Indirect role of α<Subscript>2</Subscript>-adrenoreceptors in anti-ulcer effect mechanism of nimesulide in rats

Nimesulide, a non-steroidal, anti-inflammatory drug, produces ulcerogenic effects in adrenalectomized rats but is gastro-protective in intact rats. The objective of this study was to determine whether adrenal gland hormones are involved in the anti-ulcer effects of nimesulide. The results revealed that 100 mg/kg nimesulide produces gastric ulceration in adrenalectomized rats, which is prevented by prednisolone and adrenaline. The anti-ulcer effects of adrenaline and prednisolone in adrenalectomized rats were in turn antagonized by yohimbine, a selective α₂-receptor blocker, but not by doxazosine (α₁-receptor blocker) or propranolol (β-blocker). Adrenaline prevented the formation of indomethacin-induced ulcers in both adrenalectomized and intact rats, but prednisolone increased the indomethacin-induced ulcerous area in intact rats, whereas it decreased the size of the ulcers in adrenalectomized rats. In addition, prednisolone prevented ulcer formation in intact rats in which the adrenaline concentration had been decreased by metyrosine. These results suggest that glucocorticoids are anti-ulcerogenic in not only adrenalectomized rats but also in intact rats with diminished circulating levels of adrenaline. In the light of these data, the effect of nimesulide on plasma adrenaline concentrations was studied. In comparison to the adrenaline levels found in intact control rats, the administration of nimesulide at doses of 10, 20, 40 and 100 mg/kg decreased adrenaline concentrations by 12.8, 22.6, 30.4, and 58.2%, respectively, without affecting blood corticosterone concentrations. The anti-ulcer effect of nimesulide was observed to be dose-dependent, and the strength of this effect was directly correlated the decreasing concentration of adrenaline. The concentration of adrenaline was decreased by 60.9% in rats treated with 300 mg/kg metyrosine in which prednisolone produced anti-ulcer effects. In summary, we have shown that nimesulide produces its anti-ulcer effect by decreasing endogenous adrenaline concentrations and that glucocorticoids may induce anti-ulcer effects via α₂-adrenoreceptors, but not via their own receptors. This research was conducted in the Laboratory of Pharmacology at Ataturk University, Faculty of Medicine, Department of Pharmacology, 25240 Erzurum/Turkey.     

Analgesic efficacy and pharmacokinetics of topical nimesulide gel in healthy human volunteers: double-blind comparison with piroxicam, diclofenac and placebo

Objective: The present study was conducted to compare the analgesic efficacy of a new topical gel formulation of nimesulide (10 mg of pure drug) with that of placebo, diclofenac and piroxicam gels (10 mg of pure drug) in three parallel groups in a double-blinded, randomized fashion with vehicle placebo. The analgesic activity of nimesulide was subsequently correlated with its pharmacokinetic profile. Methods: The drugs were applied on a fixed marked area on the skin of the right forearm. Pain stimulus was administered using a modification of the Hollander method, before and at 15, 30, 60, 120 min and 240 min post-treatment. The pain experienced by the subjects was ranked separately on the visual analogue scale (VAS) and the ten-point category scale. Antinociception induced by the treatments was evaluated through the placebo-related ratings (PRR) and total pain relief (TOTPAR) analysis. The plasma concentration of nimesulide was estimated using high-performance liquid chromatography (HPLC). Results: Nimesulide exhibited better efficacy than diclofenac, piroxicam and placebo. It demonstrated faster onset of action in concordance with earlier studies. Peak analgesic effect was observed at 120 min post-treatment, which correlated with the pharmacokinetic profile of the drug in gel formulation. In this study, diclofenac was found to be superior to piroxicam though both drugs exhibited peak analgesic effect at 60 min post-treatment. In the modified Hollander method, a good correlation was found between the ten point category scale and the VAS, indicating that it may serve as a sensitive and reliable method for the screening of analgesic drugs. Conclusion: The superior analgesic activity of nimesulide (as gel formulation), correlating with its pharmacokinetic profile, indicates that the topical route of administration may be a safe and effective alternative to the presently used oral and rectal routes. Received: 20 October 1997 / Accepted in revised form: 22 April 1998     

Safety of Selective COX-2 Inhibitors in Aspirin/Nonsteroidal Anti-inflammatory Drug-Intolerant Patients: Comparison of Nimesulide, Meloxicam, and Rofecoxib

