Nimesulide Group Research Articles

Evaluation of the efficacy and safety of various non-steroidal anti-inflammatory drugs in postmenopausal women with an inflammatory phenotype of osteoarthritis

Introduction. Non-steroidal anti-inflammatory drugs (NSAIDs) are currently the mainstay of the management for relieving pain syndrome in osteoarthritis (OA). NSAIDs are characterized by an individual reaction to medication, as well as a quite high frequency of gastrointestinal side effects. The issue of the disadvantages and advantages of a particular group of NSAIDs is still open.Aim. To evaluate the safety and efficacy of Meloxicam at a dose of 15 mg/day as compared with Nimesulide and placebo in postmenopausal women with an inflammatory phenotype of OA.Results and discussion. The frequency of all adverse events was comparable among the group of patients receiving meloxicam (40.0%), and lower than in the nimesulide group (48.0%), but higher than in the placebo group. A decrease in pain syndrome was observed as early as at 2 weeks of treatment in the group of patients receiving meloxicam. A significant decrease in WOMAC scores (overall result, pain syndrome, stiffness, function) was observed in the group of patients receiving meloxicam, and in the group of patients receiving nimesulide, after 3 weeks of treatment. meloxicam and nimesulide demonstrated high efficacy at 3 weeks compared with the initial VAS scores. The placebo group showed no efficacy.Conclusion. The frequency of all adverse events was lower while taking meloxicam as compared to nimesulide. Our results substantiate the concept to prescribe meloxicam at a dose 15 mg once daily for the treatment of pain and stiffness in post-menopausal women with OA.

Randomized split-mouth study for evaluating the efficacy of nimesulide and nimesulide + Thiocolchicoside combination following impacted mandibular third molar surgery.

This study aimed to evaluate acute postoperative pain management and trismus in 35 patients undergoing extractions of the two mandibular third molars, in mesioangular positions, at two different visits who consumed nimesulide + thiocolchicoside or only nimesulide. According to the medication given, the patients were divided into two groups. Following the first surgery of the impacted third molar patients were given nimesulide (100 mg) + thiocolchicoside (8 mg) together. The healing period was waited for 15 days and in the poursuite of the second surgery, only nimesulide (100 mg) was administered every 12 hours for 7 days. Visual analog scales (VAS) were used to assess the pain in the 6th, 8th, 12th, 24th, and 48th hours and on the 3rd, 5th, and 7th days postoperatively. Digital calipers were used to measure (in mm) the mouth opening capacity pre and postoperatively on the 2nd and 7th days, respectively. Regarding pain alleviation, the nimesulide + thiocolchicoside group was more effective than the nimesulide group. The VAS levels of nimesulide + thiocolchicoside at the 6th, 8th, 12th, 24th, and 48th hours and on the 3rd and 5th days were significantly lower than the nimesulide group. The mouth opening was observed higher in the nimesulide + thiocolchicoside group than in the nimesulide group (P > 0.05). In the nimesulide group, at the end of the 7th day, the trismus measurements were less than the preoperative measurements. There was no statistically significant difference in the Nimesulide + Thiocolchicoside group in the preop-7th days. Nimesulide (100 mg) + thiocolchicoside (8 mg) combination has higher analgesic efficacy and better trismus outcomes compared to only nimesulide (100 mg) when orally administered following mandibular third molar surgeries.

Can the negative effects of ketamine abuse on female genital organs be prevented by nimesulide? An experimental study.

The objective of this study is to investigate the effects of nimesulide on ketamine-induced ovarian and uterine toxicity by biochemical and histopathological examinations. Ketamine is an anesthetic agent whose use leads to overproduction of catecholamines. Nimesulide is a cyclooxygenase-2 inhibitor, which has also been reported to exert a significant antioxidant effect. Wistar albino female rats were randomly divided into three groups as follows: ketamine group (60 mg/kg), ketamine (60 mg/kg) + nimesulide (50 mg/kg) group, and a healthy control group. Then, the biochemical levels and histopathological findings in the ovaries and uteri of the rats were examined for malondialdehyde, myeloperoxidase, total glutathione and superoxide dismutase. The study demonstrated that, in the uterine and ovarian tissues of rats that have been administered ketamine, there was a decrease in the levels of total glutathione and superoxide dismutase, while malondialdehyde and myeloperoxidase was increased: however it was observed that these ratios were reversed in the ketamine+nimesulide group. It was also proved that the negative effects of ketamine can be corrected with nimesulide when the myometrial and endometrial thicknesses are compared. Antioxidants such as nimesulide may protect against the damage caused by ketamine to the genital organs in young women.

