Long chain fatty acid conjugation remarkably decreases the aggregation induced toxicity of Amphotericin B

Thanki, Kaushik; Prajapati, Rameshwar; Sangamwar, Abhay T.; Jain, Sanyog

doi:10.1016/j.ijpharm.2018.04.009

Cited by 30 publications

(30 citation statements)

References 63 publications

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“…The results were corroborated by in vivo studies in healthy mice after oral administration of AmB-OA (10 mg/kg in PBS) showing no significant increase in the levels of nephrotoxicity or hepatotoxicity biomarkers compared to control (vehicle-treated mice) despite AmB-OA conversion into the parent drug in the liver. These findings were also supported by histopathological tissue examination [161]. Further in silico studies showed that monomers in AmB-OA dimers accommodate in a head-to-head arrangement in contrast to head-to-tail arrangement in AmB dimers [161].…”

Section: Lipid Conjugatesmentioning

confidence: 72%

“…Contrary to free AmB, the concentration-dependent aggregation of AmB-OA did not result in hemolytic toxicity or nephrotoxicity in vitro, which was attributed to differential aggregation behavior of AmB-OA [161]. The results were corroborated by in vivo studies in healthy mice after oral administration of AmB-OA (10 mg/kg in PBS) showing no significant increase in the levels of nephrotoxicity or hepatotoxicity biomarkers compared to control (vehicle-treated mice) despite AmB-OA conversion into the parent drug in the liver.…”

Section: Lipid Conjugatesmentioning

confidence: 84%

“…Further in silico studies showed that monomers in AmB-OA dimers accommodate in a head-to-head arrangement in contrast to head-to-tail arrangement in AmB dimers [161]. Moreover, AmB-OA in the aggregated state retained selectivity for ergosterol over cholesterol, which was lost in AmB aggregates [161], and in vitro antifungal activity of the parent drug was retained in the AmB-OA conjugate [162]. These results suggest that lipid conjugation can be a promising strategy for oral delivery of AmB.…”

Section: Lipid Conjugatesmentioning

confidence: 99%

“…Lipid conjugation to AmB has the potential to reduce drug toxicity and increase its oral bioavailability by improving stability and absorption in the gastrointestinal tract (GIT). Oleic acid (OA), a known skin and intestinal permeation enhancer, has been conjugated to AmB via amide bond formation with the carboxylic acid group of the drug using standard carbodiimide chemistry [161]. Metabolism of the AmB-OA conjugate in liver homogenate was higher than 80% [162], which warrants prodrug bioconversion after oral administration.…”

Section: Lipid Conjugatesmentioning

confidence: 99%

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Lipid Systems for the Delivery of Amphotericin B in Antifungal Therapy

2020

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Amphotericin B (AmB), a broad-spectrum polyene antibiotic in the clinic for more than fifty years, remains the gold standard in the treatment of life-threatening invasive fungal infections and visceral leishmaniasis. Due to its poor water solubility and membrane permeability, AmB is conventionally formulated with deoxycholate as a micellar suspension for intravenous administration, but severe infusion-related side effects and nephrotoxicity hamper its therapeutic potential. Lipid-based formulations, such as liposomal AmB, have been developed which significantly reduce the toxic side effects of the drug. However, their high cost and the need for parenteral administration limit their widespread use. Therefore, delivery systems that can retain or even enhance antimicrobial efficacy while simultaneously reducing AmB adverse events are an active area of research. Among those, lipid systems have been extensively investigated due to the high affinity of AmB for binding lipids. The development of a safe and cost-effective oral formulation able to improve drug accessibility would be a major breakthrough, and several lipid systems for the oral delivery of AmB are currently under development. This review summarizes recent advances in lipid-based systems for targeted delivery of AmB focusing on non-parenteral nanoparticulate formulations mainly investigated over the last five years and highlighting those that are currently in clinical trials.

