Evaluation of the neurotoxic effects of intrathecal administration of (S)-(+)-Ketoprofen on rat spinal cords: randomized controlled experimental study / Avaliação dos efeitos neurotóxicos da administração intratecal do (S)-(+)-cetoprofeno em medula espinhal de rato: estudo experimental randômico e controlado

Abstract Background and objectives Intrathecal administration of non-steroidal anti-inflammatory drugs is more efficacious for post-operative pain management. Cyclooxygenase inhibiting non-steroidal anti-inflammatory drugs like (S)-(+)-Ketoprofen, may be effective at lower intrathecal doses than parenteral ones. Preclinical safety regarding possible neurotoxicity associated with the intrathecal (S)-(+)-Ketoprofen was not evaluated. Here we analysed the neurotoxicity of intrathecally administered (S)-(+)-Ketoprofen in rats. Methods A randomized placebo-controlled experimental study was conducted. Sprague-Dawley rats (250-300 g) aged 12-16 weeks were randomly divided into 2 treatments [100 and 800 µg (S)-(+)-Ketoprofen] and control (sterile water) groups. Intrathecal catheters were placed via the atlantoaxial space in anesthetized rats. Pinch-toe tests, motor function evaluations and histopathological examinations of the spinal cord and nerve roots were performed at days 3, 7 and 21. Spinal cord sections were evaluated by light microscopy for the dorsal axonal funiculus vacuolation, axonal myelin loss, neuronal chromatolysis, neuritis, meningeal inflammation, adhesions, and fibrosis. Results Rats in all the groups exhibited normal pinch-toe testing response (score = 0) and normal gait at each observed time (motor function evaluation score = 1). Neurotoxicity was higher with treatments on days 3 and 7 than that on day 21 (2, 3, 0, p = 0.044; 2, 5, 0, p = 0.029, respectively). On day 7, the total scores reflecting neuronal damage were higher in the 800 µg group than those in the 100 µg and Control Groups (5, 3, 0, p = 0.048, respectively). Conclusion Intrathecal (S)-(+)-Ketoprofen caused dose-dependent neurohistopathological changes in rats on days 3 and 7 after injection, suggesting that (S)-(+)-Ketoprofen should not be intrathecally administered.

Resumo Justificativa e objetivos A administração intratecal de anti-inflamatórios não esteroides é mais eficaz no tratamento da dor pós-operatória. Anti-inflamatórios não esteroides, como o (S)-(+)-cetoprofeno, pode ser eficaz em doses intratecais inferiores às parenterais. A segurança pré-clínica relativa à possível neurotoxicidade associada ao (S)-(+)-cetoprofeno intratecal não foi avaliada. Neste estudo avaliamos a neurotoxicidade do (S)-(+)-cetoprofeno administrado por via intratecal em ratos. Métodos Conduzimos um estudo experimental randomizado e controlado por placebo em ratos Sprague-Dawley (250-300 g) com idades entre 12 e 16 semanas. Eles foram randomicamente divididos em dois grupos de tratamento [100 e 800 µg de (S)-(+)-cetoprofeno] e um de controle (água estéril). Cateteres intratecais foram colocados através do espaço atlantoaxial nos ratos anestesiados. Testes de pinça, avaliações da função motora e exames histopatológicos da medula espinhal e das raízes nervosas foram realizados nos dias 3, 7 e 21 do estudo. Os cortes da medula espinhal foram avaliados por microscopia de luz para vacuolização do funículo axonal dorsal, perda de mielina axonal, cromatólise neuronal, neurite, inflamação, aderências e fibrose das meninges. Resultados Em todos os grupos, os ratos exibiram resposta normal ao teste de pinça (pontuação = 0) e marcha normal em cada tempo observado (escore de avaliação da função motora = 1). A neurotoxicidade foi maior com os tratamentos nos dias 3 e 7 do que no dia 21 (2, 3, 0, p = 0,044; 2, 5, 0, p = 0,029, respectivamente). No dia 7, os escores totais refletindo o dano neuronal foram maiores no grupo com 800 µg que nos grupos com 100 µg e controle (5, 3, 0, p = 0,048, respectivamente). Conclusão A administração intratecal de (S)-(+)-cetoprofeno causou alterações neuro-histopatológicas dose-dependentes em ratos nos dias 3 e 7 após a aplicação e sugerindo que o (S)-(+)-cetoprofeno não deve ser administrado por via intratecal.

