Safety and Efficacy of Nimesulide/Paracetamol Fixed-dose Combination in Acute Pain (SAFE Study)

Background: Nimesulide shows preferential inhibition for the cyclooxygenase-2 (COX-2) enzyme, which blocks the formation of prostaglandins critical in pain and inflammatory pathways. Few studies in the past have reported rare and unpredictable hepatic effects with nimesulide. The present study aimed to evaluate the efficacy and safety of nimesulide/paracetamol (100 mg + 325 mg) fixed-dose combination twice a day for 2 weeks in the management of acute pain in Indian population. Materials and methods: This was a multicenter study, performed on 500 patients, by 24 experienced physicians across India. The primary outcome assessed clinical safety at 2 weeks for mild/serious adverse effects (AEs), change in liver function tests (LFTs), serum bilirubin and alkaline phosphatase levels. The secondary outcomes assessed the clinical effectiveness in reduction of pain at rest and at movement. Results: Analysis of LFT at 2 weeks showed a slight increase (mean change) in the aspartate transaminase {-0.73 [95% confidence interval (CI) -1.54, 0.09; p = 0.081]}, alanine transaminase [-1.73 (95% CI -2.82, -0.64; p = 0.002)], serum bilirubin [-0.02 (95% CI -0.04, -0.001; p = 0.018)] and alkaline phosphatase levels [-1.92 (95% CI -5.84, 2; p = 0.336), not exceeding the normal range. Only one in 500 patients reported AEs. The numerical rating scale (NRS) scores for intensity of pain at rest and at movement at 2 weeks, ?7 days and >7 days were 68.38%, 68.44% and 68.39%; and 65.43%, 64.60% and 66.02%, respectively. An improvement of 96.6% was observed in patient global assessment scale (GAS) and 97.2% in physician GAS. Conclusion: Nimesulide/paracetamol combination was safe, effective and well-tolerated in acute pain conditions and did not lead to clinically significant changes in liver parameters indicating hepatic safety.

A prospective, multicentric study to determine the safety and effectiveness of fixed-dose combination of camylofin dihydrochloride and nimesulide in patients presenting with acute colicky abdominal pain in India

Background:Spasmolytics and NSAIDs are a therapy of choice in colic pain. However, the tolerability and effectiveness of this combination remains unexplored. The aim of this prospective, single-arm, open label, multicenter study was to evaluate the safety and effectiveness of Anafortan-N�(fixed-dose combination of camylofin dihydrochloride 50 mg + nimesulide 100 mg) in patients with acute colicky abdominal pain.Methods: In all, 295 patients with acute colicky abdominal pain and at least one episode of colicky pain in the last 24 hours were enrolled in this study. None of the patients were hospitalized. All patients were advised Anafortan-N畉ablets twice daily orally for 5 days. The safety of Anafortan-N畐as assessed by number and percentage of patients with adverse events (AEs) and change in the severity and frequency of AEs by the end of treatment. The tolerability was determined by number and percentage of patients who hadto discontinue the treatment due to AEs. The effectiveness was evaluated as percentage change in the mean intensity of pain score (based on a 100-mm visual analog scale) from baseline to end of treatment.Results: Overall, 14 (4.7%) patients reported 14 AEs, all of which were treatment-emergent and non-serious. Of the 14 AEs, 7 AEs were mild, 6 AEs were moderate, and 1 AE was severe. No serious adverse events (SAEs) were reported. No adjustment of the study medication was required in response to any of the AEs, and none of the AEs led to discontinuation of the study treatment. At end of treatment(EOT), the pain intensity significantly (p<0.0001) reduced to 1.7�49 with a mean change of -69.9�.42 from baseline, and the daily pain intensity significantly (p<0.0001) reduced to 0.1�38 with a mean change of -3.5�77 from baseline.Conclusions: Among Indian patients presenting with acute abdominal colicky pain, twice daily treatment with a FDC of camylofin dihydrochloride 50 mg and nimesulide 100 mg (Anafortan-N�) showed significant reduction in pain intensity with very few side effects, thereby confirming its safety, tolerability, and effectiveness in acute colicky abdominal pain.

