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Papers of the Week

Papers: 15 Feb 2020 - 21 Feb 2020

Animal Studies, Pharmacology/Drug Development

2020 Feb 16

Antioxid Redox Signal

Enhanced Analgesic Effects and GI Safety of a Novel Hydrogen Sulfide-Releasing Anti-Inflammatory Drug (ATB-352): A Role for Endogenous Cannabinoids.


Costa S, Muscara M, Allain T, Dallazen J, Santos L G, Buret AG, Vaughan D, Fowler CJ, DeNucci GN, Wallace JL
Antioxid Redox Signal. 2020 Feb 16.
PMID: 32064887.


AIMS The covalent linking of non-steroidal anti-inflammatory drugs (NSAIDs) to a hydrogen sulfide (H2S)-releasing moiety has been shown to dramatically reduce gastrointestinal (GI) damage and bleeding, as well as increasing anti-inflammatory and analgesic potency. We have tested the hypothesis that a H2S-releasing derivative of ketoprofen (ATB-352) would exhibit enhanced efficacy without significant GI damage in a mouse model of allodynia/hyperalgesia. RESULTS ATB-352 was significantly more potent as an analgesic than ketoprofen, and did not elicit GI damage. Pretreatment with a cannabinoid receptor-1 antagonist (AM251) significantly reduced the analgesic effects of ATB-352. The CB-1 antagonist exacerbated GI damage when co-administered with ketoprofen, but GI damage was not induced by the combination of ATB-352 and the CB-1 antagonist. ATB-352 was substantially more potent than ketoprofen as an inhibitor of fatty acid amide hydrolase, consistent with a contribution of endogenous cannabinoids to the analgesic effects of this drug. Blood anandamide levels were significantly depressed by ketoprofen, but remained unchanged after treatment with ATB-352. INNOVATION Ketoprofen is a potent analgesic, but its clinical use is significantly limited by its propensity to cause significant ulceration and bleeding in the GI tract. Covalently linking an H2S-releasing moiety to ketoprofen profoundly reduces the GI toxicity of the drug, while boosting the analgesic effectiveness.