Selective cyclooxygenase inhibitors increase paclitaxel sensitivity in taxane-resistant ovarian cancer by suppressing P-glycoprotein expression / 부인종양

OBJECTIVE: The purpose of this study was to investigate whether selective cyclooxygenase (COX) inhibitors promote paclitaxel-induced apoptosis in taxane-resistant ovarian cancer cells by suppressing MDR1/P-glycoprotein (P-gp) expression. METHODS: Taxane-resistant ovarian cancer cells were cultured with paclitaxel alone or combined with a selective COX inhibitors. The expression patterns of MDR1/P-gp and the ability of COX inhibitors to inhibit growth of taxane-resistant ovarian cancer cells were measured. The efficacy of prostaglandin E2 (PGE2) supplementation was measured to evaluate the mechanisms involved in suppressing MDR1 gene expression. RESULTS: P-gp was upregulated in taxane-resistant ovarian cancer cells compared to paired paclitaxel-sensitive ovarian cancer cells. An 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay showed that selective COX inhibitors significantly enhanced the cytotoxic effects of paclitaxel in taxane-resistant ovarian cancer cells via a prostaglandin-independent mechanism. These increased apoptotic effects were further verified by measuring an increased percentage of cells in sub-G1 stage using flow cytometry. Selective COX inhibitors suppressed MDR1 and P-gp expression. Moreover, combined treatment with paclitaxel and selective COX inhibitors increased poly (ADP-ribose) polymerase (PARP) cleavage in taxane-resistant ovarian cancer cells. CONCLUSION: Selective COX inhibitors significantly promote paclitaxel-induced cell death in taxane-resistant ovarian cancer cells in a prostaglandin-independent manner. COX inhibitors could be potent therapeutic tools to promote paclitaxel sensitization of taxane-resistant ovarian cancers by suppressing MDR1/P-gp, which is responsible for the efflux of chemotherapeutic agents.

Progress of study on radiosensitization and chemotherapy sensitization of selective COX-2 inhibitors for tumor / 国际肿瘤学杂志

COX-2 and tumor are closely related.Pre-clinical studies have shown that the selective COX-2 inhibitor can strengthen the tumor radiation sensitivity function and chemotherapy medicine anti-tumor activeness,selective COX-2 inhibitor may provide new method and way for tumor prevention and treatment.

Effect of flurbiprofen axetil pretreatment on LPS-induced acute lung injury in rats / 中华麻醉学杂志

Objective To investigate the effect of flurbiprofen axetil(FA)on the acute lung injury(ALI)induced by LPS in rats.Methods Forty male SD rats weighing 190-220 g were nmdomly divided into 3 groups:group Ⅰ control(C,n=8);groupⅡ LPS(n=16)and group Ⅲ FA+LPS(n=16).In group Ⅱ and Ⅲ LPS 5 mg/kg in 1 ml of normal saline(NS)w88 given iv.In group Ⅲ FA 6 mg/kg in NS 1 ml was given Ⅳ 0.5 hbefore LPS administration.In group Ⅱ and Ⅲ 8 animals were killed at 2 h(T1)and 4 h(T2)after LPS administration respectively.Blood samples were obtained at T1 and T2 for blood gas analysis and determination of serum TXB2,6-keto PGF1α(by radio-immuno assay),TNF-α,IL-1β,IL-6 and IL-10 concentrations(by ELISA).Lungs were removed for determination of W/D lung weight ratio,lung water content(LC)and microscopic examination.ResultsCompared with group C,LPS signitlcanfly decreased PaO2,PaO2/FiO2 and increased PaCO2,W/D lung weight ratio,LC,serum TXB2,6-keto-PGF1α concentrations,TXB2/6-keto-PGF1α ratio and serum IL-1β,TNF-α,and IL-6 concentrations in LPS group.Pulmonary edema and hemorrhage were observed in LPS group.FA pretreatment significantly attenuated LPS-induced blood gas,bio-chemical and pulmonary histological changes in group Ⅲ.Conclusion Flurbiprofen axetil pretreatment can protect the lungs against LPS-induced acute injury by down-regulating TXB2/6-keto-PGF1α ratio and inhibiting inflammatory response.