Design and evaluation of dental pastes Containing anti-inflammatory drugs

Abstract Periodontitis is an oral disease associated with inflammation and pain with swollen and bleeding gums. In the present study, dental pastes containing NSAIDs, namely, diclofenac sodium and nimesulide (1 % w/w) were prepared to treat periodontitis. Dental pastes of diclofenac sodium and nimesulide (1 % w/w) were prepared with/without mucoadhesive hydrocolloid polymers such as sodium carboxy methyl cellulose (NaCMC), hydroxyl ethyl cellulose (HEC) and methyl cellulose (MC) by conventional trituration method. The pH, drug content, viscosity, tube spreadability and tube extrudability of these prepared dental pastes were measured. These dental pastes of diclofenac sodium and nimesulide (1 % w/w) were characterized by FTIR analyses for drug-excipient compatibility. The in vitro drug releases from these dental pastes in 6.4 pH phosphate buffer solution displayed sustained release over longer period and the drug release rate was found to be decreased when the concentration of mucoadhesive polymer was increased. These dental pastes displayed good adhesion to the oral mucosa revealing more retention time in mouth when tested for ex vivo mucoadhesion using bovine cheek pouch. The stability study results reveal that the DC3 and NC3 dental paste formulations were found stable enough over a longer period in different storage conditions. The present study revealed that the prepared mucoadhesive dental pastes of diclofenac sodium and nimesulide (1 % w/w) had good adhesion with the oral mucosa to maintain consistent release of drugs over prolonged time.

Evaluation of eggshell membrane as an alternative biopolymeric matrix for delivery of nimesulide / Avaliação da membrana da casca do ovo como uma matriz biopolimérica alternativa para entrega de nimesulida / Evaluación de la membrana de la cáscara de huevo como una matriz de biopolímero alternativa para la administración de nimesulida

SUMMARY Introduction: Eggshell membrane (ESM) is a tissue found between the eggshell and the albumen of eggs that has attractive properties for use in drug delivery systems. Aim: To incorporate in ESM and used it as a model drug in release studies. The color change and FTIR analysis of the biopolymer proved the incorporation of nimesulide in ESM. Results: The drug uptake was 176.83 and 122.69 mg g-1 by natural and cross-linked ESM. Release studies were carried out using a spectrophotometric flow system in simulated intestinal fluid pH 7.4. The release profiles showed that after 60 minutes 54.55 and 42.58 % of the drug were released from natural and cross-linked ESM, respectively. Kinetics parameters indicated that drug release was better described by the Higuchi model and through a non-Fickian release. Conclusion: Considering these results is proved that ESM has the potential to become a polymeric matrix for drug release systems.

RESUMO Introdução: a membrana da casca do ovo (MCO) é um tecido encontrado entre a casca e o albúmen de ovos que possui propriedades atrativas para uso em sistemas de liberação de fármacos. Objetivo: incorporar à MCO e utilizá-la como fármaco modelo em estudos de liberação. Mudança de coloração e análises de FTIR do biopolímero comprovaram a incorporação da nimesulida na MCO. A incorporação do fármaco foi de 176,83 e 122,69 mg g-1 na MCO natural e reticulada, respectivamente. Resultados: os estudos de liberação foram realizados usando um sistema de fluxo espectrofotométrico em fluido intestinal simulado pH 7,4. Os perfis de liberação mostraram que após 60 minutos 54,55 e 42,58 % do medicamento foram liberados da MCO natural e reticulada, respectivamente. Os parâmetros cinéticos indicaram que a liberação do fármaco foi mais bem descrita pelo modelo de Higuchi e por meio de uma liberação não Fickiana. Conclusão: considerando estes resultados, fica comprovado que a MCO tem potencial para se tornar uma matriz polimérica para sistemas de liberação de fármacos.

