Effects Of Nimesulide Research Articles

Effect of nimesulide against indomethacin-induced oxidative liver damage in rats.

Effect of nimesulide against indomethacin-induced oxidative liver damage in rats.

In vivo antidiabetic activity of nimesulide due to inhibition of amino acid transport

AbstractInhibiting the intestinal and renal neutral amino acid transporter B0AT1 by genetic means has improved insulin sensitivity in mice, but there are no antagonists available for preclinical or clinical use. Since the anti‐inflammatory agent nimesulide selectively inhibited B0AT1 in vitro, we hypothesized that nimesulide exhibits in vivo potential to restrict neutral amino acid absorption and, therefore, may improve insulin sensitivity. The dose‐related effect of nimesulide (10 to 100 mg/kg, PO) on intestinal absorption of neutral amino acids was estimated in C57 mice. The effect of nimesulide (50 mg/kg, PO) on renal resorption of amino acids was also assessed. The effect of chronic nimesulide (50 mg/kg, PO, BID for 14 days) was assessed in high protein diet‐fed C57 mice, diet‐induced obese mice and obese and diabetic db/db mice. Acute and chronic nimesulide treatment decreased absorption of neutral amino acids and increased their urinary excretion. Nimesulide treatment improved insulin sensitivity and glycemic control, increased GLP‐1, decreased liver lipids and improved FGF‐21 in serum. Nimesulide improved insulin sensitivity and glucose tolerance by inhibiting neutral amino acid transport in the intestine and kidneys. Thus, it can serve as a tool compound for in vivo B0AT1 inhibition.

Protective effect of nimesulide on the external ear damage induced by staphylococcus aureus inoculation in rats

Protective effect of nimesulide on the external ear damage induced by staphylococcus aureus inoculation in rats

Amlodipine modulation of analgesic effect of non-steroidal anti-inflammatory drugs in rheumatoid arthritis, comorbid with arterial hypertension

With the interaction of drugs belonging to different pharmacotherapeutic groups – nonsteroidal anti-inflammatory and antihypertensive – against the background of comorbid arterial hypertension with rheumatoid arthritis, the activity and safety of drugs may change with their combined use. Changes in the analgesic activity of nonsteroidal anti-inflammatory drugs, different in their selectivity to the types of cyclooxygenase (diclofenac, nimesulide and celecoxib), under the conditions of their long-term combined use with amlodipine in different periods of inflammation against the background of hypertension should be studied. Using the model of adjuvant arthritis comorbid with hypertension, in experiments on nonlinear mature white rats, the threshold of pain sensitivity has been determined by means of the “tail flick” test. Hypertension was caused by salt load with 1% sodium chloride solution for drinking with free access to it. Adjuvant arthritis was induced by the introduction of complete Freund’s adjuvant into the plantar aponeurosis of the hind limb of each animal with the established arterial hypertension. Against the background of arterial hypertension and comorbid pathology, there was an increase in the threshold of pain sensitivity observed in rats, which indicated the development of hypoalgesia. When combined, amlodipine enhanced the analgesic activity of diclofenac during 60 days of observation, slightly heightened the analgesic effect of nimesulide – up to 42 days, the effect of Celecoxib – in the acute period and the period of manifestation of adjuvant arthritis against the background of hypertension. The antinociceptive effect of diclofenac with amlodipine and celecoxib with amlodipine exceeded the analgesic effect of the combined nimesulide with amlodipine use against the background of comorbid pathology. The results obtained can be taken into account under the conditions of prescribing drugs belonging to the studied pharmacotherapeutic groups. It is likely that the use of diclofenac for analgesia against the background of comorbid conditions is only appropriate in the acute period of rheumatoid arthritis. The use of nimesulide to achieve an analgesic effect in the recurrence of rheumatoid arthritis against the background of hypertension is appropriate in the acute period and in the period of the inflammatory process attenuation. A highly selective coxib group cyclooxygenase-2 inhibitor, celecoxib, can reduce pain during the acute period of arthritis and during the manifestation of an inflammatory reaction that has developed against the background of arterial hypertension.

