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Purpose: This study aims to compare the efficacy of two non-steroidal anti-inflammatory agents (NSAIDs), namely lornoxicam and etodolac for controlling pain, edema and trismus after removal of lower impacted third molars., Materials and Methods: A total of 20 patients comprised of both genders with bilateral impacted lower impacted third molars (in similar positions) was included in the present study. Patients were randomly assigned either to the lornoxicam group (8 mg of lornoxicam) or to the etodolac group (400 mg of etodolac). The drugs prescribed were handed out immediately after tooth extraction. Postoperative pain was assessed using visual analog scale (VAS). Edema was evaluated using reference lines on the face. Trismus was assessed using a caliper at maximum mouth opening (mm)., Results: There was no significant difference in postoperative pain, trismus, and edema between lornoxicam and etodolac group (p > 0.05)., Conclusions: Based on the results obtained in the present study, ıt has been verified that both lornoxicam and etodolac were adequately effective in the management of pain following third molar surgery. Lornoxicam and etodolac had similar impacts on pain, edema and trismus after impacted lower third molar surgical extractions., Competing Interests: Declarations Ethical approval All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. The study was approved by the Ethics Committee of Kutahya Health Science University Faculty of Medicine (acceptance number 2022-07/03) and also the Turkish Ministry of Health Medical Drugs and Device Institution with the document number 779718 (date 08/06/2022). The study was registered at clinicaltrials.gov (ID: NCT05679453). Written informed consent was obtained from each patient, all of whom were informed about the study protocol. Competing interests The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Osteoarthritis (OSA) is a prevalent joint disorder characterized by losing articular cartilage, primarily affecting the hip, knee and spine joints. The impact of OSA offers a major challenge to health systems globally. Therapeutic approaches encompass surgical interventions, non-pharmacological therapies (exercise, rehabilitation, behavioral interventions) and pharmacological treatments. Inflammatory processes within OSA joints are regulated by pro-inflammatory and anti-inflammatory cytokines. Etodolac, a COX-2-selective inhibitor, is the gold standard for OSA management and uniquely does not inhibit gastric prostaglandins. This comprehensive review offers insights into OSA's pathophysiology, genetic factors and biological determinants influencing disease progression. Emphasis is placed on the pivotal role of etodolac in OSA management, supported by both preclinical and clinical evidences in topical drug delivery. Notably, in - silico docking studies suggested potential synergies between etodolac and baicalein, considering ADAMTS-4, COX-2, MMP-3 and MMP-13 as essential therapeutic targets. Integration of artificial neural network (ANN) techniques with nanotechnology approaches emerges as a promising strategy for optimizing and personalizing topical etodolac delivery. Furthermore, the synergistic potential of etodolac and baicalein warrants in-depth exploration. Hence, by embracing cutting-edge technologies like ANN and nanomedicine, the optimization of topical etodolac delivery could guide a new era of OSA treatment.

Background: Radioresistance is found to be the main therapeutic restriction in colorectal radiation therapy. The aim of this study was to investigate the synergistic effect of Etodolac (ET) and ionizing radiation on human colorectal cancer cells., Methods: Pretreated HT-29 cells with ET were exposed to ionizing radiation. The radiosensitizing effect of ET was evaluated using MTT, flow cytometry, and clonogenic assay. The amount of nitrite oxide (NO) in irradiated cells was also measured with the Griess reagent., Results: The present study found that pretreatment of HT-29 cells with ET decreases their survival and colony formation. Higher concentrations of ET cause total apoptosis and an increase in NO levels in irradiated cells., Conclusion: Applying ET in a concentration-dependent manner had an incremental effect on the amount of apoptosis and cell death induced by radiation., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

The aim of this study is to evaluate the preemptive analgesic effects of dexamethasone (DEX) alone or combined with non-steroidal anti-inflammatory drugs (NSAIDs) in third molar surgeries. The subjects were divided into five groups (n = 20 teeth/group); subjects received only 8 mg of dexamethasone 1 h before the surgical procedure (DEX group), or in combination with etodolac (DEX + ETO), ketorolac (DEX + KET), ibuprofen (DEX + IBU), loxoprofen (DEX + LOX). Paracetamol 750 mg was provided as the number of rescue analgesics (NRA). Salivary PGE2 expression was measured preoperatively and at 48 h. Edema and Maximum mouth opening (MMO) were measured postoperatively at 48 h and 7 days. A visual analog scale (VAS) was performed postoperatively at 6, 12, 24, 48, 72 h, and 7 days. Salivary expression of PGE2 showed a decrease only for the DEX group. Edema and MMO and NRA consumption showed no significant differences among the groups (P > 0.05). The VAS showed a significantly lower pain perception at 6 h after the surgery for the DEX + ETO and DEX + KET groups (P < 0.05). The combination of DEX and NSAIDS should be considered for preemptive acute postsurgical pain management in third molar surgery. In some drug associations such as dexamethasone 8 mg + NSAIDS (ETO and KET) in the pre-operative time, only a few rescue analgesics are necessary., (© 2021. The Author(s).)

Introduction: Pancreatic cancer is the fourth-leading cause of cancer-related death in developed countries. Despite advances in systemic chemotherapy, the mainstay of curative therapy for non-metastatic disease is surgical resection. However, the perioperative period is characterised by stress and inflammatory reactions that can contribute to metastatic spread and disease recurrence. Catecholamines and prostaglandins play a crucial role in these reactions. Therefore, a drug repurposing of betablockers and cyclooxygenase inhibitors seems reasonable to attenuate tumour-associated inflammation by inhibiting psychological, surgical and inflammatory stress responses. This may cause a relevant antitumourigenic and antimetastatic effect during the perioperative period, a window for cancer-directed therapy that is currently largely unexploited., Methods and Analysis: This is a prospective, single-centre, two-arm randomised, patient and observer blinded, placebo-controlled, phase-II trial evaluating safety and feasibility of combined perioperative treatment with propranolol and etodolac in adult patients with non-metastatic cancer of the pancreatic head undergoing elective pancreatoduodenectomy. 100 patients fulfilling the eligibility criteria will be randomised to perioperative treatment for 25 days perioperatively with a combination of propranolol and etodolac or placebo. Primary outcome of interest will be safety in terms of serious adverse events and reactions within 3 months. Furthermore, adherence to trial medication will be assessed as feasibility outcomes. Preliminary efficacy data will be evaluated for the purpose of power calculation for a potential subsequent phase-III trial. The clinical trial is accompanied by a translational study investigating the mechanisms of action of the combined therapy on a molecular basis., Ethics and Dissemination: The PROSPER-trial has been approved by the German Federal Institute for Drugs and Medical Devices (reference number 4042875) and the Ethics Committee of the Medical Faculty of the University of Heidelberg (reference number AFmo-385/2018). The final trial results will be published in a peer-reviewed journal and will be presented at appropriate national and international conferences., Trial Registration Numbers: DRKS00014054; EudraCT number: 2018-000415-25., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: This study was conducted to elucidate the chemopreventive potential, cytotoxic, and suppression of cellular metastatic activity of etodolac (ETD)-loaded nanocarriers., Methods: To esteem the effect of charge and composition of the nanovectors on their performance, four types of vectors namely, negative lipid nanovesicles; phosalosomes (N-Phsoms), positive phosalosomes (P-Phsoms), nanostructured lipid carriers (NLCs) and polymeric alginate polymer (AlgNPs) were prepared and compared. ETD was used as a model cyclo-oxygenase-2 (COX-2) inhibitor to evaluate the potency of these nanovectors to increase ETD permeation and retention through human skin and cytotoxicity against squamous cell carcinoma cell line (SCC). Moreover, the chemopreventive activity of ETD nanovector on mice skin cancer model was evaluated., Results: Among the utilized nanovectors, ETD-loaded N-Phsoms depicted spherical vesicles with the smallest particle size (202.96±2.37 nm) and a high zeta potential of -24.8±4.16 mV. N-Phsoms exhibited 1.5, and 3.6 folds increase in the ETD amount deposited in stratum corneum, epidermis and dermis. Moreover, cytotoxicity studies revealed a significant cytotoxic potential of such nanovector with IC 50 =181.76 compared to free ETD (IC 50 =982.75), correlated to enhanced cellular internalization. Its efficacy extended to a reduction in the relative tumor weight with 1.70 and 1.51-fold compared to positive control and free ETD, that manifested by a 1.72-fold reduction in both COX-2 and proliferating cell nuclear antigen mRNA (PCNA-mRNA) levels and 2.63-fold elevation in caspase-3 level in skin tumors relative to the positive control group with no hepato-and nephrotoxicity., Conclusion: Encapsulation of ETD in nanovector enhances its in-vitro and in-vivo anti-tumor activity and opens the door for encapsulation of more relevant drugs., Competing Interests: The authors report no personal or financial conflicts of interest regarding this paper., (© 2019 Abo Aasy et al.)

