Doses Of Nimesulide Research Articles

Wide therapeutic time window for nimesulide neuroprotection in a model of transient focal cerebral ischemia in the rat

Results from several studies indicate that cyclooxygenase-2 (COX-2) is involved in ischemic brain injury. The purpose of this study was to evaluate the neuroprotective effects of the selective COX-2 inhibitor nimesulide on cerebral infarction and neurological deficits in a standardized model of transient focal cerebral ischemia in rats. Three doses of nimesulide (3, 6 and 12 mg/kg; i.p.) or vehicle were administered immediately after stroke and additional doses were given at 6, 12, 24, 36 and 48 h after ischemia. In other set of experiments, the effect of nimesulide was studied in a situation in which its first administration was delayed for 3–24 h after ischemia. Total, cortical and subcortical infarct volumes and functional outcome (assessed by neurological deficit score and rotarod performance) were determined 3 days after ischemia. The effect of nimesulide on prostaglandin E 2 (PGE 2) levels in the injured brain was also investigated. Nimesulide dose-dependently reduced infarct volume and improved functional recovery when compared to vehicle. Of interest is the finding that neuroprotection conferred by nimesulide (reduction of infarct size and neurological deficits and improvement of rotarod performance) was also observed when treatment was delayed until 24 h after ischemia. Further, administration of nimesulide in a delayed treatment paradigm completely abolished PGE 2 accumulation in the postischemic brain, suggesting that COX-2 inhibition is a promising therapeutic strategy for cerebral ischemia to target the late-occurring inflammatory events which amplify initial damage.

Immune Tolerance to Drugs. (II).: Long–Term Tolerability of Nimesulide in Patients with NSAID Hypersensitivity

Nimesulide is well‐tolerated as an alternative to nonsteroidal antiinflammatory drugs (NSAIDs) in patients with a previous adverse reaction to other classes of NSAIDs. However, there is little information in the literature about its long–term tolerability. The study was carried out on 625 patients who had experienced adverse reactions to one or more NSAIDs. All patients received and tolerated peroral challenges with nimesulide. On the first day, patients were given an equivalent number of placebo doses to the planned number of nimesulide doses. In a successive session, the test was administered by means of increasing doses of nimesulide at 30 min intervals until the common daily therapeutic dose of 100 mg was reached (10 mg–20 mg–30 mg–40 mg). A questionnaire was distributed to all subjects. In particular, they were asked to clarify any reactive symptoms they had developed after ingestion of the drug. It was found that only 2.1% (4/192) of subjects who were given this drug experienced urticaria during treatment. We have identified three significant risk factors: a history of chronic urticaria, a history of antibiotic hypersensitivity and a history of hypersensitivity to more than one class of NSAIDs. In patients with the above risk factors, a prior tolerance test with a selective COX2 antagonist should be administered.

Modulatory Effect of Cyclooxygenase Inhibitors on Sildenafil-Induced Antinociception

Peripheral activation of the NO-cGMP pathway has been implicated in various nociceptive conditions. The antinociceptive effect of the PDE-5 inhibitor, sildenafil, alone or in combination with cyclooxygenase inhibitor diclofenac and nimesulide, was assessed in the different animal models of peripheral nociception. In the present study we investigated the possible interaction between cyclooxygenase and NO-cGMP pathway in writhing assay and carrageenan-induced hyperalgesia in mice and rats, respectively. Sildenafil [1–2 mg/kg, i.p. or 50–100 µg/paw, intraplantar (i.pl.)], nimesulide (1–2 mg/kg, i.p. or 25–50 µg/paw, i.pl.) and diclofenac (1–2 mg/kg, i.p. or 25–50 µg/paw, i.pl.) exhibited an antinociceptive effect in both the models. When ineffective doses of sildenafil (0.5 mg/kg, i.p and 25 µg/paw, i.pl.) were co-administered with ineffective doses of nimesulide (0.5 mg/kg, i.p. and 10 µg/paw, i.pl.) and diclofenac (0.5 mg/kg, i.p. and 10 µg/paw, i.pl.), there was a significant increase in the antinociceptive effect in both the models of peripheral nociception. Further, the potentiation of the effect was blocked by L-NAME (20 mg/kg, i.p., 100 µg/paw, i.pl.), a non-selective NOS inhibitor and methylene blue (1 mg/kg, i.p.), a guanylate cyclase inhibitor. L-NAME or methylene blue itself had little or no effect on both the models of hyperalgesia. These results suggest that cyclooxygenase, NO and cGMP are relevant in the combination-induced antinociception. In conclusion, sildenafil induced antinociception, and its potentiation of the effect of the cyclooxygenase inhibitors nimesulide and diclofenac was probably mediated through the activation of the NO-cGMP pathway and inhibition of cyclic GMP degradation.

