Opioid-sparing effect of selective cyclooxygenase-2 inhibitors on surgical outcomes after open colorectal surgery within an enhanced recovery after surgery protocol

AIM: To evaluate the opioid-sparing effect of selective cyclooxygenase-2(COX-2) inhibitors on short-term surgical outcomes after open colorectal surgery.METHODS: Patients undergoing open colorectal resection within an enhanced recovery after surgery protocol from 2011 to 2015 were reviewed. Patients with combined general anesthesia and epidural anesthesia, and those with acute colonic obstruction or perforation were excluded. Patients receiving selective COX-2 inhibitor were compared with well-matched individuals without such a drug. Outcome measures included numeric pain score and morphine milligram equivalent(MME) consumption on postoperative day(POD) 1-3, gastrointestinal recovery(time to tolerate solid diet and time to defecate), complications and length of postoperative stay.RESULTS: There were 75 patients in each group. Pain score on POD 1-3 was not significantly different between two groups. However, MME consumption and MME consumption per kilogram body weight on POD 1-3 was significantly less in patients receiving a selective COX-2 inhibitor(P < 0.001). Median MME consumption per kilogram body weight on POD 1-3 was 0.09, 0.06 and nil, respectively in patients receiving a selective COX-2 inhibitor and 0.22, 0.25 and 0.07, respectively in the comparative group(P < 0.001), representing at least 59% opioidreduction. Patients prescribing a selective COX-2 inhibitor had a shorter median time to resumption of solid diet [1(IQR 1-2) d vs 2(IQR 2-3) d; P < 0.001] and time to first defecation [2(IQR 2-3) d vs 3(IQR 3-4) d; P < 0.001]. There was no significant difference in overall postoperative complications between two groups. However, median postoperative stay was significantly 1-d shorter in patients prescribing a selective COX-2 inhibitor [4(IQR 3-5) d vs 5(IQR 4-6) d; P < 0.001]. CONCLUSION: Perioperative administration of oral selective COX-2 inhibitors significantly decreased intravenous opioid consumption, shortened time to gastrointestinal recovery and reduced hospital stay after open colorectal surgery.

Cyclooxygenase-2 inhibitor inhibits hippocampal synaptic reorganization in pilocarpine-induced status epilepticus rats

Objective： To examine modulations caused by cyclooxygenase-2 （COX-2） inhibitors on altered microenvironments and overbalanced neurotransmitters in pilocarpine-induced epileptic status rats and to investigate possible mechanisms. Methods： Celecoxib （a COX-2 inhibitor） was administered 45 min prior to pilocarpine administration. The effects of COX-2 inhibitors on mlPSCs （miniature GABAergic inhibitory postsynaptic currents） of CA3 pyramidal cells in the hippocampus were recorded. Expressions of COX-2, c-Fos, newly generated neurons, and activated microgliosis were analyzed by immunohistochemistry, and expressions of c^-subunit of y-amino butyric acid （GABAA） receptors and mitogen-activated protein kinase/extracellular signal-regulated protein kinase （MAPK/ERK） activity were detected by Western blotting. Results： Pretreatment with celecoxib showed protection against pilocarpine-induced seizures. Celecoxib prevented microglia activation in the hilus and inhibited the abnormal neurogenesis and astrogliosis in the hippocampus by inhibiting MAPK/ERK activity and c-Fos transcription. Celecoxib also up-regulated the expression of GABAA receptors. NS-398 （N-2-cyclohexyloxy-4-nitrophenyl-methanesulfonamide）, another COX-2 inhibitor, enhanced the frequency and decay time of mIPSCs. Conclusion： The COX-2 inhibitor celecoxib decreased neuronal excitability and prevented epileptogenesis in pilocarpine-induced status epilepticus rats. Celecoxib regulates synaptic reorganization by inhibiting astrogliosis and ectopic neurogenesis by attenuating MAPK/ERK signal activity, mediated by a GABAergic mechanism.

Design, Synthesis and in vitro Evaluation of Thiazole Derivatives of Ibuprofen as Cyclooxygenase-2 Inhibitors

A series of thiazole derivatives of ibuprofen, as cyclooxygenase-2 Inhibitors, were designed, synthesized and in vitro evaluated.

Exacerbation of inflammatory bowel disease by nonsteroidal anti-inflammatory drugs and cyclooxygenase-2 inhibitors:Fact or fiction?

