Cyclooxygenase-2 Inhibitor Therapy Research Articles

Clinical outcome of dogs diagnosed with canine inflammatory mammary cancer treated with metronomic cyclophosphamide, a cyclooxygenase‐2 inhibitor and toceranib phosphate

Canine inflammatory mammary cancer (IMC) is highly malignant, invasive and a therapeutic challenge, because effective medical treatment is still unavailable. This retrospective study compares the efficacy of an oral cyclooxygenase-2 (COX-2) inhibitor combined with toceranib phosphate and oral cyclophosphamide (multi-drug therapy [MT]) with COX-2 inhibitor therapy alone (single-drug therapy [ST]) in dogs diagnosed with secondary IMC. Clinical response, adverse events, overall survival time (OST), disease-free survival (DFS) and time to progression (TTP) were evaluated. Sixteen patients were included, eight received MT and eight receiving ST. Median OST was significantly higher in patients receiving MT (96.0 vs. 37.5 days; p= .046) and in patients with post-surgical rather than non-surgical IMC (86.5 vs. 41.5 days; p= .038). Additionally, median TTP was significantly higher in patients treated with MT (p= .010). In patients with non-surgical IMC, the clinical benefit (CB) was reached in 100% (n= 3) of patients receiving MT and in 33% (n= 1) of those receiving ST; the response duration was significantly longer in MT cases (p= .026). The absence of disease progression at day 30 of treatment was significantly associated with longer OST, DFS and TTP (p= .018, p= .002 and p< .001, respectively). Adverse events occurred more frequently in patients treated with MT compared with ST (p= .026). The MT protocol produced primarily mild to moderate toxicities, which were resolved with supportive care; therefore, the combination of drugs was adequately tolerated by most of the patients. The combination of toceranib, a COX-2 inhibitor and oral cyclophosphamide may be a protocol with potential therapeutic efficacy for dogs with IMC.

Novel Combination of COX-2 Inhibitor and Antioxidant Therapy for Modulating Oxidative Stress Associated with Intestinal Ischemic Reperfusion Injury and Endotoxemia.

Background: Intestinal ischemic reperfusion (I/R) injury is associated with a high mortality rate; this condition is also related to significant endotoxemia and systemic inflammation. The preservation of tissue perfusion and a sufficient blood flow are required to deliver nutrients and oxygen, preserve metabolic pathways, and eliminate waste products. Oxidative stress plays a fundamental role in intestinal I/R injury and leads to disruption of the mucosal barrier and necrosis, allowing the migration of endotoxins and luminal bacteria into the systemic circulation. In this study, we evaluated the beneficial effects of a cyclooxygenase (COX)-2 inhibitor—firocoxib—plus the antioxidant vitamin C in a rat model of intestinal I/R injury. Methods: We used a rat model of I/R injury in which the superior mesenteric artery was clamped for 30 min by a vascular clamp, and the animals were then allowed 1 h of reperfusion. Results: Our results show the importance of combined anti-inflammatory and antioxidant treatment for the prevention of intestinal I/R injury that leads to reduced systemic endotoxemia. We observed a significantly synergistic effect of firocoxib and vitamin C in reducing intestinal wall damage and oxidative stress, leading to a significant reduction of inflammation and endotoxemia. Conclusions: Our results indicate that this approach could be a new pharmacological protocol for intestinal colic or ischemic injury-induced endotoxemia.

Effects of high- and low-dose aspirin on adaptive immunity and hypertension in the stroke-prone spontaneously hypertensive rat.

