Bioavailability of Edaravone Sublingual Tablet Versus Intravenous Infusion in Healthy Male Volunteers

Wang, Jiaqing; Chen, Xia; Yuan, Baoshi; Wang, Zhao; Xu, Chunmin; Zhao, Weiwei; Zhao, Peizhen; Wang, Yilong; Zhao, Xingquan; Wang, Yongjun

doi:10.1016/j.clinthera.2018.08.009

Cited by 16 publications

(4 citation statements)

References 19 publications

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“…In the present study, edaravone, a low-molecular-weight antioxidant drug targeting peroxyl radicals among many types of reactive oxygen species, was chosen as a positive drug control . Because of its capacity to scavenge free radicals, edaravone iv infusion has been approved in Japan and China as a drug to treat acute ischemic stroke. , In addition, ATXP and edaravone are freely soluble in saline (0.9%), while ATT has limited use due to its poor water solubility. Therefore, we did not establish an ATT experimental group.…”

Section: Resultsmentioning

confidence: 99%

“…29 Because of its capacity to scavenge free radicals, edaravone iv infusion has been approved in Japan and China as a drug to treat acute ischemic stroke. 29,30 In addition, ATXP and edaravone are freely soluble in saline (0.9%), while ATT has limited use due to its poor water solubility. Therefore, we did not establish an ATT experimental group.…”

Section: Resultsmentioning

confidence: 99%

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Synthesis, Characterization, and In Vivo Evaluation of Desmethyl Anethole Trithione Phosphate Prodrug for Ameliorating Cerebral Ischemia-Reperfusion Injury in Rats

Huang

Dong

et al. 2020

ACS Omega

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Anethol trithione (ATT) has a wide range of physiological activities, but its use is limited due to its poor water solubility. To improve the solubility of ATT, we synthesized and characterized a novel phosphate prodrug (ATXP) relying on the availability of the hydroxy group in 5-(4-hydroxyphenyl)-3H-1,2-dithiole3-thione (ATX), which was transformed from ATT rapidly and extensively in vivo. Our results showed that ATXP significantly improved drug solubility. ATXP was rapidly converted to ATX and reached a maximum plasma concentration with a T max of approximately 5 min after intravenous (iv) administration. Furthermore, after the oral administration of ATXP, the C max was 3326.30 ± 566.50 ng/mL, which was approximately 5-fold greater than that of the parent drug form, indicating that ATXP has greater absorption than that of ATT. Additionally, the oral phosphate prodrug ATXP increased the ATX in the area under the plasma concentration vs time curves (AUC 0−t = 3927.40 ± 321.50 and AUC 0−∞ = 4579.0 ± 756.30), making its use in practical applications more meaningful. Finally, compared to the vehicle, ATXP was confirmed to maintain the bioactivity of the parent drug for a significant reduction in infarct volume 24 h after reperfusion. Based on these findings, the phosphate prodrug ATXP is a potentially useful water-soluble prodrug with improved pharmacokinetic properties.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Synthesis, Characterization, and In Vivo Evaluation of Desmethyl Anethole Trithione Phosphate Prodrug for Ameliorating Cerebral Ischemia-Reperfusion Injury in Rats

Huang

Dong

et al. 2020

ACS Omega

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“…This route of drug delivery can be challenging for cancer patients, whereas oral administration would be preferable and may help to improve patients' quality of life by avoiding infusion-related stress, the risk of infusion-related infections or extravasations, infusion-related discomfort, and the need for further administration visits. To address this challenge, novel oral and sublingual tablet formulations of edaravone are currently under investigation to improve their oral bioavailability, yielding encouraging results [158,159]. Another concern in utilizing this drug for cancer treatment may be the risk of drug resistance by several mechanisms, including increased DNA repair ability, altered drug metabolism and targets, inhibited apoptosis, and enhanced efflux of drugs.…”

Section: Conclusion and Future Perspectivesmentioning

confidence: 99%

Edaravone: A Novel Possible Drug for Cancer Treatment?