Proteomics-based screening of the target proteins associated with antidepressant-like effect and mechanism of nimesulide

Nimesulide is an inhibitor of COX-2 with antioxidant and anti-inflammatory effects. However, few studies have explored the antidepressant mechanism of nimesulide. Here, we evaluated the therapeutic effects of nimesulide on CUMS rats. iTRAQ technology was used to identify the differentially expressed protein in the hippocampus between CUMS and nimesulide-treated rats to identify the possible molecular mechanism of its effects. We found that nimesulide had positive effects on depressive-like behaviors and inflammatory factors in depressed rats. Using proteomics technologies, we screened 16 differentially expressed proteins in CUMS-exposed rats after nimesulide treatment, 5 of which were related to inflammation. Overall, these results show that nimesulide might mediate its antidepressant effect on depressed rats through the inhibition of oxidative stress inflammatory response.

Biomimetic synthesis of proline-derivative templated mesoporous silica for increasing the brain distribution of diazepam and improving the pharmacodynamics of nimesulide

Herein a new kind of proline-derivative templated mesoporous silica with curved channels (CMS) was biomimetically synthesized and applied as carrier to improve the drug dissolution and bioavailability of hydrophobic diazepam (DZP) and nimesulide (NMS). Drugs can be incorporated into CMS with high efficiency; during this process, they successfully transformed to amorphous phase. As a result, the dissolution rate of DZP and NMS was significantly improved. Biodistribution study confirmed that CMS converted DZP distribution in mice with the tendency of lung targeting and brain targeting. At 45 min postadministration, the concentrations of DZP in plasma, lung and brain were 8.57-fold, 124.94-fold and 19.55-fold higher from 1:3 DZP/CMS sample than that of pure DZP sample, respectively. At 90 min postadministration, the content of DZP in brain was 62.31-fold higher for 1:3 DZP/CMS sample than that of pure DZP. Besides, the anti-inflammatory and analgesic effects of 1:3 NMS/CMS were systematic evaluated using mouse ankle swelling test (MAST), mouse ear swelling test (MEST) and mouse writhing test (MWT). The results indicated that after incorporating into CMS, the therapeutic effects of NMS were obviously improved, and the inhibition rates of 1:3 NMS/CMS in all pharmacodynamics tests varied from 102.2% to 904.3%.

Anti-platelet eff ects of nimesulide in isoproterenol-induced myocardial ischaemia and infarction in rabbits

Background The present study was designed to determine the eff ects of cyclooxygenase-2 (COX-2) inhibitor-nimesulide on platelet activating factor (PAF) and arachidonic acid (AA)-induced platelet aggregation during myocardial infarction (MI) and ischaemia in rabbits.Methods Rabbits were divided into three groups; group I served as control and contains normal rabbits that received saline, group II rabbits received saline before induction of MI, and group III rabbits received nimesulide (25 mg/kg) before MI induction. Myocardial infarction was induced by isoproterenol (ISP) (65 mg/kg) and confi rmed by biochemical, electrophysiological and histopathological methods. Platelet aggregation was induced with arachidonic acid (AA) and platelet activating factor (PAF), and monitored by using light transmission aggregometery.Results When platelets were challenged with two diff erent aggregating agents, nimesulide-treated infarcted rabbits showed resistance to platelet aggregation while non-treated infarcted rabbits were found prone to aggregation with both aggregating agents (P >0.05).Conclusion These results suggest platelet inhibitory eff ects of nimesulide during experimental ischaemia and infarction in rabbits.

Effects of Nimesulide, a Selective COX-2 Inhibitor, on Cardiovascular Function in 2 Rat Models of Diabetes

