Etodolac

Etodolac (Lodine) is a selective Cyclooxygenase-2 (COX-2) inhibitor with an IC50 of 53.5 nM.  Etodolac, a non-steroidal anti-inflammatory drug (NSAID), has been reported to treat osteoarthritis and rheumatoid arthritis.

Etodolac was able to abolish the cell size decrease and block caspase-3/7 activity in TNFα-induced isolated rabbit articular chondrocytes [1]. However, studies have shown that etodolac at 24h could induce cell death in human malignant rhabdoid tumor cells (FRTK-1) in a dose-dependent manner. Additionally, etodolac has shown to increase caspase-8, -9 and -3 activity 3 at 24 or 48 h in FRTK-1 [2].

References:
[1] Kumagai K1, Kubo M, Imai S, Toyoda F, Maeda T, Okumura N, Matsuura H, Matsusue Y.The COX-2 selective blocker etodolac inhibits TNFα-induced apoptosis in isolated rabbit articular chondrocytes. Int J Mol Sci. 2013 Sep 30;14(10):19705-15.
[2] Hakozaki M1, Hojo H, Kikuchi S, Abe M. Etodolac, a selective cyclooxygenase-2 inhibitor, induces apoptosis by activating caspases in human malignant rhabdoid tumor cells (FRTK-1). Oncol Rep. 2007 Jan;17(1):169-73.

Etodolac Containing Topical Niosomal Gel: Formulation Development and Evaluation.[Pubmed:27478643]

J Drug Deliv. 2016;2016:9324567.

The present study aimed to investigate the delivery potential of Etodolac (ETD) containing topical niosomal gel. Niosomal formulations were prepared by thin film hydration method at various ratios of cholesterol and Span 60 and were evaluated with respect to particle size, shape, entrapment efficiency, and in vitro characteristics. Dicetyl phosphate (DCP) was also added in the niosomal formulation. Mean particle size of niosomal formulation was found to be in the range of 2 mum to 4 mum. Niosomal formulation N2 (1 : 1) ratio of cholesterol and surfactant displayed good entrapment efficiency (96.72%). TEM analyses showed that niosomal formulation was spherical in shape. Niosomal formulation (N2) displayed high percentage of drug release after 24 h (94.91) at (1 : 1) ratio of cholesterol : surfactant. Further selected niosomal formulation was used to formulate topical gel and was characterized with respect to its various parameters such as pH, viscosity, spreadability, ex vivo study, and in vivo potential permeation. Ex vivo study showed that niosomal gel possessed better skin permeation study than the plain topical gel. Further in vivo study revealed good inhibition of inflammation in case of topical niosomal gel than plain gel and niosomal formulation. The present study suggested that topical niosomal gel formulations provide sustained and prolonged delivery of drug.

Inclusion Complexation of Etodolac with Hydroxypropyl-beta-cyclodextrin and Auxiliary Agents: Formulation Characterization and Molecular Modeling Studies.[Pubmed:28248111]

Mol Pharm. 2017 Apr 3;14(4):1231-1242.

The present investigation was aimed to prepare inclusion complexes of a therapeutically important nonsteroidal anti-inflammatory drug, Etodolac (ETD) with hydroxypropyl-beta-cyclodextrin (HP-beta-CD) and to study the effect of l-arginine (l-Arg) as an auxiliary agent on the complexation efficiency of HP-beta-CD to improve aqueous solubility and the dissolution property of ETD. The binary and ternary complexes were prepared by physical mixing, coevaporation, and spray drying methods. The complexes were characterized using differential scanning colorimetry (DSC), Fourier transform-infrared spectroscopy (FT-IR), and powder X-ray diffraction (PXRD) studies. The mechanism of inclusion interaction of guest and host was established through (1)H NMR, molecular docking, and molecular dynamics studies. On the basis of preliminary screening studies, l-Arg was found to be the most efficient auxiliary agent for the present research problem. The change in crystallinity of ETD was evident from DSC and PXRD studies which indicated the formation of new solid forms. A remarkable increase in apparent stability constant (Kc) and complexation efficiency (CE) of HP-beta-CD was observed in the presence of l-Arg in ternary complexes with improvement in solubility and dissolution of ETD than binary complexes. However, inclusion complexes of ETD obtained by computational studies is in good correlation with the results obtained through experimental methods. More stable complex formation with l-Arg was confirmed by molecular simulation studies too. Thus, the present study led to the conclusion that the ternary complex of ETD-HP-beta-CD-l-Arg could be an innovative approach to augment the solubility and dissolution behavior of ETD.

