
Candida Albicans ◽  
Mouse Model ◽  
Amphotericin B ◽  
Low Dose ◽  
Cecal Ligation ◽  
Kidney Injury ◽  
Sodium Deoxycholate ◽  
High Dose ◽  
Phagocytic Cells

Amphotericin B (Ampho B) is a fungicidal drug that causes cell wall injury. Pharmacological ascorbate induces the extracellular prooxidants, which might enter the Ampho B-induced cell wall porosity and act synergistically. We tested low-dose Ampho B with a short course of pharmacological ascorbate using a mouse model of sepsis preconditioned with an injection of Candida albicans 6 h prior to cecal ligation and puncture (CLP). In this model, candidemia reappeared as early as 6 h after CLP with a predictably high mortality rate. This characteristic mimics sepsis in the phase of immunosuppression in patients. Using the model, at 12- and 18-h post-CLP, we administered isotonic (pH neutralized) pharmacological ascorbate intravenously with low-dose Ampho B or sodium deoxycholate, vehicle-controlled, administered IP. The survival rate of low-dose Ampho B plus ascorbate was 53%, compared with <11% for low-dose Ampho B or high-dose Ampho B alone. In addition, a beneficial effect was demonstrated in terms of kidney damage, liver injury, spleen histopathology, and serum markers at 24 h after CLP. Kidney injury was less severe in low-dose Ampho B plus ascorbate combination therapy due to less severe sepsis. Moreover, ascorbate enhanced the effectiveness of phagocytosis against C. albicans in human phagocytic cells. Taken together, the data indicate that the new mouse model simulates sepsis-induced immunosuppression and that the combination of pharmacological ascorbate with an antifungal drug is a potentially effective treatment that may reduce nephrotoxicity, and perhaps also increase fungicidal activity in patients with systemic candidiasis caused by Candida albicans.

scholarly journals Advantages of Repeated Low Dose against Single High Dose of Kainate in C57BL/6J Mouse Model of Status Epilepticus: Behavioral and Electroencephalographic Studies

PLoS ONE ◽  
2014 ◽  
Vol 9 (5) ◽  
pp. e96622 ◽  
Author(s):  
Karen Tse ◽  
Sreekanth Puttachary ◽  
Edward Beamer ◽  
Graeme J. Sills ◽  
Thimmasettappa Thippeswamy
Keyword(s):  
Status Epilepticus ◽  
Mouse Model ◽  
Low Dose ◽  
High Dose ◽  
Single High Dose

scholarly journals Fluconazole plus Cyclosporine: a Fungicidal Combination Effective against Experimental Endocarditis Due to Candida albicans

2000 ◽  
Vol 44 (11) ◽  
pp. 2932-2938 ◽  
Author(s):  
O. Marchetti ◽  
J. M. Entenza ◽  
D. Sanglard ◽  
J. Bille ◽  
M. P. Glauser ◽  
...  
Keyword(s):  
Candida Albicans ◽  
Amphotericin B ◽  
Cyclosporine A ◽  
Test Organism ◽  
The Other ◽  
High Dose ◽  
Therapeutic Results ◽  
Fluconazole Therapy ◽  
High Doses

ABSTRACT Recent observations demonstrated that fluconazole plus cyclosporine (Cy) synergistically killed Candida albicans in vitro. This combination was tested in rats with C. albicansexperimental endocarditis. The MICs of fluconazole and Cy for the test organism were 0.25 and >10 mg/liter, respectively. Rats were treated for 5 days with either Cy, amphotericin B, fluconazole, or fluconazole-Cy. Although used at high doses, the peak concentrations of fluconazole in the serum of rats (up to 4.5 mg/liter) were compatible with high-dose fluconazole therapy in humans. On the other hand, Cy concentrations in serum (up to 4.5 mg/liter) were greater than recommended therapeutic levels. Untreated rats demonstrated massive pseudohyphal growth in both the vegetations and the kidneys. However, only the kidneys displayed concomitant polymorphonuclear infiltration. The therapeutic results reflected this dissociation. In the vegetations, only the fungicidal fluconazole-Cy combination significantly decreased fungal densities compared to all groups, including amphotericin B (P < 0.0001). In the kidneys, all regimens except the Cy regimen were effective, but fluconazole-Cy remained superior to amphotericin B and fluconazole alone in sterilizing the organs (P < 0.0001). While the mechanism responsible for the fluconazole-Cy interaction is hypothetical, this observation opens new perspectives for fungicidal combinations between azoles and other drugs.