Cyclooxygenase-2 (COX-2) has been found to be activated in diabetes. We investigated whether nimesulide (selective COX-2 inhibitor) alters cardiovascular responses to adrenaline in 2 rat models of diabetes. Wistar rats (5-week old) were continuously fed a normal or high-fructose diet (60% of caloric intake). At week 2, half of the rats in each diet regimen were given streptozotocin (STZ) (60 mg/kg, intravenously). At week 6, cardiovascular effects of adrenaline (6 and 16 × 10 mol·kg·min, intravenously) were measured in 4 groups of thiobutabarbital-anesthetized rats (control, fructose, STZ, and fructose-streptozotocin [F-STZ]) before and after the injection of nimesulide (3 mg/kg, intravenously). Both the STZ and F-STZ groups exhibited hyperglycemia and significantly (P < 0.05) reduced left ventricular contractility, mean arterial pressure, arterial and venous resistance, and mean circulatory filling pressure (index of venous tone) responses to adrenaline, relative to the control and fructose groups. Nimesulide did not affect responses in the control and fructose groups but increased the venous and, to a less extent, arterial constriction to adrenaline in both the groups of diabetic rats. The cardiac contractile responses, however, were not altered after nimesulide treatment. The results show that nimesulide partially restored arterial and venous constriction to adrenaline in rats with STZ- and F-STZ-induced diabetes.

Neuroprotective effect of nimesulide on astrocyte cultures exposed to LPS

Neuroprotective effect of nimesulide on astrocyte cultures exposed to LPS

The genotoxic and cytotoxic effects of nimesulide in the mouse bone marrow

Genotoxicity of nimesulide (NM) was evaluated by employing bone marrow (BM) chromosomal aberration (CA) and micronucleus assays in Swiss albino mice. For BM CA assay, mice of either sex were treated orally with 1.5, 2.5 and 5 mg body weight solution of NM in 0.2 mL of 0.05% CMC (carboxy methyl cellulose) daily for 4, 13, 28 and 40 weeks. Treatment induced dose-dependent and significantly depressed mitotic activity and increase in CAs per cell in the BM cells after 13 weeks of treatment at all dose levels. In micronucleus assay, male mice were treated orally with the same dose levels and sampling durations as for CA assay. Treatment increased the percentage of micronucleated polychromatic erythrocytes frequency and showed a statistically significant reduction in polychromatic erythrocyte/normochromatic erythrocyte ratio, as compared to control groups. Cyclophosphamide (40 mg/kg) was used as clastogen (positive control) and yielded the expected positive results. Cytotoxicity was observed in the 8-week recovery period after 40 weeks of dosing, but it was not significant. On the basis of these findings, it may be concluded that in the long term, NM, or its biotransformed product, is genotoxic and cytotoxic for BM cells of mice in vivo.

Genotoxicity of nimesulide in Wistar rats

It is mandatory for all new drugs to be tested for their potential genotoxicity in addition to general toxicity testing. Some old drugs have not been tested adequately for their genotoxic effects because these were in use before the local regulations were enforced. According to the material safety database, the toxicological effect of nimesulide is not yet fully understood. The present study therefore aimed to explore the genotoxic potential of nimesulide in Wistar albino rats. Nimesulide at the dose level of 50 (Gr-50), 100 (Gr-100) and 200 (Gr-200) mg/kg body weight (b.w.) was given orally. Each rat in treated groups (Gr-50 to Gr-200; n = 10) and negative control group (Gr-NC; n = 10) were administered orally (p.o.) with nimesulide and normal saline, respectively, for 14 days. Similarly, rats of positive control (Gr-PC; n = 10) were administered with cyclophosphamide (CPA; 20 mg/kg b.w.) intraperitoneally. CPA served as positive control, whereas normal saline served as as negative control. Approximately 1–2 mL of blood was collected from retro-orbital sinus for comet assay and subsequently rats were sacrificed to aspirate the femoral bone marrow for the micronucleus test. Structural chromosomal aberration, micronucleated polychromatic erythrocytes (MnPCEs), polychromatic erythrocytes (PCEs) and comet tail length were calculated using micronucleus assay and comet assay, respectively, which served as markers of genotoxicity. In the present study, it was observed that a significant increase in (1) different classified structural chromosomal aberrations with increase in nimesulide dose, such as gaps (50 mg/kg), gaps, breaks and pulverizations (100 mg/kg) and gaps, breaks, fragments, rings and pulverizations (200 mg/kg) and (2) % MnPCE and comet tail length was observed in animals treated with CPA (p < 0.001) or 200 mg of nimesulide (p < 0.05), as compared to negative control. In conclusion, nimesulide (200 mg/kg b.w.) produced a potential genotoxicity in rats.

