Administration Of Nimesulide Research Articles

Preemptive effects of ibuprofen and nimesulide on postoperative pain control after open flap periodontal surgeries: A randomized placebo-controlled split-mouth clinical trial.

Data on preemptive analgesia in periodontal surgeries are scarce and still diverse. The aim of this study was to evaluate and compare the analgesic effects of the preemptive administration of ibuprofen and nimesulide in open flap periodontal surgeries. The present randomized controlled clinical trial comprised 40 individuals, divided into two groups (n=20), according to the test drug (ibuprofen and nimesulide) to be administered 1hour preoperatively. Participants underwent bilateral periodontal surgeries at two different times, and were randomly given the test drug or placebo in a split-mouth design. Postoperative pain and rescue medication were evaluated at different times. Comparisons between ibuprofen and nimesulide were performed through a Generalized Estimation Equation model, using test drug and evaluation times, along with an interaction between these two variables as predictors. In intergroup comparisons regarding pain control, ibuprofen showed better effects than placebo only at the first postoperative hour, whereas nimesulide showed better effects than placebo at 1, 6, 24, and 48 postoperative hours. In intergroup comparisons, nimesulide showed better effects than ibuprofen at 24, 48, and 72 postoperative hours, demonstrating a higher overall preemptive effect. No differences were observed in relation to the number of rescue medication. Preemptive administration of nimesulide showed better overall preemptive effects on postoperative pain control when compared with ibuprofen.

Macromolecule extracted from Gracilaria caudata reduces inflammation and restores hepatic function in nimesulide-induced hepatic damage

Seaweeds are a source of novel bioactive compounds such as sulfated polysaccharides (PLS) that are not found in plants, but that may confer health-promoting properties. Sulfated polysaccharides extracted from seaweeds have several biologically beneficial effects. The PLS extracted from the red alga Gracilaria caudata are known to have anti-inflammatory, antinociceptive, and gastroprotective activities. The present study aimed to evaluate the hepatoprotective effect of PLS obtained from G. caudata on a nimesulide-induced liver damage model. Hepatic lesions were induced in mice by oral doses of nimesulide (200 mg kg−1) administered once daily for 5 days. Once a day, 30 min after administration of nimesulide, PLS was administered intraperitoneally at concentrations of 2.5, 5, and 10 mg kg−1. Subsequently, blood was collected for biochemical tests and the liver was removed to evaluate inflammatory parameters. Administration of PLS at the dose of 10 mg kg−1 led to a significant reduction in hepatic injury, liver weight/animal weight ratio, the levels of a neutrophil migration marker (myeloperoxidase), pro-inflammatory cytokines (interleukin-1β and tumor necrosis factor-α), nitrate and nitrite, oxidative stress markers, and hepatic function markers. As per our results, the PLS extracted from G. caudata was able to modulate the inflammatory response in nimesulide-induced hepatic damage in addition to re-establishing the hepatic homeostatic functions.

LC-MS/MS determination of 4-hydroxynimesulide, an active metabolite of nimesulide and application to bioequivalence study in Indian subjects.

A simple and highly sensitive bioanalytical method was developed and validated for simultaneous quantification of nimesulide (NSD) and its active metabolite 4-hydroxy-nimesulide (M1) in human plasma by liquid chromatography-tandem mass spectrometer (LC-MS/MS) and applied in a bioequivalence study performed on Indian subjects. The bioanalytical method was carried out by LC-MS/MS with celecoxib (CXB) as an internal standard (IS) using liquid-liquid extraction technique. The chromatographic separation was performed on a reversed-phase Agilent eclipse plus C18 (75 mm × 4.6 mm, particle size 3.5 µm) column with a mobile phase of acetronitrile and water containing 5 mM ammonium formate (9:1, v/v). Method validation and clinical sample were analysed as per USFDA and EMA guidelines and results met the acceptance criteria. The lower limit of quantitation of NSD and M1 was found 10 ng/mL with a large linearity range from 10 to 6000 ng/mL for both NSD and M1 using only 100 µL of plasma and reported no matrix effect. The multiple reaction monitoring transitions of m/z 307.20 → 229.20, m/z 323.00 → 245.00 and m/z 380.20 → 316.20 were used to measure NSD, M1 and CXB (IS), respectively. The assay method was successfully applied for the simultaneous quantification of both NSD and M1 in plasma samples after oral administration of nimesulide 100 mg tablet in healthy human subjects.