The existence of a possible link between inflammatory bowel disease （IBD） and nonsteroidal anti-inflammatory drugs （NSAIDs） has been repeatedly suggested. Recently, a few studies have addressed the issue of a possible, similar effect by selective cyclooxygenase-2 inhibitors （COXIBs）. The present article reviews the available scientific evidence for this controversial subject.

A Convenient Synthesis of the Substituted 2,3-Diarylindole the Potent Selective COX-2 Inhibitors

Phenyl sulfone-containing 2, 3-diarylindole derivatives were designed and identified to be selective COX-2 inhibitors. A convenient synthetic route was also developed for the synthesis of the novel inhibitors.

Selective Cyclooxygenase-2 Inhibitors: Design and Synthesis

The discovery of COX-2 provides a novel target developing more effective NSAIDs with fewer side effects. On the basis of results from the structure-activity relationships (SAR) of selective COX-2 inhibitors, we have designed and synthesized some promising compounds.

Health Related Quality of Life among Osteoarthritis Patients: A Comparison of Traditional Non-Steroidal Anti-Inflammatory Drugs and Selective COX-2 Inhibitors in the United Arab Emirates Using the SF-36

Objectives: Osteoarthritis (OA) has a dramatic impact on patients’ health related quality of life (HRQoL). Chronic use of analgesics and anti-inflammatory medications for pain management may improve symptoms but on long term may affect HRQoL negatively. The objective of the present study was to compare the impact of two different classes of analgesics, traditional non-steroidal anti-inflammatory drugs (NSAIDs) and selective cyclo-oxygenase-2 (COX-2) inhibitors on HRQoL among osteoarthritis patients using the SF-36 questionnaire. Methods: Clinic based cross-sectional study conducted at Al-Qassimi Hospital, Sharjah, United Arab Emirates (UAE), over a period of six months. Ethical Approval was obtained from the ethics committee at Al-Qassimi Clinical Research Center. Total of 200 osteoarthritis patients fulfilling the inclusion and exclusion criteria were involved in the study. Patients’ demographics were collected from their medical records. The Medical Outcome Study Short-Form 36 (SF-36) questionnaire was used to measure patients’ HRQoL. SF-36 data were scored using health outcomes scoring software 4.5. Results: Mean age of the subjects was 62.19 ± 9.81 years with females constituting 151 (75.5%) of the patients. In general, females scored lower in most of the HRQoL domains compared to males and there was significant difference between the two groups in the mental health (p = 0.005) & mental component (p = 0.042) domains. Compared to selective COX-2 inhibitors, patients on NSAIDs scored higher on all domains of SF-36 except physical functioning. There was significant difference in mental health domain for patients treated with NSAIDs (p = 0.02). Celecoxib was only better than NSAIDs in osteoarthritis patients with more than one musculoskeletal disorders in the domain of bodily pain (p = 0.009). Conclusion: NSAIDs-treated patients did not differ significantly from celecoxib-treated patients in all domains of the SF-36 except for the mental health domain.

COX-2在大鼠全肝/部分肝移植缺血再灌注损伤中的表达

目的探讨COX-2在大鼠全肝/部分肝移植缺血再灌注损伤(IRI)模型中的表达及其意义。方法雄性Wistar大鼠随机分成3组:正常对照组(O);全肝移植组(LT);50%部分肝移植组(PLT)。逆转录-聚合酶链反应(RT-PCR)半定量检测COX-2 mRNA的表达;免疫组织化学显示COX-2阳性细胞分布规律;酶联免疫吸附试验(ELISA)检测血清TNF-α和IL-10水平。结果COX-2的表达为肝移植缺血再灌注损伤机制所必需,IRI损伤较重的部分肝移植组(PLT)伴随有较高水平的COX-2 mRNA表达;且存在其表达量随再灌注后时间点的延长而逐渐下降的规律。结论COX-2参与了肝移植缺血再灌注损伤,是移植物IRI的重要效应分子,是IRI的参与者之一。