This study determined the effectiveness of the preemptive administration of etodolac on risk and intensity of tooth sensitivity and the bleaching effect caused by in-office bleaching using 35% hydrogen peroxide. Fifty patients were selected for this tripleblind, randomized, crossover, and placebo-controlled clinical trial. Etodolac (400 mg) or placebo was administrated in a single-dose 1 hour prior to the bleaching procedure. The whitening treatment with 35% hydrogen peroxide was carried out in two sessions with a 7-day interval. Tooth sensitivity was assessed before, during, and 24 hours after the procedure using the analog visual scale and the verbal rating scale. Color alteration was assessed by a bleach guide scale, 7 days after each session. Relative risk of sensitivity was calculated and adjusted by session, while overall risk was compared by the McNemar's test. Data on the sensitivity level of both scales and color shade were subjected to Friedman, Wilcoxon, and Mann-Whitney tests, respectively (α=0.05). The preemptive administration of etodolac did not affect the risk of tooth sensitivity and the level of sensitivity reported, regardless of the time of evaluation and scale used. The sequence of treatment allocation did not affect bleaching effectiveness, while the second session resulted in additional color modification. The preemptive administration of etodolac in a single dose 1 hour prior to in-office tooth bleaching did not alter tooth color, and the risk and intensity of tooth sensitivity reported by patients. A single-dose preemptive administration of 400 mg of etodolac did not affect either risk of tooth sensitivity or level of sensitivity reported by patients, during or after the in-office tooth bleaching procedure.

Objective: Osteoarthritis (OA) is a chronic progressive degenerative disease of weight-bearing joints and the leading cause of disability in elderly. Current medical management of OA is mostly palliative with nonsteroidal anti-inflammatory drugs (NSAIDs) being the mainstay of therapy. Reports of gastrointestinal adverse effects with traditional NSAIDs and cardiovascular adverse effects associated with selective cyclooxygenase-2 (COX-2) inhibitors have prompted the hunt for a better NSAID with no or minimal adverse effects. This study compares the clinical effectiveness and safety of newer NSAIDS etodolac and lornoxicam to diclofenac which has been a standard therapy in patients of OA of knee joint., Materials and Methods: It was a randomized, prospective, open-label, parallel-group study conducted in 90 patients of OA of knee joint diagnosed according to the American College of Rheumatology criteria. After obtaining the informed consent, they were randomized in three groups of 30 patients each who received tablet etodolac 400 mg b.i.d, tablet lornoxicam 8 mg b.i.d, and tablet diclofenac sodium 50 mg t.i.d, respectively. The duration of the study was 12 weeks. Data were tabulated and analyzed using analysis of variance (ANOVA) test, and level of significance was determined by its P value., Results: After 12 weeks of treatment, pain intensity and functional indices in terms of visual analog scale and Western Ontario and McMaster Universities Osteoarthritis score were significantly better ( P < 0.05) in lornoxicam group as compared to etodolac or diclofenac group along with lesser rate of adverse effects., Conclusion: It was concluded that lornoxicam was more effective and better tolerated NSAID than etodolac and diclofenac in treatment of knee joint OA., Competing Interests: There are no conflicts of interest.

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 ® and Voltaren® 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., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

Purpose: To compare the efficacy of ibuprofen (IBU) and etodolac (ETO) for controlling pain, edema, and trismus after extraction of lower third molars., Materials and Methods: Twenty adolescents and adults with 2 impacted mandibular-third molars (in similar positions) were selected for the study. Patients were randomly assigned either to the IBU group (600 mg of IBU 3 times a day for 3 days) or to the ETO group (300 mg of ETO 3 times a day for 3 days). Drugs were administered immediately after dental extraction., Results: During the first 2 days after extraction, swelling was more pronounced in the IBU group than in the ETO group (P = .033). Seven days after surgery, there was no difference in the degree of edema between the groups. At the 2- and 7-day evaluation points, mouth opening was significantly more reduced in the IBU group than in the ETO group (P < .05). After the first 6 hours, the ETO group had more effective pain relief (P < .05), but after this time point, both groups reported similar degrees of relief. Compared with the IBU group, the ETO group had a lower need for administration of additional rescue analgesics., Conclusions: After extraction of impacted lower third molars, we found that swelling, trismus, and pain were more effectively controlled with ETO than with IBU., (Copyright © 2016 American Association of Oral and Maxillofacial Surgeons. Published by Elsevier Inc. All rights reserved.)

Background/aims: To identify predictive factors for NSAIDs-related GI toxicity and to clarify whether cox-2 selective inhibitors can prevent it or not., Methodology: We have surveyed all patients received esophagogastroduodenoscopy examined at our hospital between January 2008 and September 2011. We performed the following retrospective analyses of the clinical records of the 253 patients prescribed NSAIDs. The severity of gastro duodenal mucosal lesions was evaluated using the modified gastro duodenal LANZA score. The following scores for response were used: 0 = no lesions (LANZA score 0); 1 = erosion and redness (LANZA score 1-3); 2 = ulcer (LANZA score 4). Predictors evaluated were factors potentially related to pathogenesis of NSAIDs related GI toxicity. Ordered logistic regression analysis was performed to identify predictive factors for NSAIDs related. ulcer., Results: A multivariate logistic regression identified number of risk factors (odds ratio (OR) = 6.82, confidence interval (CI) = 5.31-8.76; P = 0.01), concomitant use of anti- cancer drugs (OR = 2.17, Cl = 1.02-4.62; P = 0.04) were found to be significant factors., Conclusions: Number of risk factors and concomitant use of anticancer drugs were shown to be predictive factors for NSAID-related GI toxicity. Use of celecoxib or proton pump inhibitor was not identified as a protective factor.

Objective: To compare the three non-steroidal anti-inflammatory agents (NSAIDs) Diclofenac potassium, Etodolac and Naproxen sodium in relation to pain, swelling and trismus following impacted third molar surgery., Study Design: The study was a randomized and a double-blinded study which included 42 healthy young individuals with impacted third molars and bone retention. Patients were randomly assigned to 3 groups (n: 14) to which Diclofenac potassium, Naproxen sodium and Etodolac were administered orally an hour before the operation. Impacted third molars were surgically extracted with local anaesthesia. Visual analog scales (VAS) were used to assess the pain in the 6th, 12th hours and on the 1st, 2nd, 3rd, 5th, and 7th days postoperatively. Swelling was evaluated using ultrasound (US) and mouth opening (trismus) was measured with a composing stick pre and post operatively on the 2nd and 7th days respectively., Results: Regarding pain alleviation, Diclofenac potassium was better than Naproxen sodium and Naproxen sodium was better than Etodolac but these differences were not statistically significant. US measurements showed that the swelling on postoperative 2nd day was significantly lowest with Diclofenac potassium as compared to others (p= 0.027) while Naproxen sodium and Etodolac acted similarly (p=0.747). No difference was noted regarding trismus in any of the groups., Conclusion: NSAIDs (Diclofenac, Naproxen and Etodolac) are somehow similarly effective for controlling pain and trismus following extraction of mandibular third molars but Diclofenac potassium surpasses others in reduction of swelling.

