Development of a novel oral delivery system of edaravone for enhancing bioavailability

Parikh, Ankit; Kathawala, Krishna; Tan, Chun Chuan; Garg, Sanjay; Zhou, Xin‐Fu

doi:10.1016/j.ijpharm.2016.10.052

Cited by 41 publications

(63 citation statements)

References 39 publications

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“…Moreover, there are ongoing attempts to improve its poor oral bioavailability. If successful, these attempts may not only promote its use in chronic diseases but possibly also increase the commercial interest about its development as a licensed drug in different conditions484950.…”

Section: Discussionmentioning

confidence: 99%

A staged screening of registered drugs highlights remyelinating drug candidates for clinical trials

Eleuteri

Olla

Veroni

et al. 2017

Sci Rep

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There is no treatment for the myelin loss in multiple sclerosis, ultimately resulting in the axonal degeneration that leads to the progressive phase of the disease. We established a multi-tiered platform for the sequential screening of drugs that could be repurposed as remyelinating agents. We screened a library of 2,000 compounds (mainly Food and Drug Administration (FDA)-approved compounds and natural products) for cellular metabolic activity on mouse oligodendrocyte precursors (OPC), identifying 42 molecules with significant stimulating effects. We then characterized the effects of these compounds on OPC proliferation and differentiation in mouse glial cultures, and on myelination and remyelination in organotypic cultures. Three molecules, edaravone, 5-methyl-7-methoxyisoflavone and lovastatin, gave positive results in all screening tiers. We validated the results by retesting independent stocks of the compounds, analyzing their purity, and performing dose-response curves. To identify the chemical features that may be modified to enhance the compounds’ activity, we tested chemical analogs and identified, for edaravone, the functional groups that may be essential for its activity. Among the selected remyelinating candidates, edaravone appears to be of strong interest, also considering that this drug has been approved as a neuroprotective agent for acute ischemic stroke and amyotrophic lateral sclerosis in Japan.

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Section: Discussionmentioning

confidence: 99%

A staged screening of registered drugs highlights remyelinating drug candidates for clinical trials

Eleuteri

Olla

Veroni

et al. 2017

Sci Rep

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“…Thus, the solubility of edaravone in water is pH-dependent, being roughly constant from pH 2 to 7, and then increasing from pH 8 to 10. ( 19 ) In water/1-octanol, partitioning to water also increases with pH. In water at pH 7.4, the percentages of the neutral and anionic forms of edaravone have been calculated to be 28.5% and 71.5%, respectively.…”

Section: Properties Of Edaravonementioning

confidence: 96%

How is edaravone effective against acute ischemic stroke and amyotrophic lateral sclerosis?

Watanabe¹,

Tanaka

Yuki³

et al. 2018

J. Clin. Biochem. Nutr.

170

118

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Edaravone is a low-molecular-weight antioxidant drug targeting peroxyl radicals among many types of reactive oxygen species. Because of its amphiphilicity, it scavenges both lipid- and water-soluble peroxyl radicals by donating an electron to the radical. Thus, it inhibits the oxidation of lipids by scavenging chain-initiating water-soluble peroxyl radicals and chain-carrying lipid peroxyl radicals. In 2001, it was approved in Japan as a drug to treat acute-phase cerebral infarction, and then in 2015 it was approved for amyotrophic lateral sclerosis (ALS). In 2017, the U.S. Food and Drug Administration also approved edaravone for treatment of patients with ALS. Its mechanism of action was inferred to be scavenging of peroxynitrite. In this review, we focus on the radical-scavenging characteristics of edaravone in comparison with some other antioxidants that have been studied in clinical trials, and we summarize its pharmacological action and clinical efficacy in patients with acute cerebral infarction and ALS.