Background. Intolerance to acetylsalicylic acid (ASA) and other nonsteroidal anti-inflammatory drugs (NSAIDs) is a crucial problem in clinical practice. There is, therefore, a need for safer NSAIDs in patients with analgesic intolerance. Objective. To assess the safety of nimesulide, meloxicam, and rofecoxib, selective COX-2 inhibitors, in a group of ASA/NSAIDs-intolerant patients. Method. Tolerances to nimesulide, meloxicam, and rofecoxib were assessed by single-blind placebo-controlled oral challenges. One hundred twenty-seven subjects with history of adverse reaction to ASA/NSAIDs received oral challenges with nimesulide, 61 subjects were challenged with meloxicam, 51 subjects were challenged with rofecoxib, and 37 subjects were challenged with all three drugs. Placebos were given to all patients on the first day of the study. On the second day, one-fourth and three-fourths of the therapeutic doses of the active drugs (nimesulide 100 mg, meloxicam 7.5 mg, or rofecoxib 25 mg) were given at 60-minute intervals. There was at least a 3-day interval between challenge tests. Erythema, pruritus accompanied by erythema, urticaria/angioedema, rhinorrhea, nasal obstruction, sneezing, dyspnea, or cough associated with a decrease of at least 20% in the forced expiratory volume (FEV₁) and hypotension were considered as positive reactions. Results. Positive reactions to the nimesulide, meloxicam, and rofecoxib challenges were observed in 18/127 (14.3%), 5/61 (8.1%), and 1/51 (2.0%) patients, respectively. In each group of nine patients, there were two patients with asthma and four who developed skin type reactions and asthmatic reactions, respectively, to the nimesulide challenge. Among five patients who reacted to the meloxicam challenge, asthmatic type reactions were detected in two asthmatics. Only one urticarial type reaction was observed with rofecoxib challenge in one patient who presented with anaphylaxis to ASA/NSAIDs. All patients with asthma tolerated rofecoxib without any adverse effects. None of the patients reacted to the placebo. Among 37 patients challenged with all three drugs, 11 reacted to nimesulide, and one patient reacted only to meloxicam. Three patients reacted to more than one of the drugs tested, and one of them reacted to all drugs. Conclusion. This is the first placebo-controlled report comparing these three drugs. The results indicate that among these alternative drugs for ASA/NSAIDs-intolerant patients, rofecoxib seems to have the most favorable tolerability.     

Effects of dexamethasone and nimesulide on bisphosphonate-related osteonecrosis of the jaw: An experimental study

ObjectiveTo evaluate the effects of dexamethasone (DEX) and nimesulide (NIM) on Bisphosphonate-related Osteonecrosis of the Jaw (BRONJ) in rats.DesignBRONJ was induced by zoledronic acid (ZA) infusion (0.2 mg/kg) in Wistar rats (n = 8), followed by extraction of the left lower first molar (BRONJ groups). Control groups (n = 40) received saline (IV). For eight weeks, DEX (0.04, 0.4, 4 mg/kg) or saline (SAL) were administered by gavage 24 h before each infusion of ZA or saline (IV), or NIM (10.3 mg/kg) was administered 24 h and 12 h before each infusion of ZA or saline (IV). The haematological analyses were conducted weekly. After euthanasia (day 70), the jaws were submitted to radiographic and microscopic analysis. Kidney, liver, spleen and stomach were analysed histopathologically.ResultsThe BRONJ groups showed a higher radiolucent area compared with the control groups (p < 0.05). Histomorphometric analysis revealed healing and new bone formation in the control groups, while the BRONJ groups exhibited devitalized bone with bacterial colonies and inflammatory infiltrate. The BRONJ-DEX 0.4 and 4 mg/kg groups had a greater number of bacterial colonies (p < 0.05) and an increased polymorphonuclear cell count compared to the saline-BRONJ group, while the BRONJ-NIM group had a lower polymorphonuclear count (p < 0.05). The BRONJ groups had leucocytosis, which was reduced by DEX administration. Treatments with DEX with or without ZA caused white pulp atrophy.ConclusionThus, DEX or NIM therapy was not effective in preventing radiographic and histopathologic events associated with BRONJ. Treatment with DEX attenuated leucocytosis post-infusion with ZA.     

滥用尼美舒利颗粒致不良反应7例临床分析

目的分析7例滥用尼美舒利颗粒致不良反应的临床资料,防止滥用尼美舒利颗粒提供借鉴。方法对7例因发热家长自购尼美舒利颗粒服用引起不良反应的患儿临床资料进行回顾性分析。结果 7例患儿均有不同程度的消化、神经系统症状,且预后不良,其中1例死亡。结论 1岁以内小儿滥用尼美舒利颗粒可导致严重不良反应和致死风险,应遵医嘱和说明书合理用药。     

Validated high-throughput HPLC assay for nimesulide using a short monolithic column

High samples analysis rate is a key demand in modern pharmaceutical analysis, especially during new product development and validation of industrial-scale manufacturing process. The present study reports a validated HPLC assay for the dissolution studies of nimesulide-containing tablets (Lizepat 100 mg/tab, Cosmopharm Ltd., Korinthos, Greece). Using a 50 mm x 4.6 mm i.d. monolithic column (Chromolith, Merck) and acetonitrile-phosphate buffer (pH 7.0; 10 mM) (34:66, v/v) as the mobile phase, the separation cycle was completed in 60s at a flow rate of 4.0 ml min(-1). The assay was validated in terms of selectivity against potential impurities of the active ingredient, detection and quantification limits, linearity, accuracy and inter-/intra-day precision. Results from the application of the HPLC method to the accelerated and long-term dissolution stability control of Lizepat tablets (Lot 005) are reported.     