Background: Cyclooxygenase-2 (COX-2) is a key enzyme in the conversion of arachidonic acid to prostanoids, and its activation is associated with carcinogenesis as well as inflammation. The antitumor effect of selective COX-2 inhibitors has been noted in various malignancies. Malignant peripheral nerve sheath tumor (MPNST) is a rare and aggressive soft tissue sarcoma for which effective treatments have not yet been established. The purpose of this study was to investigate a potential therapeutic role of COX-2 in MPNST., Methods: We evaluated the expression of COX-2 in 44 cases of high-grade MPNST using immunohistochemical staining and compared the staining results with the characteristics and outcome of the patients. We also investigated the antitumor effect of etodolac, a selective COX-2 inhibitor, on MPNST cells in vitro using the MPNST cell line, FMS-1., Results: Overexpression of COX-2 (≥50% positive cells) was observed in 29 cases (65.9%), was significantly associated with a poor overall survival (P = 0.0495), and was considered an independent risk factor for a poor outcome by the results of both univariate and multivariate analysis. Etodolac induced apoptosis of FMS-1 cells through the activation of caspase-8, -9, and -3. Moreover, several caspase inhibitors significantly inhibited etodolac-induced apoptosis., Conclusions: Selective COX-2 inhibitors including etodolac had an antitumor effect on MPNST cells, and their use holds promise as a novel therapeutic strategy for patients with MPNST to improve their prognoses.

Purpose: To evaluate the renal function in healthy dogs submitted to nonselective and preferential COX-2 nonsteroidal anti-inflammatory drug (NSAID) therapy., Methods: Twenty four healthy dogs were distributed into four groups (G) (n=6): ketoprofenG--treated with ketoprofen; nimesulideG--treated with nimesulid; meloxicanG--treated with meloxican; and etodolacG--treated with etodolaco. All the dogs received the NSAIDs for 10 days by oral route. Physical examination and renal function (urinalysis, urinary sodium and gamma-glutamyl transpeptidase (GGT), serum urea, creatinine, potassium and sodium, and endogenous creatinine clearance) were evaluated before, after five and ten days (T0, T5 and T10) of the treatment in all groups., Results: Changes were observed in urinalysis, with a significant increase in renal cells in the urine at T5 and T10 in nimesulideG. Significant reduction in urinary sodium in nimesulideG at T5 was observed. The clearance values were lower in ketoprofenG at T10., Conclusions: Meloxicam and etodolac were the drugs that have proven to be safer for short-term therapy in healthy dogs in relation to renal function. NSAIDs ketoprofen and nimesulide should be used judiciously in dogs with renal dysfunction, since there are promoted changes in renal function.

Background: Quality of life (QOL) is a concern for patients with lumbar spinal stenosis (LSS). In this study, QOL was examined using the 5-item EuroQol (EQ-5D)., Methods: QOL and activities of daily living (ADL) were surveyed for 91 patients who visited 18 medical institutions in our prefecture and were diagnosed with LSS-associated intermittent claudication. A second survey was performed after ≥6 weeks for 79 of the subjects to evaluate therapy with limaprost (an oral prostaglandin E1 derivative) or etodolac (an NSAID). Symptoms, maximum walking time, QOL, ADL items, and relationships among these variables were investigated for all 91 patients. Leg pain, leg numbness, and low back pain while walking were surveyed by use of VAS scores (0-100)., Results: Leg pain, leg numbness, and low back pain while walking (VAS ≥25) were present in 83.5, 62.6, and 54.9 % of the patients in the first survey, and approximately half of the patients had a maximum walking time <15 min. The mean EQ-5D utility value for QOL was 0.59 ± 0.12. This value was significantly associated with maximum walking time (p = 0.030) based on classification of patients into groups with walking times <7.5, 7.5-15, 15-30, and >30 min, showing that maximum walking time affected health-related QOL. Of the 79 patients who completed the second survey, 56 had taken limaprost and 23 (control group) had received etodolac. Limaprost improved possible walking time, reduced ADL interference, and significantly increased the EQ-5D utility score, whereas no significant changes occurred in the control group. Maximum walking time was prolonged by ≥10 min and the EQ-5D utility value was improved by ≥0.1 points in significantly more patients in the limaprost group than in the control group., Conclusion: According to the findings of this survey, at an average of 8 weeks after administration limaprost improved symptoms, QOL, and ADL in LSS patients whereas treatment with an NSAID reduced pain but did not have any other effects.

Background and Methods: There is increasing evidence that a change in glomerular hemodynamics may promote the development of glomerulosclerosis. In this study, we focused on the pharmacological effects of 2 contrasting agents, etodolac, a preferential cyclooxygenase-2 inhibitor, and beraprost sodium (BPS), a prostaglandin I(2) analog, delivered renally, on the disease course of progressive anti-Thy-1 (ATS) glomerulonephritis., Results: Intravital microscopic analysis showed that the diameters of glomerular capillaries and glomerular blood flow in unilaterally nephrectomized (Nx) rats treated locally with BPS were significantly increased, as compared to those of Nx rats treated locally with normal saline (NS) or etodolac. We then examined the effects of BPS and etodolac on the course of progressive glomerulosclerosis. Mesangial cell proliferation, adhesion of glomerular capillary tufts and crescent formation in the BPS-treated group appeared to be more severe compared to the ATS + NS and the ATS + etodolac groups. Scoring of mesangial proliferation and glomerulosclerosis revealed that local BPS treatment significantly worsened glomerular pathology. At day 28, there were significant differences in blood flow between the ATS + etodolac group and both the ATS + NS and ATS + BPS groups, indicating that local treatment with etodolac enhanced the recovery of glomerular circulation., Conclusion: This study provides hemodynamic-based evidence showing that disturbance of intraglomerular microcirculation is a critical marker for progressive glomerulonephritis.

Background and Purpose: The excitability of nociceptors is modulated by the transient receptor potential cation channel, ankyrin subfamily, member 1 (TRPA1). We have previously reported that etodolac, a nonsteroidal anti-inflammatory drug, attenuates mechanical allodynia in a mouse model of neuropathic pain by a mechanism that is independent of cyclooxygenase inhibition. Here, we investigate the role of TRPA1 in the mechanism of the antinociceptive action of etodolac in vitro and in vivo., Experimental Approach: Ca(2+) influx was measured in HEK-293 cells expressing mouse TRPA1 and in mouse dorsal root ganglion (DRG) neurons. The effect of etodolac on the nociceptive behavior induced in mice by the TRPA1 agonist allyl isothiocyanate (AITC) was also measured., Results: Etodolac induced Ca(2+) influx in HEK-293 cells expressing mouse TRPA1 and in mouse DRG neurons. The Ca(2+) influx induced by etodolac was inhibited by pretreatment with the TRPA1-specific antagonist HC-030031. In contrast, etodolac did not induce Ca(2+) influx in cells expressing TRPV1, TRPV2 or TRPM8. In addition, pretreatment with etodolac inhibited the Ca(2+) influx induced by AITC., Conclusion and Implication: Etodolac showed a selective TRPA1 agonist action, providing evidence that etodolac desensitizes nociceptors by the selective activation of TRPA1. Etodolac may be clinically useful in the treatment of neuropathic pain., (Copyright © 2012 S. Karger AG, Basel.)

