HEPATOPROTECTIVE POTENTIAL OF EUGENIA?UNIFLORA?L AGAINST GENTAMYCIN INDUCED HEPATOXICITY

Hepatotoxicity is a common drug adverse effect and gentamycin has been linked to hepatotoxic adverse reactions. Folklore and ethnobotanical studies indicate Eugenia uniflora L is used in the treatment of gastrointestinal ailments and has exhibited diverse biological activities. We investigated the hepatoprotective potential of this plant in treating gentamycin-induced hepatoxicity and compared the effect with Celebrex a COX2 selective inhibitor. Twenty-eight male adult Wistar rats average of 225g were used for the study and randomised into groups as described: normal control( normal saline), negative control: Gentamycin (40mg/kg. i.p), positive control; Gentamycin (40mg/kg. i.p) +5mg/kg Celebrex. Extract low dose: Gentamycin (40mg/kg i.p)+(50mg/kg) Eugenia uniflora L. leaves, intermediate-dose: Gentamycin (40mg/kg i.p) +100mg/kg Eugenia uniflora L leaves, high dose : Gentamycin (40mg/kg, i.p)+ (200mg/kg, ) of Eugenia uniflora L leaves. Our findings indicate that the body weight was unaffected throughout the experiment, as clearly demonstrated by the lack of significant variability (p<0.05). Hepatotoxicity was confirmed by dose-dependent alteration in Liver marker enzymes, including AST, ALT, and ALP. Eugenia uniflora L leaves were able to ameliorate the levels of these liver enzymes to a normal level. Liver tissue revealed a dose-dependent curative effect with Eugenia uniflora L compared to the COX2 inhibitor (Celebrex) treatment. Consequently, we hereby report, for the first time, that an aqueous extract of Eugenia uniflora L leaves confers hepatoprotection against gentamycin-induced hepatoxicity in Wistar rats.

Narrative Review of Nimesulide in Adults: Current Scenario

Nimesulide, a nonsteroidal anti-inflammatory drug (NSAID), has been used as an effective treatment regimen for patients aged >12 years for fever, acute pain, acute tendinitis, osteoarthritis and dysmenorrhea. It is reported to be a superior antipyretic and anti-inflammatory drug than paracetamol and aspirin, respectively, and is equal to any of the NSAIDs alone in terms of analgesia. This paper reviews the current scenario of nimesulide in adult patients, concerning clinical evidence, use in special population and expert opinion. Overall, in comparison to other NSAIDs, including coxibs, nimesulide has a promising overall efficacy, safety and tolerability profile, as well as a satisfactory benefit/risk evaluation.

Safety and Efficacy of Nimesulide/Paracetamol Fixed-dose Combination in Acute Pain (SAFE Study)

Background: Nimesulide shows preferential inhibition for the cyclooxygenase-2 (COX-2) enzyme, which blocks the formation of prostaglandins critical in pain and inflammatory pathways. Few studies in the past have reported rare and unpredictable hepatic effects with nimesulide. The present study aimed to evaluate the efficacy and safety of nimesulide/paracetamol (100 mg + 325 mg) fixed-dose combination twice a day for 2 weeks in the management of acute pain in Indian population. Materials and methods: This was a multicenter study, performed on 500 patients, by 24 experienced physicians across India. The primary outcome assessed clinical safety at 2 weeks for mild/serious adverse effects (AEs), change in liver function tests (LFTs), serum bilirubin and alkaline phosphatase levels. The secondary outcomes assessed the clinical effectiveness in reduction of pain at rest and at movement. Results: Analysis of LFT at 2 weeks showed a slight increase (mean change) in the aspartate transaminase {-0.73 [95% confidence interval (CI) -1.54, 0.09; p = 0.081]}, alanine transaminase [-1.73 (95% CI -2.82, -0.64; p = 0.002)], serum bilirubin [-0.02 (95% CI -0.04, -0.001; p = 0.018)] and alkaline phosphatase levels [-1.92 (95% CI -5.84, 2; p = 0.336), not exceeding the normal range. Only one in 500 patients reported AEs. The numerical rating scale (NRS) scores for intensity of pain at rest and at movement at 2 weeks, ?7 days and >7 days were 68.38%, 68.44% and 68.39%; and 65.43%, 64.60% and 66.02%, respectively. An improvement of 96.6% was observed in patient global assessment scale (GAS) and 97.2% in physician GAS. Conclusion: Nimesulide/paracetamol combination was safe, effective and well-tolerated in acute pain conditions and did not lead to clinically significant changes in liver parameters indicating hepatic safety.