Despite its well-known antithrombotic properties, the effect of aspirin on blood pressure (BP) and hypertension pathology is unclear. The hugely varying doses used clinically have contributed to this confusion, with high-dose aspirin still commonly used due to concerns about the efficacy of low-dose aspirin. Because prostaglandins have been shown to both promote and inhibit T-cell activation, we also explored the immunomodulatory properties of aspirin in hypertension. Although the common preclinical high dose of 100 mg/kg/d improved vascular dysfunction and cardiac hypertrophy, this effect was accompanied by indices of elevated adaptive immunity, renal T-cell infiltration, renal fibrosis, and BP elevation in stroke-prone spontaneously hypertensive rats and in angiotensin II-induced hypertensive mice. The cardioprotective effects of aspirin were conserved with a lower dose (10 mg/kg/d) while circumventing heightened adaptive immunity and elevated BP. We also show that low-dose aspirin improves renal fibrosis. Differential inhibition of the COX-2 isoform may underlie the disparate effects of the 2 doses. Our results demonstrate the efficacy of low-dose aspirin in treating a vast array of cardiovascular parameters and suggest modulation of adaptive immunity as a novel mechanism underlying adverse cardiovascular profiles associated with COX-2 inhibitors. Clinical studies should identify the dose of aspirin that achieves maximal cardioprotection with a new awareness that higher doses of aspirin could trigger undesired autoimmunity in hypertensive individuals. This work also warrants an evaluation of high-dose aspirin and COX-2 inhibitor therapy in sufferers of inflammatory conditions who are already at increased risk for cardiovascular disease.-Khan, S. I., Shihata, W. A., Andrews, K. L., Lee, M. K. S., Moore, X.-L., Jefferis, A.-M., Vinh, A., Gaspari, T., Dragoljevic, D., Jennings, G. L., Murphy, A. J., Chin-Dusting, J. P. F. Effects of high- and low-dose aspirin on adaptive immunity and hypertension in the stroke-prone spontaneously hypertensive rat.

Combination COX-2 inhibitor and metformin attenuate rate of joint replacement in osteoarthritis with diabetes: A nationwide, retrospective, matched-cohort study in Taiwan.

BackgroundOsteoarthritis (OA) is the most common form of arthritis associated with an increased prevalence of type 2 diabetes mellitus (T2DM), however their impact on decreasing joint replacement surgery has yet to be elucidated. This study aimed to investigate if the combination of COX-2 inhibitor and metformin therapy in OA with T2DM were associated with lower the rate of joint replacement surgery than COX-2 inhibitor alone.MethodsIn total, 968 subjects with OA and T2DM under COX-2 inhibitor and metformin therapy (case group) between 1 January to 31 December 2000 were selected from the National Health Insurance Research Database of Taiwan, along with 1936 patients were the 1:2 gender-, age-, and index year-controls matched without metformin therapy (control group) in this study. Cox proportional hazards analysis was used to compare the rate of receiving joint replacement surgery during 10 years of follow-up.ResultsAt the end of follow-up, 438 of all enrolled subjects (15.08%) had received the joint replacement surgery, including 124 in the case group (12.81%) and 314 in the control group (16.22%). The case group tended to be associated with lower rate of receiving the joint replacement surgery at the end of follow-up than the control group (p = 0.003). Cox proportional hazards regression (HR) analysis revealed that study subjects under combination therapy with metformin had lower rate of joint replacement surgery (adjusted HR 0.742 (95% CI = 0.601–0.915, p = 0.005)). In the subgroups, study subjects in the combination metformin therapy who were female, good adherence (>80%), lived in the highest urbanization levels of residence, treatment in the hospital center and lower monthly insurance premiums were associated with a lower risk of joint replacement surgery than those without.ConclusionsPatients who have OA and T2DM receiving combination COX-2 inhibitors and metformin therapy associated with lower joint replacement surgery rates than those without and this may be attributable to combination therapy much more decrease pro-inflammatory factors associated than those without metformin therapy.

An increased CD25-positive intestinal regulatory T lymphocyte population is dependent upon Cox-2 activity in the Apcmin/+ model.

Only mismatch repair (MMR)-deficient colorectal cancer (CRC) appears to respond well to programmed death (PD)-1 inhibition at the present time. Emerging evidence suggests a role for micro-environmental factors such as CD25+ cells modulating response to PD-1 inhibition. In the ApcMin/+ model of familial adenomatous polyposis (MMR-proficient CRC), increased Cyclooxygenase-2 (Cox-2) expression by cells which include alternatively activated mononuclear phagocytes promotes intestinal tumorigenesis by mechanisms which may include immune suppression. To gain insight into this, we compared regulatory T cell (Treg ) populations between ApcMin/+ and wild-type mice prior to and after the phase of increased intestinal Cox-2-dependent prostaglandin E2 (PGE2 ) production. There was no difference in systemic Treg function or numbers between ApcMin/+ and wild-type mice. However, increased numbers of small intestinal CD25+ Tregs were observed with increased Cox-2 activity in the absence of any difference in the expression of Tgf-β or Tslp between ApcMin/+ and wild-type mice. Cox-2 inhibitor therapy (Celecoxib) reversed the increase in ApcMin/+ intestinal CD25+ Treg numbers, without decreasing numbers of CD25+ systemic Tregs . Forkhead box protein 3 (FoxP3+ ) and Cox-2+ cells were co-localized to the interstitium of adenomas of Apcmin/+ mice. These results suggest selective dependence of an 'activated Treg ' phenotype on paracrine Cox-2 activity in ApcMin/+ small intestine. For therapeutic potential, further studies are required to evaluate the relevance of these findings to human cancer as well as the functional significance of CD25+ intestinal Tregs in cancer.