Antifungal resistance-modifying multiplexing action of Momordica charantia protein and phosphorylated derivatives on the basis of growth-dependent gene coregulation in Candida albicans

2020 ◽  
Author(s):  
Qiao Yuan-Biao ◽  
Zhang Lan-Fang ◽  
Qiao Qi ◽  
Niu Jia-Hui ◽  
Ren Ze-Mei ◽  
...  
Keyword(s):  
Candida Albicans ◽  
Translation Initiation ◽  
Low Dose ◽  
Fungal Growth ◽  
Momordica Charantia ◽  
Antifungal Resistance ◽  
Translation Initiation Factor ◽  
Initiation Factor ◽  
High Dose ◽  
Rrna Processing

Abstract Fungal growth-dependent gene coregulation is strongly implicated in alteration of gene-encoding target proteases ruling with an antifungal resistance niche and biology of resistant mutants. On the basis of multi-alterative processes in this platform, the resistance-modifying strategy is designed in ketoconazole resistant Candida albicans and evaluated with less selective Momordica charantia protein and allosterically phosphorylated derivatives at the Thr102, Thr24 and Thr255 sites, respectively. We demonstrate absolutely chemo-sensitizing efficacy regarding stepwise-modifying resistance in sensitivity, by a load of only 26.23–40.00 μg/l agents in Sabouraud's dextrose broth. Five successive modifying-steps realize the decreasing of ketoconazole E-test MIC50 from 11.10 to a lower level than 0.10 mg/l. With the ketoconazole resistance-modifying, colony undergoes a high-frequency morphological switch between high ploidy (opaque) and small budding haploid (white). A cellular event in the first modifying-step associates with relatively slow exponential growth (ie, a 4-h delay)-dependent action, mediated by agents adsorption. Moreover, multiple molecular roles are coupled with intracellularly and extracellularly binding to ATP-dependent RNA helicase dbp6; the 0.08–2.45 fold upregulation of TATA-box-binding protein, rRNA-processing protein and translation initiation factor 5A; and the 7.52–55.33% decrease of cytochrome P450 lanosterol 14α-demethylase, glucan 1, 3-β glucosidase, candidapepsin-1 and 1-acylglycerol-3-phosphate O-acyltransferase. Spatial and temporal gene coregulation, in the transcription and translation initiation stages with rRNA-processing, is a new coprocessing platform enabling target protease attenuations for resistance-impairing. An updated resistance-modifying measure of these agents in the low-dose antifungal strategic design may provide opportunities to a virtually safe therapy that is in high dose-dependency. Lay Summary A new platform to modify resistance is fungal growth-dependent gene coregulation. MAP30 and phosphorylated derivatives are candidate resistance-modifying agents. Low-dose stepwise treatment absolutely modifies azole resistance in model fungus.

scholarly journals Efficacy of NS-718, a Novel Lipid Nanosphere-Encapsulated Amphotericin B, againstCryptococcus neoformans

1998 ◽  
Vol 42 (7) ◽  
pp. 1722-1725 ◽  
Author(s):  
Mohammad Ashraf Hossain ◽  
Shigefumi Maesaki ◽  
Hiroshi Kakeya ◽  
Tetsuhiro Noda ◽  
Katsunori Yanagihara ◽  
...  
Keyword(s):  
Amphotericin B ◽  
Antifungal Agent ◽  
Low Dose ◽  
Yeast Cells ◽  
High Dose ◽  
Pulmonary Cryptococcosis ◽  
High Dose Therapy ◽  
Dose Therapy

ABSTRACT In vitro and in vivo efficacies of NS-718, a lipid nanosphere-encapsulated amphotericin B (AMPH-B), have been studied. Of the tested AMPH-B formulations, NS-718 had the lowest MIC forCryptococcus neoformans. In a murine model, low-dose therapy (0.8 mg/kg of body weight) with NS-718 showed higher efficacy than that with AmBisome. High-dose therapy (2.0 mg/kg) with NS-718 was much more effective than those with Fungizone and AmBisome. In mice treated with a high dose of NS-718, only a few yeast cells had grown in lung by 7 days after inoculation. A pharmacokinetic study showed higher concentrations of AMPH-B in lung following administration of NS-718 than after administration of AmBisome. Our results indicated that NS-718, a new AMPH-B formulation, is a promising antifungal agent for treatment of pulmonary cryptococcosis and could be the most effective antifungal agent against C. neoformans infections.

scholarly journals High-dose versus low-dose haemofiltration for the treatment of critically ill patients with acute kidney injury: an updated systematic review and meta-analysis

BMJ Open ◽  
2017 ◽  
Vol 7 (10) ◽  
pp. e014171 ◽  
Author(s):  
Peng Li ◽  
Li-ping Qu ◽  
Dong Qi ◽  
Bo Shen ◽  
Yi-mei Wang ◽  
...  
Keyword(s):  
Systematic Review ◽  
Acute Kidney Injury ◽  
Hospital Mortality ◽  
Hospital Stay ◽  
Critically Ill ◽  
Critically Ill Patients ◽  
Low Dose ◽  
Meta Analysis ◽  
Kidney Injury ◽  
High Dose