尼美舒利与布洛芬治疗高热患儿疗效比较

目的对非甾体类解热镇痛药尼美舒利颗粒、布洛芬混悬液治疗高热患儿效果和不良反应的比较。方法选择1～13岁的高热患儿120例,随机分为两组,在常规治疗基础上,一组使用尼美舒利颗粒口服3mg/kg,另一组使用布洛芬混悬液口服5mg/kg。测定治疗前、治疗后30min、1h、2h、6h体温,并观察疗效及不良反应。结果尼美舒利组在1h内体温下降幅度比布洛芬组大,而且维持时间长。结论口服尼美舒利颗粒治疗高热患儿较布洛芬混悬液起效快,不良反应小,使用较安全,临床上值得推广使用。     

Nimesulide and antibiotics in the treatment of acute infections of the respiratory tract

Summary

A double-blind, placebo-controlled trial was carried out in 45 hospitalized adult patients requiring antibiotic therapy for acute or chronic respiratory tract infection to compare the effectiveness of antibiotic treatment alone or with the concomitant use of nimesulide, a new non-steroidal anti-inflammatory agent. Patients were allocated at random to receive antibiotic treatment plus either nimesulide (100?mg twice daily) or placebo over a period of 15 to 23 days. The results showed that the patients in the nimesulide group had significantly greater and more rapid improvement in signs and symptoms such as chest pain, cough, oropharyngeal hyperaemia, asthenia, as well as osteoarticular pain in those arthrosis-affected patients, than those treated with antibiotic plus placebo. Treatment was well-tolerated and very few, mild side-effects were reported.     

Nimesulide抗肺癌作用的体内及体外研究

目的：探讨选择性CoX-2抑制剂Nimesulide对肺腺癌体内、体外的影响及其机制。方法：（1）采用MrITr比色法观察Nimesulide对肺腺癌A549细胞生长的影响,免疫细胞化学法测定肺癌A549细胞中PCNA、bcl-2基因蛋白表达水平;（2）建立肺腺癌裸鼠移植瘤模型,绘制肿瘤生长曲线并计算肿瘤抑制率。结果：（1）Nimesulide呈时间、剂量依赖性抑制A549细胞增殖,抑制率最低22．73％,最高72．04％;Nimesulide可抑制A549细胞PCNA、bcl-2的蛋白表达;（2）尼关舒利处理组的裸鼠移植瘤瘤体的平均重量为0．76±0．4g,显著低于对照组的1．56±1．02g（P〈0．05）;实验结束时尼美舒利对裸鼠移植瘤的体积抑制率为41．59％,重量抑制率为51．28％。结论：Nimesulide以时间、剂量依赖性方式抑制肺癌A549细胞增殖,其机制可能与下调A549细胞Pc—NA、bcl-2的蛋白表达有关。选择性COX-2抑制剂Nimesulide有可能在肺癌防治中发挥重要作用。     

Spectrophotometric monitoring of nimesulide photodegradation by a combined hard-soft multivariate curve resolution-alternative least square method

Nimesulide, a Cox-2 inhibitor anti-inflammatory drug, is a light sensitive compound and its biological activity is decreased upon photodegradation. The photodegradation kinetic of nimesulide was investigated spectrophotometrically using multivariate curve resolution analysis to overcome spectral overlapping of reactant and degradation products. The absorbance spectra of the nimesulide methanolic solution, exposed to daily sunlight, were recorded at different times. Three absorbing chemical species, coexisted in the reaction system, were detected by application of factor analysis to the absorbance data matrix. The soft-modeling multivariate curve resolution-alternative least square (MCR-ALS) analysis of the evolutionary absorbance data revealed that nimesulide undergoes photodegradation through a two-step consecutive manner, where both steps obey first-order kinetic. By application of the kinetic hard model constraint to the MCR-ALS analysis, an excellent agreement was obtained between the fitted concentration profiles and those obtained by soft method. The first-order rate constants of the first and second degradation products were calculated as 0.052 (+/-0.007) and 0.009 (+/-0.001)h(-1), respectively. Finally, the pure spectra of the resolved chemical species were calculated, where that of nimesulide was the same as that obtained experimentally.