COX-2和Ki67在鲍恩病皮损中的表达

目的研究COX-2和Ki67在鲍恩病皮损中的表达情况,并探讨两者之间的关系。方法应用免疫组化SP染色法对27例鲍恩病患者皮损及15份正常皮肤组织进行COX-2和Ki67染色。结果 COX-2与Ki67在正常皮肤组织中表达非常低,而在鲍恩病皮损中染色强度显著增高(P<0.05)。COX-2与Ki67在鲍恩病皮损中的表达水平呈显著正相关(r=0.451,P<0.05)。结论 COX-2与鲍恩病的发生密切相关,过度表达的COX-2蛋白可能参与肿瘤细胞的增生过程。

Role of cyclooxygenase-2 in the carcinogenesis of gastrointestinal tract cancers: A review and report of personal experience

Selective cyclooxygenase （COX）-2 inhibitors （coxibs） were developed as one of the anti-inflammatory drugs to avoid the various side effects of non-steroidal anti-inflammatory drugs （NSAIDs）. However, coxibs also have an ability to inhibit tumor development of various kinds the same way that NSAIDs do. Many experimental studies using cell lines and animal models demonstrated an ability to prevent tumor proliferation of COX-2 inhibitors. After performing a randomized study for polyp chemoprevention study in patients with familial adenomatous polyposis （FAP）, which showed that the treatment with celecoxib, one of the coxibs, significantly reduced the number of colorectal polyps in 2000, the U.S. Food and Drug Administration （FDA） immediately approved the clinical use of celecoxib for FAP patients. However, some coxibs were recently reported to increase the risk of serious cardiovascular events including heart attack and stroke. In this article we review a role of COX-2 in carcinogenesis of gastrointestinal tract, such as the esophagus, stomach and colorectum, and also analyze the prospect of coxibs for chemoprevention of gastrointestinal tract tumors.

COX-2 as a potential biomarker and therapeutic target in melanoma

With a constantly increasing incidence,cutaneous melanoma has raised the need for a better understanding of its complex microenvironment that may further guide therapeutic options.Melanoma is a model tumor in immuno-oncology.Inflammation represents an important hallmark of cancer capable of inducing and sustaining tumor development.The inflammatory process also orchestrates the adaptative immunosuppression of tumor cells that helps them to evade immune destruction.Besides its role in proliferation,angiogenesis,and apoptosis,cyclooxygenase-2(COX-2)is a well-known promoter of immune suppression in melanoma.COX-2 inhibitors are closely involved in this condition.This review attempts to answer two controversial questions:is COX-2 a valuable prognostic factor?Among all COX-2 inhibitors,is celecoxib a suitable adjuvant in melanoma therapy?

Expressions of cyclooxygenase-2 and matrix metalloproteinase-9 in cervical carcinoma and their clinical significance

Objective: To investigate the expressions of cyclooxygenase (COX)-2 and matrix metalloproteinase (MMP)-9 in cervical carcinoma and their clinical significance. Methods: Immunohistochemistry SP method was used to detect the expres- sions of COX-2 and MMP-9 in 72 cases of invasive carcinoma of cervix (ICC) and 16 cases of normal cervical epithelium remote from tumor (NCE). The relationships between the expressions of COX-2, MMP-9 in ICC and some characteristics relating to clinical pathology of cervical carcinoma such as histological grading, lymph node metastasis, stromal invasion and FIGO stage were analyzed statistically. Results: The rates of the positive expressions of COX-2 and MMP-9 in ICC were significantly higher than those in NCE. COX-2: 88.9% (64/72) in group ICC and 12.5% (2/16) in group NCE, P = 0.000; MMP-9: 94.4% (68/72) in group ICC and 43.8% (7/16) in group NCE, P = 0.000. The expression of COX-2 was positively correlated with lymph node metastasis (r = 0.296, P = 0.012) and stromal invasion (r = 0.257, P = 0.029). The expression of MMP-9 was positively correlated with FIGO stage (r = 0.329, P = 0.005) and histological grading (r = 0.351, P = 0.003). The expression of COX-2 was positively correlated with the expression of MMP-9 in ICC (r = 0.297, P = 0.011). Conclusion: The overexpressions of COX-2 and MMP-9 were closely related to the invasion and growth of cervical carcinoma. The tissue with the overexpression of COX-2 had strong invasion ability. COX-2 and MMP-9 had synergistic effect on proliferation, invasion and metastasis of cancer cells. Detecting the coexpression of COX-2 and MMP-9 may be of value in further understanding the biological behavior and predicting the prognosis of cervical carcinoma.

