Eplerenone nanocrystals engineered by controlled crystallization for enhanced oral bioavailability

Khan, Muhammad Ayub; Ansari, Muhammad Mohsin; Arif, Sadia Tabassam; Raza, Abida; Choi, Ho-Ik; Lim, Chang-Wan; Noh, Ha-Yeon; Noh, Jin-Su; Akram, Salman; Nawaz, Hafiz Awais; Ammad, Muhammad; Alamro, Abir; Alghamdi, Amani; Kim, Jin‐Ki; Zeb, Alam

doi:10.1080/10717544.2021.2008051

Cited by 13 publications

(4 citation statements)

References 71 publications

(87 reference statements)

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“…The mean particle size and PDI value for optimized LSP-NLCs were determined by a dynamic light scattering technique using a Zetasizer Nano ZSP (Malvern Instruments, Worcestershire, UK), whereas the zeta potential was measured using a phase analysis light scattering approach. The formulation was properly diluted with ultrapure water before measurements were taken and the analysis was carried out in triplicates [ 30 ].…”

Section: Methodsmentioning

confidence: 99%

Enhanced Antidepressant Activity of Nanostructured Lipid Carriers Containing Levosulpiride in Behavioral Despair Tests in Mice

Arif,

Khan,

Zaman

et al. 2023

Pharmaceuticals

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The potential of levosulpiride-loaded nanostructured lipid carriers (LSP-NLCs) for enhanced antidepressant and anxiolytic effects was evaluated in the current study. A forced swim test (FST) and tail suspension test (TST) were carried out to determine the antidepressant effect whereas anxiolytic activity was investigated using light–dark box and open field tests. Behavioral changes were evaluated in lipopolysaccharide-induced depressed animals. The access of LSP to the brain to produce therapeutic effects was estimated qualitatively by using fluorescently labeled LSP-NLCs. The distribution of LSP-NLCs was analyzed using ex vivo imaging of major organs after oral and intraperitoneal administration. Acute toxicity studies were carried out to assess the safety of LSP-NLCs in vivo. An improved antidepressant effect of LSP-NLCs on LPS-induced depression showed an increase in swimming time (237 ± 51 s) and struggling time (226 ± 15 s) with a reduction in floating (123 ± 51 s) and immobility time (134 ± 15 s) in FST and TST. The anxiolytic activity in the light–dark box and open field tests exhibited superiority over LSP dispersion. Near-infrared images of fluorescently labeled LSP-NLCs demonstrated the presence of coumarin dye in the brain after 1 h of administration. An acute toxicity study revealed no significant changes in organ-to-body weight ratio, serum biochemistry or tissue histology of major organs. It can be concluded that nanostructured lipid carriers can efficiently deliver LSP to the brain for improved therapeutic efficacy.

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Section: Methodsmentioning

confidence: 99%

Enhanced Antidepressant Activity of Nanostructured Lipid Carriers Containing Levosulpiride in Behavioral Despair Tests in Mice

Arif,

Khan,

Zaman

et al. 2023

Pharmaceuticals

Self Cite

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“…Additionally, Etidronate, Melatonin, and Albendazole were excluded due to poor bioavailability [107][108][109] , and Eplerenone was excluded due to solubility concerns 110 . The remaining 13 drugs were tested for glutathione levels post-irradiation in doselimiting experiments (1 -100 µM) to identify effective concentrations.…”

Section: Hit Down-selection Using Drug Promiscuity Data and Ec50 Valuesmentioning