Objective: We previously reported that oral administration of the selective cyclooxygenase-2 (COX-2) inhibitor etodolac results in antitumor effects in endometrial cancer tissue. Herein, we investigated whether these antitumor effects could be assessed using endometrial cytological findings., Study Design: Etodolac (400 mg b.i.d. for 2 weeks) was administered preoperatively to 21 endometrial cancer patients: 16 had COX-2-positive disease and 5 had COX-2-negative disease. Twenty-one pairs of pre- and post-etodolac-treatment endometrial cytological samples were collected to review changes in the cytological features., Results: In the COX-2-positive patients, nuclear atypia was slightly decreased in 3 of the 16 cases, while the mitotic index was decreased in all cases. Cellular overlapping and tumor cell cluster outlines were somewhat affected in 6 and 8 cases, respectively. Nuclear/cytoplasmic ratio, anisokaryosis and hyperchromasia were also reduced in 6, 4, and 2 cases, respectively; however, tumor diathesis and nucleoli features were unchanged. In contrast, endometrial cytological features did not appear to be affected in the 5 COX-2-negative patients., Conclusions: We conclude that the antitumor effects observed in endometrial cancer tissues following oral administration of etodolac are reflected in and can be easily assessed by evaluating endometrial cytological features., (Copyright © 2012 S. Karger AG, Basel.)

Objective: The objective of this study was to compare the analgesic efficacy of etodolac injection and diclofenac injection in patients with postoperative orthopedic pain., Methods: This was multicentric, randomized, assessor-blind and parallel-group study. A group of 158 patients with moderate to severe pain following orthopedic surgery were randomly assigned to receive either etodolac 400 mg twice a day (n = 78) or diclofenac 75 mg thrice a day (n = 80)., Main Outcome Measures: The primary efficacy outcome measures were pain intensity difference, sum of pain intensity differences and pain relief whereas secondary efficacy variables included maximum fall in pain intensity, number of doses of study medication consumed, number of patients who required rescue medication and overall response to therapy., Results: Mean pain intensity differences assessed on 10 cm VAS were significantly better for etodolac arm compared to diclofenac arm at 4, 8, 20 and 24 hours (p < 0.05). Sum of pain intensity differences over the first 8 hours (-21.31 ± 6.26 for etodolac vs. -19.13 ± 6.98 for diclofenac; p = 0.041) and over the 24 hours (-39.83 ± 10.70 for etodolac vs. -35.25 ± 12.00 for diclofenac; p = 0.012) for the etodolac group was significantly superior than diclofenac group. Assessment of pain relief showed that etodolac injection was significantly more effective than diclofenac injection (p < 0.0001) over the 24 hour assessment period. Maximum fall in pain intensity score, number of doses of study medication consumed and patients' and investigators' overall response to the drug at the end of treatment period were also significantly superior in the etodolac arm as compared to the diclofenac arm (p < 0.05). However, the number of patients who were rescued was comparable in both the treatment arms. A change in emotional functioning of the patients was not captured in this study. Both the study medications were well tolerated with no incidence of SAE throughout the study., Conclusion: Etodolac can be considered as an effective alternative to traditional NSAIDS in the treatment of post operative pain.

Purpose: On the basis of the results of our preliminary trial suggesting that aberrant crypt foci (ACF) could be eradicated by short-term administration of sulindac, in the present study, we explored the feasibility of using ACF as surrogate markers for chemoprevention of colorectal cancer., Experimental Design: Randomly assigned to sulindac (300 mg daily), etodolac (400 mg daily), and placebo groups were 189 subjects without polyps or who had undergone polypectomy. Drugs were administered for 2 months. ACF in the rectal region were counted by magnifying endoscopy. Occurrence of polyps was evaluated at 12 months. A planned interim analysis was conducted., Results: ACF number at 2 months was significantly suppressed in the sulindac group (P = 0.0075), but not in the etodolac group (P = 0.73). In the sulindac group, the numbers of adenomas plus hyperplastic polyps (total polyps) and adenomas at 12 months were significantly (P = 0.02) and marginally (P = 0.064) lower, respectively, in comparison with the placebo group; no such difference was observed in the etodolac group. In analysis of only polypectomized subjects, the numbers of total polyps and adenomas in the sulindac group were even more markedly lower, with P values of 0.014 and 0.034, respectively. A similar tendency was confirmed by analyses of the incidence of polyps at 12 months. Suppression rates of total polyps and adenomas in ACF responders to sulindac were significantly greater than in nonresponders. In all groups, compliance was more than 90% and no intolerable adverse effects were observed., Conclusions: ACF may be useful as surrogate lesions for chemoprevention of colorectal cancer., (©2011 AACR.)

Colorectal cancer is one of the most serious complications of ulcerative colitis (UC), and the risk of UC-associated neoplasia increases as the region and duration of the disease increase. Selective cyclooxygenase (COX)-2 inhibitors effectively diminish carcinogenesis in a murine UC model. However, this may exacerbate colitis. The selective COX-2 inhibitor etodolac is marketed as a racemic mixture of the R- and S-enantiomers. The biochemical and pharmacological effects of etodolac are caused by the S-enantiomer, while the R-enantiomer lacks COX-inhibitory activity. In this study, we evaluated the effect of R-etodolac on colitis-related mouse colon tumorigenesis. The mice received 1,2-dimethlhydrazine (DMH), and then chronic colitis was induced by administration of two cycles of DSS (each cycle: 3% DSS for 7 days followed by distilled water for 14 days). The mice were sacrificed 28 days after the completion of both cycles. Mice were divided into the following groups: group A served as a disease control; group B received a low (2-mg/kg) dose of R-etodolac every 3 days during the entire period; group C received a high (10-mg/kg) dose of R-etodolac on the same schedule as group B; and group D served as a normal control. Administration of R-etodolac decreased the disease activity index during the DSS administration cycle. The mean number of tumors was 17.8, 15.2, 6.0, and 0 in groups A-D, respectively. In group C, R-etodolac significantly suppressed the occurrence of neoplasia (p<0.05). Although R-etodolac treatment did not affect COX-2 expression, it significantly enhanced expression of E-cadherin in both neoplastic lesions and background mucosa (i.e., lesion-free colon). Thus, administration of R-etodolac exerts a suppressive effect on the development of neoplasia in a murine model of DSS-induced colitis without exacerbation of the colitis. These results suggest that R-etodolac could be useful in the prevention of UC-associated neoplasia.

Nuclear factor-kappaB (NF-κB) upregulates the transcription of proteins that promote cell survival, stimulate growth, induce angiogenesis and reduce susceptibility to apoptosis. NF-κB signaling pathway is constitutively activated in myelodysplastic syndrome (MDS), acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL), chronic myeloid leukemia (CML), chronic lymphocytic leukemia (CLL), lymphomas and in multiple myeloma (MM). Inactive NF-κB is bound in the cytoplasm to its inhibitor IκB, which masks its nuclear localisation signal. Two protein kinases with a high degree of sequence similarity, IKKα and IKKβ, mediate phosphorylation of IκB proteins and represent a convergence point for most signal transduction pathways leading to NF-κB activation. The overexpression of NF-κB and its anti-apoptotic cytoprotective effect suggest that it might be a useful therapeutic target for the treatment of hematologic malignancies. Several drugs effective for the treatment of MM, including proteasome inhibitors, thalidomide, lenalidomide and arsenic trioxide, block NF-κB activation. New agents with NF-κB inhibitory activity enhance the anti-MM effects of conventional chemotherapeutic agents and reduce different side-effects. Triptolide (diterpenoid triepoxyde), a purified component of a traditional Chinese medicine, extracted from a shrub-like vine named Trypterygium wilfordii Hook F (TWHF) inhibits transcriptional activation of NF-κB and downregulates the expression of various NF-κB-regulated genes. Triptolide (10-80 ng/ml) induces apoptosis of MM cells and effectively inhibits cell growth of MM cells. NF-κB activation can be also inhibited by IKKβ-selective inhibitors, PS-1145dihydrochloride, MLN120B (both Millennium Pharmaceuticals, Cambridge, MA) and BMS-345541 (Bristol-Myers Squibb, Princeton, NJ). LC-1, the dimethylamino-parthenolide (DMAPT) derivative demonstrated significant cytotoxicity to AML blasts targeting NF-κB.