Effect of COX-2 inhibitors on postoperative delirium in elderly patients undergoing orthopedic surgery and its possible mechanism / 中国临床药理学与治疗学

AIM: To observe the effects of cyclooxygenase-2 (COX-2) inhibitors on the levels of inflammatory factors, nerve damage-related factors and antioxidant factors, as well as pain and delirium scores in the plasma of elderly patients with orthopaedic surgery, to clarify the role of COX-2 inhibitors in the prevention and treatment of POD and explore its possible mechanism. METHODS: Eighty patients undergoing elective hip arthroplasty were randomly divided into parecoxib sodium group (P group, n =40) and control group (C group, n = 40). Group C was injected with the same volume of normal saline at the same time point, and the preoperative cognitive function was screened 1 d (T

A Case of Basal Cell Nevus Syndrome Improved with Oral COX-2 Inhibitor / 대한피부과학회지

No abstract available.

<b>A Case of Hyponatremia Complicated with </b><b>Small Cell Lung Cancer Successfully Treated with Goreisan </b> / 日本東洋医学雑誌

We report a case of a 74-year-old male with hyponatremia complicated with small cell lung cancer. His hyponatremia worsened even with water restriction. Oral administration of sodium was difficult because of nausea and vomiting. We recognized this patient as having illness caused by excessive water accumulation within the body, and so prescribed goreisan 7.5 g/day to treat his hyponatremia. His hyponatremia improved after the administration of goreisan. Later his hyponatremia deteriorated while being administered of meloxicam, a cyclooxygenase-2 inhibitor. This case suggests that goreisan might inhibit water reabsorption by antidiuretic hormone at the collecting duct of the kidneys via stimulation of prostaglandin synthesis.

Dipyrone & 2,5-dimethylcelecoxib suppress Th2-related chemokine production in monocyte.

Background & objectives: Selective cyclooxygenase-2 (COX-2) inhibitor is a form of non steroidal anti-inflammatory drug (NSAID) and is commonly used in autoimmune and rheumatic diseases to control inflammation and alleviate pain. Tumour necrosis factor-alpha (TNF-α) production and an imbalance of T helper 1 (Th1)/Th2 contribute to the pathogenesis of autoimmune and also anti-tumour activity. Dipyrone is a NSAID used to treat pain worldwide. The celecoxib analogue, 2,5-dimethylcelecoxib (DMC), lacks COX-2 inhibitory activity but exhibits anti-tumour properties. However, the effects and the mechanisms of dipyrone and 2,5-dimethylcelecoxib on tumour necrosis factor (TNF)-α and Th1- and Th2-related chemokines in monocytes remain poorly defined. This study was carried out to investigate the effects of dipyrone and 2,5-dimethylcelecoxib on the expression of Th1 (IP-10) and Th2 (I-309 and MDC) and TNF-α in human monocytes and the associated intracellular mechanism. methods: THP-1 cells and peripheral blood mononuclear cells (PBMCs) were pre-treated with dipyrone (10-9 – 10-4 M) and 2,5-dimethylcelecoxib (10-9 – 10-5 M) 2 h before lipopolysaccharide (LPS) stimulation. Cell supernatant was collected 24 h after LPS stimulation. TNF-α, I-309, MDC and IP-10 concentrations of cell supernatants were determined using ELISA. Intracellular signaling was evaluated by western blot. results: Dipyrone and 2,5-dimethylcelecoxib downregulated LPS-induced Th2-related chemokine I-309 and macrophage derived chemokine (MDC) production. Only high dose of 2,5-dimethylcelecoxib (10-5 M), but not dipyrone downregulated LPS-induced IP-10. Only very high dose of 2,5-dimethylcelecoxib had effect on LPS-induced TNF-α expression in PBMCs. Dipyrone and 2,5-dimethylcelecoxib suppressed LPS-induced p65 and JNK MAPK (C-Jun N-terminal kinase mitogen activated protein kinase). expression. Interpretation & conclusions: Dipyrone and 2,5-dimethylcelecoxib downregulated LPS-induced Th2-related chemokine I-309 and MDC in THP-1 cells. The suppressive effect on Th2-related

