The Effect of Sterols on Amphotericin B Self-Aggregation in a Lipid Bilayer as Revealed by Free Energy Simulations

Neumann, Anna; Bagiński, Maciej; Winczewski, Szymon

doi:10.1016/j.bpj.2013.02.029

Cited by 34 publications

(21 citation statements)

References 65 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Furthermore, while there was a substantial reduction in renal toxicity for mAmB versus Fungizone ® , there was not change in the minimal inhibitory concentration against Candida albicans for mAmB versus Fungizone ® (data not shown). This is consistent with the aggregation state hypothesis and many in vitro studies that have shown that monomeric AmB is selectively toxic for fungal cells, whereas aggregated species of AmB form damaging pores in fungal and mammalian cell membranes [6, 13]. …”

Section: Resultssupporting

confidence: 89%

Pharmacokinetics and Renal Toxicity of Monomeric Amphotericin B in Rats after a Multiple Dose Regimen

Kang

Gao

Shin

et al. 2016

PNT

View full text Add to dashboard Cite

Background Delivery of monomeric Amphotericin B (AmB), i.e. deaggregated AmB, has been a major tactic in the reduction of renal toxicity at a membrane level, taking advantage of the selectivity of monomeric AmB for binding ergosterol over cholesterol. Objective The aim of this study was to characterize the pharmacokinetic (PK) and renal toxicity of monomeric AmB in rats following a multiple dose regimen. Method AmB existed primarily in a monomeric state in poly(ethylene glycol)-block-poly(N-hexyl stearate L-aspartamide) (PEG-b-PHSA) micelles (mAmB) at 2:1 ratio (mol:mol), whereas AmB as its standard formulation, Fungizone®, was highly self-aggregated based on absorption spectroscopy. Results After single intravenous injection, mAmB significantly (p < 0.001) increased the area under the plasma drug concentration-time curve (AUC) and reduced the volume of distribution (Vd) and total systemic clearance (CL) relative to Fungizone®. After daily intravenous injections at dose of 1.0 mg/kg for 7 days, PK parameters of mAmB and Fungizone® were similar to day 1. The treatment of Fungizone® also significantly (p < 0.05) increased levels of urinary enzymes, N-acetyl-β-D-glucosaminidase (NAG) and kidney injury molecule-1 (KIM-1) by 3.1- and 3.0 fold, respectively, whereas levels of NAG and KIM-1 were unchanged for mAmB, consistent with hematoxylin and eosin (H&E) staining of excised kidneys. Conclusion In summary, mAmB has less renal toxicity than AmB as Fungizone® in rats after a multiple dose regimen, validating the aggregation state hypothesis of AmB in vivo.

show abstract

Section: Resultssupporting

confidence: 89%

Pharmacokinetics and Renal Toxicity of Monomeric Amphotericin B in Rats after a Multiple Dose Regimen

Kang

Gao

Shin

et al. 2016

PNT

View full text Add to dashboard Cite

show abstract

“…Ergosterol has been proposed as a target molecule in the medical treatment of fungal infections, following mainly two routes: (i) the inhibition of the biosynthesis of ergosterol, as in the case of ketoconazole and clotrimazole drugs action, and (ii) direct interaction, as in the case of amphotericin B, where two reaction mechanisms have been proposed . The first mechanism proposed for direct interaction of ergosterol with amphotericin B has been widely studied.…”

Section: Introductionmentioning

confidence: 99%

Mechanism and kinetics of the oxidative damage to ergosterol induced by peroxyl radicals in lipid media: a theoretical quantum chemistry study

Medina

Iuga

Trigos

2015

J of Physical Organic Chem

View full text Add to dashboard Cite

In this work, we have studied the mechanisms and kinetics of the initial damage to ergosterol induced by• OOH and• OOCH 3 peroxyl radicals in a lipid media, using quantum chemistry and computational kinetics methods. The initial damage to ergosterol induced by these radicals occurs predominantly through the hydrogen transfer mechanism (HT) from the allylic position C14 of ergosterol. For the reaction of ergosterol with• OOH, the HT-9 pathway represents~90.8% of the overall rate constant, while in the case of• OOCH 3 , the HT-14 pathway represents more than~97.2% of the overall rate constant. The calculated overall reaction rates for the initial damage to ergosterol caused by the• OOH and • OOCH 3 are 2.05 × 10 6 and 6.26 × 10 4 M À1 s À1 , respectively, indicating that the oxidative damage to ergosterol initiated by these radicals, and probably other alkyl-peroxyl radicals, could be significantly dangerous to their integrity. Taking into account the calculated values of the overall rate coefficients, we can conclude that ergosterol is more susceptible to damage produced by peroxyl radicals than cholesterol and fatty acids. This suggests that fungal cells might be more sensitive to these radicals than animal cells, coinciding with the fact that one of the targets in combating fungi is precisely ergosterol. Finally, theoretical calculations confirm the antioxidant potential of ergosterol and could help explaining the nutraceutical activity of edible and medicinal mushrooms.

show abstract

“…The AmB has fungicidal effects and its efficacy is based on the drug capacity to link with ergosterol, and the main sterol constituting the cell membrane. It disturbs osmotic equilibrium in the cell membrane, increases the permeability of the cell membrane and consequently results in the subsidence of the cell ingredients and the death of fungal cells (7)(8)(9).…”

Section: Polyenes (Amphotericin B)mentioning

confidence: 99%

Liposomal Amphotericin B Usefulness in Critical Care Unit: A Review Study

2016

View full text Add to dashboard Cite

During the last 3 decades, the prevalence and variety of invasive fungal infections increased, especially in the critically ill patients thanks to advances in medical sciences, modification of the instruments, drugs, and protective-therapeutic methods. Such infections are administered by 4 pharmaceutical classes as follows: 1. Polyenes; 2. Azoles; 3. Echinocandins; 4. Pyrimidine analogues. One of these drugs is polyenes consisting of amphotericin and its lipid-based formulation. The lipid formulation of this drug is used due to its fewer side effects compared with the conventional type of the drug that makes it possible to enhance the drug efficacy by increasing the administered dosage. This pharmaceutical class is used to treat the following diseases in the critically ill patients: candidiasis, invasive aspergillosis, mucorales infection, cryptococcal meningoencephalitis, visceral leishmaniosis, persistent fever and neutropenia, renal replacement therapy (RRT) in intensive care unit (ICU), kidney transplantation, and liver problems. Now, the word health organization (WHO) approved liposomal amphotericin B (AmB) as the first-line treatment of visceral leishmaniosis in the Eastern Africa. It was even used with a single dose of 10 mg/kg with 95% efficacy. The current study aimed at investigating the effect of amphotericin and its lipid formulation to treat the aforementioned diseases.

show abstract

The Effect of Sterols on Amphotericin B Self-Aggregation in a Lipid Bilayer as Revealed by Free Energy Simulations

Cited by 34 publications

References 65 publications

Pharmacokinetics and Renal Toxicity of Monomeric Amphotericin B in Rats after a Multiple Dose Regimen

Pharmacokinetics and Renal Toxicity of Monomeric Amphotericin B in Rats after a Multiple Dose Regimen

Mechanism and kinetics of the oxidative damage to ergosterol induced by peroxyl radicals in lipid media: a theoretical quantum chemistry study

Liposomal Amphotericin B Usefulness in Critical Care Unit: A Review Study

Contact Info

Product

Resources

About