Introduction: Bisphosphonates have anti-inflammatory properties in arthritic conditions. This study was conducted to assess the therapeutic potential of intravenous pamidronate in nonsteroidal anti-inflammatory drug (NSAID) refractory/intolerant cases of ankylosing spondylitis (AS)., Methods: A total of 35 NSAID refractory/intolerant AS patients with Bath AS Disease Activity Index (BASDAI) score 4 or above were recruited for the study. Monthly pamidronate infusions (60 mg) were administered to the patients for six months. Treatment outcomes were assessed by comparing baseline values with the values after six infusions using BASDAI, Bath AS Functional Index (BASFI), Metrology Index (BASMI) and Global Score (BAS-G), C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR). An improvement was defined according to the Assessments in Ankylosing Spondylitis (ASAS)-20 and BASDAI-50., Results: 26 patients received all the six infusions. Of these, 22 (85 percent) achieved ASAS-20 and 20 (77 percent) achieved BASDAI-50 responses. Decrements were noted in the mean BASDAI (56.4 percent), BASFI (52.66 percent), BASMI (55.72 percent), BAS-G (66.71 percent), ESR (52.12 percent) and CRP (72.84 percent) after six months. The tender and swollen joint counts of 14 (54 percent) patients with peripheral arthritis were respectively reduced to a mean value of 0.85 and nil, from the baseline of 2.57 and 1.2. Early feel good response was noted in 16 (62 percent) patients within 48 hours of the first infusion. Fever, arthralgia and myalgia were observed in six cases after the first infusion, and in one case, after the second infusion. These symptoms resolved spontaneously within 24 hours., Conclusion: Intravenous pamidronate has good efficacy for the treatment of AS.

Objective: To evaluate the efficacy and safety of etodolac-paracetamol combination in comparison with etodolac alone in patients with knee osteoarthritis (OA) flare-up., Methods: In this double-blind, double-dummy, randomized, comparative, multicentric, parallel group study, 220 patients of either sex in the age range of 40 to 70 years with an OA flare-up were randomized either to etodolac (300 mg)-paracetamol (500 mg) combination or etodolac (300 mg) alone twice a day for 10 days. Efficacy outcomes were an average daily pain intensity score on 11-point visual analog scale, Western Ontario and McMaster score (WOMAC), and Lequesne Severity Index; total pain relief score at 30 minutes, 1, 2, and 4 hours after first-dose administration; OA flare-up symptoms resolution; patient's and investigator's overall assessment of study treatments., Results: Etodolac-paracetamol was significantly superior to etodolac alone in reducing pain intensity (P<0.001), achieving pain relief (P<0.05) during the first 4 hours after the study dose administration, and resolution of the clinical signs and symptoms of OA flare-up such as morning stiffness, swelling/inflammation, and erythema. The combination showed significantly greater improvement in WOMAC scores and Lequesne Severity Index (P<0.001) than in etodolac monotherapy. Peak pain intensity difference over a period of 10 days was also significantly (P<0.001) higher in combination-treated patients compared with monotherapy-treated patients. The combination had significantly better patient's and investigator's global efficacy assessment (P=0.001). Both treatments were well tolerated and safe in patients with OA flare-up., Discussion: For the treatment of painful OA flare-ups, the etodolac-paracetamol combination can offer improved clinical outcomes by targeting multiple pain pathways. The results of the current study show that etodolac-paracetamol is more effective in the treatment of OA flare-up than etodolac alone.

Objective: To compare the efficacy and safety of S-etodolac with etodolac in the treatment of osteoarthritis in Indian patients., Materials and Methods: This was a double-blind, multicentric, comparative clinical trial conducted in 108 Indian patients with osteoarthritis. All patients received either S-etodolac ER 300 mg or etodolac ER 600 mg tablets once daily. Assessment was done on the basis of WOMAC score and VAS pain score, patient's and physician's global assessment of the arthritic condition. All patients were evaluated after every 2 weeks for 4 weeks for efficacy and safety variables., Results and Discussion: Total 49 patients in the test group and 52 patients in the reference group completed the study. There was significant improvement (p < 0.0001) in all WOMAC subscales (pain, stiffness and physical function), WOMAC total score and VAS pain score in both the groups. Patient's and physician's global assessment of the arthritic condition also improved significantly (p < 0.0001). All patients showed improvement in WOMAC and VAS pain score by (3) 20%. There was no significant difference between the groups for the efficacy parameters. The adverse events reported were few and no serious adverse events were reported. Total 5 patients in S-etodolac group and 2 patients in etodolac group dropped out of the study. Only 1 patient dropped out because of the side effects of burning sensation, palpitations and anxiety in the test group., Conclusion: The present study has established the efficacy, tolerability and safety of S-etodolac extended release tablets in the treatment of osteoarthritis in Indian patients.

We report a case of acute sacroiliitis with severe disability after only 3 weeks of isotretinoin therapy with graduate reduction of pain, limitation and muscle incompetence after discontinuation of the drug and ACTH-depo injection and Ethodolac therapy. Naranjo probability scale indicated a probable relationship between isotretinoin therapy and bilateral sacroiliitis. We discussed possible mechanisms of sacroiliitis and disability due to isotretinoin treatment.

The present study investigated the preventive effects of etodolac, a selective cyclo-oxygenase (COX)-2 inhibitor, on metachronous cancer development after endoscopic resection of early gastric cancer. Among 267 early gastric cancer patients who underwent endoscopic resection, 47 patients with extensive metaplastic gastritis were selected based on endoscopic findings and our previously described criteria of serum pepsinogen (PG) test-positive and Helicobacter pylori antibody-negative conditions. Nonrandomized etodolac treatment (300 mg/day) was administered to 26 patients (Group A), while the remaining 21 patients were untreated (Group B). No significant differences in age, sex distribution, lifestyle factors or extent of metaplastic gastritis at baseline were identified between groups. Patients were followed for metachronous cancer development with endoscopy every 6-12 months for up to 5 years. Mean (standard deviation) follow-up period was 4.2 (0.9) years. In Group B, 5 cancers developed (incidence rate = 6,266/100,000 person-years), significantly more than the 1 cancer in Group A (incidence rate = 898/100,000 person-years; p < 0.05). Long-term etodolac treatment did not influence the extent of metaplastic gastritis as revealed by endoscopic findings or by serum PG levels, but effectively reduced metachronous cancer development in patients with extensive metaplastic gastritis. These results strongly suggest that chemoprevention of cancer in the metaplastic stomach is possible by controlling COX-2 expression.

