Licofelone

IC50: Inhibitor of COX-1, COX-2 and 5-LOX with IC50 values of 0.16 M, 0.37 M and 0.23 M respectively in human.

Licofelone (ML3000), developed by the German pharmaceutical company - Merckle GmbH, is a potent suppressor of both COX and LOX. As the first member of this new class of analgesic and anti-inflammatory drugs, Licofelone is suggested as a novel treatment for osteoarthritis (OA), the most common form of arthritis. [1]

In vitro: The 5-LOX and COX inhibitory effect of licofelone was firstly identified via bovine thromobocyte intact cell assay and intact bovine PMN leukocytes. Licofelone was also reported to inhibit PGE2 in a dose-dependent manner in human whole blood assay. Moreover, Licofelone was found to suppress in vitro generation of reactive oxygen species and to reduce release of elastase from PMN leukocytes. All above findings revealed that Licofelone had an inhibitory effect on COX-1/-2 and 5-LOX. [1]

In vivo: The pharmacodynamic properties of Licofelone were evaluated in various animal models and compared with those of commonly used NSAIDs. Based on studies from a rat model of incisional pain, orally administration of Licofelone had a longer duration of action and was more effective than indomethacin and zileuton. [1]

Clinical trials: Two double-blind phase-II studies had been conducted to detect the efficacy of licofelone in OA. In the first study, 107 patients were treated with different doses of licofelone or placebo for 4 weeks. It was reported that licofelone at 200 or 400 mg twice a day could significantly ameliorate the symptoms of OA. In the second study, licofelone at doses of 100, 200 and 400 mg was administered to 404 patients twice a day, WOMAC pain subscore showed a notable decrease of 37%, 40% and 42% respectively. Licofelone at 400 mg twice a day was found to cause adverse events including diarrhea and abdominal pain. [1]

Reference:
[1]Kulkarni SK and Singh VP.  Licofelone-a novel analgesic and anti-inflammatory agent. Curr Top Med Chem. 2007; 7(3): 251-63.

Anticonvulsive Effects of Licofelone on Status Epilepticus Induced by Lithium-pilocarpine in Wistar Rats: a Role for Inducible Nitric Oxide Synthase.[Pubmed:28101475]

J Epilepsy Res. 2016 Dec 31;6(2):51-58.

BACKGROUND AND PURPOSE: Status epilepticus (SE) is a neurological disorder with high prevalence and mortality rates, requiring immediate intervention. Licofelone is a cyclooxygenase (COX) and 5-lipoxygenase (5-LOX) inhibitor, which its effectiveness to treat osteoarthritis has been approved. Increasing evidence suggests an involvement of COX and LOX enzymes in epileptic disorders. Thus, in the present study we investigate possible effects of Licofelone on prevention and termination of SE. We also evaluated whether the nitrergic system could participate in this effect of Licofelone. METHODS: We have utilized lithium-pilocarpine model of SE in adult Wistar rats to assess the potential effect of Licofelone on seizure susceptibility. Licofelone was administered 1 h before pilocarpine. To evaluate probable role of nitric oxide (NO) system, L-arginine (60 mg/kg, i.p.), as a NO precursor; L-NAME (15 mg/kg, i.p.), as a non-selective nitric oxide synthase (NOS) inhibitor; aminoguanidine (100 mg/kg, i.p.), as an inducible NOS (iNOS) inhibitor and 7-nitroindazole (60 mg/kg, i.p.), as a neuronal NOS inhibitor were injected 15 min before Licofelone. Also, Licofelone and diazepam 10 mg/kg were administered 30 minutes after onset of SE. RESULTS: Pre-treatment with Licofelone at the dosage of 10 mg/kg, significantly prevented the onset of SE in all subjects (p < 0.001). L-arginine significantly inverted this anticonvulsant effect (p < 0.05). However, L-NAME and aminoguanidine, potentiated the anticonvulsant effect of Licofelone (p < 0.05, p < 0.01). Licofelone could not terminate seizures after onset which was terminated by diazepam. CONCLUSIONS: Our findings showed that anticonvulsive effects of Licofelone on SE could be mediated by iNOS. Also, we suggest that COX/5-LOX activation is possibly required in the initial stage of onset but SE recruits extra excitatory pathways with prolongation.

A COX/5-LOX Inhibitor Licofelone Revealed Anticonvulsant Properties Through iNOS Diminution in Mice.[Pubmed:26216049]

Neurochem Res. 2015 Sep;40(9):1819-28.