STUDY ON THE EXPRESSION OF CYCLOOXYGENASE-2 IN HEPATOCELLULAR CARCINOMA CELL LINES AND ON THE GROWTH INHIBITION EFFECT OF NS-398

Objective： To investigate the expression of cyclooxygenase -2 （COX-2） in hepatocellular carcinoma cell lines and to explore the effect of NS-398, a selective inhibitor for COX-2, on HepG-2 cell line. Methods： lmmunohistochemistry and RT-PCR were used to investigate COX-2 expression in 6 HCC cell lines. MTT and Flowcytometry were used to evaluate the effect of the selective inhibitor of COX-2, NS-398, on HepG-2 cell lines. Results： All six HCC cell lines showed COX-2 expression at protein level. Five out of 6 cell lines showed COX-2 expression at mRNA level. NS-398 could suppress the growth of HepG-2 cell line, in a time and dose dependant manner. Conclusion： NS-398, a selective inhibitor of COX-2, showed inhibition effect on HepG-2 HCC cell line. The efficacy of inhibition was time and dose dependent, providing a new evidence for chemoprovention of hepatocellular carcinorma with COX-2 selective inhibitors.

Protective effect of notoginsenoside and tanshinone IIA on inflammation-related colorectal cancer mice and the inhibition effect on COX-2 expression

Objective To explore the preventive effects and possible mechanisms of action of notoginsenoside(NGS)and tanshinone IIA(TSN)in inflammation-related colorectal cancer(IRCC)in mice.Methods Eighty-eight male C57BL/6 mice were randomly assigned to 11 groups(n=8 each group).Azomethane oxide+dextran sulfate(AOM+DSS)model control(model),NGS lowdose(l-NGS),NGS medium-dose(m-NGS),NGS high-dose(h-NGS),TSN low-dose(l-TSN),TSN medium-dose(m-TSN),TSN high-dose(h-TSN),(NGS+TSN)low-dose[l-(NGS+TSN)],(NGS+TSN)medium-dose[m-(NGS+TSN)],(NGS+TSN)high-dose[h-(NGS+TSN)],and blank groups were established.The first 10 groups were intraperitoneally injected with AOM to induce inflammatory colon cancer,whereas the blank group was intraperitoneally injected with 0.9%NaCl solution.The first 10 groups drank a 2.5%sodium DSS aqueous solution continuously from day 5 for three cycles(one cycle:five days,every three weeks),and the blank group was allowed free access to water.Drug groups were administered NGS(low,medium,or high dose),TSN(low,medium,or high dose),or NGS+TSN(low,medium,or high dose),and the model and blank groups were administered saline by lavage until the end of the experiment.The general activity,body weight,and survival rate of and incidence of adenocarcinoma in mice were detected and the expression of cyclooxygenase 2(COX-2)was detected by immunohistochemistry.Results(1)The survival rate of mice with IRCC in the h-NGS,m-TSN,h-TSN,m-(NGS+TSN),and h-(NGS+TSN)groups was significantly increased than that in other groups(P<0.05).(2)The incidence of tumors in the h-(NGS+TSN),m-TSN,and l-NGS groups was significantly lower than that in the model group(P<0.05).(3)The expression level of COX-2 in tumor tissues of mice in the m-(NGS+TSN)and h-(NGS+TSN)groups was significantly lower than that in the model group(P<0.05).Conclusion Tumor formation was inhibited by m-TSN and h-(NGS+TSN)treatments in mice with IRCC,and h-(NGS+TSN)treatment inhibited the COX-2 pathway.

The clinical significance of CD97, NF-kB and COX-2 ingastric MALT lymphomas

Background and Objectives: Increased expression of the CD97, nuclear factor-kB (NF-kB) and cyclooxygenase-2 (COX-2) has been found to play an important role in development of many cancers, including gastric neoplasm. However, the expression and biological behavior of CD97, NF-kB and COX-2 in gastric MALT (mucosa-associated lymphoid tissue) lymphoma has not been well investigated. Methods: The expressions of CD97, COX-2 and NF-kB in 47 cases of gastric MALT lymphoma were detected immunohistochemically, and the relevance between their expressions and the biological behavior was analyzed retrospectively. Results: 1) The expressions of CD97, NF-kB and COX-2 were 87.2%, 36.2% and 48.9%, respectively;2) The difference of CD97 expression between depth of invasion limited in mucosa and submucosa and beyond muscularis propria was significant (100.0% vs. 71.4%, P < 0.01). Moreover, the expression of nuclear CD97 between stage IIE, III, IV and stage I patients showed significant difference (96.4% vs. 73.7%, P < 0.05);3) The expression of NF-kB was significantly correlated with tumor size, depth of invasion and stage;4) The expression of COX-2 was significantly correlated with Helicobacter pylori infection, clinical stage, depth of invasion and tumor size (P < 0.05). Conclusions: Expressions of CD97, NF-κB and COX-2 were correlated with tumor invasion and metastasis in gastric MALT lymphoma.