Abstract 161: Effect of Simvastatin and Nimesulide on inflammation and cardiovascular risk biomarkers in a phase II breast cancer prevention trial.

Abstract Background: Almost one-third of breast cancers (BC) will not be influenced by hormonal interventions because of the absence of ER expression. Thus, there is an urgent need to confirm in the clinical setting the potential efficacy of new compounds in contrasting hormone non-responsive BC, which are often marked by higher biological aggressiveness, early onset and worse prognosis. Over expression of COX-2 and HMG-CoA pathway seems to be involved in breast carcinogenesis and several studies have shown the ability of NSAIDs and statins to reduce the incidence of BC. Material and Methods: We conducted a randomized phase II, double blind, placebo controlled trial with simvastatin (20 mg/day) and nimesulide (100 mg/day) for 1 year in 150 high risk women for ER negative BC in a 1:1:1 fashion. Participants were treated for one year and followed-up for an additional year. The primary endpoint was the change in prevalence of atypical cells obtained by ductal lavage or ultrasound guided fine needle aspirate and cellular proliferation (measured by Ki-67), while the secondary objective was to analyze the efficacy of these drugs in modifying the levels of circulating inflammatory and cardiovascular risk biomarkers. Circulating concentrations of high-sensitivity C-reactive protein (hsCRP), triglycerides, total cholesterol, LDL-cholesterol, HDL-cholesterol, antithrombin III and fibrinogen were measured on morning fasting blood samples drawn at baseline and after 12 and 24 months. Results: Analysis of the primary endpoint is ongoing and here we present results on circulating biomarkers. After 12 months of treatment, simvastatin was associated to a statistically significant mean decrease of hsCRP compared to the placebo arm (0,90 mg/L vs 3,57 mg/L; p=0.008), while an attenuated effect of nimesulide was observed (1.61 mg/L vs 3.57 mg/L; p=0.077). As expected, simvastatin significantly decreased LDL and total cholesterol levels with respect to placebo (89.1 vs 130 mg/dL and 176.8 vs 218 mg/dL respectively; both p&amp;lt;0.0001). Interestingly, after 1 year of treatment interruption, at 24 months from baseline, hsCRP serum levels were significantly lower with both simvastatin (p = 0.012) and nimesulide (p = 0.017) as compared to placebo. We did not observe a significant change in mean concentrations of triglycerides, antithrombin III and fibrinogen during treatment and follow-up. Conclusions: Our findings demonstrate a favourable anti-inflammatory effect of both agents on circulating levels of hsCRP, although simvastatin achieved a greater decrease. These results will be correlated with the main endpoint to further assess the potential role of simvastatin and nimesulide in breast carcinogenesis and the potential use of hsCRP as a surrogate endpoint biomarker. Citation Format: Valentina Aristarco, Davide Radice, Harriet Joahnsson, Debora Macis, Serena Mora, Massimiliano Cazzaniga, Laura Cortesi, Isabella Marchi, Maria Teresa Sandri, Bernardo Bonanni. Effect of Simvastatin and Nimesulide on inflammation and cardiovascular risk biomarkers in a phase II breast cancer prevention trial. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 161. doi:10.1158/1538-7445.AM2013-161

尼美舒利对人喉鳞癌Hep-2细胞祼鼠移植瘤CD44和MMP-7表达的影响

Objective To evaluate the inhibitory effect of Nimesulide on tumor growth of human laryngeal squamous carcinoma in nude mice and to explore the possible mechanism involved in the inhibition.Methods Nude mice model bearing human laryngeal squamous carcinoma cell line(Hep-2)was established.The volumes of the subcutaneous tumor were observed after Nimesulide treatment.The levels of COX-2,CD44 and MMP-7 protein and mRNA in transplantation tumor were examined by immunohistochemistry and RT-PCR,respectively.Results The growth of the carcinoma transplanted was significantly inhibited in the treatment group.Compared with the control group,the Nimesulide treatment group had significantly reduced weight and volume of tumor(all P0.05).There was no significantly difference in weights of mice increasing between the two groups.The levels of COX-2,CD44 and MMP-7 protein and mRNA of the treatment group were lower than those of the control group(all P0.05).Conclusion NIM has obvious inhibitory effect on the growth of human laryngeal squamous cell carcinoma Hep-2 cell xenografts in nude mice,through the down-regulation COX-2,CD44 and MMP-7.