ObjectiveThe purpose of this study was to perform a systematic review and meta-analysis to evaluate the effect of high-dose versus low-dose haemofiltration on the survival of critically ill patients with acute kidney injury (AKI). We hypothesised that high-dose treatments are not associated with a higher risk of mortality.DesignMeta-analysis.SettingRandomised controlled trials and two-arm prospective and retrospective studies were included.ParticipantsCritically ill patients with AKI.InterventionsContinuous renal replacement therapy.Primary and secondary outcome measuresPrimary outcomes: 90-day mortality, intensive care unit (ICU) mortality, hospital mortality; secondary outcomes: length of ICU and hospital stay.ResultEight studies including 2970 patients were included in the analysis. Pooled results showed no significant difference in the 90-mortality rate between patients treated with high-dose or low-dose haemofiltration (pooled OR=0.90, 95% CI 0.73 to 1.11, p=0.32). Findings were similar for ICU (pooled OR=1.12, 95% CI 0.94 to 1.34, p=0.21) and hospital mortality (pooled OR=1.03, 95% CI 0.81 to 1.30, p=0.84). Length of ICU and hospital stay were similar between high-dose and low-dose groups. Pooled results are not overly influenced by any one study, different cut-off points of prescribed dose or different cut-off points of delivered dose. Meta-regression analysis indicated that the results were not affected by the percentage of patients with sepsis or septic shock.ConclusionHigh-dose and low-dose haemofiltration produce similar outcomes with respect to mortality and length of ICU and hospital stay in critically ill patients with AKI.This study was not registered at the time the data were collected and analysed. It has since been registered on 17 February 2017 athttp://www.researchregistry.com/, registration number: reviewregistry211.

scholarly journals Recently published papers: Renal support in acute kidney injury - is low dose the new high dose?

Critical Care ◽  
2009 ◽  
Vol 13 (6) ◽  
pp. 1014
Author(s):  
Yadullah Syed ◽  
James AP Tomlinson ◽  
Lui G Forni
Keyword(s):  
Acute Kidney Injury ◽  
Low Dose ◽  
Kidney Injury ◽  
High Dose ◽  
Renal Support

scholarly journals Putative Role of β-1,3 Glucans in Candida albicans Biofilm Resistance

2006 ◽  
Vol 51 (2) ◽  
pp. 510-520 ◽  
Author(s):  
Jeniel Nett ◽  
Leslie Lincoln ◽  
Karen Marchillo ◽  
Randall Massey ◽  
Kathleen Holoyda ◽  
...  
Keyword(s):  
Cell Wall ◽  
Candida Albicans ◽  
Cell Viability ◽  
Amphotericin B ◽  
Cell Walls ◽  
Positive Impact ◽  
Indirect Evidence ◽  
Phenotypic Properties

ABSTRACT Biofilms are microbial communities, embedded in a polymeric matrix, growing attached to a surface. Nearly all device-associated infections involve growth in the biofilm life style. Biofilm communities have characteristic architecture and distinct phenotypic properties. The most clinically important phenotype involves extraordinary resistance to antimicrobial therapy, making biofilm infections very difficulty to cure without device removal. The current studies examine drug resistance in Candida albicans biofilms. Similar to previous reports, we observed marked fluconazole and amphotericin B resistance in a C. albicans biofilm both in vitro and in vivo. We identified biofilm-associated cell wall architectural changes and increased β-1,3 glucan content in C. albicans cell walls from a biofilm compared to planktonic organisms. Elevated β-1,3 glucan levels were also found in the surrounding biofilm milieu and as part of the matrix both from in vitro and in vivo biofilm models. We thus investigated the possible contribution of β-glucans to antimicrobial resistance in Candida albicans biofilms. Initial studies examined the ability of cell wall and cell supernatant from biofilm and planktonic C. albicans to bind fluconazole. The cell walls from both environmental conditions bound fluconazole; however, four- to fivefold more compound was bound to the biofilm cell walls. Culture supernatant from the biofilm, but not planktonic cells, bound a measurable amount of this antifungal agent. We next investigated the effect of enzymatic modification of β-1,3 glucans on biofilm cell viability and the susceptibility of biofilm cells to fluconazole and amphotericin B. We observed a dose-dependent killing of in vitro biofilm cells in the presence of three different β-glucanase preparations. These same concentrations had no impact on planktonic cell viability. β-1,3 Glucanase markedly enhanced the activity of both fluconazole and amphotericin B. These observations were corroborated with an in vivo biofilm model. Exogenous biofilm matrix and commercial β-1,3 glucan reduced the activity of fluconazole against planktonic C. albicans in vitro. In sum, the current investigation identified glucan changes associated with C. albicans biofilm cells, demonstrated preferential binding of these biofilm cell components to antifungals, and showed a positive impact of the modification of biofilm β-1,3 glucans on drug susceptibility. These results provide indirect evidence suggesting a role for glucans in biofilm resistance and present a strong rationale for further molecular dissection of this resistance mechanism to identify new drug targets to treat biofilm infections.

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