Self-Assembling Organogels Based on Pluronic and Lecithin for Sustained Release of Etodolac: In Vitro and In Vivo Correlation.[Pubmed:27593184]

Curr Drug Deliv. 2017;14(7):926-934.

BACKGROUND: Etodolac, a member of non steroidal anti-inflammatory drugs (NSAIDs), has a poor aqueous solubility. Long term administration of Etodolac causes severe gastrointestinal disturbances such as peptic ulcer and bleeding. These disturbances could be overcome by alternative routes such as a topical administration. METHOD: In the present study, pluronic lecithin organogels (PLOs) were prepared by simple mixing of pluronic solution with lecithin solution. Etodolac was loaded into the prepared gels or added during the gel formation. The physicochemical properties of the modified organogels were investigated by different analysis including visual inspection, pH determination, viscosity, spreadability and extrudability. Also, the in vitro release studies of Etodolac in the presence of different penetration enhancers were carried out. The anti-inflammatory behavior of the prepared Etodolac organogel was investigated using carrageenan induced paw edema test. RESULTS: The results indicated that the prepared organogels showed good physicochemical properties. The organogels, containing a combination of tween 80 and oleic acid as penetration enhancers, showed the highest percentage of drug release. CONCLUSION: All tested organogels showed a significant oedema inhibition compared with oral indomethacin (R) and Voltaren(R) as a topical marketed anti-inflammatory drug. Moreover, the increase of drug concentration from 1% to 5% w/w is accompanied with a longer duration of action up to 12 hrs. Therefore, the formulated organogels are considered as a promising vehicle for controlled topical delivery of Etodolac.

Quantification of Etodolac in Human Plasma for Pharmacokinetics and Bioequivalence Studies in 27 Korean Subjects.[Pubmed:28093968]

Drug Metab Lett. 2017;10(4):286-294.

OBJECTIVE: We developed a simple and validated liquid chromatography tandem mass spectrometry( LC-MS/MS) for quantification of Etodolac using pioglitazone as an internal standard (IS) to assess pharmacokinetics and to appraise bioequivalence of two formulations of Etodolac (reference and tested) in 27 healthy Korean subjects. METHODS: Isocratic mobile phase consisted of 10 mM ammonium formate and acetonitrile were used to separate the analytes on a Gemini C18 column. Also, analytes were analyzed by MS/MS in multiple reaction monitoring (MRM) mode using the transitions of (M+H)+ ions, m/z 288.2--> 172.3 and m/z 357.1--> 134.2 for quantification of Etodolac and IS each. The standard calibration curves displayed significant linearity within the range of 0.2-30.0 mu g/mL (r2=0.9956, 1/x2 weighting) with LLOQ of 0.1 mug/mL. RESULTS: The retention times of Etodolac and the IS were 0.77 min and 0.57 min each, indicating the high-throughput potential of the proposed method. The pharmacokinetic parameters were calculated from the plasma samples and data form the reference and test drugs were represented as follows; Area under plasma concentration-time curve (AUCt) (78.03 vs. 84.00 mugxh/mL), AUCinfinity (86.67 vs. 93.92 mugxh/mL), maximal plasma concentration (Cmax) (19.49 vs. 18.94 mug/mL), time for maximal concentrations (Tmax) (2.13 vs. 2.26 h), Plasma elimination half-life (T1/2) (8.12 vs. 8.47 h), elimination rate constant (lambdaz) (0.0853 vs. 0.0818 h-1). Pharmacokinetic parameters with 90% confidence interval fall within the bioequivalence range of 80-125%. CONCLUSION: Thus, the new testified method was successfully applied for the pharmacokinetic and bioequivalence studies for two Etodolac formulations.