Immunohistochemical staining with non-phospho \u03b2-catenin as a diagnostic and prognostic tool of COX-2 inhibitor therapy for patients with extra-peritoneal desmoid-type fibromatosis

BackgroundImmunohistochemical staining with conventional anti-β-catenin antibody has been applied as a diagnostic tool for desmoid-type fibromatosis (DF). This study aimed to evaluate the diagnostic and prognostic value of immunohistochemical staining with anti-non-phospho β-catenin antibody, which might more accurately reflect the aggressiveness of DF, in comparison to the conventional anti-β-catenin antibody.MethodsBetween 2003 and 2015, 40 patients with extra-peritoneal sporadic DF were prospectively treated with meloxicam or celecoxib, a COX-2 inhibitor, therapy. The efficacy of this treatment was evaluated according to Response Evaluation Criteria in Solid Tumors (RECIST). Immunohistochemical staining was performed on formalin-fixed material to evaluate the expression of β-catenin and non-phospho β-catenin, and the positivity was grouped as negative, weak, moderate, and strong. DNA was isolated from frozen tissue or formalin-fixed materials, and the CTNNB1 mutation status was determined by direct sequencing.ResultsOf the 40 patients receiving COX-2 inhibitor treatment, there was one with complete remission, 12 with partial remission, 7 with stable disease, and 20 with progressive disease. The mutation sites in CTNNB1 were detected in 22 (55%) of the 40 cases: T41A (17 cases), S45F (3 cases), and T41I and S45P (1 each). The positive nuclear expression of non-phospho β-catenin showed a significant correlation with positive CTNNB1 mutation status detected by Sanger method (p = 0.025), and poor outcome in COX-2 inhibitor therapy (p = 0.022). In contrast, nuclear expression of β-catenin did not show a significant correlation with either CTNNB1 mutation status (p = 0.43) or outcome of COX-2 inhibitor therapy (p = 0.38).ConclusionsNuclear expression of non-phospho β-catenin might more appropriately reflect the biological behavior of DF, and immunohistochemical staining with non-phospho β-catenin could serve as a more useful diagnostic and prognostic tool of COX-2 inhibitor therapy for patients with DF.

Abstract P1-05-02: COX-2 expression in normal mammary epithelium is estrogen responsive and predicts expression in DCIS and invasive ductal carcinoma

Abstract Background: Cyclooxygenase-2 (COX-2) overexpression is implicated in the poor prognosis of young women's breast cancer. Understanding the regulation of COX-2 expression in normal premenopausal breast tissue and its relationship to malignancy is anticipated to provide insight into COX-2 as a potential therapeutic target for young breast cancer patients. Methods: To investigate COX-2 regulation and expression, quantitative COX-2 immunohistochemistry was performed on adjacent normal and breast cancer tissues from 83 premenopausal women with known clinical reproductive histories as well as on rat mammary glands with distinct estradiol and progesterone exposures. To determine the stability of COX-2 expression over time, a small cohort of women with serial breast biopsies 2-3 weeks apart was evaluated. Results: COX-2 expression in normal adjacent breast tissue was predominantly epithelial, varied &amp;gt;40-fold between individual women, and was independent of proximity to tumor and tumor biology. COX-2 upregulation occurred in alveoli during pregnancy and with estradiol and progesterone exposure in the rat. Though these data demonstrate ovarian hormone regulation, COX-2 expression was relatively stable for each individual premenopausal woman over a 2-3 week assessment window. Furthermore, COX-2 expression levels in normal epithelium independently predicted COX-2 expression levels in tumors. Conclusions: COX-2 expression in the adjacent normal breast epithelium is highly variable across premenopausal women, and may be further modified by ovarian hormone exposure. Moreover, COX-2 expression in the normal breast independently predicts COX-2 expression in tumors, implicating women with high COX-2 expression in the normal breast epithelium as high risk patients who may benefit from COX-2 inhibitor therapy. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P1-05-02.