Objectives: The objective of this study was to prepare a self-emulsifying drug delivery system (SEDDS) for oral bioavailability enhancement of a poorly water-soluble drug, etodolac. The SEDDS formulations were optimized by evaluating their ability to self-emulsify when introduced to an aqueous medium under gentle agitation, and by determination of the particle size of the resulting emulsion., Methods: An optimized formulation of SEDDS (composed of 20% etodolac, 30% oil Labrafac WL1349, 10% Lauroglycol 90 and 40% Labrasol) was selected for bioavailability assessment in rabbits. The anti-inflammatory effect was also determined in rats, and compared with powder drug and etodolac suspension in water (50 mg/kg)., Key Findings: The peak plasma concentration of 16.4 +/- 1.1 microg/ml appeared after 1.3 +/- 0.2 h, whereas with powder drug and etodolac suspension the values were 7.5 +/- 0.5 and 10.6 +/- 0.7 microg/ml at 4.2 +/- 0.4 and 2.4 +/- 0.2 h, respectively. The AUC(0-8) of the etodolac SEDDS formulation was 2.3 times that of the pure drug and 1.4 times that of the suspension form. SEDDS formulation exhibits a 21% increase in paw thickness compared with a 39% increase on oral administration of etodolac suspension after 4 h at the same dose of the drug (20 mg/kg)., Conclusions: The result indicates the utility of SEDDS for the oral delivery of etodolac and potentially other lipophilic drugs.

A 28-year-old woman had thunderclap headache (TCH), after 7 days she had left hemiparesis. She had a history of oral contraceptive and citalopram medications. Brain magnetic resonance (MR) angiography demonstrated multiple stenotic segments. Digital subtraction angiography (DSA) showed multiple segments of narrowing in vessel calibre. Two probable diagnoses performed; primary angiitis of the central nervous system and reversible cerebral vasoconstriction syndrome (RCVS). Because of clinical characteristics and normal cerebrospinal fluid findings she was set on medication for probable RCVS. Follow-up MR angiography after 4 weeks and DSA after 7 weeks demonstrated improvement in vessel calibre. Thus, diagnosis RCVS was established. Diagnosis and management of TCH contain many potential difficulties. Clinicians should consider the imaging of cerebral arteries, even if computed tomography scan and lumbar puncture are normal in TCH. Potential precipitating factors and triggers should also be known and avoided.

We have divided the analysis of pharmacology studies into studies on local anesthetics and studies on all other pharmacologic agents. This division reflects the large number of studies focusing on methods for obtaining effective anesthesia in patients and permits an independent focus on those clinical studies evaluating nonanesthetic drugs. In this section, we review that alternative class of agents, with an emphasis this year on clinical studies evaluating oral analgesics.

Purpose: To examine the effects of COX inhibitors on suppressing HSV-1 reactivation in a mouse model., Methods: BALB/c mice were latently infected with HSV-1 and treated by 0.1% bromfenac Na eye drops, 0.1% pranoprofen eye drops, 0.1 mg oral etodolac 4 times/day, and saline for 4 days. After reactivating the latent HSV-1, we swabbed the mouse ocular surface for the culture of the infectious virus and assessed the viral loads in the eyes and trigeminal ganglia (TGs) using real-time PCR to determine the treatment efficacies., Results: With stimulated reactivation, 10 of 24 (41.7%), 5 of 10 (50.0%), 17 of 25 (68%), and 16 of 22 eyes (72.7%) showed positive swab results in the bromfenac Na, etodolac, pranoprofen, and saline groups, respectively; and a significant difference was seen only between the bromfenac Na and saline groups (p = 0.033). None of the three drug-treated groups showed any significant difference from the saline group in the viral DNA in the eyes and TGs (p > 0.05)., Conclusions: Bromfenac Na eye drops can suppress HSV-1 reactivation.

Background and Objective: Cyclooxygenase (COX) is an enzyme that converts arachidonic acid to prostanoids. There are two isoforms of COX, namely COX-1 and COX-2. COX-2 is highly inducible by several stimuli and is associated with inflammation. Recent studies have shown that COX-2 is upregulated in the airway epithelium of patients with asthma but little is known about the role it plays in cough, a common symptom of bronchial asthma. This study was designed to investigate the role of COX-2 in cough reflex sensitivity in patients with asthma., Patients and Methods: The effect of etodolac, a potent COX-2 inhibitor, on cough response to inhaled capsaicin was examined in 17 patients with stable asthma in a randomized, placebo-controlled crossover study. Capsaicin cough threshold, defined as the lowest concentration of capsaicin eliciting 5 or more coughs, was measured as an index of airway cough reflex sensitivity., Results: The geometric mean (geometric SEM) cough threshold was significantly increased after a 2-week treatment program with oral etodolac (200 mg twice a day) compared with placebo (36.7 [1.2] vs 21.6 [1.2] gM, P<.02)., Conclusions: These findings indicate that COX-2 may be a possible modulator augmenting airway cough reflex sensitivity in asthmatic airways.

The biochemical and cellular changes that occur following the administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) are remarkably similar to that seen in idiopathic Parkinson's disease(PD). There is growing evidence indicating that reactive oxygen species (ROS), reactive nitrogen species (RNS) and inflammation are a major contributor to the pathogenesis and progression of PD. Hence, we investigated whether 7-nitroindazole [neuronal nitric oxide synthase (nNOS) inhibitor], edaravone (free radical scavenger), minocycline [inducible NOS (iNOS) inhibitor], fluvastatin [endothelial NOS (eNOS) activator], pitavastatin (eNOS activator), etodolac [cyclooxygenase-2 (COX-2) inhibitor] and indomethacin (COX inhibitor) can protect against MPTP neurotoxicity in mice under the same conditions. For the evaluation of each drug, the levels of dopamine, DOPAC and HVA were quantified using HPLC with an electrochemical detector. Four administrations of MPTP at 1-h intervals to mice produced marked depletion of dopamine, DOPAC (3,4-dihydroxyphenylacetic acid) and HVA (homovanilic acid) in the striatum after 5 days. 7-Nitroindazole prevented dose-dependently a significant reduction in dopamine contents of the striatum 5 days after MPTP treatment. In contrast, edaravone, minocycline, fluvastatin, pitavastatin, etodolac and indomethacin did not show the neuroprotective effect on MPTP-induced striatal dopamine, DOPAC and HVA depletions after 5 days. The present study demonstrates that the overexpression of nNOS may play a major role in the neurotoxic processes of MPTP, as compared with the production of ROS, the overexpression of iNOS, the modulation of eNOS and the involvement of inflammatory response. Thus our pharmacological findings provide further information for progressive neurodegeneration of the nigrostriatal dopaminergic neuronal pathway.

The present study was designed to determine whether etodolac, a selective cyclooxygenase-2 inhibitor, prevents chemically induced intraductal papillary carcinoma (IPC) in the main pancreatic duct of hamsters. Hamsters were subjected to cholecystoduodenostomy with dissection of the distal end of the common duct. Four weeks after surgery, the surviving hamsters received subcutaneous injections of N-nitrosobis(2-oxopropyl)amine four times at a dose of 10 mg/kg body wt, every 2 weeks. The animals were divided into three groups according to the simultaneous oral intake of a standard pelleted diet containing etodolac at 0% (group CE, n = 30), 0.01% (group ET, n = 21) and 0.04% (group ET4, n = 25), respectively. Hamsters were killed for pathological examination at 36 weeks after the operation. The incidence of induced pancreatic carcinoma was 93, 81 and 72% in groups CE, ET and ET4, respectively. The pancreatic carcinomas were histologically classified into four types, i.e. tubular, papillary, cyst adenocarcinoma and IPC. The incidence of IPC and the number of IPCs per animal were significantly lower in groups ET4 (36% and 0.48) and ET (48% and 0.62) when compared with group CE (67% and 1.30). The proliferating cell nuclear antigen labeling indices in the non-cancerous epithelial cells of the main pancreatic duct were 2.8 and 6.8% in groups ET4 and ET, respectively, and were significantly lower than that in group CE (10.8%). In conclusion, etodolac inhibited N-nitrosobis(2-oxopropyl)amine-induced IPC in hamsters. Suppression of epithelial cell proliferation of the main pancreatic duct was considered as a possible mechanism of cancer prevention in this hamster model.