Hepatoprotective effects of Yulangsan polysaccharide against nimesulide-induced liver injury in mice

Ethnopharmacological relevanceYulangsan polysaccharide (YLSPS) is often used in popular folk medicine in the Guangxi Zhuang Autonomous Region of China as a chief ingredient of Millettia pulchra, which is used as a hepatic protection, anti-aging and memory improving agent. Aim of the studyThis study was designed to investigate the protective effects of polysaccharides from Millettia pulchra Kurz var.laxior (Dunn) (Yulangsan polysaecharide, YLSPS) against nimesulide-induced hepatotoxicities in mice. Materials and methodsLiver injury was induced in mice by administering nimesulide. Simultaneously, YLSPS was administered 2h prior to the administration of nimesulide. Dimethyl diphenyl bicarboxylate (DDB) was used as a reference drug. ResultsCompared with the nimesulide group, YLSPS significantly decreased the activities of alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP) and the content of bilirubin in the serum. The anti-oxidative effect of YLSPS was observed from the increase of the superoxide dismutase (SOD) and catalase and glutathione peroxidase (GSH-Px) activities in the liver, both of which were decreased by nimesulide. Moreover, the content of malondialdehyde (MDA) was reduced, and histological findings also confirmed the anti-hepatotoxic activity. In addition, YLSPS significantly inhibited proinflammatory mediators, such as tumor necrosis factor-alpha (TNF-α) and interleukin 6 (IL-6). Additionally, YLSPS also enhanced the mitochondrial antioxidant and inhibited dead cells by preventing the down-regulation of Bcl-2, up-regulation and release of Bax along with caspase 9 and 3 activity, confirming the involvement of mitochondria in the nimesulide-induced apoptosis. ConclusionThe protective effect of YLSPS against nimesulide-induced hepatic injury may rely on its ability to reduce oxidative stress and prevent nimesulide-induced hepatotoxicity by inhibiting critical control points of apoptosis.

Comparative efficacy of nimesulide and ketoprofen on inflammatory events in third molar surgery: a split-mouth, prospective, randomized, double-blind study

This study aimed to compare the effect of nimesulide and ketoprofen on inflammatory parameters related to the surgical removal of third molars. A split-mouth, prospective, randomized, double-blind study was conducted in patients undergoing removal of four third molars. Eighteen eligible patients were allocated to one of two groups to receive treatment two times a day with either ketoprofen 100mg or nimesulide 100mg for a period of 3 days. The rescue medication intake (number) and pain intensity were evaluated at 6, 12, 24, and 48h, and at 7 days postoperatively. Swelling and maximum mouth opening were evaluated at 24h, 72h, and 7 days postoperatively. The peak pain score occurred at 6h after surgery in the nimesulide group and at 12h in the ketoprofen group. There was no statistically significant difference between the groups, although pain relief was observed after 48h in the nimesulide group and after 7 days in the ketoprofen group. For each group, there was a statically significant difference in pain scores among the studied periods (P<0.0001). None of the patients required rescue medication. There was a statistically significant difference in maximum mouth opening between the preoperative and postoperative periods (P<0.0001). Ketoprofen and nimesulide were effective at controlling pain, swelling, and trismus after the surgical removal of third molars.

Haemato-biochemical and Immunological Study on NSAIDs Induced Acute Toxicity in Broiler Chicken

The present study was aimed to elucidate the effect of Non steroidal anti-inflammatory drugs (NSAIDs) induced toxicity in the broiler chicken. For this purpose, 120 broiler chicks were utilized and divided into 4 major groups (C, D, B and N) and within each major group the chicks were divided into 3 sub groups having 10 chicks each. The control chicks received normal diet without any medicine. Diclofenac was used @ 10, 20 and 30 mg/kg b.wt. in D1, D2 and D3 group respectively. Ibuprofen was fed @ 15, 30, 45 mg/kg b.wt in B1, B2 and B3 group respectively. The nimesulide group viz. N1, N2 and N3 were given Nimesulide @ 10, 20 and 30 mg/kg b.wt respectively. NSAIDs induced toxicity showed no effect on the haematological parameters of broiler chicks in the present study, however, there was increase in the serum alkaline phosphatase level in intoxicated birds indicating hepatotoxicity compared to the control group with highest value of 173.33 ± 0.80 IU/L in B3. Further, atrophy of spleen and bursa of fabricius was observed in intoxicated birds. Highest atrophy of spleen (1.1 gm/kg body weight) was observed in N3 and D3 while as maximum bursal atrophy of 1.20 ± 0.06 gm/kg body weight was recorded in B3.

