- 10 November 2020
- journal article
- Published by Mary Ann Liebert Inc
Abstract
Aims: The covalent linking of nonsteroidal anti-inflammatory drugs to a hydrogen sulfide (H2S)-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 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 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 H2S-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 H2S-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.Keywords
This publication has 37 references indexed in Scilit:
- Anti-inflammatory effect of ATB-352, a H2S −releasing ketoprofen derivative, on lipopolysaccharide-induced periodontitis in ratsPharmacological Research, 2018
- The Risk of Major NSAID Toxicity with Celecoxib, Ibuprofen, or Naproxen: A Secondary Analysis of the PRECISION TrialAmerican Journal Of Medicine, 2017
- Periarticular multimodal drug injection improves post-operative pain and functional recovery after total knee arthroplastyJournal of Orthopaedic Science, 2015
- A novel orally administered trimebutine compound (GIC‐1001) is anti‐nociceptive and features peripheral opioid agonistic activity and Hydrogen Sulphide‐releasing capacity in miceEuropean journal of pain, 2015
- Proton Pump Inhibitors Increase Incidence of Nonsteroidal Anti-Inflammatory Drug–Induced Small Bowel Injury: A Randomized, Placebo-Controlled TrialClinical Gastroenterology and Hepatology, 2015
- Hydrogen sulfide-based therapeutics: exploiting a unique but ubiquitous gasotransmitterNature Reviews Drug Discovery, 2015
- Inhaled hydrogen sulfide prevents neuropathic pain after peripheral nerve injury in miceNitric Oxide, 2015
- H2S-releasing drugs: Anti-inflammatory, cytoprotective and chemopreventative potentialNitric Oxide, 2015
- Risk factors for severe nonsteroidal anti-inflammatory drug-induced small intestinal damageDigestive and Liver Disease, 2013
- AM-251 and rimonabant act as direct antagonists at mu-opioid receptors: Implications for opioid/cannabinoid interaction studiesNeuropharmacology, 2012