Effects of Cyclooxygenase Inhibitors on Neuropathic Pain following Spinal Nerve Ligation in Rats / 대한마취과학회지

BACKGROUND: The facilitatory effect of spinal prostaglandins (PGs) on nociceptive transmission suggests that early PG synthesis after nerve injury could be important in the development of allodynia. METHODS: The aim of this study is to examine the effects of diclofenac (nonselective COX inhibitor), SC-560 (selective COX-1 inhibitor), and NS-398 (selective COX-2 inhibitor) on mechanical allodynia and thermal hyperalgesia in the neuropathic pain model. The rats underwent right L5 spinal nerve ligation (SNL) and were assigned to three COX inhibitor groups to be injected intraperitoneally with different administration dosages (0.2 mg, 1 mg, 5 mg) 30 minutes before, and at 1, 2, and 3 days after SNL. The withdrawal threshold of both hindpaws in response to mechanical stimulation was measured by dynamic plantar anesthesiometer and the withdrawal ratio of right to left hindpaw was calculated. The thermal stimulation applied to both hindpaws by the plantar test was calculated different administration dosages were compared with the vehicle group. RESULTS: There were no differences in mechanical allodynia among the lower dosage groups (0.2 mg) until 14 days after SNL. However, 1 mg of NS-398 decreased mechanical allodynia compared with the vehicle group at 14 days after SNL, and 5 mg of NS-398 decreased mechanical allodynia at 3 days after SNL. However, there was no difference in thermal hyperalgesia between the groups. CONCLUSIONS: These results suggest that intraperitoneal administration of COX inhibitor (especially selective COX-2 inhibitor) after nerve ligation injury can attenuate the development of mechanical allodynia.

Effects of Nimesulide on Expression of Matrix Metalloproteinase-2 in Human Colonic Cancer Cell Lines / 中国普外基础与临床杂志

Objective To investigate the effects of selective cyclooxygenase-2(COX-2) inhibitor nimesulide on the proliferation of colon adenocarcinoma cells in vitro and the expression of matrix metalloproteinase-2(MMP-2).Methods The human colon cancer cell lines HT-29 and HCT-116 were employed in the study,grouped as nimesulide group,DMSO control group and blank control group.After treatment with nimesulide,the inhibitory effect of nimesulide on the proliferation of cancer cells was quantified by MTT assay,and the expression of MMP-2 in the cells was detected by quantitative zymography.Results Nimesulide inhibited the proliferation of HT-29 and HCT-116 cells in time and dose-dependent manners.The inhibitory effect on HT-29 cells was stronger than that on HCT-116 cells.Nimesulide down-regulated the MMP-2 expression in HT-29 cells,whereas the expression in HCT-116 cells remained unchanged.Conclusion Nimesulide can obviously inhibit the growth of colon cancer HT-29 cells with positive COX-2 protein,suggesting that nimesulide may down-regulate the expression of MMP-2 by inhibiting the activity of COX-2.