Radiosensitization effects of celecoxib on glioblastoma: comparison with oligodendrocyte cell line / 中华放射医学与防护杂志

Objective To compare the radiosensitivity effect of celecoxib on oln93 and u373 cells,and to explore the related mechanism.Methods Both oln93 cells and u373 cells were respectively divided into control group,drug group,radiation group and combined group when treated with celecoxib and irradiation.Cell survival ratio was evaluated by MTT assay and clogenic assay.Flow cytometry and Western blot assay were used to measure cell cycle and protein expression.Results Celecoxib had a similar effect on oln93 and u373 cells in enhancing the radiosensitivity (t =2.215-30.996,P ＜ 0.05 ; t =0.383-11.732,P＜0.05)and blocking cellcycle in G0/G1(t=-6.1-5.141,P＜0.05).Compared with the radiation group,the combined group showed S phase arrest(t =-18.174,P ＜ 0.05),and increase of Cyclin A protein (t =-8.087,P ＜ 0.05) in oln93 cells,and G2/M arrest and decrease of Cyclin B1 and DNA-PKcs and MRE11 protein (t =-8.838-10.45,P ＜ 0.05) in u373 cells.Conclusions Celecoxib illustrates a more sensitive radiosensitivity to u373 cells by regulating its cell cycle and DNA damage repair.

Can an Aspirin a Day Keep the Colorectal Cancer Away?

Colorectal cancer (CRC) is a major health concern. The progression of normal mucosa through adenoma to overt adenocarcinomas span over more than a decade. It provides a window of opportunities for early detection as well as the use of chemopreventive agents such as aspirin. Indeed, CRC can be prevented in up to 80-90% of the cases providing that physicians and patients compliance with current preventive strategies is high. Epidemiological and clinical randomised studies have clearly demonstrated an association between increasing aspirin use and incidence, prevalence and mortality from CRC. Although the evidence supporting the effect of aspirin on colorectal adenomas (CRA) and CRC prevention is consistent, a greater understanding of its mode of action is still needed. Incorporating CRC and CRA benefits into ischemic heart disease (IHD) and Alzheimer disease risk scores would be particularly useful for determining the benefit-to-risk ratio for aspirin use in borderline cases. For instance, patients with a border line annual IHD risk, around 0.7-1.4%, but with a high risk for CRC may still benefit from aspirin usage.

Roles of Serotonergic and Adrenergic Receptors in the Antinociception of Selective Cyclooxygenase-2 Inhibitor in the Rat Spinal Cord

BACKGROUND: The analgesic mechanisms of cyclooxygenase (COX)-2 inhibitors have been explained mainly on the basis of the inhibition of prostaglandin biosynthesis. However, several lines of evidence suggest that their analgesic effects are mediated through serotonergic or adrenergic transmissions. We investigated the roles of these neurotransmitters in the antinociception of a selective COX-2 inhibitor at the spinal level. METHODS: DUP-697, a selective COX-2 inhibitor, was delivered through an intrathecal catheter to male Sprague-Dawley rats to examine its effect on the flinching responses evoked by formalin injection into the hindpaw. Subsequently, the effects of intrathecal pretreatment with dihydroergocristine, prazosin, and yohimbine, which are serotonergic, alpha1 adrenergic and alpha2 adrenergic receptor antagonists, respectively, on the analgesia induced by DUP-697 were assessed. RESULTS: Intrathecal DUP-697 reduced the flinching response evoked by formalin injection during phase 1 and 2. But, intrathecal dihydroergocristine, prazosin, and yohimbine had little effect on the antinociception of intrathecal DUP-697 during both phases of the formalin test. CONCLUSIONS: Intrathecal DUP-697, a selective COX-2 inhibitor, effectively relieved inflammatory pain in rats. Either the serotonergic or adrenergic transmissions might not be involved in the analgesic activity of COX-2 inhibitors at the spinal level.