Duranti,

Cordani,

Villa

2024

IJMS

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Despite significant advancements in understanding the causes and progression of tumors, cancer remains one of the leading causes of death worldwide. In light of advances in cancer therapy, there has been a growing interest in drug repurposing, which involves exploring new uses for medications that are already approved for clinical use. One such medication is edaravone, which is currently used to manage patients with cerebral infarction and amyotrophic lateral sclerosis. Due to its antioxidant and anti-inflammatory properties, edaravone has also been investigated for its potential activities in treating cancer, notably as an anti-proliferative and cytoprotective drug against side effects induced by traditional cancer therapies. This comprehensive review aims to provide updates on the various applications of edaravone in cancer therapy. It explores its potential as a standalone antitumor drug, either used alone or in combination with other medications, as well as its role as an adjuvant to mitigate the side effects of conventional anticancer treatments.

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“…In human and animal studies, pharmacokinetic (PK) measurements such as peak plasma edaravone concentration (C max ) and area under the plasma concentration–time curve (AUC) were found to increase as the dose increased 8‐11 . The principal route of excretion of edaravone and of its glucuronide and sulfate metabolites is urinary, 8‐10 and the amount of unchanged edaravone excreted to urine is approximately 1% of the administered dose 8 . Edaravone is highly protein‐bound (91%–92%) and is not accumulated after repeated administrations 12 .…”

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confidence: 99%

A Randomized, Single‐Blind, Placebo‐Controlled, 3‐Way Crossover Study to Evaluate the Effect of Therapeutic and Supratherapeutic Doses of Edaravone on QT/QTc Interval in Healthy Subjects

Shimizu

Inoue

Endo

et al. 2020

Clinical Pharm in Drug Dev

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This randomized, single‐blind, 3‐way crossover study assessed the effect of edaravone on QT interval, including an exposure‐response analysis. Twenty‐seven healthy Japanese male volunteers, aged 20 to 49 years, were randomly assigned to receive a single intravenous dose of each treatment in 1 of 3 sequences (n = 9 each): ACB, BAC, and CBA, where A was edaravone 60 mg (therapeutic dose), B was edaravone 300 mg (supratherapeutic dose), and C was normal saline (placebo). Electrocardiographs were collected to assess treatment effects. In an exposure‐response analysis, a linear model was determined to be valid and indicated no statistically significant positive slope for the relationship between change from baseline in QTcF (ΔQTcF) and edaravone concentration (0.000155 ms/(ng/mL); P = .1478); upper bounds of 2‐sided 90% confidence intervals after placebo adjustment (ΔΔQTcF) were <10 milliseconds at the geometric mean maximum concentration for each edaravone dose. Overall estimated values by time point of ΔΔQTcF ≤0.9 milliseconds, no outlier values, and no morphologic changes suggestive of repolarization abnormalities were observed. Analysis of heart rate, PR interval, and QRS duration also revealed no adverse findings. These data indicate that edaravone, even at supratherapeutic doses, does not produce clinically meaningful QT prolongation and has no clinically relevant cardiac effects.

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Bioavailability of Edaravone Sublingual Tablet Versus Intravenous Infusion in Healthy Male Volunteers

Cited by 16 publications

References 19 publications

Synthesis, Characterization, and In Vivo Evaluation of Desmethyl Anethole Trithione Phosphate Prodrug for Ameliorating Cerebral Ischemia-Reperfusion Injury in Rats

Synthesis, Characterization, and In Vivo Evaluation of Desmethyl Anethole Trithione Phosphate Prodrug for Ameliorating Cerebral Ischemia-Reperfusion Injury in Rats

Edaravone: A Novel Possible Drug for Cancer Treatment?

A Randomized, Single‐Blind, Placebo‐Controlled, 3‐Way Crossover Study to Evaluate the Effect of Therapeutic and Supratherapeutic Doses of Edaravone on QT/QTc Interval in Healthy Subjects

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