Effects of Cyclooxygenase and Lipoxygenase Inhibitors on the Proliferation of Colon Cancer Cells and Their Production of Eicosanoids / Journal of the Korean Cancer Association, 대한암학회지

PURPOSE: Epidemiological and laboratory studies suggest that nonsteroidal antiinflammatory drugs (NSAIDs) reduce the risk of colon cancer and that the inhibition of colon cancer is mediated through modulation of eicosanoid production. The present study examined the effect of cyclooxygenase (COX) and lipoxygenase (LOX) inhibitors on colon cancer cell growth and prostaglandin E(2) (PGE(2)) or leukotriene B(4) (LTB(4)) secretion by these cells. MATERIALS AND METHODS: The human colon adenocarcinoma cell lines, Caco-2 and HT-29 cells, were cultured in serum-free medium with various concentrations of indomethacin, piroxicam or esculetin in the presence of 0.15nM or 10nM linoleic acid. Cell number was estimated by MTT assay and PGE(2) and LTB(4) were analyzed by enzyme immunoassay. RESULTS: The NSAIDs inhibited cell proliferation in a concentration-dependent manner. However, the potency and efficacy of each drug varied in the two cell lines. In Caco-2 cells, the effect of esculetin was higher than that of indomethacin, and piroxicam had no effect. In HT-29 cells, only indomethacin significantly inhibited cell proliferation. All three agents inhibited PGE(2) secretion in a dose-dependent manner; the effect of indomethacin was highest and that of esculetin lowest. The secretion of LTB4 was increased by indomethacin and piroxicam but decreased by esculetin. The effects of these drugs on cell proliferation and eicosanoid secretion were not influenced by linoleic acid concentrations in the culture media. Neither exogenous PGE2 nor LTB4 affected cell proliferation. The results of Pearson correlation analyses revealed that changes in cell proliferation were somewhat related to both concentrations of NSAIDs in the culture medium and production of PGE(2) and LTB(4). CONCLUSION: The present data suggests that the anti-proliferative effect of NSAIDs may not be entirely attributed to changes in the production of PGE2 and/or LTB4 in the two colon cancer cell lines. These NSAIDs may inhibit cell proliferation largely independent of their ability to modulate eicosanoid synthesis.

Morphometric Study of the Effects of Various Analgesic Compound in Experimental Arthritis Model / 대한해부학회지

Arthritis is the most common disease of joint in old age and almost all the old human are suffering from arthritis. Arthritis gives so severe pain hard to endure that it can devastate human. But we still do not know where the arthritic pain comes from and the generation mechanism of it. For the study of effects of anti-inflammatory drugs on the c-fos immunoreactive neurons, substance P-and CGRPimmunoreactive neurons in dorsal horn and DRG, cyclooxygenase (COX) inhibitors indomethacin (0.5 mg/kg), piroxicam (0.5 mg/kg), NMDA receptor antagonist MK 801 (2 mg/kg), and capsaicin (50 mg/kg) were administered to the experimental arthritis model. Male Sprague-Dawley rats were used for this study. Arthritis was induced by injection of 4% kaolin followed by 2% carrageenan into the articular capsule of left knee. Two hours, 24 hours and 7 days after injection, animals were sacrificed and processed for imunohistochemical staining for c-fos in spinal dorsal horn, for substance P (SP) and CGRP in DRG. The results were as follows; 1. The number of c-fos immunoreactive neurons were significantly decreased at 2 h after piroxicam and MK-801 administration and 1 week after indomethacin, MK-801 and capsaicin treatment in the inflamed side of dorsal horn. 2. There were the significant decrease of SP-and CGRP-immunoreactive area 2 h after indomethacin administration and 1week after capsaicin treatment in the inflamed side of dorsal horn. 3. The number of SP- and CGRP-immunoreactive neurons in DRG were decreased after drugs administration and no difference is in the degree of effectiveness between drugs. Indomethacin and piroxicam which is an inhibitors of COX, significantly reduced the expression of c-fos proteins and desensitized nociceptive primary afferents at the early time, and capsaicin, a pungent algesic substance, decreased the level of c-fos protein, SP and CGRP over a wider time in dorsal horn and DRG.

