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Substrates of Human CYP2D6
Published in Shufeng Zhou, Cytochrome P450 2D6, 2018
Licofelone (ML-3000), a dual inhibitor of COX-1 and COX-2 and 5-lipoxygenase under development for treatment of osteoarthritis, is hydroxylated by CYP2C8, 2J2, and 2D6 to a minor extent (Albrecht et al. 2008). In human liver microsomes, two hydroxylated metabolites, M2 and M4, are formed from licofelone. CYP2J2 is the major enzyme for the formation of M2, with minor contribution from CYP2C8 and 2C9. M4 is generated by CYP2J2, 3A4, 2C8, 2C19, and 2D6 (Albrecht et al. 2008). In human plasma, M2 achieves values of ~20% compared with that of the parent drug. Alternatively, licofelone is rapidly converted into the corresponding acyl glucuronide (M1). After glucuronidation by UGT2B7, 1A9, and 1A3, M1 is converted into the hydroxy-glucuronide M3 by CYP2C8 (Albrecht et al. 2008).
Clinical pharmacology and therapeutics: nonopioids
Published in Nigel Sykes, Michael I Bennett, Chun-Su Yuan, Clinical Pain Management, 2008
When NSAIDs block COX, arachidonic acid degradation is shunted mainly into the production of leukotrienes via lipoxygenase (LOX) (Figure 11.1). Leukotrienes attract neutrophils to inflammatory sites, causing the release of proteolytic enzymes, toxic oxygen radicals, chemokines and cytokines, inducing inflammation.301 They also probably reduce gastric mucosal blood flow, potentiating mucosal damage. Agents which block COX-1, COX-2, and LOX (LOX-COX inhibitors),302 theoretically and experimentally are less gastrotoxic303, 304, 305 and nephrotoxic than nonselective NSAIDs, and have antithrombotic, analgesic, anti-inflammatory, antihyperalgesic, antipyretic, antiasthmatic, and even chondroprotective properties.306 Indeed, licofelone, the first LOX-COX inhibitor, interfered with platelet function in vitro more than acetylsalicylic acid did.307 In rabbits, it also reduced neointimal formation and inflammation.308 Early human trials confirm low gastric toxicity.309
Investigational drugs for the treatment of osteoarthritis, an update on recent developments
Published in Expert Opinion on Investigational Drugs, 2018
Zhaohua Zhu, Jia Li, Guangfeng Ruan, Guoliang Wang, Cibo Huang, Changhai Ding
Licofelone is an anti-inflammatory drug that can inhibit both cyclooxygenase (COX) and 5-lipooxygenase [44]. It has been shown to reduce OA structural changes and suppress expression of proteolytic enzymes such as MMP-13 and Cathepsin-k [45]. In a multicenter clinical trial, patients with knee OA were randomly assigned to either licofelone or naproxen groups. Licofelone and naproxen were found to be equally effective in reducing OA symptoms, but licofelone significantly reduced cartilage volume loss overtime [46]. This indicated structural modifying effect of licofelone. However, more clinical studies are required to confirm its efficacy.
An update of cyclooxygenase (COX)-inhibitors in epilepsy disorders
Published in Expert Opinion on Investigational Drugs, 2019
Licofelone is another dual inhibitor of COX and 5-LOX and approved for the treatment of osteoarthritis [80]. Licofelone at doses of 10 mg/kg, IP and up in mice demonstrated an anticonvulsant property in the PTZ seizure model [81]. The anticonvulsant-like effect of licofelone in this animal model involved nitric oxide signaling mechanism [81]. Similarly, licofelone when administered as a pretreatment strategy prevented the onset of SE caused by lithium–pilocarpine in rats [80]. However, licofelone was found to be ineffective when the seizures have already set in due to the pilocarpine challenge [80].
Systemic drugs with impact on osteoarthritis
Published in Drug Metabolism Reviews, 2019
Dragos Apostu, Ondine Lucaciu, Alexandru Mester, Daniel Oltean-Dan, Mihaela Baciut, Grigore Baciut, Simion Bran, Florin Onisor, Andra Piciu, Roxana D. Pasca, Andrei Maxim, Horea Benea
Licofelone is a LOX/COX inhibitor that decreases leukotrienes and prostaglandins (Cicero and Laghi 2007). Preclinical data showed that licofelone reduces cartilage lesion in surgically removed anterior cruciate ligament animal model (Cicero and Laghi 2007). This result is explained by a reduction in IL-1β and PGE2 (Cicero and Laghi 2007). A multicenter study on 355 patients with knee osteoarthritis showed that 200 mg twice a day reduces symptoms similar to naproxen, but cartilage volume loss is significantly reduced (Raynauld et al 2009).