Neuroprotective efficacy of nimesulide against hippocampal neuronal damage following transient forebrain ischemia

Cyclooxygenase-2 is involved in the inflammatory component of the ischemic cascade, playing an important role in the delayed progression of the brain damage. The present study evaluated the pharmacological effects of the selective cyclooxygenase-2 inhibitor nimesulide on delayed neuronal death of hippocampal CA1 neurons following transient global cerebral ischemia in gerbils. Administration of therapeutically relevant doses of nimesulide (3, 6 and 12 mg/kg; i.p.) 30 min before ischemia and at 6, 12, 24, 48 and 72 h after ischemia significantly (P<0.01) reduced hippocampal neuronal damage. Treatment with a single dose of nimesulide given 30 min before ischemia also resulted in a significant increase in the number of healthy neurons in the hippocampal CA1 sector 7 days after ischemia. Of interest is the finding that nimesulide rescued CA1 pyramidal neurons from ischemic death even when treatment was delayed until 24 h after ischemia (34±9% protection). Neuroprotective effect of nimesulide is still evident 30 days after the ischemic episode, providing the first experimental evidence that cyclooxygenase-2 inhibitors confer a long-lasting neuroprotection. Oral administration of nimesulide was also able to significantly reduce brain damage, suggesting that protective effects are independent of the route of administration. The present study confirms the ability of cyclooxygenase-2 inhibitors to reduce brain damage induced by cerebral ischemia and indicates that nimesulide can provide protection when administered for up to 24 h post-ischemia.

Inhibition of premature labor in sheep by a combined treatment of nimesulide, a prostaglandin synthase type 2 inhibitor, and atosiban, an oxytocin receptor antagonist

Objective: The aim of this study was to compare the effects of the selective prostaglandin synthase type 2 inhibitor nimesulide, alone or in combination with the oxytocin receptor antagonist atosiban, on the progression of glucocorticoid-induced premature labor in sheep. Effects on circulating maternal and fetal prostaglandin concentrations and on fetal well-being were also examined. Study Design: Premature labor was induced in ewes with long-term catheterized fetuses by infusion of dexamethasone (1 mg/d) starting at 138 ± 1 days’ gestation. Ewes also received an infusion of either nimesulide and atosiban (20.0 and 4.12 mg/kg per day, respectively; n = 5), nimesulide alone (20.0 mg/kg per day; n = 5), or vehicle only (n = 9). Plasma 13,14-dihydro-15-keto-prostaglandin F2α and prostaglandin E2 concentrations were measured before and during infusions in plasma samples obtained from the maternal and fetal carotid arteries and the utero-ovarian vein. Results: No fetuses from ewes treated with nimesulide and atosiban were delivered during treatment. These animals were killed electively 98.0 ± 6.8 hours after the commencement of dexamethasone induction. This was significantly longer than the delivery times for those ewes treated with nimesulide alone (71.2 ± 3.9 hours; n = 5) and for vehicle-treated ewes (51.4 ± 1.7 hours; n = 9). Both maternal and fetal plasma 13,14-dihydro-15-keto-prostaglandin F2α and prostaglandin E2 concentrations in nimesulide and atosiban–treated ewes and in nimesulide-treated ewes decreased during treatment. In contrast, vehicle-treated ewes showed a significant increase in maternal and fetal plasma 13,14-dihydro-15-keto-prostaglandin F2α and prostaglandin E2 concentrations during dexamethasone induction. Uterine electromyographic activity observed in nimesulide and atosiban–treated ewes was significantly suppressed with respect to activities in both vehicle- and nimesulide-treated ewes during the treatment period. All fetuses were alive at delivery or scheduled death. Conclusions: These results indicate that the combination of an inhibitor of prostaglandin endoperoxidase H synthase type 2 with an oxytocin receptor antagonist is more effective in inhibition of preterm labor than is treatment with a prostaglandin endoperoxidase H synthase type 2 inhibitor alone. The clinical use of atosiban to prevent the oxytocin-stimulated increase in uterine activity associated with labor in combination with nimesulide may permit reduction of the dose of nimesulide used to a level that has minimal impact on fetal well-being. (Am J Obstet Gynecol 2000;183:649-57.)