Cyclooxygenase-2 inhibition improves antioxidative defense during experimental hypercholesterolemia.

Scientific literature shows that inflammation and oxidative stress contribute in the pathogenesis of atherosclerosis. The oxidative stress is the consequence of an imbalance between the free radical generation and elimination. One source of free oxygen radicals is cyclooxygenase (COX)-2 and, therefore, inhibiting the activity of this enzyme is likely to reduce oxidative stress. In the present study an experimental rabbit model of hypercholesterolemia was developed and the effects of COX-2 inhibitors, nimesulide and celecoxib were observed on the activities of antioxidant enzymes, superoxide dismutase (SOD), glutathione peroxidase (GPx) and total antioxidant status (TAS). Rabbits were divided into four groups- control, saline, nimesulide and celecoxib, with all groups fed a high cholesterol diet, which only received saline. Low activities of SOD, GPx and TAS were measured in the hypercholesterolemic rabbits pretreated with saline. In the same group, a reciprocal relationship was observed between the LDL-cholesterol concentration and the plasma activities of GPx, SOD and TAS. Rabbits in nimesulide and celecoxib group showed significantly higher activities of SOD, GPx and TAS in hypercholesterolemic rabbits compared to saline group (p<0.05). Our study shows that selective and timely use of COX-2 inhibitors would be useful in preventing the onset and development of atherosclerosis by enhancing antioxidant defence system.

Inhibitory effect of nimesulide and oxaliplatin on tumor growth and lymphatic metastasis of transplanted human lung cancer in nude mice

This study was designed to evaluate the inhibitory effect of nimesulide in combination with oxaliplatin on tumor growth, expression of COX-2, VEGF-C, VEGFR-3, survivin and β-catenin, and lymphatic metastasis in lung cancer xenograft in nude mice, and to discuss the possible synergistic effect of nimesulide in combination with oxaliplatin. Human lung cancer A549 cells were injected into BALB/c nude mice subcutaneously. Thirty-three healthy male nude mice were randomly divided into 4 groups: the control group, nimesulide group, oxaliplatin group and nimesulide combined with oxaliplatin group. Transplanted tumor tissues were collected and the expressions of COX-2, VEGF-C, VEGFR-3, survivin, β-catenin protein were detected by immunohistochemistry, and RT-PCR assay was used to assess the expression of tumor COX-2, VEGF-C, VEGFR-3, survivin and β-catenin mRNA. SPSS 16.0 was used for statistical analysis. Data were present as (x(-) ± s), and the means were compared by analysis of variance test. Tumor inhibition rates of the nimesulide group, oxaliplatin group and nimesulide + oxaliplatin group were 39.73%, 48.04% and 65.94%, respectively. Immunohistochemical and RT-PCR analysis showed that compared with the control group, the expression levels of COX-2, VEGF-C, VEGFR-3, survivin and β-catenin of the nimesulide group were significantly reduced (all P < 0.05). Compared with the control group, statistical analysis of variance showed that the expression levels of COX-2, VEGF-C and VEGFR-3 of the oxaliplatin group were significantly increased (P < 0.05), the expression levels of survivin and β-catenin protein and mRNA of the oxaliplatin group were significantly reduced (P < 0.05). Compared with the control group, the expression levels of COX-2, VEGF-C, VEGFR-3, survivin and β-catenin of the nimesulide + oxaliplatin group were significantly reduced (all P < 0.05). Both nimesulide alone or in combination with oxaliplatin can significantly inhibit the growth of lung cancer xenografts in nude mice and the expression levels of COX-2, VEGF-C, VEGFR-3, survivin and β-catenin. Oxaliplatin can significantly inhibit the growth of lung cancer xenografts in nude mice, and the expression of survivin and β-catenin. Nimesulide in combination with oxaliplatin enhances the antitumor effect of oxaliplatin.