Effects of NSAIDs on the Release of Calcitonin Gene-Related Peptide and Prostaglandin E2 from Rat Trigeminal Ganglia.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are frequently used to treat migraine, but the mechanisms of their effects in this pathology are not fully elucidated. The trigeminal ganglia and calcitonin gene-related peptide (CGRP) have been implicated in the pathophysiology of migraine. The release of CGRP and prostaglandin E2 (PGE2) from freshly isolated rat trigeminal ganglia was evaluated after oral administration of nimesulide, etoricoxib, and ketoprofen, NSAIDs with different pharmacological features. Thirty minutes after oral administration, nimesulide, 10 mg/Kg, decreased the GCRP release induced by an inflammatory soup, while the other NSAIDs were ineffective at this point in time. Two hours after oral nimesulide (5 and 10 mg/Kg) and ketoprofen (10 mg/Kg), but not of etoricoxib, a significant decrease in the CGRP release was observed. All drugs reduced PGE2, although with some differences in timing and doses, and the action on CGRP does not seem to be related to PGE2 inhibition. The reduction of CGRP release from rat trigeminal ganglia after nimesulide and ketoprofen may help to explain the mechanism of action of NSAIDs in migraine. Since at 30 minutes only nimesulide was effective in reducing CGRP release, these results suggest that this NSAID may exert a particularly rapid effect in patients with migraine.

Safety Evaluation of Nimovet® in Poultry Birds

Nimesulide, a NSAID causes toxicity to poultry birds and indirectly to human through residue present in poultry meat. Birds of control and treated group (Gr-C, Gr-50, Gr-100 and Gr-200) received 10% ethanol, 50, 100 and 200 ppm Nimesulide (Nimovet®) in drinking water up to 42 days, respectively. Statistical analysis done by ANOVA and LSD by Turkey's test. No mortality was observed in treated groups. There was progressive and a significant reduction in feed and water intake in birds of Gr-200 at day 21, 28 and 42 as compared to control birds. The % body weight gain was significantly reduced in Gr-50&Gr-100 at 21 day and Gr-200 from 14 to 42 day interval. Urea level was significantly increased in birds of Gr-50 &100 by 1.5 fold and Gr-200 by 2 fold as compared to the birds of Gr-C. The serum ALT, AST and ALP activity was significantly increased in the birds of Gr-200 as compared to birds of Gr-C. Histo-pathological alterations were observed in heart, liver, lungs and kidney leaving brain, intestine, thymus, spleen and bursa intact in the birds of Gr-200 at 42 day interval. Cumulative administration of Nimesulide (Nimovet®) in poultry birds is (i) safe up to 100 ppm for 6 week period and (ii) unsafe with organic toxicity at 200 ppm. In consideration of the present findings it could be predicted that Nimesulide (Nimovet®) at higher dose could cause toxicity to poultry birds itself and ultimate consumers including scavenger birds and animals.

ADMINISTRATION OF H2 BLOCKERS IN NSAID INDUCED GASTROPATHY IN RATS: effect on histopathological changes in gastric, hepatic and renal tissues.