Nimesulide limits kainate-induced oxidative damage in the rat hippocampus

Kainate induces a marked expression of cyclooxygenase-2 after its systemic administration. Because cyclooxygenase-2 activity is associated to the production of reactive oxygen species, we investigated the effects of nimesulide, a selective cyclooxygenase-2 inhibitor, on kainate-induced in vivo oxidative damage in the rat hippocampus. A clinically relevant dose of nimesulide (6 mg/kg, i.p.) was administered three times following kainate application (9 mg/kg, i.p.). After 24 h of kainate administration, the drastic decrease in hippocampal glutathione content and the significant increase in lipid peroxidation were attenuated in nimesulide-treated rats, suggesting that the induction of cyclooxygenase-2 is involved in kainate-mediated free radicals formation.

Rapid and sensitive method for determination of nimesulide in human plasma by high-performance liquid chromatography

A rapid and sensitive high-performance liquid chromatographic method for determination of nimesulide in human plasma has been developed. The chromatographic system uses a reversed-phase C 18 column with UV–Vis detection at 230 nm. Mobile-phase consisted of phosphate buffer (pH 5.5)–methanol–acetonitrile (50:20:30, v/v) at a flow-rate of 1.4 ml/min. Nimesulide was extracted in a single step into dichloromethane.The overall mean extraction recoveries were above 98% for both inter- and intra-assay reproducibility,with CVs from 0.3 to 1%. The calibration curve was linear in the concentration range of 0.05–5 μg/ml, and the lower limit of detection was 30 ng/ml. This simple and sensitive method allows for determination of the range of plasma concentrations that is observed after administration of clinically relevant doses of nimesulide.

Dual effects of nimesulide, a COX-2 inhibitor, in human platelets

Nimesulide (CAS 51803-78-2) has been shown to exert marked anti-inflammatroy effect in several in vivo models of inflammation. Since nimesulide is considered to be a selective inhibitor of COX-2, it has not been studied in detail in relation to its mechanistic effects on platelets, which express COX-1. This study was conducted to investigate the effects of nimesulide in platelet aggregation. We show that nimesulide (1–100 μM) inhibited platelet aggregation induced by adrenaline (20–200 μm). It also inhibited thromboxane A 2 (TXA 2) formation by platelets at low concentration (IC 50; 1 μM). However, much lower concentrations of nimesulide (0.01–0.1 μM) potentiated the aggregatory response of subthreshold concentrations of adrenaline (0.2–2 μM). Such an effect was blocked by Ca 2+-channel blockers, verapamil and diltiazem (IC 50: 7 and 46 μM, respectively), nitric oxide donor, SNAP (IC 50; 2 μM) and cinchonine (10 nM) but not by genistein (up to 10 μM). These results are indicative of the concentration-dependent dual effects of nimesulide on human platelet aggregation. The synergistic effect of low doses of nimesulide and adrenaline seems to be mediated through inhibition of multiple signalling pathways.

Renal effects of nimesulide in furosemide-treated subjects.