Effect of selective and non-selective cyclooxygenase inhibitors on doxorubicin-induced cardiotoxicity and nephrotoxicity in rats

Context: Doxorubicin (DX) is a highly effective chemotherapeutic agent used widely in the treatment of solid tumors; however, its optimal use was associated with cardiotoxicity and nephrotoxicity. The exact mechanism of DX-induced cardiotoxicity and nephrotoxicity is not fully explored. Induction of cyclooxygenase-2 (COX-2) activity in either cardiac or renal tissue by DX has been previously reported, indicating a possible role of COX-2 in DX-induced tissue injury. However, the nature of this role in either tissue injury is an issue of controversy.Objective: This study was the first that simultaneously evaluated the effects of a selective COX-2 inhibitor, nimesulide, and a non-selective COX-inhibitor, indomethacin, on DX-induced cardiotoxicity and nephrotoxicity in male Wistar rats.Materials and methods: Rats were allocated into four groups. Control group, DX group (received 15 mg/kg, ip), DX + nimesulide (10 mg/kg/day, po) group, and DX + indomethacin (2 mg/kg/day, po) group. Nimesulide and indomethacin were started at the same day of DX injection and continued for 5 days.Results: The results of the present study showed that inhibition of COX-2 either by selective or non-selective COX-2 inhibitor ameliorated DX-induced cardiotoxicity but aggravated DX-induced nephrotoxicity in rats, as evidenced biochemically and histopathologically.Discussion and conclusion: Our study indicates that production of COX-2 is organ specific; consequently, the differential effect of COX-inhibitors should be considered in DX-treated patients. However, a wide scale experiment is needed for further confirmation and testing other members of COX-inhibitors (e.g. celecoxib and diclofenac).

Effect of Partially Selective Cyclooxygenase-2 Inhibitor in the Removal of Third Molars

A randomized, double-blind clinical trial was carried out involving 25 patients scheduled for the removal of symmetrically positioned lower third molars in separate procedures. Either 100 mg of nimesulide or 7.5 mg of meloxicam was administered 1 hour before surgery and every 12 hours after surgery for 2 days. Evaluations were carried out in the preoperative period as well as on the second and seventh days after surgery. Objective and subjective parameters were recorded for comparison purposes. The patients having received nimesulide had less of a need for additional pain medication in the first 48 hours and had lower pain scale values (P < 0.05). There was less trismus in the meloxicam group (P > 0.05). Postoperative swelling was lower in the nimesulide group (P < 0.05). All measurements on the second day were lower in the nimesulide group (P < 0.001), and only one of these parameters was lower on the seventh day in the nimesulide group, distance from the lower edge of the tragus to the lip commissure on the operated side (P = 0.009, P < 0.001) compared with another group. Nimesulide proved effective in controlling pain and swelling after surgical removal of the lower third molars, with few adverse effects. Meloxicam proved effective in diminishing trismus.

Effect and mechanism of nimesulide combined with cisplatin on proliferation and apoptosis of lung cancer

Objective To evaluate the effects of selective cyclooxygenase-2 inhibitor nimesulide lone and combined with cisplatin on tumor growth,and Ki67 and Caspase-3 expression in lung cancer xenografts in nude mice. Methods The mice were randomly divided into 4 groups:the control group,the nimesulide group,the cisplatin group and the nimesulide combined with cisplatin group. A549 cells were injected into BALB/c nude mice subcutaneously.On the 21st day after treatment tumor tissues were collected,and the xenografts growth were observed. The expression of Ki67 and Caspase-3 were detected by immunohistochemical method.Results Nimesulide combined with cisplatin could significantly inhibited the xenografts growth compared with nimesulide or cisplatin.The tumor inhibition rate was 44.33％ in the nimesulide group,53.61％ in the cisplatin group and 80.41％ in the nimesulide combined with cisplatin group (P ＜ 0.05).Immunohistochemical analysis showed that the expression rates of Caspase-3 was significantly increased in the nimesulide combined with cisplatin group (67.43 ± 23.57 ) ％,the cisplatin group (48.40 ± 20.37 ) ％,and the nimesulide group (38.65 ± 15.37)％,compared with the control group (27.63 ± 13.03)％ (P ＜ 0.05).The expression rate of Caspase-3 was significantly increased in the nimesulide combined with cisplatin group compared with the nimesulide group or the cisplatin group (P ＜ 0.05 ).The expression rate of Ki67 was significantly decreased in the nimesulide group combined with cisplatin group (24.34 ± 15.90)％,the cisplatin group (40.85 ± 22.47)％ and the nimesulide group (53.33 ± 19.67)％ compared with the control group ( 80.43 ± 16.88 ) ％ ( P ＜ 0.05 ).The expression of Ki67 was significantly decreased in the nimesulide combined with cisplatin group compared with the nimesulide group or the cisplatin group ( P ＜ 0.05 ).Conclusion Nimesulide can inhibit human lung cancer A549 cells xenografts in nude mice growth,Nimesulide enhanced the inhibitory effects of cisplatin.The mechanism may be related to inhibition of tumor cell Ki-67 expression,increased expression of Caspase-3,inhibition of tumor cell proliferation,and inducing tumor cell apoptosis. Key words: Lung neoplasms ; Cisplatin ; Cell proliferation ; Apoptosis ; Nimesulide