Nonsteroidal anti-inflammatory drugs induces gastric mucosal lesions because of its acidic properties. Ranitidine, an H2 receptor antagonist, has proved beneficial in patients with gastric ulcers. The present study was performed to assess the effect of administering ranitidine in Nonsteroidal anti-inflammatory drugs (diclofenac, nimesulide) induced gastropathy, and their effect on the histopathology of stomach, kidney and liver. Diclofenac, nimesulide, and ranitidine were administered in doses of 2, 4, and 6 mg/kg, p.o. once daily for 14 days, and their effect on gastric volume, acidity, mean ulcer number, and gastric pH. In addition, histopathological examination was also performed on sections of stomach, kidney and liver. Following the administration of diclofenac or nimesulide, all the gastric parameters were significantly altered as well as the histopathology of stomach, liver and kidney. In the control group, the renal sections showed normal glomeruli with no thickening of glomerular basement membrane, while in diclofenac alone, nimesulide alone, and ranitidine with nimesulide groups, the thickening of glomerular basement membrane was observed. These alterations were observed to be reversed in the ranitidine with diclofenac group. In the sections from the liver, the control group showed anastomosing plates and cords of cuboidal hepatocytes with round well stained nuclei and abundant cytoplasm. In the ranitidine with diclofenac, and ranitidine with nimesulide groups, mild dilatation of sinusoids is seen coupled with prominence of central vein. In the diclofenac alone and nimesulide alone groups, the proximal and distal convoluted tubules show mild focal tubular necrosis. In the gastric sections, the control group showed several folds forming villi, and the epithelial lining surface of the mucosa. In the ranitidine with diclofenac, and ranitidine with nimesulide groups, the duodenum showed scattered inflammatory cells composed predominantly of lymphocytes. In diclofenac alone and nimesulide alone group, the sections from the gastric areas showed partial necrosis and mild chronic inflammation respectively. The study, therefore, has provided therapeutic rationale towards simultaneous administration of H2 receptor blocker ranitidine with diclofenac to be more beneficial as compared to ranitidine with nimesulide, to minimise the gastric intolerance of diclofenac in long term treatment of inflammatory conditions.

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.

Effects of Subchronic Treatment with Ibuprofen and Nimesulide on Spatial Memory and NMDAR Subunits Expression in Aged Rats.

Several studies point to an important function of cyclooxygenase (COX) and prostaglandin signaling in models of synaptic plasticity which is associated with N-methyl-D-aspartate receptors (NMDARs). Cyclooxygenase gene is suggested to be an immediate early gene that is tightly regulated in neurons by NMDA dependent synaptic activity. Nonsteroid Antiinflammatory Drugs (NSAIDs) exert their antiinflammatory effect by the inhibion of COX have controversial effects on learning and memory. We administered ibuprofen as a non-selective COX-2 inhibitor and nimesulide as a selective COX-2 inhibitor for 8 weeks for determining the cognitive impact of subchronic administration of NSAIDs to aged rats. Wistar albino rats (16 mo, n = 30) were separated into control (n = 10), ibuprofen (n = 10) and nimesulide (n = 10) treated groups. First we evaluated hippocampus-dependent spatial memory in the radial arm maze (RAM) and than we evaluated the expression of the NMDAR subunits, NR2A and NR2B by western blotting to see if their expressions are effected by subchronic administration with these drugs. Ibuprofen and nimesulide treated rats completed the task in a statistically significant shorter time when compared with control group (p < 0.01), but there was no statistically significant difference between groups about choice accuracy data in RAM. Furthermore, no statistically significant difference was detected for the protein expressions of NR2A and NR2B of the subjects. Oral administration of ibuprofen and nimesulide for 8 weeks showed no impairment but partly improved spatial memory.

Breast ductal lavage for biomarker assessment in high risk women: rationale, design and methodology of a randomized phase II clinical trial with nimesulide, simvastatin and placebo