The present study investigated whether the endogenous pro-inflammatory cytokines [interleukin (IL)-1beta and tumor necrosis factor-alpha (TNF-alpha)]-dependent expression of cyclooxygenase-2 (COX-2) mRNA within the spinal cord could be involved in the development of chronic inflammatory pain-like behaviors in mice. We demonstrated that the expression of COX-2 mRNA on the ipsilateral side of the spinal cord was significantly increased 6 h and 3 days after intraplantar injection of complete Freund's adjuvant (CFA), compared with the expression in saline-treated mice. In addition, the chronic pain-like behaviors following CFA injection were markedly suppressed by repeated intrathecal (i.t.) pre-treatment with the COX-2 inhibitor etodolac, but not with the COX-1 inhibitor mofezolac. The cytosolic level of the activated form of nuclear factor-kappa B (NF-kappaB), which is a major contributor to the induction of COX-2, on the ipsilateral side of the mouse spinal cord was also increased compared with that in the saline-treated mice. The key finding in the present study was that a single i.t. injection with either IL-1beta or TNF-alpha induced a marked increase in spinal COX-2 mRNA and persistent thermal hyperalgesia in mice. Furthermore, CFA-induced hypersensitivity to inflammatory pain was significantly reduced by repeated i.t. pre-injection of the recombinant Fc chimera of IL-1 receptor I or soluble TNF receptor I, which sequesters endogenous IL-1beta or TNF-alpha, respectively. In contrast, the expression of spinal COX-2 mRNA in CFA-treated mice was similar to that in saline-treated mice at 7 days after CFA injection. The present findings strongly indicate the early intrathecal use of the COX-2 inhibitor for the relief of chronic inflammatory pain. Furthermore, together with the result in a previous study that pro-inflammatory cytokines lead to stimulation of a NF-kappaB-dependent transcriptional pathway, these findings suggest that a spinal cytokine/NF-kappaB/COX-2 pathway may play an important role in the development, but not maintenance, of chronic pain following peripheral tissue inflammation.

Non-steroidal anti-inflammatory drugs (NSAIDs) and cyclooxygenase-2 (COX-2) inhibitors are representative agents for the chemoprevention of sporadic colorectal neoplasia. However, few reports have described the chemopreventive effects of such agents on colitis-associated tumorigenesis. To clarify whether treatment with the COX-2 inhibitor may reduce the risk of colitis-associated neoplasia, we investigated the effect of one such agent, etodolac, on tumorigenesis in the colitis-associated neoplasia model using p53-deficient mice treated with dextran sulfate sodium (DSS). The p53-/- mice were divided into four groups: i) treatment with DSS + etodolac, then after two cycles of DSS, the mice were given distilled water for 84 days. In addition, etodolac was administered three times a week at a dose of 10 mg/kg body weight throughout the experiment. ii) Treatment with two cycles of DSS only, followed by distilled water for 84 days. iii) Treatment with etodolac alone. iv) Distilled water alone was administered to the control group. The incidence of mice with neoplasia was 82.4% in the DSS + etodolac group and 100% in the DSS-alone group. No neoplasia was observed in the etodolac-alone and control groups. The mean (+/- SEM) number of total neoplasias per mouse was 1.29+/-0.2 in the DSS + etodolac group and 3.0+/-0.52 in the DSS-alone group, the inter-group difference being significant (p<0.01). There was no significant difference in the inflammation score between these two groups. These results showed that treatment with etodolac significantly reduced the occurrence of neoplasia, suggesting that this COX-2 inhibitor has chemopreventive activity against colitis-associated tumorigenesis.

Objectives: Cyclooxygenase-2 (COX-2) is highly expressed in several human cancers, including bladder cancer. Thus, a selective COX-2 inhibitor could be useful as an antitumor agent for a range of cancers. In the present study, we investigated the antitumor effect and E-cadherin induction of etodolac, a highly selective COX-2 inhibitor, on human bladder cancer cells in vitro and in vivo., Methods: We examined the cytotoxicity of etodolac against three human bladder cancer cell lines, T24, 5637, and KK47, and performed quantitative reverse transcriptase-polymerase chain reaction to measure the mRNA expression of COX-2, and E-cadherin., Results: Etodolac showed significant cytotoxicity only to T24 cells, which expressed the greatest level of COX-2 mRNA and the lowest level of E-cadherin mRNA among the three cell lines. Etodolac also increased the E-cadherin mRNA expression in T24 cells in vitro. We also found that etodolac suppressed tumor growth and induced E-cadherin expression and cell apoptosis in a T24 tumor xenograft mouse model., Conclusions: Etodolac exhibited antitumor activity and induced E-cadherin expression in bladder cancer cells and might be useful for the clinical treatment and prevention of bladder cancer, especially in poorly differentiated bladder cancer with high COX-2 and low E-cadherin expression.

Purpose: The purpose of this study was to test the effect of etodolac on a dog model of osteoarthritic temporomandibular joints (TMJ)., Material and Methods: Ten adult beagle dogs underwent surgery to induce osteoarthritis in the right TMJ, and were then randomly divided into two groups each of 5 dogs. From 2 to 6 weeks after surgery, the dogs in group 1 (control group) were given an empty gelatin capsule daily, and the dogs in group 2 (study group) were given 15 mg/kg of etodolac daily. All joints were examined radiologically and histologically 8 weeks postoperatively., Results: In group 1, the operated right joints showed severe osteoarthritic changes in the condyle and severe morphological differences in comparison with the unoperated (left joint). Group 2 showed fewer morphological differences between the unoperated control (left) and the operated (right) TMJ. Osteoarthritic changes in the TMJ were significantly less severe in group 2 (etodolac) than in group 1., Conclusion: Oral administration of etodolac at a dose of 15 mg/kg minimized the continuation of experimentally induced osteoarthritic changes in the canine TMJ, when compared with the placebo. Thus, etodolac may play a role in preventing progression of human TMJ osteoarthritis.

Non-steroidal anti-inflammatory drugs have been shown to inhibit carcinogenesis in colon cancer, and to induce apoptosis in a variety of tumor cell lines. Some anti-tumor effects are thought to be related to their cyclooxygenase-2-inhibitory activity, but recent studies have shown that non-steroidal anti-inflammatory drugs exert their anti-tumor effect via cyclooxygenase-2-independent mechanism. SDX-308 (CEP-18082) is a non-cyclooxygenase-2-inhibiting indole-pyran analog and is structurally related to SDX-101, an R-enantiomer of etodolac. SDX-308 has a potent anti-myeloma effect and shows synergism in combination with other drugs for the treatment of chronic lymphocytic leukemia. In addition SDX-308 inhibits osteoclast formation and activity and thereby might be an attractive drug for the treatment of diseases with increased osteoclast activity such as osteolytic lesions in multiple myeloma and metastatic carcinomas, as well as osteoporosis. This review covers future application of SDX-308 as an anti-myeloma drug regulating increased osteoclast activity.

Multiple myeloma (MM) is a hematologic malignancy characterized by dysregulated proliferation of plasma cells and increased osteoclast activity that results in bone destruction and lytic lesions. Therefore, novel treatment modalities targeting both myeloma cell and osteoclast function may dramatically improve MM patient outcome. As an R-enantiomer of the cyclooxygenase (COX) inhibitor etodolac, SDX-101 has shown favorable antimyeloma effects. More recently, another structural analogue of etodolac, SDX-308, has displayed in vitro cytotoxic activity on tumor lines and in vivo antitumor efficacy in mice. SDX-308 has high antimyeloma activity and shows synergism in combination with other drugs for the treatment of chronic lymphocytic leukemia (CLL). In addition SDX-308 inhibits osteoclast (OCL) formation resulting in complete abrogation of bone resorption. Therefore, SDX-308 might be an attractive drug for the treatment of diseases with increased OCL activity, such as osteolytic lesions in multiple myeloma and metastatic carcinomas as well as osteoporosis. In the present review, we discuss SDX-308 as a new therapeutic candidate for the treatment of MM and diseases with increased osteoclast activity.