Treatment of severe radiation proctitis with high dosage of vitamin C in combination with cyclooxygenase-2 inhibitor

Objective:To explore the new treatment strategies for radiation proctitis,which is the most common complication of pelvic tumor malignancies.Methods:Four cases of patients with severe radiation proctitis were treated with high-dosage vitamin C(VC,12–24 g/d,iv)combined with cyclooxygenase-2(cyclooxygenase-2,COX-2)inhibitors.Results:For these four cases,the diarrhea,hematochezia,tenesmus,pain,and other symptoms were significantly improved.The edema of the rectal wall is also significantly improved in the imaging review.Conclusion:The high-dosage VC combined with the treatment of severe radiation proctitis is safe and effective.

The effects of the same target on malignant proliferation of human lung cancer cells with different expression levels of COX-2 protein

Objective: The aim of the study was to explore the effects of the same target (si-10) on lung cancer cells with different expression levels of cyclooxygenase-2 (COX-2) protein by RNAi and malignant proliferation of these cells. Methods: COX-2 was selected as the target and one siRNA expression vector with the best effect was selected and thought as the subject from three COX-2 siRNA expression vectors with human U6 promoter. The siRNA expression vector (psi-10) and the vacant vector (pEGFP) were transfected into these cells with different COX-2 expression states (801D, A549 and LTEP-A2) with lipofectamine respectively and the transfected cell strains were constructed. The change of COX-2 expression levels was examined by Western blot and RT-PCR. The effects on the proliferation of lung cancer cells were studied by cell growth curve and clonogenic assay. Results: The siRNA and U6 promoter were validated by PCR, restriction endonucleases identification and DNA sequencing and BLAST alignment and cloned into the pEGFP vector. The cell strains transfected that 801D was used as maternal line were named as 801D-p and 801D-10 respectively. The cell strains transfected that A549 was used as maternal line were named as A549-p and A549-10 respectively. The cell strains transfected that LTEP-A2 was used as maternal line were named as LTEP-A2-p and LTEP-A2-10 respectively. These cells transfected pEGFP (801D-p, A549-p and LTEP-A2-p) had the expression of GFP and 801D-10, A549-10 and LTEP-A2-10 cells had not in 24, 48 and 72 hours after transfected. The results of RT-PCR and Western blot showed the siRNA expression vector produced marked effects in two cells (A549 and LTEP-A2) expressing COX-2 and the expression of COX-2 was inhibited. But the inhibited effects were differ- ent and the expression of COX-2 was more inhibited obviously in LTEP-A2 cells than in A549 cells though the expression of COX-2 was also inhibited obviously in A549 cells. In contract to their maternal line, the levels of COX-2 mRNA of LTEP-A2-10 and A549-10 cells reduced 64.2% and 61.2% respectively; the levels of COX-2 protein reduced 60.2% and 56.2% respectively. But the levels of COX-2 mRNA and protein had not change in 801D cells not expressing COX-2. The results of cell growth curve and clonogenic assay showed the growth of LTEP-A2-10 cells slowed and the clonal formation rate reduced and the size of the colonies became small; the growth of A549-10 cells showed slow and more obviously in the cell growth curve especially. But the growth of 801D-10 cells had not obvious change. Conclusion: The si-10 target of COX-2 has different inhibition effects on lung cancer cells with different COX-2 expression levels and the different inhibition effects have different effects on cells malignant proliferation.