In clinical settings where effective plasma volume is decreased, nonsteroidal anti-inflammatory drugs (NSAIDs) may induce acute renal failure. We have evaluated the effects of single and repeated doses of nimesulide on renal haemodynamics and electrolyte excretion in 8 healthy volunteers during a prolonged course of furosemide (frusemide). Under these study conditions, renal prostaglandin synthesis is expected to be elevated, with renal function being dependent upon increased levels of prostaglandins. Nimesulide induced an acute but transient decrease in indices of renal haemodynamics. Furosemide-induced increases in plasma renin activity and aldosterone levels were blunted, and urinary excretion of prostaglandin E2 was markedly reduced by nimesulide. The magnitude and time course of the natriuretic, kaliuretic and diuretic effects of furosemide were attenuated by nimesulide. Although the transient nature of the observed renal haemodynamic changes suggests that the risk of developing acute renal failure is small, the rise should be taken into account in patients with renal dysfunction. Sodium and potassium retention, and the blunting of the diuretic-induced electrolyte excretion, could be of clinical relevance. Nimesulide appears, therefore, to share the prostaglandin-dependent renal effects of other NSAIDs.

Nimesulide in dysmenorrhoea.

Nimesulide does not affect active intrauterine pressure, as measured using microsensors, or the direction and velocity of the propagation of uterine activity, but nevertheless alleviates pain significantly by 30 minutes after oral administration. In dysmenorrhoeic patients, resting pressure is high only in the fundus. Nimesulide reduces the pressure during the maximal but not during the submaximal pain period, with concomitant alleviation of pain. The drug changes the painful state of uterine contracture to painless cyclic contractions. With a single oral dose of 100mg, nimesulide is evenly distributed in female genital tissues (uterine fundus and cervix, oviduct and ovaries), reaching peak concentrations and peak plasma: tissue ratio (0.5) 3 hours after administration. Tissue concentrations range from 0.3 to 1.8 micrograms/g. Two 100mg oral doses of nimesulide administered to dysmenorrhoeic women in a double-blind placebo-controlled cross-over study reduced prostaglandin F2 alpha levels in menstrual blood from 382 to 94 micrograms/L. Double-blind placebo-controlled studies also confirmed that nimesulide relieves pain in dysmenorrhoeic patients.

A clinical assessment of the potential for pharmacological interaction between nimesulide and digoxin in patients with heart failure.

The potential interaction between nimesulide, a nonsteroidal anti-inflammatory drug, and digoxin was studied in 9 patients [6 males, 3 females; mean age 67 (range 57 to 70) years] with mild heart failure. All patients were receiving maintenance therapy with digoxin (0.25 mg/day, orally) and were treated with oral nimesulide 100mg twice daily for 7 days. Blood samples were collected at 8am and 6pm for 4 days before and throughout the nimesulide treatment period for determination of serum digoxin concentrations. Physical health, electrocardiographic recordings and blood and urine samples were also monitored. Mean serum digoxin concentrations remained within the normal therapeutic range throughout the study despite large interindividual variation. Furthermore, there were no significant differences between the morning and afternoon serum digoxin concentrations and there was no major change in the clinical condition of any patient. These results indicate that short term administration (7 days) of conventional therapeutic doses of nimesulide (100mg twice daily) does not modify the serum digoxin profile in patients with low class heart failure treated with a maintenance dose (0.25 mg/day) of this cardiac glycoside.

Antipyretic effects of nimesulide in paediatric practice: A double-blind study

A double-blind, multi-centre study was carried out in 42 hospitalized children, aged 6 months to 8 years, suffering from acute respiratory tract infections with fever, to investigate the antipyretic activity of nimesulide. On entry, patients were allocated at random to receive either nimesulide oral suspension, 5 mg/kg/day divided into 3 daily doses, for 5 days or placebo. Both groups were treated simultaneously with antibiotics: children under 5 years of age received 100 mg amoxycillin/kg/day, those over 5 years received 40 to 50 mg erythromycin/kg/day. Measurements of rectal temperature before and during the 6 hours after the first dose of nimesulide showed a significant mean decrease from a baseline value of 38.89 +/- 0.74 degrees C to 37.28 +/- 0.76 degrees C at 6 hours. In the placebo group, no significant changes were observed between baseline (38.82 +/- 0.67 degrees C) and the 6-hour value (38.28 +/- 1 degree C). Morning temperatures remained within the normal range on the following days. Nimesulide was well tolerated. The results indicate that nimesulide has a prompt antipyretic effect which may well be clinically helpful before the correct antibiotic therapy is effectively established.