BackgroundDespite positive results from large phase III clinical trials proved that it is possible to prevent estrogen-responsive breast cancers with selective estrogen receptor modulators and aromatase inhibitors, no significant results have been reached so far to prevent hormone non-responsive tumors. The Ductal Lavage (DL) procedure offers a minimally invasive method to obtain breast epithelial cells from the ductal system for cytopathologic analysis. Several studies with long-term follow-up have shown that women with atypical hyperplasia have an elevated risk of developing breast cancer. The objective of the proposed trial is to assess the efficacy and safety of a daily administration of nimesulide or simvastatin in women at higher risk for breast cancer, focused particularly on hormone non-responsive tumor risk. The primary endpoint is the change in prevalence of atypical cells and cell proliferation (measured by Ki67) in DL or fine needle aspirate samples, after 12 months of treatment and 12 months after treatment cessation.Methods-DesignFrom 2005 to 2011, 150 women with a history of estrogen receptor negative ductal intraepithelial neoplasia or lobular intraepithelial neoplasia or atypical hyperplasia, or unaffected subjects carrying a mutation of BRCA1 or with a probability of mutation >10% (according to BRCAPRO) were randomized to receive nimesulide 100mg/day versus simvastatin 20mg/day versus placebo for one year followed by a second year of follow-up.DiscussionThis is the first randomized placebo controlled trial to evaluate the role of DL to study surrogate endpoints biomarkers and the effects of these drugs on breast carcinogenesis. In 2007 the European Medicines Agency limited the use of systemic formulations of nimesulide to 15 days. According to the European Institute of Oncology Ethics Committee communication, we are now performing an even more careful monitoring of the study participants. Preliminary results showed that DL is a feasible procedure, the treatment is well tolerated and the safety blood tests do not show any significant liver toxicity. There is an urgent need to confirm in the clinical setting the potential efficacy of other compounds in contrasting hormone non-responsive breast cancer. This paper is focused on the methodology and operational aspects of the clinical trial.Trial Registration(ClinicalTrials.gov Identifier: NCT01500577)

Thermosensitive and mucoadhesive in situ gel based on poloxamer as new carrier for rectal administration of nimesulide

Poloxamer 407 has excellent thermo-sensitive gelling properties. Nevertheless, these gels possess inadequate poor bioadhesiveness and high permeability to water, which limited its’ application as a thermoresponsive matrix. The main aim of the present investigation was to develop thermosensitive and mucoadhesive rectal in situ gel of nimesulide (NM) by using mucoadhesive polymers such as sodium alginate (Alg–Na) and HPMC. These gels were prepared by addition of mucoadhesive polymers (0.5%) to the formulations of thermosensitive gelling solution containing poloxamer 407 (18%) and nimesulide (2.0%). Polyethylene glycol (PEG) was used to modify gelation temperature and drug release properties. The gelation temperature and drug release rate of the prepared in situ gels were evaluated. Gelation temperature was significantly increased with incorporation of nimesulide (2.0%) in the poloxamer solution, while the addition of the mucoadhesive polymers played a reverse role on gelation temperature. The addition of PEG polymers increased the gelation temperature and the drug release rate. Among the formulations examined, the poloxamer 407/nimesulide/sodium alginate/PEG 4000 (18/2.0/0.5/1.2%) exhibited the appropriate gelation temperature, acceptable drug release rate and rectal retention at the administration site. Furthermore, the micrographic results showed that in situ gel, given at the dose of 20mg/kg, was safe for no mucosa irritation. In addition, it resulted in significantly higher initial serum concentrations, Cmax and AUC of NM compared to the solid suppository.

Abstract A72: A phase II randomized trial with nimesulide, simvastatin, and placebo in subjects at increased risk for breast cancer

