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

Publisher: Mary Ann Liebert, Inc Country of Publication: United States NLM ID: 100888899 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1557-7716 (Electronic) Linking ISSN: 15230864 NLM ISO Abbreviation: Antioxid Redox Signal Subsets: MEDLINE

Original Publication: Larchmont, NY : Mary Ann Liebert, Inc., 1999-

Anti-Inflammatory Agents, Non-Steroidal/*pharmacology ; Gastrointestinal Tract/*drug effects ; Hydrogen Sulfide/*pharmacology; Analgesics/pharmacology ; Animals ; Anti-Inflammatory Agents, Non-Steroidal/adverse effects ; Anti-Inflammatory Agents, Non-Steroidal/chemistry ; Cannabinoids/metabolism ; Cannabinoids/pharmacology ; Disease Models, Animal ; Dose-Response Relationship, Radiation ; Drug Synergism ; Fatty Acids/metabolism ; Gastric Mucosa/drug effects ; Gastric Mucosa/metabolism ; Gastric Mucosa/pathology ; Hydrogen Sulfide/adverse effects ; Hydrogen Sulfide/chemistry ; Ketoprofen/pharmacology ; Mice ; Pain/drug therapy ; Pain/etiology

Aims: The covalent linking of nonsteroidal anti-inflammatory drugs to a hydrogen sulfide (H 2 S)-releasing moiety has been shown to dramatically reduce gastrointestinal (GI) damage and bleeding, as well as increase anti-inflammatory and analgesic potency. We have tested the hypothesis that an H 2 S-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 and effective as an analgesic than ketoprofen and did not elicit GI damage. Pretreatment with an antagonist of the CB1 cannabinoid receptor (AM251) significantly reduced the analgesic effects of ATB-352. The CB1 antagonist exacerbated GI damage when coadministered with ketoprofen, but GI damage was not induced by the combination of ATB-352 and the CB1 antagonist. In vitro , 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, even in the short term, is significantly limited by its propensity to cause significant ulceration and bleeding in the GI tract. Covalently linking an H 2 S-releasing moiety to ketoprofen profoundly reduces the GI toxicity of the drug, while boosting analgesic effectiveness. Conclusion: This study demonstrates a marked enhancement of the potency and effectiveness of ATB-352, an H 2 S-releasing derivative of ketoprofen, in part, through the involvement of the endogenous cannabinoid system. This may have significant advantages for the control and management of pain, such as in a postoperative setting.

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Keywords: analgesic; cannabinoid; hydrogen sulfide; inflammation; ketoprofen; pain; ulcer

0 (Analgesics)
0 (Anti-Inflammatory Agents, Non-Steroidal)
0 (Cannabinoids)
0 (Fatty Acids)
90Y4QC304K (Ketoprofen)
YY9FVM7NSN (Hydrogen Sulfide)

Date Created: 20200218 Date Completed: 20210901 Latest Revision: 20210901

20240105

PMC7578177

10.1089/ars.2019.7884

32064887