NS-398, a selective cyclooxygenase-2 inhibitor, can down-regulate the expression of P-glycoprotein in the gastric cancer cell / 中华消化杂志

Objective To investigate the effect of NS-398, a selective cyclooxygenase-2 (COX-2) inhibitor, on the expression of P-glycoprotein(P-gp) in a gastric cancer cell line SGC-7901. Methods SGC-7901 cells were treated with NS-398 in different concentrations (0, 10 ?mol/L and 100 ?mol/L) respectively. Prostaglandin E2(PGE2) was detected by ELISA. Twenty four hs and 48 hs later, the expression of mdr1 mRNA were detected by RT-PCR. P-gp protein expression in SGC-7901 cells was detected by immunocytochemical technique after NS-398 treatment.Results NS-398 can inhibit the expression of PGE2 in a dose-dependent manner(P

Signification and expression of cyclooxygenase-2 in rats with bleomycin-induced pulmonary fibrosis / 中国免疫学杂志

Objective:To investigate the distribution and expression of the cyclooxygenase-2(COX-2)in lung tissues and the effect of its inhibition in bleomycin(BLM)-induced pulmonary fibrosis in rats.Methods:72 male SD rats were randomly divided into three groups:the control group,model group and celecoxib group.Immunohistochemical method was used to detect the distribution of COX-2 in the stage of acute pulmonary alveolitis.HE and Masson staining methods were used to evaculate the degree of alveolitis and pulmonary fibrosis.Results:(1)In early stage of pulmonary fibrosis except in the control group,COX-2 expression was found in small bronchial epithelial cells in the other two groups,especially the model group.(2)Compared with the control group,the other two groups had alveolitis(P

Analgesic Effects of Intraperitoneal Morphine, Nalbuphine, and Ketorolac on the Formalin Test in Rats / 대한마취과학회지

BACKGROUND: The antinociceptive effect and the potency of systemically administered morphine (micro-agonist), nalbuphine (agonist-antagonist), and ketorolac (cyclooxygenase inhibitor) was examined in rats using the formalin test. METHODS: Male Sprague-Dawley rats (250~300 g) received intraperitoneal injection of either saline or 3 doses of each test drug (0.3, 1.0, 3.0 mg/kg of morphine, 0.3, 1.0, 3.0 mg/kg of nalbuphine, and 10, 30, 100 mg/kg of ketorolac) 30 minutes prior to formalin injection. 50 microliter of 10% formalin was injected into the dorsal surface of the right hindpaw after 1 minute of 4% halothane induction. The construction of the dose-response curves and the determination of doses producing 50% maximum possible effect (ED50) were computed. RESULTS: Intraperitoneal injection of morphine, nalbuphine and ketorolac resulted in the significant, dose-dependent supression of both phases, but nalbuphine has a ceiling effect at high dose for analgesia at the phase I of the formalin test. The rank order of relative potency in rats to the formalin test was nalbuphine (1.16)>morphine (1)>>ketorolac (0.1) in phase I, morphine (1)>nalbuphine (0.61)>>ketorolac (0.02) in phase IIa, and morphine (1)>nalbuphine (0.57)>>ketorolac (0.03) in phase IIb. CONCLUSION: Comparing the systemic analgesic potency, nalbuphine and ketorolac will be needed in dosages 1.5 and 50 times that of morphine, respectively. These results suggest that ketorolac is not good enough as a single analgesic drug in preemptive analgesia for major surgery.

The inhibitory effect of cyclooxygenase inhibitor on human breast cancer line MDA-MB-231 in vitro / 重庆医科大学学报

Objective:To investigate the inhibitory effect of cyclooxygenase inhibitor acetylsalicylic acid(ASA),and a selective COX-2 inhibitor(Nimesulide) on the growth of human breast cancer cell line MDA-MB-231 in vitro.Methods:The inhibitory effect was detected by MTT assay.Immunohistochemical assay was performed to examine the expressions of COX-2 and c-erbB-2 in SKOV3 cell line treated by NSAIDs.Results:A decrease in cell number compared with controls was observed in all of the cell line treated with ASA and Nimesulide.It was a dose-dependent inhibition of cell proliferation.COX-2 was expressed positive in MDA-MB-231 and the expression of cerbB-2 was found to decrease by immunohistochemical assay.Conclusion:NSAIDs can inhibit the growth of human breast cancer cell line MDA-MB-231 in vitro.