Nimesulide inhibits the proliferation of HepG2 by up-regulation of Smad4

Objectives:Hepatocellular carcinoma (HCC) is receiving increased attention. This study was designed to investigate the effect of selective Cyclooxygenase-2 (COX-2) inhibitor, nimesulide, on the expression of Smad4 in human hepatocellular carcinoma HepG2.Materials and Methods:HepG2 cells were incubated in various concentrations of nimesulide (25, 50, 100, 200, 400 μmol/L) to detect the effect of proliferation by MTS. The apoptosis of HepG2 was determined by TUNEL; fluorescence microscope was used to observe the expression of Smad4.Results:The result showed that nimesulide inhibited the proliferation of HepG2 cell in a concentrations-dependent manner, and promoted the karyopyknosis and fragmentation of HepG2 cell nucleus, induced its apoptosis, the number of fluorescence labeling of Smad4 in Nimesulide group was higher than control group (P<0.05).Conclusions:Nimesulide inhibits the proliferation and promotes apoptosis of HepG2 by up-regulation of Smad4 in HepG2.

The benefits and risks of short-term therapy with nimesulide for children with high fever

Objective To investigate the safety and efficacy of short-term therapy with nimesulide for children with high fever. Methods The efficacy of two types of antifebrile drug was assessed. 99 children with upper respiratory tract infection were randomly assigned to receive oral nimesulide (group Ⅰ), acetami-nophen (group Ⅱ), or Ibuprofen (group Ⅲ) for 3 days or shorter. The adverse reactions and the changes in body temperature after the first treatment were observed. Results The total effective rates of body temperature decrease and defervesce time in group Ⅰ were compared with those in the other two groups (P<0.01). The incidence of adverse reactions was compared between group Ⅰ and groups Ⅱ and Ⅲ(P<0.05). More children has profuse sweating in group Ⅰ than in groups Ⅱ and Ⅲ(P<O.05). Conclusions Nimesulide has a quicker onset of antifebrile, longer lasting time, less adverse reactions but causes profuse sweating more obviously. The short-term therapy with nimesulide is safe. Key words: Nimesulide; Children; High fever; Non-steroidal anti-inflammatory drugsAcetaminophen; lbuprofen

Efficacy of nimesulide versus meloxicam in the control of pain, swelling and trismus following extraction of impacted lower third molar

This study compared the efficacy of nimesulide and meloxicam in the control of pain, swelling and trismus, following the extraction of impacted inferior third molars. Twenty patients with two impacted inferior third molars, in similar positions, were selected. The patients were designated randomly to the meloxicam group (MEL: 7.5mg twice a day for 5 days) or the nimesulide group (NIM: 100mg for 5 days). Following the extractions, swelling was more pronounced in the MEL group than in the NIM group (P<or=0.001). There were no significant differences in pain intensity between the treatment groups (P>0.05). At the 72-h evaluation, reduction was significantly larger in mouth opening in the MEL group compared with the NIM group (P<0.05). In conclusion, pain control was similar in both treatment groups. NIM was more effective than MEL in the control of swelling and trismus following the extraction of impacted lower third molars.