Abstract Background: Breast cancer (BC) prevention has been successful for estrogen receptor positive cancer, whereas no significant results have been reached so far to prevent hormone non-responsive tumors. Epidemiological and in vitro studies have suggested the possible preventive role of several compounds, in particular NSAIDs (nonsteroidal anti-inflammatory drugs) and more recently statins. Several data suggest the ability of NSAIDs to reduce the risk of many tumors including BC. Nimesulide is a NSAID largely used in several European countries. It is defined as a preferential COX-2 inhibitor, because it maintains a modest inhibitory activity on COX-1. The incomplete COX-2 selectivity of nimesulide gives a favorable profile, avoiding most side effects of the nonspecific COX inhibitors and the super-selective COX-2 inhibitors. Statins are widely used for the treatment of lipid disorders in cardiovascular disease prevention. They have shown a possible role in cancer prevention through the modulation of cell cycle arrest and apoptosis. The objective of the proposed trial is to assess the efficacy and safety of a daily administration of nimesulide or simvastatin in women at higher risk for BC, focused particularly on hormone nonresponsive tumor risk. Study design: 150 women will be randomized to receive nimesulide versus simvastatin versus placebo for one year followed by a second year of follow-up. Eligible subjects are: patients with previous estrogen receptor negative ductal intraepithelial neoplasia (DIN) or lobular intraepithelial neoplasia (LIN) or atypical hyperplasia (AH), and unaffected subjects carrying a mutation of BRCA1/2 or with a probability of mutation &amp;gt;10% (according to BRCAPRO). At baseline, 6, 12 and 24 month clinical examination, blood tests and annual mammography are scheduled. Ductal lavage (DL) or fine needle aspirate (FNA) — if for any reason the DL is not possible or result inadequate — is performed annually to obtain a breast cell sample. For safety reasons the blood tests are performed also at 3 and 9 month time. The primary endpoint is the change in prevalence of atypical cells and cell proliferation (measured by Ki67) in DL or FNA samples, after 12 months of treatment and 12 months after treatment suspension. Secondary endpoints are: treatment safety and the modulation of a large set of cell and circulating surrogate endpoint biomarkers (SEBs) of breast cancerogenesis. Recruitment and preliminary results: at August 2010 we have randomized 140 subjects of which 64 ER neg DIN, 48 LIN and AH and 28 subjects with mutation or mutation probability. So far 83 subjects completed the study. The treatment is very well tolerated and the safety blood tests did not show any significant liver toxicity, only few subjects had grade 1 liver enzyme alterations. CPK alteration was seen in 9 subjects (grade 1 toxicity). One case was included in the study with a baseline level of CPK grade 2, the patient was withdrawn from the study. Including this last case five subjects dropped out: two for gastrointestinal symptoms, one for muscle ache, and one refused to continue. To our knowledge this is the first randomazied placebo controlled trial to study SEBs and their modulation after intervention with DL. Citation Information: Cancer Prev Res 2010;3(12 Suppl):A72.

Prenatal Undernutrition Changes Renovascular Responses of Nimesulide in Rat Kidneys

Several studies in the Northeastern region of Brazil have demonstrated an association between hypertension in adult populations and prenatal and postnatal undernutrition. The central hypothesis we proposed was that hypertension could be favoured by programmed alterations in branches of the renal arachidonic pathway and consequently in counter-balancing the renin angiotensin system, especially during treatments with cyclooxygenase inhibitors. We assessed the influence of subchronic (21 days) and acute administration of nimesulide, a preferential cyclooxygenase-2 (COX-2) inhibitor, on mean blood pressure (MAP), renal blood flow (RBF), glomerular filtration rate (GFR) and urinary output (U(v)) in adult rats that were prenatally undernourished. Undernutrition per se led to the onset of mild hypertension in adult offspring, whereas subchronic nimesulide treatment increased MAP in control and elicited further augmentation in undernourished animals. The drug (i) decreased RBF and GFR in controls by 50%, whereas no effect was detected in the undernourished group, and (ii) increased U(v) by 25% in controls, an effect that was potentiated by 200% in programmed animals. In contrast, acute nimesulide administration decreased U(v) , with the hypertensive effect of the drug being potentiated during dehydration. These findings demonstrate that prenatal nutritional programming differentially modulates adult renovascular responses to nimesulide in the cortex and medulla, which may exacerbate the deleterious effects of COX-2 inhibition in the kidney.

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.

Interaction of nimesulide, a cyclooxygenase-2 inhibitor, with cisplatin in normotensive and spontaneously hypertensive rats