Clinical Effects of Cycloxygenase-2 Inhibitor on Nocturia

PURPOSE: This study aimed to examine the effects of cyclooxgenase-2 inhibitors on patients with nocturia, whose symptoms persisted after the use of first-line drug therapy, such as alpha blockers and/or anticholinergics. MATERIALS AND METHODS: Thirty-three patients whose symptoms persisted after more than three months of first-line drug therapy were chosen to receive additional COX-2 inhibitors or antidiuretic hormones orally. Seven patients (group 1) were given 80mg of zaltoprofen at night, while 15 (group 2) were given 100mg of nimesulide at night. Desmopressin acetate (0.2mg) was administered at night to 11 patients (group 3) as a control group. Median follow up was 35 days (range, 28~90 days). RESULTS: In 25 patients (75.8%), the severity of nocturia was reduced. The median decline of nocturia in the COX-2 inhibitor groups (groups 1 and 2) was once, and it was statistically significant (p<0.001), while the median decline in each of these groups was twice (p=0.026) and once (p=0.002), respectively. The reduction of nocturia in the control group was once (p=0.011). The differences in reduction between the COX-2 inhibitor group and the control group were not statistically significant (p=0.418). CONCLUSIONS: The effects of the COX-2 inhibitors were not significantly different from those of desmopressin. Combination therapy with COX-2 inhibitors can effectively reduce nocturia in patients with refractory nocturia, following first-line drug therapy.

The Effect of COX-2 Inhibitor on the Expression of MMP-13 during Early Fracture Healing Phase in Rats

PURPOSE: This study investigated the effect of COX-2 inhibitor on the expression of MMP-13 in the healing process of fracture. MATERIAL AND METHODS: Adult Sprague-Dawley rats were divided into two groups of twenty five rats each. Unilateral femoral shaft fractures were created artificially under displacement in all two groups. COX-2 inhibitor was only given to the experimental group from the postoperative day 1. At 2 weeks after fracture the rats were sacrificed and the callus from each group was used for histologic examination and real time RT-PCR for MMP-13 expression. RESULTS: Histologically, proliferation of osteoblasts and formation of osteoid was less abundant in the experimental group. In real time RT-PCR, the mean expression of MMP-13 is 2.84+/-2.50 in the control group compared with 1.16+/-1.05 in the experimental group. CONCLUSION: In the early stage of fracture healing, COX-2 inhibitor suppress the expression of MMP-13.

Radiosensitizing effects of cyclooxygenase-2 selective inhibitor LM-1685 on A549 human lung adenocarcinoma cells / 中华放射医学与防护杂志

Objective To investigate the radiosensitizing effects of cyclooxygenase-2 selective inhibitor LM-1685 on A549 cells in vitro.Methods A549 human lung adenocarcinoma cell line was used in this study.Cell growth kinetics Was determined using MTT assay.Cell survival was analyzed by clonogenic assay.The change of cell cycle Was measured by flow cytometry.Results LM-1685 inhibited the growth of A549 cells,showing a dose-dependent and time-dependent manner.LM-1685(50/μmol/L),either with or without IL-1β,showed the radiosensitizing effects on A549 cells,and the sensitizing enhancement ratio(SER)was 1.12 and 1.06,respectively.LM-1685(50 μmol/L)abrogated radiation-induced G2/M arrest of the tested A549 cells.Conclusions Cyclooxygenase-2 selective inhibitor can enhance the radiosensitivity of A549 cell line.Abrogation of radiation-induced G2/M arrest could be part of the mechanism.

COX-2 induced angiogenesis and peritoneal adhesion / 国际外科学杂志

Postoperative peritoneal adhesion represents a major complication of surgery. Recently, the angiogenesis which cyclooxygenase-2 enzyme induced was found to play an important role in the adhesion synthesis. This review summarized the relationship between COX-2 induced angiogenesis and peritoneal ad- hesion.