Reply to the letter regarding “Comparison of gastrointestinal adverse effects between cyclooxygenase-2 inhibitors and non-selective, non-steroidal anti-inflammatory drugs plus proton pump inhibitors: a systematic review and meta-analysis”

To the Editor:We thank Dr. Lai and his colleagues for their commentsrelated to our article ‘‘Comparison of gastrointestinaladverse effects between cyclooxygenase-2(COX-2) inhib-itors and non-selective, non-steroidal anti-inflammatorydrugs (ns-NSAID) plus proton pump inhibitors (PPI)’’ [1].According to our analyses, the risk of major gastrointesti-nal (GI) complications was lower in COX-2 inhibitors, ascompared to ns-NSAIDs plus PPI. We agree that patientswho take COX-2 inhibitors are still at risk for GI adverseevents, when compared to patients who do not take thesemedications. As shown in a metaanalysis by Rostrom et al.[2], high-dose COX-2 inhibitors insignificantly increasedthe risk of gastric (relative risk or RR 1.22; 95% CI0.83–1.80) and duodenal (RR, 1.29; 95% CI 0.63–2.66)ulcers, as compared to placebo. However, when comparedto ns-NSAIDs, the risk of major GI complications includ-ing perforation, ulceration, bleeding, and obstruction werelower in COX-2 inhibitors.The increased risk of peptic ulcer in a cohort studyneeds to be cautiously interpreted because this study designis susceptible to selection bias resulting in imbalancedprognostic characteristics at baseline. In daily practice,physicians usually prescribe COX-2 inhibitors for patientswho are at high risk of developing GI complications, e.g.,old age, prior GI ulcer or bleeding, aspirin or anti-coagu-lant user, and steroid use, whereas patients with low riskare usually treated with ns-NSAIDs. Therefore, the risk ofGI complications between COX-2 inhibitors vs. ns-NSA-IDs may be comparable or even higher in COX-2inhibitors.We totally agree that COX-2 inhibitors are associatedwith increased risk of GI complication. Patients requiringNSAID therapy who are at high risk should receive COX-2inhibitor and GI protective therapy (e.g., misoprostol orPPI) or alternative therapy for pain control.Reference

COX-2 inhibitors in prostate cancer treatment—hold your horses?

COX-2 inhibitors in prostate cancer treatment—hold your horses?

Microsomal prostaglandin E synthase-1 enhances bone cancer growth and bone cancer-related pain behaviors in mice

Aims Nonsteroidal anti-inflammatory drugs are a therapeutic modality for chronic cancer pain arising from bone metastases. Chronic administration of a cyclooxygenase (COX)-2 inhibitor is effective to bone cancer-related pain. However, adverse cardiovascular effects have limited COX-2 inhibitor therapy, and elucidation of better targets for blocking prostaglandin (PG) biosynthesis is necessary. Microsomal PGE synthase-1 (mPGES-1) is an inducible enzyme that catalyzes isomerization of the endoperoxide PGH 2 to PGE 2. To investigate the validity of mPGES-1 as a therapeutic target, we evaluated bone cancer pain-related behaviors in mPGES-1 knockout (PGES-1−/−) mice. Main methods Lewis lung carcinoma cells (LLCCs) were injected into the intramedullary space of the femur of wild-type (WT) and PGES-1−/− mice. Pain-related behaviors were evaluated. Key findings PGES-1−/− mice exhibited reduced tumor growth in bone marrow compared to WT. The expression of pro-calcitonin gene-related peptide (CGPR) in the dorsal root ganglia of L 1–5 was significantly higher in WT mice at day 14, whereas it was unchanged in mPGES-1 mice. In the observation of pain-related behaviors, mPGES-1−/− mice exhibited significantly fewer spontaneous flinches and their onset was several days later than WT. The appearance of other pain-related behaviors in mPGES-1−/− mice was also delayed as compared to WT. LLCC-injected WT mice treated with a COX-2 inhibitor, celecoxib, exhibited similar temporal changes to mPGES1−/−. Significance The present results suggest that mPGES-1 plays a crucial role in the enhancement of bone cancer growth and bone cancer pain, and that inhibition of mPGES-1 may have clinical utility in the management of bone cancer pain.