We investigated the effect of administration of nimesulide, a selective cyclooxygenase-2 (COX-2) inhibitor, on cisplatin (CP)-induced nephrotoxicity in rats. WKY rats and SHRs were divided into four groups, each. The first and second groups received saline and oral nimesulide (20 mg/kg/day for 6 days), respectively, whereas the third and fourth groups received a single intraperitoneal (i.p.) injection of CP (5 mg/kg) and CP (5 mg/kg) and nimesulide (20 mg/kg/day for 5 days), respectively. At the end of the experiment, rats were anesthetized and blood pressure and renal blood flow (RBF) were monitored, followed by intravenous (i.v.) injection of norepinephrine (NE). Nephrotoxicity was evaluated histopathologically and biochemically. CP caused a reduction in baseline RBF in both WKY and SHRs. It increased the concentrations of urea and creatinine and kidney relative weight, and decreased body weight in both WKY and SHRs. Histopathologically, CP caused remarkable renal damage in both WKY rats and SHRs. Treatment with nimesulide alone did not produce any significant change in any of the above measurements. However, nimesulide aggravated CP-induced renal tissue damage in SHRs, but not in WKY rats. The results show that administration nimesulide augmented the histopathological indices of nephrotoxicity in SHRs, but not in WKY rats.

Efficacy and safety of nimesulide long term administration in patients with osteoarthritis: results of 12-months open controlled study DINAMO (long term administration of nimesulide in osteoarthritis multifactor assessment)

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Cholestatic hepatitis associated with nimesulide: A case report

A toxic effect of drugs, including non-steroidal anti-inflammatory drugs, may be one of aetiological factors for the occurrence of acute hepatitis. Nimesulide is a selective cyclooxygenase-2 inhibitor, whose adverse effects on the liver range from acute hepatitis to more serious conditions, involving the development of acute liver failure and fatal outcome. A female patient, aged 73, was admitted to the Gastroenterology and Hepatology Clinic of the Clinical Centre of Serbia in Belgrade because of liver failure. Due to the pain in the right knee, she received a therapy of 100 mg nimesulide in tablets, two times a day, for two months before admission to the Clinic. The analysis of the results of clinical, laboratory and radiographic examinations, and of histopathological findings of the liver biopsy showed that acute hepatitis was associated with the administration of nimesulide. Once the patient discontinued the intake of this drug, she fully convalesced. The patient who received nimesulide over a period of two months developed acute hepatitis. In view of the similar cases described in literature and the fact that the use of nimesulide has been discontinued in a number of European countries and restricted by the European Medicines Agency, restriction or ban on the use of nimesulide on the Serbian market should be considered.

Four-week administration of nimesulide, a cyclooxygenase-2 inhibitor, improves endothelial dysfunction in the hindlimb vasculature of streptozotocin-induced diabetic rats

The aim of this study was to examine the effect of chronic administration of nimesulide, a cyclooxygenase-2 inhibitor, on endothelial dysfunction in streptozotocin-induced diabetic rats. Three groups of Sprague-Dawley rats (300-350 g, n=6) were used. The first group served as normoglycemic control and the second and third groups were rendered diabetic by an intraperitoneal injection of streptozotocin (60 mg/kg). The third group received the selective COX-2 inhibitor, nimesulide (20 mg/kg/day), orally by gavage for 4 weeks while the second group received only drinking water and served as diabetic control. At the end of the treatment period, the rats were anesthetized with urethane (1.2 g/kg) and mean arterial pressure, heart rate and hindlimb blood flow were monitored. This was followed by the injection of acetylcholine (endothelium-dependent vasodilator, 0.1-0.8 microg/kg) and sodium nitroprusside (endothelium-independent vasodilator 1-4 microg/kg). Mean arterial pressure was significantly reduced and hindlimb vascular conductance was not significantly affected in the control diabetic group when compared to the normoglycemic control group. Nimesulide treatment did not cause any significant change in any of the measured hemodynamic parameters. Acetylcholine and sodium nitroprusside induced dose-dependent increases in hindlimb vascular conductance in control normoglycemic rats which were attenuated in diabetic control rats. Nimesulide reversed the attenuation of acetylcholine-induced increase in hindlimb vascular conductance. In conclusion, chronic administration of the selective COX-2 inhibitor, nimesulide improved endothelial dysfunction in the hindlimb vasculature of streptozotocin induced diabetic rats. This suggests that COX-2 products might be involved in the pathogenesis of endothelial dysfunction in streptozotocin-induced diabetic rats.