Anti-inflammatory effect and low ulcerogenic activity of etodolac, a cyclooxygenase-2 selective non-steroidal anti-inflammatory drug, on adjuvant-induced arthritis in rats.[Pubmed:12711837]

Pharmacology. 2003 Jun;68(2):96-104.

Adjuvant arthritic rats are known to be more susceptible to gastric damage induced by non-steroidal anti-inflammatory drugs (NSAIDs) than are normal rats. We compared the relative gastric safety profile of Etodolac with those of meloxicam, diclofenac sodium and indometacin in adjuvant arthritic rats and normal rats or mice. As a measure of the safety profiles of NSAIDs, we used the safety index, the ratio of the dose that elicits gastric mucosal lesions to the effective dose as an anti-inflammatory or analgesic compound. The anti-inflammatory or analgesic effects of NSAIDs were assessed by paw swelling in adjuvant arthritic rats, and either carrageenin-induced paw edema or brewer's yeast-induced hyperalgesia, as well as acetic acid-induced writhing, in normal rats or mice. In addition, we also investigated the effects of these NSAIDs on human COX-1 and COX-2 activity. Etodolac and other NSAIDs inhibited paw swelling and caused gastric mucosal lesions in adjuvant arthritic rats in a dose-dependent manner. Etodolac showed the highest UD(50) value and safety index among these NSAIDs in arthritic rats. In normal rats, Etodolac also showed the highest UD(50) value and safety index, except when its effects were assessed by acetic acid-induced writhing. Etodolac and meloxicam showed selectivity for human COX-2 over COX-1. In contrast, diclofenac sodium and indometacin were selective for COX-1. These results suggest that Etodolac, a COX-2 selective NSAID, has anti-inflammatory effects with a better safety profile for the stomach than do non-selective NSAIDs, including diclofenac sodium and indometacin, in adjuvant arthritic as well as normal rats.

Cyclooxygenase-1 and cyclooxygenase-2 selectivity of non-steroidal anti-inflammatory drugs: investigation using human peripheral monocytes.[Pubmed:11804398]

J Pharm Pharmacol. 2001 Dec;53(12):1679-85.

Since the pharmacological profiles of various non-steroidal anti-inflammatory drugs (NSAIDs) might depend on their differing selectivity for cyclooxygenase 1 (COX-1) and 2 (COX-2), we developed a new screening method using human peripheral monocytes. Monocytes from healthy volunteers were separated, and the cells were incubated with or without lipopolysaccharide (LPS). Monocytes without LPS stimulation exclusively expressed COX-1 on Western blotting analysis, whereas LPS stimulation induced COX-2 expression. Unstimulated monocytes (COX-1) and LPS-stimulated monocytes (COX-2) were then used to determinethe COX selectivity of various NSAIDs. The respective mean IC50 values for COX-1 and COX-2 IC50 (microM), and the COX-1/COX-2 ratio of each NSAID were as follows: celecoxib, 82, 6.8, 12; diclofenac, 0.076, 0.026, 2.9; Etodolac, > 100, 53, > 1.9; ibuprofen, 12, 80, 0.15; indometacin, 0.0090, 0.31, 0.029; meloxicam, 37, 6.1, 6.1; 6-MNA (the active metabolite of nabumetone), 149, 230, 0.65; NS-398, 125, 5.6, 22; piroxicam, 47, 25, 1.9; rofecoxib, > 100, 25, > 4.0; S-2474, > 100, 8.9, > 11; SC-560, 0.0048, 1.4, 0.0034. The percentage inhibition of COX-1 activity at the IC50 of COX-2 also showed a wide variation among these NSAIDs. The bioassay system using human monocytes to assess the inhibitory effects of various NSAIDs on COX-1 and COX-2 may become a clinically useful screening method.