Selective Cyclooxygenase-2 Inhibitor Suppresses Renal Thromboxane Production but Not Proliferative Lesions in the MRL/lpr Murine Model of Lupus Nephritis

IntroductionProliferative lupus nephritis (LN) is marked by increased renal thromboxane (TX) A2 production. Targeting the TXA2 receptor or TXA2 synthase effectively improves renal function in humans with LN and improves glomerular pathology in murine LN. This study was designed to address the following hypotheses: (1) TXA2 production in the MRL/MpJ-Tnfrsf6lpr/J (MRL/lpr) model of proliferative LN is cyclooxygenase (COX)-2 dependent and (2) COX2 inhibitor therapy improves glomerular filtration rate (GFR), proteinuria, markers of innate immune response and glomerular pathology. MethodsTwenty female MRL/lpr and 20 BALB/cJ mice were divided into 2 equal treatment groups: (1) SC-236, a moderately selective COX2 inhibitor or (2) vehicle. After treatment from the age of 10 to 20 weeks, the effectiveness of inhibition of TXA2 was determined by measuring urine TXB2. Response endpoints measured at the age of 20 weeks were renal function (GFR), proteinuria, urine nitrate + nitrite (NOx) and glomerular histopathology. ResultsSC-236 therapy reduced surrogate markers of renal TXA2 production during early, active glomerulonephritis. When this pharmacodynamic endpoint was reached, therapy improved GFR. Parallel reductions in markers of the innate immune response (urine NOx) during therapy were observed. However, the beneficial effect of SC-236 therapy on GFR was only transient, and renal histopathology was not improved in late disease. ConclusionsThese data demonstrate that renal TXA2 production is COX2 dependent in murine LN and suggest that NO production is directly or indirectly COX2 dependent. However, COX2 inhibitor therapy in this model failed to improve renal pathology, making COX2 inhibition a less attractive approach for treating LN.

Celecoxib steigert die Strahlenempfindlichkeit von sekundären Knochentumoren eines nicht-kleinzelligen humanen Lungenkarzinoms durch Anti-Angiogenese in vivo

Cyclooxygenase-2 (COX-2) inhibitors mediate a systemic antitumor activity via antiangiogenesis and seem to enhance the response of primary tumors to radiation. Radiosensitizing effects of COX-2 inhibition have not been reported for bone metastases. Therefore, the aim of this study was the investigation of the radiosensitizing effects of the selective COX-2 inhibitor celecoxib in secondary bone tumors of a non-small cell lung carcinoma in vivo. Human A549 lung carcinomas were implanted into a cranial window preparation in male SCID mice (n = 24). Animals were treated with either celecoxib or radiation (7 Gy single photon dose) alone or a combination of celecoxib and radiation, respectively. Untreated animals served as controls. The impact of radiation and COX-2 inhibition on angiogenesis, microcirculation, and tumor growth was analyzed over 28 days by means of intravital microscopy and histological methods. Monotherapies with radiation as well as celecoxib had significant antitumor effects compared to untreated controls. Both therapies reduced tumor growth and vascularization to a similar extent. The simultaneous administration of celecoxib and radiation further enhanced the antitumor and antiangiogenic effects of single-beam radiation. With the combined treatment approach, tumor vascularization and tumor size were decreased by 57% and 51%, respectively, as compared to monotherapy with radiation. The combined application of radiation therapy and COX-2 inhibition showed synergistic effects concerning the inhibition of tumor growth and tumor angiogenesis. Therefore, the combination of radiation with COX-2 inhibitor therapy represents a promising approach to improve the therapeutic efficacy of radiotherapy of bone metastases.