Objective: To characterize features and response to treatment of keratoconjunctivitis sicca (KCS) associated with oral administration of etodolac in dogs., Design: Retrospective case series., Sample Population: 65 cases obtained from a survey of veterinary ophthalmologists (group A) and 146 cases reported to Fort Dodge Animal Health (group B)., Procedures: Data analyzed included breed, sex, age, weight, dose and duration of etodolac administration, results of Schirmer tear test at the time of diagnosis and last follow-up, treatments, and response to treatments. Groups A and B were analyzed separately by use of forward stepwise logistic regression models developed to predict probability of complete remission or clinical improvement as a function of several variables., Results: Most dogs developed severe KCS (84 eyes of 50 dogs [group A]; 111 eyes of 62 dogs [group B]). Resolution of KCS occurred in 7 of 65 (A) and 23 of 146 (B) dogs. No response to treatment was observed in 26 of 65 (A) and 27 of 146 (B) dogs. Fifty-one (A) and 52 (B) dogs had records that were sufficiently complete to use in models. In group B, dogs with etodolac treatment intervals < 6 months prior to the onset of KCS were 4.2 times as likely to have remission as were dogs with treatment intervals > or = 6 months., Conclusions and Clinical Relevance: Shorter duration of etodolac administration (< 6 months) was associated with improved outcome in 1 population of dogs. Monitoring of tear production should be considered prior to and during administration of etodolac in dogs.

Renal dysfunction and urinary abnormalities, which are usually related to drug toxicity, secondary amyloidosis, or those which overlap with other autoimmune conditions, are frequently observed in patients with rheumatoid arthritis. This is the first case report of membranous nephropathy in a patient with early-stage rheumatoid arthritis treated with the relatively selective cyclooxygenase-2 inhibitor, etodolac. The present case suggests that any kind of non-steroidal anti-inflammatory drug can cause membranous nephropathy; thus, physicians should be aware of this renal toxicity when prescribing these drugs.

Over the past decade, there have been several nonsteroidal anti-inflammatory drugs (NSAIDS) introduced in veterinary medicine with an increased gastrointestinal safety profile consistent with a cyclooxygenase (COX)-1-sparing effect. More recently, an NSAID with additional 5-lipoxygenase (5-LOX) activity has also been approved for use. Although it is tempting to equate in vitro COX-2/COX-1 and 5-LOX inhibition to overall in vivo safety, the data do not support this approach. The true overall safety for any individual compound is based on its evaluation in laboratory margin-of-safety studies, reproductive safety studies, and blind multicenter field studies in client-owned animals. Therefore, when choosing a COX-2-selective or dual-inhibitor NSAID for clinical use, all in vivo data must be taken into account to understand comparative safety, and continued use must be based on the drug's performance in the individual being treated. Until head-to-head trials in multicenter blind studies are published, comments on comparative safety and effectiveness must be reserved.

Cyclooxygenase 2 (COX-2) and retinoid X receptor alpha (RXRalpha) are suggested to have roles in carcinogenesis. COX-2 inhibitors have been reported to suppress growth of hepatocellular carcinoma (HCC) cell lines in vitro. However, little is known about the preventive effect of these drugs on spontaneous hepatocarcinogenesis in vivo. Etodolac exists in a racemic mixture containing S- and R-etodolac. S-etodolac is responsible for COX-2 inhibitory activity and R-etodolac is related to the downregulation of RXRalpha. Here, the effect of etodolac on spontaneous development of HCC in fatty liver Shionogi mice is evaluated. Etodolac was administered at a low (2 mg/kg) or high (10 mg/kg) dose three times a week for 16 months starting at the age of 3 months. The development of HCC was suppressed slightly in the high-dose group, and suppressed markedly in the low-dose group, although the development of fatty liver was not inhibited in either group. Plasma prostaglandin E2 levels were also decreased significantly in the low-dose group, consistent with the suppression of HCC. The expression of RXRalpha and proliferating cell nuclear antigen in non-tumorous liver tissues was decreased significantly in both the low-dose and high-dose groups. These findings show that etodolac treatment at an optimum dose suppresses hepatocarcinogenesis in vivo, and may be useful for preventing the development of HCC in humans.

Acute rheumatic fever is a delayed inflammatory disease that follows streptococcal infection of the throat. Poststreptococcal reactive arthritis is a sterile arthritis associated with antecedent streptococcal infection in patients not fulfilling the Jones criteria for acute rheumatic fever. Poststreptococcal reactive arthritis has been reported to have lower-extremity predominance and, therefore, should be included in the differential diagnosis of patients with lower-extremity arthritis. A review of the literature, distinguishing poststreptococcal reactive arthritis from acute rheumatic fever, and treatment options are discussed here. A case report is also presented.

A 37-year-old man was admitted with an extrathoracic desmoid tumor invading the brachial plexus. Magnetic resonance imaging (MRI) of the thorax demonstrated a 20 x 9 x 14 cm mass in the supraclavicular fossa, axillary fossa and the right side of the chest. It invaded the brachial plexus and circumscribed the subclavian and axillary arteries concentrically. Biopsy revealed desmoid tumor which was resected subtotally with the brachial plexus. The gross residual mass was treated postoperatively with radiotherapy (60 Gy) which resulted in major regression of the mass. Following radiotherapy, ethodolac with ascorbic acid were administered. The tumor was clinically indiscernible 35 months post-radiotherapy. This case shows the high effectiveness of radiotherapy along with less toxic medical treatment modalities in instances where local control is hard to achieve with surgery and highlights the importance of using multidisciplinary treatments to maintain good functional results.

Glucocorticoids have been widely used in the treatment of multiple myeloma (MM) both as single agents and in combination with other drugs. However, primary or acquired glucocorticoid resistance occurs in most cases. It was recently reported that R-etodolac induced in vitro cytotoxicity in MM cell lines and in primary MM cells, as well as synergistically enhanced dexamethasone (Dex)-induced apoptosis in Dex-sensitive MM.1S cells. This study examined the in vitro and in vivo effects of combination treatment with R-etodolac and Dex on Dex-resistant OPM1 cells. Treatment with R-etodolac and Dex was found to enhance cytotoxicity, inhibit nuclear factor kappaB activity via upregulation of IkappaBalpha, as well as enhance Dex-induced caspase activation and poly (ADP)-ribose polymerase cleavage in OPM1 cells. R-etodolac also enhanced Dex cytotoxicity in patient MM cells that were resistant to glucocorticoids. The in vivo anti-tumour effect of this combination on MM cells was evaluated by using severe combined immunodeficient mice engrafted with OPM1. Treatment with R-etodolac or Dex alone did not induce a significant reduction of tumour volume; in contrast, combination treatment with R-etodolac and Dex induced significant synergistic inhibition of tumour growth. These data indicate that R-etodolac overcomes resistance to Dex in glucocorticoid-resistant MM cells, providing the framework for clinical trials of R-etodolac combined with Dex, to improve patient outcome in MM.

A total of 249 client-owned dogs with osteoarthritis were treated with firocoxib (5 mg/kg/day) or a positive control, etodolac (10-15 mg/kg/day), for 30 days. Veterinary examinations were performed on approximately days 0 (visit 1), 14 (visit 2), and 29 (visit 3). Based on defined noninferiority criteria, firocoxib and etodolac were comparable. Based on the magnitude of the change from baseline, improvement with firocoxib was significantly greater than with etodolac for lameness at a trot (visits 2 and 3) and for lameness at a walk, pain on manipulation, and range of motion (visit 3) (P < .05). In weekly owner evaluations, firocoxib provided significantly greater improvement than etodolac (P < .05) at each scoring.