Nimesulide improves the disease modifying anti-rheumatic profile of methotrexate in mice with collagen-induced arthritis

Methotrexate is a disease modifying anti-rheumatic drug that is widely used for the treatment of rheumatoid arthritis. Nimesulide is a non-steroidal anti-inflammatory drug which is frequently used as adjuvant therapy for symptomatic alleviation of rheumatoid arthritis. In this study, we have evaluated the potential influence of nimesulide on the disease modifying anti-rheumatic properties of methotrexate using the collagen-induced arthritis model. Mice were immunized with collagen type II for the induction of arthritis and treated with methotrexate (2.5mg/kg) twice a week, nimesulide (20mg/kg) every other day or a combination of both drugs. Treatment started one week after the onset of arthritis until day 40. An arthritic index was used to compare the severity of arthritis between different treatments. In addition, articular hyperalgesia, joint stiffness, radiological deterioration and intra-articular leucocytic infiltration were evaluated. Methotrexate alone showed modest but significant analgesic and anti-inflammatory effects, and the effects of nimesulide were comparable. On the other hand, nimesulide significantly improved the disease modifying anti-rheumatic profile of methotrexate in terms of arthritic index and joint mobility. Furthermore, although nimesulide failed to show any radiological evidence of articular protection, it significantly improved methotrexate-induced joint protection as judged by X-ray analysis.

Effects of COX‐2 inhibition on spinal nociception: the role of endocannabinoids

Recent studies suggest that the effects of cyclooxygenase-2 (COX-2) inhibition are mediated by cannabinoid receptor activation. However, some non-steroidal anti-inflammatory drugs inhibit the enzyme fatty acid amide hydrolase, which regulates levels of some endocannabinoids. Whether COX-2 directly regulates levels of endocannabinoids in vivo is unclear. Here, the effect of the COX-2 inhibitor nimesulide, which does not inhibit fatty acid amide hydrolase, on spinal nociceptive processing was determined. Effects of nimesulide on tissue levels of endocannabinoids and related compounds were measured and the role of cannabinoid 1 (CB(1)) receptors was determined. Effects of spinal and peripheral administration of nimesulide (1-100 microg per 50 microL) on mechanically evoked responses of rat dorsal horn neurones were measured, and the contribution of the CB(1) receptor was determined with the antagonist AM251 (N-(piperidin-1-yl)-5-(-4-iodophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide), in anaesthetized rats. Effects of nimesulide on spinal levels of endocannabinoids and related compounds were quantified using liquid chromatography-tandem mass spectrometry. Spinal, but not peripheral, injection of nimesulide (1-100 microg per 50 microL) significantly reduced mechanically evoked responses of dorsal horn neurones. Inhibitory effects of spinal nimesulide were blocked by the CB(1) receptor antagonist AM251 (1 microg per 50 microL), but spinal levels of endocannabinoids were not elevated. Indeed, both anandamide and N-oleoylethanolamide (OEA) were significantly decreased by nimesulide. Although the inhibitory effects of COX-2 blockade on spinal neuronal responses by nimesulide were dependent on CB(1) receptors, we did not detect a concomitant elevation in anandamide or 2-AG. Further understanding of the complexities of endocannabinoid catabolism by multiple enzymes is essential to understand their contribution to COX-2-mediated analgesia.

Assessment of cytotoxic and clastogenic effects of nimesulide: an NSAID drug in somatic cells of BALB/c mice in vivo

The in vivo genotoxicity of nimesulide, a sulfononilide nonsteroidal anti-inflammatory drug (NSAID) with anti-inflammatory, analgesic, and antipyretic effects, was evaluated by employing a mouse in vivo chromosomal aberration test in bone marrow cells. Oral treatment of animals for 5 consecutive days with 1, 2.5, 5, and 7.5 mg/kg body weight of the drug resulted in a statistically nonsignificant reduction in mitotic index and increase in CAs/cell and percent abnormal metaphase. The results indicated that nimesulide does not induce cytotoxicity and is a weak clastogen in the bone marrow cells of the mouse in vivo. Thus, the drug presents a very weak genotoxic risk.