Economic evaluation of nonsteroidal anti-inflammatory drug strategies in rheumatoid arthritis

Although disease modifying antirheumatic drugs (DMARDs) are the first choice drugs in the treatment of rheumatoid arthritis, many patients still take nonsteroidal anti-inflammatory drugs (NSAIDs) as well. These drugs may cause serious gastric adverse events with continuous usage. Cyclooxygenase-2 (COX2) inhibitors were supposed to have a gastrointestinal (GI) friendly side effect profile. The aim of the study is to compare three therapeutic strategies: conventional NSAIDs, NSAID in combination with proton pump inhibitors (PPIs), and the selective COX2 inhibitor therapy (celecoxib). A decision tree model was developed, for 1 year, to simulate cohorts within the three arms (NSAIDs, NSAID + PPI, celecoxib). The efficacy of the different active agents of NSAIDs in therapeutically relevant doses was assumed to be the same, consequently differences can be seen in the side effect profile of the drugs. Medical costs, the costs of the side effects (GI, cardiovascular [CV] events), and quality-adjusted life-years (QALYs) were calculated to gain an incremental cost-effectiveness ratio (ICER). Evaluations were made from a third party payer's perspective. We performed one-way deterministic sensitivity analyses; the results were displayed in tornado diagrams. Our model indicates that NSAID + PPI offers extra health gain for extra costs compared with conventional NSAIDs (ICER:14,287 euro/QALY), while it dominates celecoxib because of celecoxib's higher costs and lower effectiveness. According to the sensitivity analyses, QALYs had the highest influence on ICER. Although COX2 inhibitors have elevated GI efficacy compared with NSAIDs, celecoxib seems to be an adequate choice only for a limited group of patients with specific conditions because of the significantly higher price and CV risk profile.

Renal Tissue Damage After Experimental Pyelonephritis: Role of Anti-Oxidants and Selective Cyclooxygenase-2 Inhibitors

Purpose Our aim was to examine the effect of anti-oxidant and selective cyclooxygenase-2 inhibitor therapy given adjunct to the conventional treatment of acute pyelonephritis on renal tissue damage. Material and Methods 48 wistar rats were divided into 4 groups according to their treatment modalities which were started one day after inoculation of all rats with 0.1 ml of E.Coli(ATCC 25922 1010 cfu/ml).First group received only antibiotic treatment with ceftriaxone(50 mg/kg, IM), second and third group received L-Carnitine(500 mg/kg, IM) and Meloxicam(.mg/kg,IM) in addition to the conventional treatment, respectively. Fourth group received combination therapy(L-Carnitine and Meloxicam)in addition to group one. 3 and 7 days after E.Coli inoculation rats were sacrificed and kidney samples were obtained for histologic determination of tubular atrophy, acute and chronic inflammation, interstitial fibrosis and biochemical determination of catalase activity(CAT), total antioxidant capacity(TAC) and malondialdehyde(MDA). Results Interstitial fibrosis(p:0.06),chronic inflammation(p:0.536) and tubular atrophy(p:0.094) decreased in group 4 compared to the other groups but there was statistically significant decrease only in acute inflammation(p:0.015). In addition,if the day of nephrectomy is considered, there was again a significant decrease in acute inflammation findings in day 7 compared to day 3 in group 2,3 and 4(p:0.002). CAT significantly increased in group 2(p:0.029),group 3(p:0.02) and group 4(p:0.014) and decreased in group 1(p:0.012) in day 7. Conclusions Acute renal inflammatory injury can be prevented much more effectively by combination therapy than conventional therapy. This process is probably due to the prevention of free oxygen radical generation by anti-oxidants and inhibition of chemotaxis by selective cyclooxygenase-2 inhibitors.

Nonselective and Cyclooxygenase-2-Selective NSAIDs and Acute Kidney Injury

Objective The association between nonsteroidal anti-inflammatory drugs (NSAIDs) and acute kidney injury is well established, but it is less clear whether this risk is focused with specific agents. We undertook a large pharmacoepidemiologic analysis of the risk of acute kidney injury among older adults using nonselective NSAIDs or cyclooxygenase (COX)-2 inhibitors. Methods Medicare beneficiaries from 2 large states with drug benefit were eligible for study. Patients were included if they filled a prescription for a nonselective NSAID or COX-2 inhibitor after more than 6 months without any such prescriptions and without a previous diagnosis of acute kidney injury. Incident acute kidney injury was ascertained from hospitalization claims within 45 days of initiating nonselective NSAID or COX-2 inhibitor therapy. Adjusted proportional hazards models estimated the relative risk of acute kidney injury associated with each agent compared with celecoxib. Results We included 183,446 patients whose mean age was 78 years; 80% were women. Acute kidney injury was identified in 870 (0.47%) of nonselective NSAID or COX-2 inhibitor users. The agents with significantly elevated risk compared with celecoxib were indomethacin (rate ratio [RR] = 2.23; 95% confidence interval [CI], 1.70-2.93), ibuprofen (RR = 1.73; 95% CI, 1.36-2.19), and rofecoxib (RR = 1.52; 95% CI, 1.26-1.83). These findings were robust in several subgroups. Conclusion Acute kidney injury requiring hospitalization is a relatively rare adverse event among older adults after initiation of nonselective NSAIDs or COX-2 inhibitor treatment, observed in approximately 1 in 200 new users within 45 days. There seems to be a marked gradient of risk for acute kidney injury across agents, specifically for indomethacin, ibuprofen, and rofecoxib.