RESUMEN Introducción: La membrana de cáscara de huevo (MCH) es un tejido que se encuentra entre la cáscara de huevo y la albúmina de los huevos que tiene propiedades atractivas para su uso en sistemas de administración de fármacos. Objetivo: Incorporar en MCH y utilizarla como fármaco modelo en estudios de liberación. El cambio de color y el análisis FTIR del biopolímero demostraron la incorporación de nimesulida en MCH. Resultados: La captación del fármaco fue de 176,83 y 122,69 mg g-1 por MCH natural y reticulado. Los estudios de liberación se llevaron a cabo utilizando un sistema de flujo espectrofotométrico en líquido intestinal simulado pH 7,4. Los perfiles de liberación mostraron que después de 60 minutos el 54,55 y el 42,58 % del fármaco se liberó de la MCH natural y reticulada, respectivamente. Los parámetros cinéticos indicaron que la liberación del fármaco se describió mejor mediante el modelo de Higuchi y mediante una liberación no Fickian. Conclusión: De acuerdo con estos resultados, el MCH tiene el potencial de convertirse en una matriz polimérica para sistemas de liberación de fármacos.

Effects of experimental conditions on solubility measurements for BCS classification in order to improve the biowaiver guidelines

Among the methods described for determining the solubility, shake-flask is suitable to evaluate the equilibrium solubility according to the BCS. Nevertheless, experimental conditions related to the shake-flask method are not well described. Evaluating the effects of experimental conditions on solubility measurements by shake-flask method is important and contributes in biowaiver decision. For this work, propranolol hydrochloride and nimesulide were used as model compound of high and low solubility, respectively. Equilibrium solubility was evaluated at 37 ºC, 100 rpm during 48 hours in buffer media. Effects of the rotation speed, temperature, substance in excess and aliquot withdrawn were evaluated. Small variations of temperature caused significant differences in the solubility and then this parameter must be controlled. Excess of raw material influenced the results of the nimesulide, then, little excess is recommended. Rotation speed did not cause differences in the equilibrium solubilities, but at 150 rpm the equilibrium was reached faster. Aliquot did not present significant differences, but excessive withdrawn should be avoided. Therefore, the evaluation of equilibrium solubility using shake-flask method must be performed in physiological pH conditions, 37 ± 1 ºC, substance in excess 10% above saturation, 50, 100 or 150 rpm and aliquot withdrawn not more than 10% of the media volume.

Anti-inflammatory and ulcerogenic activities of thiazolidine-4-ones in rats

Background: NSAIDS are associated with side effects and research should continue for developing safer drugs. This study aims to evaluate newer thiazolidine-4-ones for their anti-inflammatory and ulcerogenic activities in wister rats.Methods: Five groups of wister rats, 6 in each were used. Anti-inflammatory and ulcerogenic activities of diclofenac (30mg/kg), nimesulide (50mg/kg), thia-1 (50mg/kg) and thia-2 (50mg/kg) are compared with control group (4% Gum Acacia). Carrageenin-induced paw edema, formaline induced acute peritonitis and cotton pellet-induced granulomatous tissue formation models were used for evaluating anti-inflammatory activity. After removing cotton pellets with granuloma on 8th day gastric ulcerogenicity was assessed by using macroscopic and microscopic scoring of ulcers.Results: Diclofenac, nimesulide and thia 2 reduced both paw edema and peritoneal exudate volume significantly (p <0.01). Wet weight of cotton pellets reduced significantly (p <0.01) by diclofenac, nimesulide and thia 2. Diclofenac (p <0.01) and thia 2 (p <0.05) reduced dry weight of cotton pellets significantly. nimesulide and thia-1 reduced it by 19.14% and 2.68% respectively and was considered statistically not significant (p>0.05). Nimesulide, thia-1 and thia-2 did not increase gastric ulcer score significantly (p >0.05). Diclofenac increased ulcer score significantly (p <0.01).Conclusions: Thia-2 demonstrated significant anti-inflammatory activity in acute and chronic models. In addition to inhibition of cyclooxygenase pathway, PPAR agonistic activity may be involved in its anti-inflammatory activity. No significant ulcerogenicity was observed on comparing with nimesulide and control. Further in-vitro and in-vivo studies are recommended to confirm the results of this study.