Morphine, opioids, and the feline pulmonary vascular bed

Opioid-induced vasodepressor responses have been reported in a variety of species and laboratory models. The aim of this study was to ascertain the relative potencies of different clinically relevant opioids compared with traditional vasodepressor agents in the feline pulmonary vascular bed. A second aim was to study the effects of morphine and to identify the receptors involved in the mediation or the modulation of these effects. This was a prospective vehicle-controlled study involving an intact chest preparation of adult mongrel cats. The effects of various opioids, morphine, fentanyl, remifentanil, sufentanil, and meperidine were compared with other vasodepressor agents. Additionally, the effects of L-N(5)-(1-iminoethyl) ornithine hydrochloride (L-NIO) (nitric oxide synthase inhibitor), nimesulide [selective cyclooxygenase (COX)-2 inhibitor], glibenclamide (ATP-sensitive K+ channel blocker), naloxone (non-selective opioid receptor antagonist), and diphenhydramine (histamine H(1)-receptor antagonist) were investigated on pulmonary arterial responses to morphine and other selected agonists in the feline pulmonary vascular bed. The systemic pressure and lobar arterial perfusion pressure were continuously monitored, electronically averaged, and recorded. In the cat pulmonary vascular bed of the isolated left lower lobe, morphine, remifentanil, fentanyl, sufentanil, and meperidine induced a dose-dependent moderate vasodepressor response and it appeared that sufentanil was the most potent on a nanomolar basis. The effects of morphine were not significantly altered after administration of L-NIO, nimesulide, and glibenclamide. However, the vascular responses to morphine were significantly attenuated following administration of naloxone and diphenhydramine. The results of the present study suggest that sufentanil appears to have slightly more potency and morphine the least of the five opioid agonists studied on a nanomolar basis. Morphine-induced vasodilatory responses appeared to be mediated or modulated by both opioid receptor and histamine-receptor-sensitive pathways.

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.

Effects of cyclooxygenase inhibition on canine coronary artery blood flow and thrombosis

This study was designed to determine the effect of inhibitors of cyclooxygenase (COX)-1, COX-2, and the nonselective COX inhibitor naproxen on coronary vasoactivity and thrombogenicity under baseline and lipopolysaccharide (LPS)-induced inflammatory conditions. We hypothesize that endothelial COX-1 is the primary COX isoform in the canine normal coronary artery, which mediates arachidonic acid (AA)-induced vasodilatation. However, COX-2 can be induced and overexpressed by inflammatory mediators and becomes the major local COX isoform responsible for the production of antithrombotic prostaglandins during systemic inflammation. The interventions included the selective COX-1 inhibitor SC-560 (0.3 mg/kg iv), the selective COX-2 inhibitor nimesulide (5 mg/kg iv), or the nonselective COX inhibitor naproxen (3 mg/kg iv). The selective prostacyclin (IP) receptor antagonist RO-3244794 (RO) was used as an investigational tool to delineate the role of prostacyclin (PGI(2)) in modulating vascular reactivity. AA-induced vasodilatation of the left circumflex coronary artery was suppressed to a similar extent by each of the COX inhibitors and RO. The data suggest that AA-induced vasodilatation in the normal coronary artery is mediated by a single COX isoform, the constitutive endothelial COX-1, which is reported to be susceptible to COX-2 inhibitors. The effect of the COX inhibitors on thrombus formation was evaluated in a model of carotid artery thrombosis secondary to electrolytic-induced vessel wall injury. Pretreatment with LPS (0.5 mg/kg iv) induced a systemic inflammatory response and prolonged the time-to-occlusive thrombus formation, which was reduced in the LPS-treated animals by the administration of nimesulide. In contrast, neither SC-560 nor naproxen influenced the time to thrombosis in the animals pretreated with LPS. The data are of significance in view of reported adverse cardiovascular events observed in clinical trials involving the use of selective COX-2 inhibitors, thereby suggesting that the endothelial constitutive COX-1 and the inducible vascular COX-2 serve important functions in maintaining vascular homeostasis.