Cyclooxygenase-2 Expression in Equine Tumors

The enzyme cyclooxygenase-2 (COX-2) is expressed in some tumor and stromal tissues, and catalyzes production of prostaglandins with growth stimulatory, antiapoptotic, proangiogenic, and immunosuppressive properties. Pharmacologic inhibition of COX-2 is associated with antitumor activity in various human and canine malignancies. The purpose of this study was to assess COX-2 expression in a series of equine sarcoids, melanomas, and squamous-cell carcinomas (SCC). COX-2 expression was assessed in formalin-fixed paraffin-embedded tissues from 14 sarcoids, 11 melanomas, and 37 SCC that represent various anatomic sites by using standard immunohistochemical methods. COX-2 was expressed in 2 of 14 sarcoids, 7 of 11 melanomas, and 32 of 37 SCC, 56% of which demonstrated moderate-to-strong immunoreactivity. There were no differences in expression between anatomic sites. In conclusion, most equine SCC and many melanomas appear to express COX-2 and thus could respond to COX-2 inhibitor therapy.

Changes in the characteristics of patients prescribed selective cyclooxygenase 2 inhibitors after the 2004 withdrawal of rofecoxib

To evaluate the impact of rofecoxib withdrawal on the characteristics of patients prescribed selective cyclooxygenase 2 (COX-2) inhibitors. The General Practice Research Database was used to identify patients age > or =18 years who were prescribed a selective COX-2 inhibitor. Various patient characteristics were noted at the start of therapy: age, sex, nonsteroidal antiinflammatory drug-related risk factors for upper gastrointestinal (GI) events, and the Framingham risk score for cardiovascular disease. Logistic regression was used to compare patients using selective COX-2 inhibitors before and after September 2004. The study population included 171,645 patients receiving selective COX-2 inhibitors. The number of users substantially increased over time until September 2004 and sharply declined thereafter. Approximately 80% stopped selective COX-2 inhibitor therapy within 6 months. Patients receiving selective COX-2 inhibitors after September 2004 were younger and included more men compared with those receiving therapy before September 2004. There was no change before and after September 2004 in the proportion of patients with GI risk factors or high Framingham risk scores, after adjustment for age and sex. A correlation was found between presence of GI risk factors and high Framingham risk scores. Only 20% of patients receiving selective COX-2 inhibitors had GI risk factors but low Framingham risk score, which did not change after September 2004. There was no channeling in the usage of selective COX-2 inhibitors toward patients with a high risk of GI and low risk of cardiovascular disease following the withdrawal of rofecoxib.

Effects of a selective cyclooxygenase-2 inhibitor, nimesulide, on the growth of ovarian carcinoma in vivo