Descripción y cuantificación de riesgos atribuidos a analgésicos antiinflamatorios no esteroides no selectivos consumidos por la población mexicana / Description and quantification of risks attributed to non-selective non-steroidal anti-inflammatory drugs consumed by Mexican population

Resumen OBJETIVO Analizar las reacciones adversas a medicamentos asociadas con la administración de antiinflamatorios no esteroides (AINEs) no selectivos reportadas al Centro Nacional de Farmacovigilancia durante el periodo 2011-2014. MATERIAL Y MÉTODO Estudio en el que para el análisis descriptivo se utilizó la base de datos del Centro Nacional de Farmacovigilancia 2011-2014 que contiene las reacciones adversas a medicamentos asociadas con la administración de analgésicos provenientes de los diferentes integrantes del Programa Permanente de Farmacovigilancia, que se agruparon de acuerdo con edad y sexo del paciente, procedencia de la reacción adversa a medicamentos, principio activo sospechoso, gravedad y causalidad de la reacción. RESULTADOS 4553 reacciones adversas a medicamentos se asociaron con la administración de un AINE (3.9%). El metamizol fue el más reportado con 21.1% del total de reacciones adversas registradas para este grupo de medicamentos. CONCLUSIONES El metamizol fue el medicamento con más reacciones adversas a medicamentos reportadas. Las reacciones dermatológicas de importancia (necrólisis epidérmica tóxica, síndrome de Stevens-Johnson y síndrome de Lyell) se manifestaron mayormente con nimesulida.

Abstract OBJECTIVE To analyze drug-adverse reactions related to the administration of non-selective non-steroidal anti-inflammatory drugs (NSAIDS) reported to the National Pharmacovigilance Center from 2011 to 2014. MATERIAL AND METHOD A study was done in which for the descriptive analysis was used the database of the National Pharmacovigilance Center 2011-2014 containing the drug-adverse reactions related to the administration of analgesic drugs coming from the different members of the Permanent Program of Pharmacovigilance, that were grouped according to: age and sex of patient, proceeding of the drug-adverse reaction, suspect active principle, severity and causality of reaction. RESULTS 4553 drug-adverse reactions were related to the administration of an NSAID (3.9%). Metamizol was the most reported with 21.1% of the total of adverse reaction registered for this group of drugs. CONCLUSIONS Metamizol was the drug with more drug-adverse reactions reported. The dermatological reactions of importance (toxic epidermal necrolysis, Stevens-Johnson syndrome and Lyell syndrome) were higher reported with nimesulide.

Desenvolvimento de comprimidos de liberação prolongada de nimesulida contendo ferrita para avaliação do trânsito gastrintestinal por meio de técnica biomagnética / Development of prolonged release tablets of nimesulide containing ferrite for evaluation of gastrointestinal transit by means of biomagnetic technique