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Section: Lipid Conjugatesmentioning

confidence: 72%

Section: Lipid Conjugatesmentioning

confidence: 84%

Section: Lipid Conjugatesmentioning

confidence: 99%

Section: Lipid Conjugatesmentioning

confidence: 99%

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Lipid Systems for the Delivery of Amphotericin B in Antifungal Therapy

2020

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“…The resulting formulation, purposefully optimized with various lipids, nonionic surfactants, and cosolvents, exhibited maximum drug solubilization under GI conditions, increased transmembrane permeation, and subsequently facilitated oral absorption of drug [ 98 ]. Recently, a lipophilic conjugation approach has also been reported in the development of antifungal agents with improved oral bioavailability and metabolic stability [ 99 , 100 ]. Together, SLPs with an optimal delivery system provide an effective platform for enabling the oral delivery of challenging drugs.…”

Section: The Advantages Of Slps-based Drug Deliverymentioning

confidence: 99%

Engineering of small-molecule lipidic prodrugs as novel nanomedicines for enhanced drug delivery

et al. 2022

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A widely established prodrug strategy can effectively optimize the unappealing properties of therapeutic agents in cancer treatment. Among them, lipidic prodrugs extremely uplift the physicochemical properties, site-specificity, and antitumor activities of therapeutic agents while reducing systemic toxicity. Although great perspectives have been summarized in the progress of prodrug-based nanoplatforms, no attention has been paid to emphasizing the rational design of small-molecule lipidic prodrugs (SLPs). With the aim of outlining the prospect of the SLPs approach, the review will first provide an overview of conjugation strategies that are amenable to SLPs fabrication. Then, the rational design of SLPs in response to the physiological barriers of chemotherapeutic agents is highlighted. Finally, their biomedical applications are also emphasized with special functions, followed by a brief introduction of the promising opportunities and potential challenges of SLPs-based drug delivery systems (DDSs) in clinical application. Graphical Abstract

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Combined in vitro/in silico approaches, molecular dynamics simulations and safety assessment of the multifunctional properties of thymol and carvacrol: A comparative insight

Akermi,

Smaoui,

Chaari

et al. 2024

Chemistry & Biodiversity

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Bioactive compounds derived from medicinal plants have acquired immense attentiveness in drug discovery and development. The present study investigated in vitro and predicted in silico the antibacterial, antifungal, and antiviral properties of thymol and carvacrol, and assessed their safety. The performed microbiological assays against Pseudomonas aeruginosa, Escherichia coli, Salmonella enterica Typhimurium revealed that the minimal inhibitory concentration values ranged from (0.078 to 0.312 mg/mL) and the minimal fungicidal concentration against Candida albicans was 0.625 mg/mL. Molecular docking simulations, stipulated that these compounds could inhibit bacterial replication and transcription functions by targeting DNA and RNA polymerases receptors with docking scores varying between (‐5.1 to ‐6.9 kcal/mol). Studied hydroxylated monoterpenes could hinder C. albicans growth by impeding lanosterol 14α‐demethylase enzyme and showed a (ΔG = ‐6.2 and ‐6.3 kcal/mol). Computational studies revealed that thymol and carvacrol could target the SARS‐Cov‐2 spike protein of the Omicron variant RBD domain. Molecular dynamics simulations disclosed that these compounds have a stable dynamic behavior over 100 ns as compared to remdesivir. Chemo‐computational toxicity prediction using Protox II webserver indicated that thymol and carvacrol could be safely and effectively used as drug candidates to tackle bacterial, fungal, and viral infections as compared to chemical medication.

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Long chain fatty acid conjugation remarkably decreases the aggregation induced toxicity of Amphotericin B

Cited by 30 publications

References 63 publications

Lipid Systems for the Delivery of Amphotericin B in Antifungal Therapy

Lipid Systems for the Delivery of Amphotericin B in Antifungal Therapy

Engineering of small-molecule lipidic prodrugs as novel nanomedicines for enhanced drug delivery

Combined in vitro/in silico approaches, molecular dynamics simulations and safety assessment of the multifunctional properties of thymol and carvacrol: A comparative insight

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