New therapies against cancer are based on targeting cyclooxygenase-2 (COX-2). Whether COX-2 inhibitor therapy would be beneficial in the prevention and/or treatment of ovarian cancer still remains unclear. This study was designed to investigate whether nimesulide, a COX-2 selective inhibitor, could suppress tumor growth in implanted ovarian carcinoma mice and to explore the molecular mechanisms. Human ovarian SKOV-3 carcinoma cells xenograft-bearing mice were treated with nimesulide 62.5 mg/kg or 250 mg/kg alone i.g., daily for 21 days. Microvessel density (MVD) of ovarian carcinoma was determined with anti-CD(34) as the label. Prostaglandin E2 (PGE2) levels were also determined by ELISA. In addition, the expression of COX-2 and COX-1 at protein and mRNA levels in the control groups was also detected by immunohistochemistry and reverse-transcription polymerase chain reaction (RT-PCR). Nimesulide treatment showed a dose-dependent growth-inhibitory effect of human ovarian SKOV-3 tumors. The inhibitory rates in nimesulide 62.5 mg/kg group and 250 mg/kg group were 20.40% and 50.55% respectively, however, which is not significant statistically compared with that of control group (P > 0.05). In treatment groups, nimesulide significantly reduced intratumor PGE2 levels (all, P < 0.01). Microvessel densities in treatment groups were 61.20 +/- 1.67 (62.5 mg/kg) and 66.27 +/- 1.20 (250 mg/kg), which are significant statistically compared with that of control group (79.97 +/- 1.07) (all, P < 0.01). However, COX-1, not COX-2, mRNA, and protein levels are elevated in tumor tissues. Nimesulide decreased microvessel density is associated with the reduction of PGE2 levels but without affecting growth inhibition and the expression of COX-2. Importantly, tumor growth implanted in SKOV-3 mice was not significantly attenuated suggesting that COX-1 in ovarian carcinoma tissue also has an important role in tumor growth. These findings may implicate COX-1 as a suitable target for the treatment of ovarian cancer.

Expression of cyclooxygenase-2 and vascular endothelial growth factor in primary central nervous system lymphomas

Cyclooxygenase (COX) is the rate-limiting enzyme that catalyzes the initial step in biosynthesis of prostaglandins (PGs) from arachidonic acid. COX-2 has been associated with inflammatory processes and tumorigenesis. In order to investigate the correlation between VEGF, COX-2 expression, and tumorigenesis in primary central nervous system lymphomas (PCNSLs), the present study assessed 26 cases of PCNSL by immunostaining for VEGF and COX-2. Immunohistochemical studies were evaluated as follows: (-), no staining; (1+), 0-30% positive cells; (2+), 30-60% positive cells; (3+), >60% positive cells. VEGF expression was detected in 21 of 26 cases; of these, 14, 1 and 6 were scored as 3+, 2+ and 1+, respectively. COX-2 expression was detected in 22 of 26 cases; of these, 14, 4 and 4 were scored as 3+, 2+ and 1+, respectively. For double immunofluorescence, 20 of 26 cases that were detected with both VEGF and COX-2 were examined and almost all tumor cells coexpressed both VEGF and COX-2 in the examined cases. However, COX-2 and VEGF expression in PCNSLs did not correlate with neoangiogenesis and patient survival in the present study, in contrast to previous findings in systemic lymphomas. It is suggested that the high frequency of COX-2 and VEGF coexpression in PCNSLs may be associated with tumorigenesis of PCNSLs and could possibly lead to a future therapeutic trial of PCNSLs with selective COX-2 inhibitor therapy.

Pre-prostatectomy study of the effect of celecoxib versus placebo on androgen receptor (AR) expression in prostate cancer

15538 Background: Cyclooxygenase (COX) inhibitor drug use is associated with a reduction in prostate cancer incidence and mortality. Numerous potential mechanisms for the COX-2 inhibitor, celecoxib have been proposed, including a reduction in AR transactivation (Clin Cancer Res 10:7727, 2004). We hypothesized that pre-prostatectomy celecoxib therapy would result in reduced tissue AR levels. Methods: 28 patients with localized prostate cancer were randomized to celecoxib (400 mg bid) or placebo for 4 weeks prior to prostatectomy. Both benign and cancerous tissues were embedded in a tissue microarray. A single blinded pathologist quantified the percent of positive nuclei in benign versus malignant epithelial cells. Results: An increased number of AR-positive nuclei were observed in the malignant versus benign cells (65.9± 35.2% versus 49.9 ± 33.5 %, p &lt;.001). There was no difference in AR expression between treatment and placebo groups in either benign or cancerous tissue (p = .9, .85, respectively). The median serum PSA at baseline was 6.0 and 6.2 ng/ml for the celecoxib and placebo groups. Over the treatment period, there was no detectable effect of celecoxib on serum PSA (p=0.91). Conclusions: Short-term COX-2 inhibitor therapy did not result in a significant change in either tissue AR or serum PSA. If celecoxib has inhibitory effects on prostate cancer, these may occur without an effect of AR activity. No significant financial relationships to disclose.