Licofelone is a COX/5-LOX inhibitor, which recently was approved as an effective treatment for osteoarthritis. Beside its analgesic and anti-inflammatory effects, some reports show neuro-protective properties for this agent in central nervous system. Several lines of evidence declare the involvement of COX or LOX isoenzymes in epileptic disorders. To set the foundation for future research into the neurobiology of Licofelone as a potential therapeutic agent, we studied the effect of Licofelone in an animal model of epilepsy. Although different neurotransmitters and neuro-modulators like nitric oxide were introduced as suggested targets of Licofelone, the underlying mechanisms of central effects of this drug are not still fully understood. We have utilized pentylenetetrazole-induced clonic seizure model to investigate the behavioral consequences of Licofelone administration and its possible mechanisms in seizure susceptibility. Licofelone revealed anticonvulsant properties at the dose of 10 mg/kg (i.p) or higher in mice. Pre-treatment with NO (nitric oxide) donor, L-arginine, reversed this anticonvulsant effects dose dependently. L-NAME, as a non-selective nitric oxide synthase (NOS) inhibitor, potentiated the anticonvulsant effects of Licofelone. A neuronal NOS inhibitor, 7-NI did not affect seizure threshold alone or in combination with Licofelone. Using non-effective doses of selective inhibitors of inducible NOS, aminoguanidine or 1400W, significantly increased the seizure threshold when were accompanied by Licofelone in low doses. These data support the involvement of NO as an important role player in the central neuro-protective properties of Licofelone. Furthermore, it implies that down regulation of iNOS seems crucial for anticonvulsant properties of this COX/5-LOX inhibitor in seizure susceptibility.

Modulation by licofelone and celecoxib of experimentally induced cancer and preneoplastic lesions in mice exposed to cigarette smoke.[Pubmed:25687474]

Curr Cancer Drug Targets. 2015;15(3):188-95.

Chronic inflammation plays a crucial role in cigarette smoke-related carcinogenesis. Accordingly, anti-inflammatory agents, such as nonsteroidal anti-inflammatory drugs (NSAIDs), provide a rational strategy in cancer chemoprevention. We assayed celecoxib, a selective cyclooxygenase-2 (COX-2) inhibitor, and Licofelone, an inhibitor of COX-1, COX-2, and 5- lipoxygenase (5-LOX), for the ability to modulate carcinogenesis in neonatal mice exposed to mainstream cigarette smoke (MCS) for 4 months and thereafter kept in filtered air for 3.5 months. A preliminary toxicity study and a chemoprevention study involved the use of 591 Swiss H mice. Exposure to MCS caused a variety of pulmonary emphysema, alveolar and bronchial epithelial hyperplasias, proliferation of blood vessels, microadenomas, adenomas and malignant tumors, as well as kidney tubular and urinary bladder papillary epithelial hyperplasias. Celecoxib (1600 mg/kg diet) and even better Licofelone (960 mg/kg diet) were able to significantly attenuate the MCS-induced alterations of inflammatory nature, including pulmonary emphysema, alveolar epithelial hyperplasias and microadenomas and urinary tract hyperplastic lesions when given to mice according to a protocol that mimics an intervention in current smokers. Moreover, celecoxib attenuated the yield of lung adenomas and both NSAIDs showed some involvement in lowering the progression to cancer in the lung. Celecoxib exhibited some protective effects even when given according to a protocol involving its administration after discontinuation of exposure to MCS. However, both agents and especially celecoxib showed some hepatotoxicity and affected survival and body weight gain of mice when administered to MCS-exposed mice in the long term.

Improved Antitumor Activity of a Therapeutic Melanoma Vaccine through the Use of the Dual COX-2/5-LO Inhibitor Licofelone.[Pubmed:27994586]

Front Immunol. 2016 Dec 5;7:537.

Immune-suppressive cell populations impair antitumor immunity and can contribute to the failure of immune therapeutic approaches. We hypothesized that the non-steroidal anti-inflammatory drug Licofelone, a dual cyclooxygenase-2/5-LO inhibitor, would improve therapeutic melanoma vaccination by reducing immune-suppressive cell populations. Therefore, Licofelone was administered after tumor implantation, either alone or in combination with a peptide vaccine containing a long tyrosinase-related protein 2-peptide and the adjuvant alpha-galactosylceramide, all formulated into cationic liposomes. Mice immunized with the long-peptide vaccine and Licofelone showed delayed tumor growth compared to mice given the vaccine alone. This protection was associated with a lower frequency of immature myeloid cells (IMCs) in the bone marrow (BM) and spleen of tumor-inoculated mice. When investigating the effect of Licofelone on IMCs in vitro, we found that the prostaglandin E2-induced generation of IMCs was decreased in the presence of Licofelone. Furthermore, pre-incubation of BM cells differentiated under IMC-inducing conditions with Licofelone reduced the secretion of cytokines interleukin (IL)-10 and -6 upon lipopolysaccharides (LPS) stimulation as compared to untreated cells. Interestingly, Licofelone increased IL-6 and IL-10 secretion when administered after the LPS stimulus, demonstrating an environment-dependent effect of Licofelone. Our findings support the use of Licofelone to reduce tumor-promoting cell populations.

Licofelone (ML-3000) is a dual COX/5-lipoxygenase (5-LOX) inhibitor (IC50=0.21/0.18 μM, respectively) for the treatment of osteoarthritis. Licofelone exerts anti-inflammatory and anti-proliferative effects. Licofelone induces apoptosis, and decreases the production of proinflammatory leukotrienes and prostaglandins.

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