美洛昔康对急性肺损伤兔肺组织 COX －2与 PPAR －γmRNA 表达的影响

目的：观察美洛昔康对内毒素（endotoxin， ET）复制急性肺损伤（ALI）时兔肺组织环氧合酶－2（ cyclooxygenase －2， COX －2）和过氧化物酶增殖体激活受体－γ（ peroxisome proliferation activated receptor －γ， PPAR－γ） mRNA变化的影响，来探讨其对ALI保护作用的机制。方法将24只日本大耳白兔随机分为生理盐水对照组（ A组）、内毒素致伤组（ B组）、美洛昔康干预组（C组）。用ET（700μg／kg）静脉注射复制兔子ALI模型，美洛昔康（2．5 mg／kg）进行干预，观测兔动脉血气、光镜肺组织病理、肺组织中COX－2 mRNA与PPAR－γmRNA的表达。结果 COX－2 mRNA 表达 B 组显著高于 A 组（P ＜0．01），C 组显著低于 B 组（P＜0．01）。PPAR－γmRNA表达B组显著低于A组（P＜0．01），C组显著高于B组（P＜0．01）。结论美洛昔康可通过下调COX－2 mRNA和上调PPAR－γmRNA的表达，在一定程度上对兔内毒素性ALI产生保护作用。

Enhanced macrophage polarization induced by COX-2 inhibitor-loaded Pd octahedral nanozymes for treatment of atherosclerosis

Inhibition of foam cell formation is considered a promising treatment method for atherosclerosis,the leading cause of cardiovascular diseases worldwide.However,currently available therapeutic strategies have shown unsatisfactory clinical outcomes.Thus,herein,we design aloperine(ALO)-loaded and hyaluronic acid(HA)-modified palladium(Pd)octahedral nanozymes(Pd@HA/ALO)that can synergistically scavenge reactive oxygen species(ROS)and downregulate cyclooxygenase-2(COX-2)expression to induce macrophage polarization,thus inhibiting foam cell formation to attenuate atherosclerosis.Due to the targeted effect of HA on stabilin-2 and CD44,which are overexpressed in atherosclerotic plaques,Pd@HA/ALO can actively accumulate in atherosclerotic plaques.Subsequently,the antioxidative effects of Pd octahedral nanozymes are mediated by their intrinsic superoxide dismutase-and catalase-like activities capable of effective scavenging of ROS.In addition,anti-inflammatory effects are mediated by controlled,on-demand near-infrared-triggered ALO release leading to inhibition of COX-2 expression.Importantly,the combined therapy can promote the polarization of macrophages to the M2 subtype by upregulating Arg-1 and CD206 expression and downregulating expression of TNF-α,IL-1βand IL-6,thereby inhibiting atherosclerosis-related foam cell formation.In conclusion,the presented in vitro and in vivo data demonstrate that Pd@HA/ALO enhanced macrophage polarization to reduce plaque formation,identifying an attractive treatment strategy for cardiovascular disease.

Clinical Use of COX-2 Inhibitors Containing Quinoline Heterocycle as a Selective Therapeutic Agents for Complementary Medicine

Inflammation represents an initial response of immune system and is involved in a number of biochemical inci-dents.Such incidents may multiply and further develop the provocative response.Over the past 15 years,various classes of secondary metabolites that were isolated from plant and marine sources have been described as natural cyclooxygenase(COX)inhibitors.The majority of natural COX inhibitors could be used as a selective therapeutic agent for complementary medicine and clinical applications.Currently,the inflammation is commonly treated by non-steroidal anti-inflammatory drugs(NSAIDs),several medications of which,however,have been linked to renal and gastrointestinal side effects.A variety of inhibitors of COX-2 that are selective(celecoxib,rofecoxib,valdecoxib and others)have been designed as NSAIDs mostly with enhanced stomach safety profiles.This helps to improve the compliance and functions in the geriatric patients as they have so many complications and problems associated with the diseases.The use of complementary medicine in combination with clinical therapy might give better results than medicine alone.Some disease condition like cancer which shows the COX-2 expressions could also have treatment related problems in such cases the selective inhibitors used as a complementary medicine.On the other hand,elevated cardiovascular risks have brought increasing worries about the safety of using specific inhibitors of COX-2.This current review focuses on how quinoline heterocycle was used for creation of inhibitors of COX-2 since 2009 along with its clinical significance in complementary medicine.These agents included the variety of substituents on the ring or ring attached to other heterocycles.As a result,the quinoline heterocycle will be used for creating and finding anti-inflammatory COX-2 medicines.