Effect of Nimesulide and PGE2 Therapy, Alone and in Combination, in a Cutaneous Wound Model in Rats

Effect of Nimesulide and PGE2 Therapy, Alone and in Combination, in a Cutaneous Wound Model in Rats

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

Selective increase of neuronal cyclooxygenase-2 (COX-2) expression in vulnerable brain regions of rats with experimental Wernicke’s encephalopathy: effect of nimesulide

Thiamine deficiency (TD) in both humans and experimental animals results in severe mitochondrial dysfunction and leads to selective neuronal cell death in diencephalic and cerebellar structures. We have investigated cyclooxygenase-2 (COX-2) expression in vulnerable (medial thalamus, inferior colliculus) and spared (frontal cortex) regions of rats with thiamine deficiency. Expression of COX-2 mRNA was selectively increased (twofold, p < 0.001) in vulnerable regions at symptomatic stages of encephalopathy (14 days) of TD compared to pair-fed controls or presymptomatic (days 12) rats. Induction of COX-2 expression was accompanied by a significant increase (two- to threefold, p < 0.001) in prostanglandin E2 (PGE2) synthesis in vulnerable regions at symptomatic stages of TD. COX-2 immunolabeling revealed a neuronal localization and COX-2 immunoreactive neurons were significantly increased at symptomatic stages of encephalopathy. Administration of nimesulide, a highly specific COX-2 inhibitor, significantly reduced PGE-2 levels in vulnerable regions but, rather than being neuroprotective, precipitated encephalopathy and exacerbated neuronal cell death due to TD. These findings suggest that newly synthesized prostanoids exert a neuroprotective role in TD.

Cyclooxygenase-2 Inhibitor Nimesulide Blocks Ultraviolet B-induced Photocarcinogenesis in SKH-1 Hairless Mice

Cyclooxygenase-2 (COX-2) inhibition can inhibit UVB-induced carcinogenesis in the skin. We have shown that COX-2 is overexpressed in UVB-induced squamous cell carcinomas (SCCs). Celecoxib, a specific inhibitor of COX-2, blocks UVB-induced papillomas and carcinomas in murine skin. However, as COX-2 inhibitors of this type are associated with an increased risk of adverse cardiovascular events, we decided to study nimesulide, a different class of COX-2 inhibitor, an N-arylmethanesulfonamide derivative not known to have these untoward effects. To assess the antitumor-promoting effects of nimesulide, 90 mice were equally divided into three groups. Group I animals received no test agent or UVB and served as age-matched controls; group II animals were irradiated with UVB (180 mJ cm(-2), twice weekly for 35 weeks) and group III animals received 300 p.p.m. nimesulide in drinking water and were irradiated with UVB as described for group-II. Nimesulide treatment reduced the growth of UVB-induced tumors both in terms of tumor number and tumor volume. By weeks 25, 30 and 35, the tumor numbers in the nimesulide-treated group were 79%, 49% and 53% less than the number occurring in UVB-treated animals whereas tumor volume was reduced 69%, 54% and 53%, respectively, compared to the UVB-irradiated control group. Nimesulide also inhibited the malignant progression of SCCs. The reduction in tumorigenesis was paralleled by a decrease in cell cycle regulatory proteins (cyclins A, B1, D1, E, CDK2/4/6) and the antiapoptotic protein (Bcl2); concomitantly there was an increase in proapoptotic markers, poly (ADP-ribose) polymerase (PARP) and caspase-3. Nimesulide also decreased ornithine decarboxylase expression and the nuclear accumulation of nuclear factor kappa B transcriptionally active protein complexes. These results show that alternative classes of COX-2 inhibitors may likely be efficacious as cancer chemopreventive agents and may have an improved therapeutic index.