confidence: 99%

Identifying novel radioprotective drugs via salivary gland tissue chip screening

Piraino

Chen

Mereness

et al. 2023

Preprint

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During head and neck cancer treatment, off-target ionizing radiation damage to the salivary glands commonly causes a permanent loss of secretory function. Due to the resulting decrease in saliva production, patients have trouble eating, speaking and are predisposed to oral infections and tooth decay. While the radioprotective antioxidant drug Amifostine is approved to prevent radiation-induced hyposalivation, it has intolerable side effects that limit its use, motivating the discovery of alternative therapeutics. To address this issue, we previously developed a salivary gland mimetic (SGm) tissue chip platform. Here, we leverage this SGm tissue chip for high-content drug discovery. First, we developed in-chip assays to quantify glutathione and cellular senescence (β-galactosidase), which are biomarkers of radiation damage, and we validated radioprotection using WR-1065, the active form of Amifostine. Following validation, we tested other reported radioprotective drugs, including, Edaravone, Tempol, N-acetylcysteine (NAC), Rapamycin, Ex-Rad, and Palifermin, confirming that all drugs but NAC and Ex-Rad exhibited robust radioprotection. Next, a Selleck Chemicals library of 438 FDA-approved drugs was screened for radioprotection. We discovered 25 hits, with most of the drugs identified with mechanisms of action other than antioxidant activity. Hits were down-selected using EC50 values and pharmacokinetics and pharmacodynamics data from the PubChem database leading to testing of Phenylbutazone (anti-inflammatory), Enoxacin (antibiotic), and Doripenem (antibiotic) for in vivo radioprotection in mice using retroductal injections. Results confirm that Phenylbutazone and Enoxacin exhibited equivalent radioprotection to Amifostine. This body of work demonstrates the development and validation of assays using a SGm tissue chip platform for high-content drug screening and the successful in vitro discovery and in vivo validation of novel radioprotective drugs with nonantioxidant primary indications pointing to possible, yet unknown novel mechanisms of radioprotection.

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“…Drugs with high activity (>10%) were excluded from further testing. Additionally, Etidronate, Melatonin, and Albendazole were excluded due to poor bioavailability [109][110][111] , and Eplerenone was excluded due to solubility concerns 112 .…”

Section: Identi Cation Of Potential Radioprotective Drug Mechanismsmentioning

confidence: 99%

Identifying novel radioprotective drugs via salivary gland tissue chip screening

Piraino,

Chen,

Mereness

et al. 2023

Preprint

View full text Add to dashboard Cite

During head and neck cancer treatment, off-target ionizing radiation damage to the salivary glands commonly causes a permanent loss of secretory function. Due to the resulting decrease in saliva production, patients have trouble eating, speaking and are predisposed to oral infections and tooth decay. While the radioprotective antioxidant drug Amifostine is FDA approved to prevent radiation-induced hyposalivation, it has intolerable side effects that limit its use, motivating the discovery of alternative therapeutics. To address this issue, we previously developed a salivary gland mimetic (SGm) tissue chip platform. Here, we leverage this SGm tissue chip for high-content drug discovery. First, we developed in-chip assays to quantify glutathione and cellular senescence (β-galactosidase), which are biomarkers of radiation damage, and we validated radioprotection using WR-1065, the active form of Amifostine. Other reported radioprotective drugs including Edaravone, Tempol, N-acetylcysteine (NAC), Rapamycin, Ex-Rad, and Palifermin were also tested to validate the ability of the assays to detect cell damage and radioprotection. All of the drugs except NAC and Ex-Rad exhibited robust radioprotection. Next, a Selleck Chemicals library of 438 FDA-approved drugs was screened for radioprotection. We discovered 25 hits, with most of the drugs identified exhibiting mechanisms of action other than antioxidant activity. Hits were down-selected using EC50 values and pharmacokinetic and pharmacodynamic data from the PubChem database. This led us to test Phenylbutazone (anti-inflammatory), Enoxacin (antibiotic), and Doripenem (antibiotic) for in vivo radioprotection in mice using retroductal injections. Results confirm that Phenylbutazone and Enoxacin exhibited radioprotection equivalent to Amifostine. This body of work demonstrates the development and validation of assays using a SGm tissue chip platform for high-content drug screening and the successful in vitro discovery and in vivo validation of novel radioprotective drugs with non-antioxidant primary indications pointing to possible, yet unknown novel mechanisms of radioprotection.

show abstract

Eplerenone nanocrystals engineered by controlled crystallization for enhanced oral bioavailability

Cited by 13 publications

References 71 publications

Enhanced Antidepressant Activity of Nanostructured Lipid Carriers Containing Levosulpiride in Behavioral Despair Tests in Mice

Enhanced Antidepressant Activity of Nanostructured Lipid Carriers Containing Levosulpiride in Behavioral Despair Tests in Mice

Identifying novel radioprotective drugs via salivary gland tissue chip screening

Identifying novel radioprotective drugs via salivary gland tissue chip screening

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