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“…We show that the drug edaravone, an ROS scavenger indicated for human use in ALS in the U.S. and cerebral infarction in Japan (Miyaji et al, 2015; Watanabe et al, 2018), inhibits cipro induction of mutagenesis but not its antibiotic (killing) activity. Edaravone, at concentrations seen in new formulations (100μM) (Corporation, 2014; Li et al, 2012; Parikh et al, 2016), inhibited the appearance of σ S -high cells (Figure 3C), accumulation of σ S -fusion protein (Figure S3F), appearance of ROS-high cells (Figure 3D), and most (82% ± 1% of) RifR mutagenesis (Figure 3E). Edaravone did not affect cipro induction of DSBs (Figure 3F), SOS activation (Figure 3G), cell growth (Figure S2A), colony formation (Figures S2B), or negative-control β-gal activity (Figure S5B), implying that its inhibition of mutagenesis reflects specific inhibition of σ S -response activation (Figure 3I).…”

Section: Resultsmentioning

confidence: 99%

Gamblers: an Antibiotic-induced Evolvable Cell Subpopulation Differentiated by Reactive-oxygen-induced General Stress Response

Pribis¹,

Garcı́a-Villada²,

Zhen³

et al. 2018

Preprint

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32Antibiotics can induce mutations that cause antibiotic resistance. Yet, despite their importance, 33 mechanisms of antibiotic-promoted mutagenesis remain elusive. We report that the 34 fluoroquinolone antibiotic ciprofloxacin (cipro) induces mutations that cause drug resistance by 35 triggering differentiation of a mutant-generating cell subpopulation, using reactive oxygen species 36 (ROS) to signal the sigma-S (σ S ) general-stress response. Cipro-generated DNA breaks activate 37 the SOS DNA-damage response and error-prone DNA polymerases in all cells. However, 38 mutagenesis is restricted to a cell subpopulation in which electron transfer and SOS induce ROS, 39 which activate the σ S response, allowing mutagenesis during DNA-break repair. When sorted, 40 this small σ S -response-"on" subpopulation produces most antibiotic cross-resistant mutants. An 41FDA-approved drug prevents σ S induction specifically inhibiting antibiotic-promoted mutagenesis. 42 Furthermore, SOS-inhibited cell division, causing multi-chromosome cells, is required for 43 mutagenesis. The data support a model in which within-cell chromosome cooperation together 44 with development of a "gambler" cell subpopulation promote resistance evolution without risking 45 most cells. 46 47 48 49 51 break repair, reactive oxygen species (ROS), RpoS (σ S ) stress response, SOS response, 52 starvation stress response, stress-induced mutagenesis, transient differentiation 53 54 100 once antibiotics have gone (Lewis, 2010). Persister formation can occur stochastically, leaving 101 populations ready for a stress that they have not encountered (Balaban et al., 2004), and can also 102 be induced responsively via stress-response regulons including the SOS- (Dorr et al., 2009) and 103 σ S -response (Radzikowski et al., 2016) regulons. It is unknown whether antibiotics induce 104 4 transient differentiation that could promote resistance through mutagenesis, e.g., (Frenoy and 105 Bonhoeffer, 2018). 106Here we show that low, sub-inhibitory doses of cipro induce transient differentiation of a 107 small cell subpopulation with high ROS and σ S -response activity, that generates mutants, 108 including cross-resistant mutants: a "gambler" subpopulation. We show that the ROS promote 109 mutagenesis in gamblers by activating the σ S response, which allows mutagenic repair of cipro-110 triggered DSBs-a novel signaling/differentiating role of ROS in mutagenesis. We elaborate the 111 regulatory chain from cipro to ROS to σ S response to mutant production, and also discover a 112 requirement for SOS-induced inhibition of cell division, causing multiple chromosomes per cell. 113Mathematical analysis supports a model in which multiple chromosomes allow sharing of cellular 114 resources (e.g., recombination, complementation), avoiding deleterious consequences of some 115 mutations during mutagenesis and repair. Thus, multiple chromosomes allow higher mutation 116 rates to be maintained -resulting in faster adaptation. The findings imply a highly regulated, novel 117 transie...

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Development of a novel oral delivery system of edaravone for enhancing bioavailability

Cited by 41 publications

References 39 publications

A staged screening of registered drugs highlights remyelinating drug candidates for clinical trials

A staged screening of registered drugs highlights remyelinating drug candidates for clinical trials

How is edaravone effective against acute ischemic stroke and amyotrophic lateral sclerosis?

Gamblers: an Antibiotic-induced Evolvable Cell Subpopulation Differentiated by Reactive-oxygen-induced General Stress Response

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