As Formas Farmacêuticas de Liberação Prolongada (FFLP) têm sido uma alternativa eficaz na terapia, pois proporcionam maior adesão do paciente ao tratamento em função da redução da frequência de dosagem ao longo do dia, sendo sua principal característica, a modulação da liberação/dissolução do fármaco. Entretanto, esta etapa pode ser influenciada por diferentes fatores, dentre eles: os físico-químicos relacionados ao fármaco; os farmacêuticos, principalmente relacionados aos excipientes empregados e às técnicas de obtenção da forma farmacêutica (FF) e os fisiológicos do trato gastrintestinal (TGI), como por exemplo, o pH dos líquidos do TGI, o tempo de esvaziamento gástrico, a motilidade intestinal, entre outros. Desse modo, a avaliação do trânsito da FF no TGI, após a sua administração, permite uma melhor compreensão dos fatores que podem afetar as etapas de liberação/dissolução do fármaco in vivo. Dentre as técnicas empregadas com esse objetivo, destacam-se: a cintilografia e os métodos biomagnéticos. A Biosusceptometria de Corrente Alternada (BAC) é um método biomagnético que tem se mostrado promissor para este tipo de estudo, por ser não invasivo, portátil, livre de radiação ionizante, e por apresentar acurácia e versatilidade. Diante do exposto, o presente trabalho teve como objetivos, desenvolver e caracterizar sob o aspecto biofarmacotécnico in vitro, um sistema de liberação prolongada contendo nimesulida (fármaco-modelo) e marcador magnético (ferrita), visando obtenção de ferramenta para avaliação do trânsito gastrintestinal por meio de técnica biomagnética. Para isto foram desenvolvidas quatro formulações de comprimidos de liberação prolongada contendo nimesulida, ferrita e diferentes concentrações de hidroxipropilmetilcelulose (HPMC): NF1 (30% HPMC); NF2 (23% HPMC); NF3 (17% HPMC) e NF4 (10% HPMC). Essas foram avaliadas quanto ao comportamento de dissolução por meio de ensaios com aparato 4 e avaliação da cinética e da eficiência de dissolução (ED%). Posteriormente, estudos biomagnéticos, in vitro e in vivo, foram conduzidos com emprego da técnica de BAC para a formulação selecionada. Os resultados obtidos mostraram que as 04 formulações desenvolvidas apresentaram porcentagens de dissolução distintas em função das diferentes concentrações de HPMC (NF1 = 13,2%; NF2 = 40,1%; NF3 = 72,5% e NF4 = 91,5%). A formulação NF4, com menor concentração de HPMC, foi escolhida para os estudos por meio de BAC em função dos resultados de ED% (54,3%) e por apresentar comportamento mais próximo de uma formulação de liberação prolongada. Em relação aos resultados de BAC in vitro, destaca-se que a formulação NF4 (10%HPMC) apresentou aumento de área magnética de forma independente do pH do meio, sugerindo que a hidratação/intumescimento da HPMC independe do pH. Em relação à avaliação do trânsito intestinal (estudo in vivo) foram obtidos os seguintes dados: Tempo médio de Residência Gástrica (TTR) - 89 minutos; Tempo médio do Trânsito Orocecal (TTO) - 313 minutos e Tempo médio do Trânsito Intestinal (TTI) - 224 minutos. Os dados de BAC in vivo permitiram observar que o aumento de área magnética atingiu um platô em cerca de 80 minutos após a administração da formulação NF4. A comparação dos dados de BAC in vitro e BAC in vivo, relacionados ao trânsito gastrintestinal, indica que a formulação NF4, após apresentar o ápice de intumescimento, foi capaz de manter sua estrutura permanente ao longo do TGI, favorecendo assim a liberação modulada do fármaco. Os resultados obtidos demonstraram que a formulação desenvolvida foi eficiente para avaliar e caracterizar o trânsito no TGI por meio da técnica de BAC e também permitiram uma estimativa do comportamento do fármaco em relação a solubilidade em cada porção do TGI, proporcionando assim uma ferramenta adequada para avaliação do trânsito do TGI e desenvolvimento de FFLP

Extended Release (ER) dosage forms have been an effective alternative in therapy, since they provide greater patient adherence to treatment as a function of the reduction of the frequency of dosing throughout the day, its main characteristic being the release / dissolution modulation of the drug. However, this stage can be influenced by different factors, among them: the physical and chemical related to the drug; the pharmacists, mainly related to the excipients employed and the techniques of obtaining the form dosage and the physiological ones of the gastrointestinal tract (GI tract), as for example, the pH of the liquid of the GI tract, gastric emptying time, intestinal motility, among others. Thus, assessment of dosage forms transit in GI tract after its administration allows a better understanding of the factors that may affect the drug release / dissolution steps in vivo. Among the techniques used for this purpose, the following stand out: scintigraphy and biomagnetic methods. Alternating Current Biosensiometry (ACB) is a biomagnetic method that has shown promise for this type of study, since it is non-invasive, portable, free of ionizing radiation, and because of its accuracy and versatility. In view of the above, the aim of this work was to develop and characterize a sustained release system containing nimesulide (study drug) and magnetic marker (ferrite) under the in vitro biopharmaceutical aspect, aiming to obtain a tool to evaluate the GI tract transit through means of biomagnetic technique. For this, four formulations of extended release tablets containing nimesulide, ferrite and different concentrations of hydroxypropylmethylcellulose (HPMC): NF1 (30% HPMC) were developed; NF2 (23% HPMC); NF3 (17% HPMC) and NF4 (10% HPMC). These were evaluated for dissolution behavior by apparatus 4, assays and kinetics and dissolution efficiency (ED%). Subsequently, biomagnetic studies, in vitro and in vivo, were conducted using the ACB technique for the selected formulation. The results showed that the formulations developed showed different percentages of dissolution as a function of the different concentrations of HPMC (NF1 = 13.2%, NF2 = 40.1%, NF3 = 72.5% and NF4 = 91.5%). The NF4 formulation, with a lower concentration of HPMC, was chosen for the ACB studies as a function of ED% results (54,3%) and because of the behavior of a sustained release formulation. In relation to the in vitro ACB results, the NF4 formulation (10% HPMC) showed an increase in magnetic area independently of the pH of the medium, suggesting that the HPMC hydration / swelling is independent of pH. In relation to intestinal transit evaluation (in vivo study) the following data were obtained: Mean Time of Gastric Residency (TTR) - 89 minutes; Mean Time of Orocecal Transit (OCTT) - 313 minutes and Mean Time of lntestinal Transit (TTI) - 224 minutes. ACB data in vivo showed that the increase in magnetic area reached a plateau in about 80 minutes after administration of the NF4 formulation. Comparison of in vitro ACB and ACB data in vivo, related to gastrointestinal transit, indicates that the NF4 formulation, after showing the swelling apex, was able to maintain its permanent structure throughout the GI tract, thus favoring the modulated release of the drug. The obtained results demonstrated that the developed formulation was efficient to evaluate and characterize the transit in the GI tract by means of the ACB technique and allowed a prediction of the behavior of the drug in relation to the solubility in each portion of the GI tract, thus providing a suitable tool for evaluation of the GI tract transit and the development of sustained release formulation