Survivin expression in endometriosis and normal human endometrium and effects of GnRH-a and COX-2 inhibitor on its expression / 中国综合临床

Objective To investigate the role of survivin gene in the pathogenesis of endometriosis (EMs). Methods The expressions of survivin in endometriosis and normal endometrium tissue were determined ; the effects of GnRHa and COX-2 on the expression of survivin mRNA in endometriosis and normal endometrium in vitro and the effects of GnRHa and COX-2 on the apoptosis index in the cultured ectopie endometrial cells were investigated. Re-sults ①The expression of survivin mRNA was higher in patients with endometriosis than that of healthy controls (P <0.01) ,with no cyclical variation. ②GnBHa exerted a dose-dependent suppression of survivin mRNA expres-sion in cultured ectopic endometrioma cells as well as COX-2. The significant suppression was observed at the 100μg/L concentration of GnRHa and at the 40 μmol/L concentration of COX-2. No cooperation was found between them (P > 0.05). Conclusion ①The up-regulation of survivin mRNA expression may reduce the sensitivity of en-dometriotic cells to apeptosis. Elevated expression of survivin mRNA in ectopic endometrium may have important im-plications for the survival and proliferation of the ectopic endometrial tissue.②Both GnRHa and COX-2 can promote apoptosis by inhibiting survivin mRNA expression in ectopic endometrioma cells in vitro.

Down-regulation of survivin in growth inhibition of hepatoma cells induced by a selective cyclooxygenase-2 inhibitor / 대한간학회지

BACKGROUND/AIMS: Cyclooxygenase-2 (COX-2) inhibitors reportedly inhibit the growth of hepatocellular carcinoma (HCC) via caspase-dependent or caspase-independent apoptosis, which is due to COX-2 being associated with hepatocarcinogenesis. Survivin is highly expressed in most human cancers, but the mechanism regulating survivin expression remains unclear. We investigated the regulatory expression of survivin in selective-COX-2-inhibitor-induced growth inhibition of hepatoma cells. METHODS: After treatment with NS-398 (a selective COX-2 inhibitor) at various concentrations (10, 50, 100, 150, and 200 micrometer), the growth inhibition of Hep3B hepatoma cells was assessed by an MTT cell-viability assay, DNA fragmentation gel analysis, and flow cytometry. The expression of survivin transcript was analyzed by reverse-transcription polymerase chain reactions. RESULTS: NS-398 inhibited the growth of hepatoma cells by an amount dependent on the concentration and the time since treatment. Apoptotic DNA ladder and flow-cytometry shifting to the sub-G1 phase were revealed in NS-398-induced growth inhibition of hepatoma cells. NS-398 suppressed the expression of the survivin gene in a concentration- and time-dependent manner. CONCLUSIONS: Survivin was down-regulated in the growth inhibition of hepatoma cells induced by a selective COX-2 inhibitor, NS-398, in a concentration- and time-dependent manner. These results suggest the therapeutic inhibition of COX-2 via suppression of survivin in HCC.

Effects of selective Cox-2 inhibitor in preventing postoperative recurrence of colorectal cancer / 上海第二医科大学学报

0.05),but the 3-year recurrent rates were significantly different(P

A Case of Complete Regression of Hepatocellular Carcinoma during Administration of COX-2 Inhibitor / 대한간학회지

Overexpression of cyclooxygenase-2 (COX-2) has been associated with hepatocarcinogenesis. Inhibitors of COX-2 have proapoptotic and antiproliferative effects on malignant tumors and inhibit tumor invasion to the surrounding tissues. We report here a case of complete regression of advanced hepatocellular carcinoma (HCC) during COX-2 inhibitor administration. An eighty-year-old female was diagnosed as an advanced HCC, which was associated with HCV infection. She received COX-2 inhibitor for 3 months due to degenerative arthritis of both knees. Tumor enhancement on arterial phase CT completely disappeared without specific treatment for the HCC, and the tumor size decreased on the follow-up CT scan.

Inhibitory Effect on Angiogenesis of a Selective Cyclooxygenase-2 Inhibitor with using Mouse Mammary Tumor cells / 한국유방암학회지