Clinical course and outcomes of drug-induced liver injury: Nimesulide as the first implicated medication

Drug-induced liver injury (DILI) is the most common cause of death from acute liver failure, and accounts for approximately 13% of cases of acute liver failure in the United States. The clinical presentation of DILI covers a wide spectrum, from asymptomatic liver test abnormalities to symptomatic acute liver disease, prolonged jaundice and disability, or overt acute or subacute liver failure. The aim of our study was to evaluate the number of DILI cases admitted to our Unit and to identify the drugs responsible. Thus, we reviewed all clinical records of patients with DILI admitted to our Unit from 1996 to 2006. A database was constructed, reporting demographic, clinical features at onset, laboratory results, suspected drugs and follow-up. Liver damage was defined as hepatocellular, cholestatic or mixed, according to clinical and laboratory data. Forty-six patients were admitted with a diagnosis of DILI. Presentation was jaundice in 22 patients and hepatic failure in 3 (all attributed to nimesulide). Liver damage was of a cytolytic pattern in 19 cases (41%), cholestatic in 15 (33%) and mixed in 12 (26%). Jaundice was found to be higher in nimesulide-induced liver damage compared to other drugs (p=0.007). Three out of 14 patients with nimesulide-induced DILI developed encephalopathy and/or ascites. Time of recovery in the nimesulide group was significantly lower than DILI from other drugs (p<0.001). Non-steroidal anti-inflammatory drugs, psychotropic drugs and antimicrobials are the most common causes of DILI. Nimesulide-induced DILI is usually reversible upon discontinuation of the drug, but occasionally progresses to liver failure.

Analgesic effect of nimesulide in withdrawing nasal packing after endoscopic sinus surgery

Sixty four patients undergoing endoscopic sinus surgery were randomly divided into two groups.In nimesulide group (n=32) patients were given nimesulide capsule 100 mg after surgery and 32 patients in control group were given 100 mg vitamin C as placebo.The visual analogue scale (VAS) was used to evaluate the degree of pain during withdrawing nasal packing.The VAS value of the nimesulide group was 2.8±1.1 3 h after surgery and 2.7±1.2 during with drawing nasal packing,that of control group was 6.7±0.6 and 8.3±0.6,respectively (both P<0.01).The results revealed that nimesulide had a siguificant analgesic effect in endoscopic sinus surgery. Key words: Anti-inflammatory,agents; Analgesics

Inhibition of Nimesulide on metastasis of orthotopic implantation of human gastric carcinoma

Objective To investigate the effect of a selective cyclooxygenase-2 inhibitor on tumor metastasis,tumor angiogenesis,and vascular endothelial growth factor(VEGF)of orthotopic implanted human gastric carcinoma in non.obesity diabetes(NOD)severe combined immune deficiency(SCID)mice.Methods Human gastric cancer SGC-7901 tissues were orthotopically implanted into the stomach of the NOD SCID mice.Forty mice were randomly divided into two groups which received either intravenous injections of 0.9% Nacl solution (0.9% NaCL solution group)or 50mg/kg.d Nimesulide(Nimesulide group)twice weekly for two weeks.Mice were sacrificed in the 5th week after implantation.Tissues from stomach and other organs were obtained for histopathologieal evaluation.The intratumoral microvessel density(MVD)and VEGF protein expression in tumor were evaluated by immunochemical method.Results The tumor metastasis rates were 18/20 in 0.9% Nacl solution group and 5/20 in Nimesulide group(P＜0.05).MVD was 9.5±2.9 in 0.9% NaCl solution group and 3.9±2.1 in Nimesulide group(P＜0.01).VEGF protein expression was 90% in 0.9%NaCl solution group and 25% in Nimesulide group(P＜0.01).Conclusions Nimesulide can inhibit the metastasis or gastric cancer through inhibiting tumor VEGF expression and tumor angiogenesis with no obvious anticoagulant activity. Key words: Cyclooxygenase inhibitors/PD; Stomach neoplasms/PC; Vascular endothelial growth factors

Nimesulide 90 mg Orally Twice Daily Does Not Influence Postoperative Morphine Requirements After Major Chest Surgery

