Evaluation of the clinical efficacy of idebenone in patients affected by chronic cerebrovascular disorders

Lingetti, M; Porfido, Francesco Antonio; Ciarimboli, M; Oliviero, Ugo; Cocozza, Manlio; Coto, Vincenzo; Policicchio, Domenico; Carifi, Saverio; Piermatteo, Efrem; Lombardi, Rosanna; Tranfaglia, Emilio; Grazia, Francesco Di

doi:10.1016/0167-4943(92)90058-c

Cited by 8 publications

(4 citation statements)

References 24 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The reference compound PhIP increased transformation only up to 30 μM in our test system, since cytotoxicity at higher concentrations has been reported [ 46 ]. In contrast, the clinically used idebenone [ 47 , 48 ] as well as the test compounds also did not appear to promote cellular transformation in this test system, but their toxicities were mirrored in the agar invasion assay in a concentration dependent manner.…”

Section: Discussionmentioning

confidence: 77%

Comparative In Vitro Toxicology of Novel Cytoprotective Short-Chain Naphthoquinones

et al. 2020

View full text Add to dashboard Cite

Short-chain quinones (SCQs) have been identified as potential drug candidates against mitochondrial dysfunction, which largely depends on the reversible redox characteristics of the active quinone core. We recently identified 11 naphthoquinone derivatives, 1–11, from a library of SCQs that demonstrated enhanced cytoprotection and improved metabolic stability compared to the clinically used benzoquinone idebenone. Since the toxicity properties of our promising SCQs were unknown, this study developed multiplex methods and generated detailed toxicity profiles from 11 endpoint measurements using the human hepatocarcinoma cell line HepG2. Overall, the toxicity profiles were largely comparable across different assays, with simple standard assays showing increased sensitivity compared to commercial toxicity assays. Within the 11 naphthoquinones tested, the L-phenylalanine derivative 4 consistently demonstrated the lowest toxicity across all assays. The results of this study not only provide useful information about the toxicity features of SCQs but will also enable the progression of the most promising drug candidates towards their clinical use.

show abstract

Section: Discussionmentioning

confidence: 77%

Comparative In Vitro Toxicology of Novel Cytoprotective Short-Chain Naphthoquinones

et al. 2020

View full text Add to dashboard Cite

show abstract

“…caspase-mediated apoptosis) [146–149]. Both Auranofin (an organogold compound with anti-inflammatory abilities) and Idebenone (a benzoquinone that has previously been used in Alzheimer’s patients) are speculated to interfere with inflammasome activation.…”

Section: Anti-toxin Therapiesmentioning

confidence: 99%

“…Specifically, Auranofin inhibits LT-mediated caspase-1 activation and catalytic activity while Idebenone inhibits the voltage-gated potassium channels. When combined, these two compounds work synergistically to strongly inhibit the LT activity of B. anthracis [146–149]. …”

Section: Anti-toxin Therapiesmentioning

confidence: 99%

Alternative pre-approved and novel therapies for the treatment of anthrax

2016

View full text Add to dashboard Cite

Background Bacillus anthracis, the causative agent of anthrax, is a spore forming and toxin producing rod-shaped bacterium that is classified as a category A bioterror agent. This pathogenic microbe can be transmitted to both animals and humans. Clinical presentation depends on the route of entry (direct contact, ingestion, injection or aerosolization) with symptoms ranging from isolated skin infections to more severe manifestations such as cardiac or pulmonary shock, meningitis, and death. To date, anthrax is treatable if antibiotics are administered promptly and continued for 60 days. However, if treatment is delayed or administered improperly, the patient’s chances of survival are decreased drastically. In addition, antibiotics are ineffective against the harmful anthrax toxins and spores. Therefore, alternative therapeutics are essential. In this review article, we explore and discuss advances that have been made in anthrax therapy with a primary focus on alternative pre-approved and novel antibiotics as well as anti-toxin therapies.MethodsA literature search was conducted using the University of Manitoba search engine. Using this search engine allowed access to a greater variety of journals/articles that would have otherwise been restricted for general use. In order to be considered for discussion for this review, all articles must have been published later than 2009.ResultsThe alternative pre-approved antibiotics demonstrated high efficacy against B. anthracis both in vitro and in vivo. In addition, the safety profile and clinical pharmacology of these drugs were already known. Compounds that targeted underexploited bacterial processes (DNA replication, RNA synthesis, and cell division) were also very effective in combatting B. anthracis. In addition, these novel compounds prevented bacterial resistance. Targeting B. anthracis virulence, more specifically the anthrax toxins, increased the length of which treatment could be administered.ConclusionsSeveral novel and pre-existing antibiotics, as well as toxin inhibitors, have shown increasing promise. A combination treatment that targets both bacterial growth and toxin production would be ideal and probably necessary for effectively combatting this armed bacterium.

show abstract

“…We show that auranofin acts as an inhibitor of the Nlrp1b and Nlrp3 inflammasomes in addition to directly inhibiting recombinant caspase-1 catalytic activity. Furthermore, tests of drug combinations identified idebenone, a synthetic analogue of coenzyme Q10, originally developed for the treatment of Alzheimer's disease (29) and more recently evaluated in clinical trials for the treatment of Freidrich's ataxia (33), as a potassium channel blocker that synergizes with auranofin to increase its protective index.…”

mentioning

confidence: 99%

Auranofin Protects against Anthrax Lethal Toxin-Induced Activation of the Nlrp1b Inflammasome

Newman

Sirianni²,

Mawhinney³

et al. 2011

Antimicrob Agents Chemother

View full text Add to dashboard Cite

Anthrax lethal toxin (LT) is the major virulence factor for Bacillus anthracis. The lethal factor (LF) component of this bipartite toxin is a protease which, when transported into the cellular cytoplasm, cleaves mitogen-activated protein kinase kinase (MEK) family proteins and induces rapid toxicity in mouse macrophages through activation of the Nlrp1b inflammasome. A high-throughput screen was performed to identify synergistic LT-inhibitory drug combinations from within a library of approved drugs and molecular probes. From this screen we discovered that auranofin, an organogold compound with anti-inflammatory activity, strongly inhibited LT-mediated toxicity in mouse macrophages. Auranofin did not inhibit toxin transport into cells or MEK cleavage but inhibited both LT-mediated caspase-1 activation and caspase-1 catalytic activity. Thus, auranofin inhibited LT-mediated toxicity by preventing activation of the Nlrp1b inflammasome and the downstream actions that occur in response to the toxin. Idebenone, an analog of coenzyme Q, synergized with auranofin to increase its protective effect. We found that idebenone functions as an inhibitor of voltage-gated potassium channels and thus likely mediates synergy through inhibition of the potassium fluxes which have been shown to be required for Nlrp1b inflammasome activation.

show abstract

Evaluation of the clinical efficacy of idebenone in patients affected by chronic cerebrovascular disorders

Cited by 8 publications

References 24 publications

Comparative In Vitro Toxicology of Novel Cytoprotective Short-Chain Naphthoquinones

Comparative In Vitro Toxicology of Novel Cytoprotective Short-Chain Naphthoquinones

Alternative pre-approved and novel therapies for the treatment of anthrax

Auranofin Protects against Anthrax Lethal Toxin-Induced Activation of the Nlrp1b Inflammasome

Contact Info

Product

Resources

About