PURPOSE: Angiogenesis plays a key role in the growth and metastasis of malignant tumor. Angiogenesis is reportedly enhanced by prostaglandins (PGs). Cyclooxygenase (COX)-2 is an inducible enzyme that catalyzes the formation of PGs from arachidonic acid. The COX enzyme system is composed of two isoenzymes, COX-1 and COX-2. Recent sources of experimental and epidemiological evidence suggest a significant role for the COX enzymes, particularly COX-2, in the pathogenesis of breast cancer. COX-2 overexpression in a murine mammary gland is sufficient to cause tumor formation. We performed our study to determine the effect of COX-2 inhibitor in a in vivo mouse mammary tumor (MMT) cell line. METHODS: In order to test our study, 24 C57BL/6 type mice (Jackson Laboratory, Bar Harbor, USA) were randomized to receive 35 days of either placebo supplemented diet (n=11) or a 1,500ppm celecoxib (CELEBREX, Pfizer Inc. St. Louis, USA) supplemented diet (n=13) beginning at day 0. At 14 days after the beginning day, 30 microliter of a 1% India ink solution that contained 500,000 of MMT cells or dye alone (control) was intradermally inoculated at each flank (day 14). The animals were sacrificed 21 days later (day 35) and skin specimens were harvested/processed for quantification of the microvessel density (MVD) that was associated with each inoculated site. The aortas that were isolated according to each treatment group at the time of animal sacrifice were used to create identical aortic ring angiogenesis assays (media 199 supplemented with 20% FBS). Explants were evaluated for 14 days in culture to determine both the rate of angiogenesis initiation (% of explants exhibiting the angiogenic phenotype) and the neovessel growth rate (using a subjective angiogenic index score for the wells exhibiting initiation). Analysis of variance (ANOVA) was used to evaluate the differences between groups for each assay. RESULTS: According to the immunohistochemical staining, celecoxib administration resulted in a parallel decrease in the MVD at both the control and MMT inoculated sites (22% and 21%, p = 0.025 and p = 0.010 respectively). On the aortic ring assay, the dietary treatment group was not significantly inhibited compared with the placebo group (75% and 63.3%, respectively, p = NS). However, dietary celecoxib administration significantly inhibited the angiogenic index of the neovessel growth rate (5.0 +/- 2.38 and 8.9 +/- 3.44, respectively, p < 0.001). CONCLUSION: These results suggest that a selective COX-2 inhibitor had an antiangiogenic effect on the in vivo tumor cells. We will perform more investigations of a selective COX-2 inhibitors, and these may will be crucial drugs to use as new chemotherapy agents for treating in cancer.

The Modulation of Radiosensitivity by Combined Treatment of Selective COX-2 Inhibitor, NS 398 and EGF Receptor Blocker AG 1478 in HeLa Cell Line / 대한방사선종양학회지

PURPOSE: Selective inhibition of multiple molecular targets may improve the antitumor activity of radiation. Two specific inhibitors of selective cyclooxygenase-2 (COX-2) and epidermal growth factor receptor (EGFR) were combined with radiation on the HeLa cell line. To investigate cooperative mechanism with selective COX-2 inhibitor and EGFR blocker, in vitro experiments were done. MATERIASL AND METHODS: Antitumor effect was obtained by growth inhibition and apoptosis analysis by annexin V-Flous method. Radiation modulation effects were determined by the clonogenic cell survival assay. Surviving fractions at 2 Gy (SF2) and dose enhancement ratio at a surviving fraction of 0.25 were evaluated. To investigate the mechanism of the modulation of radiosensitivity, the cell cycle analyses were done by flow cytometry. The bcl-2 and bax expressions were analyzed by western blot. RESULTS: A cooperative effect were observed on the apoptosis of the HeLa cell line when combination of the two drugs, AG 1478 and NS 398 with radiation at the lowest doses, apoptosis of 22.70% compare with combination of the one drug with radiation, apoptosis of 8.49 %. In cell cycle analysis, accumulation of cell on G0/G1 phase and decrement of S phase fraction was observed from 24 hours to 72 hours after treatment with radiation, AG 1478 and NS 398. The combination of NS 398 and AG 1478 enhanced radiosensitivity in a concentration-dependent manner in HeLa cells with dose enhancement ratios of 3.00 and SF2 of 0.12 but the combination of one drug with radiation was not enhanced radiosensitivity with dose enhancement ratios of 1.12 and SF2 of 0.68 (p=0.005). The expression levels of bcl-2 and bax were reduced when combined with AG 1478 and NS 398. CONCLUSION: Our results indicate that the selective COX-2 inhibitor and EGFR blocker combined with radiation have potential additive or cooperative effects on radiation treatment and may act through various mechanisms including direct inhibition of tumor cell proliferation, suppression of tumor cell cycle progression and inhibition of anti-apoptotic proteins.