Cyclooxygenase 2 inhibition has proven analgesic efficacy in a variety of surgical procedures. We postulated that perioperative cyclooxygenase 2 inhibition significantly reduces postoperative morphine requirements after major thoracic surgery and investigated the site of this potential analgesic effect. Ninety-two patients participated in this single-center, double-blind, randomized, placebo-controlled, parallel-group trial. Patients between the ages of 18 and 80 yr undergoing a thoracotomy or median sternotomy were randomized to receive either nimesulide or placebo in combination with a standard analgesic regimen perioperatively. Nimesulide was administered orally the evening before surgery and at 12-h intervals for 5 days postoperatively. The primary efficacy variables were morphine consumption and pain scores for the first 48 h postoperatively. The secondary efficacy variable was the effect of nimesulide on cyclooxygenase activity in cerebrospinal fluid (CSF). Pain scores at rest or with movement, and total morphine consumption for the first 48 h postoperatively, were not statistically different between the groups. The mean difference in total morphine consumption up to 48 h postoperatively between the nimesulide and placebo group was a 9.0 mg reduction (95% CI: -28.9 to 10.9 mg) (P = 0.37). Adjusted mean (se) CSF 6-keto-PGF1alpha (6-keto-PGF1alpha) concentrations increased by 54.7 (25.7) pg/mL from preoperatively to Day + 2 postoperatively in the placebo group, whereas adjusted mean (se) CSF 6-keto-PGF1alpha concentration decreased by 0.6 pg/mL (18.2 pg/mL) in the nimesulide group. These changes were not statistically different between the groups (P = 0.095). Nimesulide, at a dose of 90 mg twice daily in combination with a standard analgesic regimen, does not influence pain scores, morphine requirements, or CSF prostaglandin levels after major thoracic surgery.

Nimesulide in the Treatment of Postoperative Pain: A Double-blind, Comparative Study in Patients Undergoing Arthroscopic Knee Surgery

To evaluate the efficacy and tolerability of nimesulide in the relief of postoperative pain after orthopedic surgery compared with naproxen and placebo. In this multicenter, double-blind, double-dummy, randomized, parallel group study, 94 patients with at least moderate postoperative pain after arthroscopy and meniscectomy were randomized to receive nimesulide 100 mg b.i.d., naproxen 500 mg b.i.d., or placebo for a maximum of 3 days. Nimesulide was significantly more effective than placebo for the treatment of postoperative pain, as measured by the primary efficacy variable of summed pain intensity difference within 6 hours after first treatment (10.91 vs. 6.29). Furthermore, nimesulide also provided significantly better pain relief than naproxen on this parameter. Overall, nimesulide demonstrated superior analgesic activity compared with naproxen and placebo for the majority of secondary efficacy variables. All 3 treatments were well tolerated, with a lower number of patients reporting adverse events in the nimesulide group. Nimesulide recipients reported no gastrointestinal disorders. This study demonstrates that nimesulide is an effective, fast-acting and well-tolerated oral anti-inflammatory drug with a distinct analgesic activity after out-patient orthopedic surgery.

Cyclooxygenase‐1 and ‐2 inhibition alter hypothalamic‐pituitary‐adrenal axis (HPA) activity and COX expression in fetal brain.

In fetal sheep, reflex responses to hypotension are in part mediated by generation of prostaglandins (PG) in the CNS. We have previously demonstratd that inhibition of COX1 reduces the responsiveness of the fetal HPA to hypotension and increases expression of COX2 in specific regions of the fetal CNS. We hypothesized that generation of PG alters the transcription of COX2. The present study was designed to test this hypothesis. Chronically catheterized twin fetal sheep received cerebral ventricular infusions of inhibitor or vehicle. We used either the COX2 inhibitor nimesulide (NIM) at 1mg (HD) or 10 ug/day (LD), or the COX1 inhibitor resveratrol (RES) at 1 mg/day. Blood samples were collected to measure fetal blood gases, proopiomelanocortin (POMC), ACTH, and cortisol. After 5 days, fetal hypothalami and pituitaries were harvested, and COX1 and 2 mRNA were analyzed by real-time PCR. Arterial blood gases were unchanged by HD nimesulide or resveratrol. LD nimesulide significantly decreased pO2 of vehicle treated fetuses. HD NIM significantly reduced hypothalamic COX1 and 2 mRNA, but did not alter pituitary levels. COX1 and 2 were unchanged in the RES and LD NIM groups. Hypothalamic AVP, CRH, and POMC mRNA levels were unchanged in all groups. Plasma ACTH, POMC, and cortisol concentrations were unchanged in the HD NIM group, yet RES and LD NIM treatment significantly reduced plasma cortisol without changing POMC or ACTH. We conclude that blockade of COX2 with HD NIM alters the expression of COX1 and 2 mRNA; and 2) unstimulated fetal ACTH secretion is not altered by blockade of CNS COX isoforms, although adrenal sensitivity to ACTH appears to be influenced by both COX1 and 2 activity in the CNS. Supported by HD42135 and a Predoctoral Fellowship from the American Heart Association.