Effects of Nimesulide Combined with Oxaliplatin on Transplanted Tumor Growth and Immune Function of Rats with Esophageal Cancer / 中国药房

OBJECTIVE:To study the effects of nimesulide combined with oxaliplatin on transplanted tumor growth and im-mune function of rats with esophageal cancer. METHODS:Rats were randomly divided into model group(intragastrically given So-dium carboxymethyl cellulose solution+intravenously given 5% Glucose injection in tail),nimesulide group(intragastrically given 20 mg/kg),oxaliplatin group(intravenously given 13.6 mg/kg in tail)and combination group,10 in each group. Esophageal can-cer Eca109 cells were subcutaneously injected to develop transplanted tumor model. After modeling,rats in each group received rel-evant medicines by corresponding ways,once a day for ig,once every 4 d for iv in tail. Rats were sacrificed after 8 weeks,tumor volume and quality of rats were measured,tumor inhibition rate was calculated,and contents of tumor markers(CEA,CYFRA21-1,SCCAg),percentages of immune cells(CD3+,CD4+,CD8+T cells and NK cell)in peripheral blood were detected. RESULTS:Compared with model group,tumor volume and quality in other 3 groups were decreased (P<0.05);contents of tumor markers were decreased (P<0.05). Percentages of CD3+,CD4+ T cells and NK cell in nimesulide group were increased,percentages of CD8+T cell was decreased(P<0.05). Percentages of CD3+,CD4+T cells and NK cell in oxaliplatin group and combination group were decreased,percentages of CD8+ T cell was increased(P<0.05). Compared with nimesulide group and oxaliplatin group,tu-mor inhibition rate in combination group was increased(P<0.05);contents of tumor markers were decreased(P<0.05);percent-ages of immune cells were lower than nimesulide group and higher than oxaliplatin group(P<0.05). CONCLUSIONS:Nimesulide can enhance the oxaliplatin's antitumor effect on esophageal cancer,and decrease its inhibition degree on immune functions.

A Randomized Controlled Trial of Ozone Injection plus Electrothermal Acupuncture for Treatment of Knee Osteoarthritis / 上海针灸杂志

Objective To compare the efficacy of ozone injection plus electrothermal acupuncture versus oral glucosamine and nimesulide in treating knee osteoarthritis and investigate the effects of the two treatments on the WOMAC total score and the pain, stiffness and physical function scores.Method Eighty patients with knee osteoarthritis were randomly allocated to combination and Western medicine groups, 40 cases each. The combination group received a combined treatment with intra-articular ozone injection and electrothermal acupuncture and the Western medicine group took glucosamine hydrochloride and nimesulide sustained-release tablets. The WOMAC score was recorded in the patients before and after treatment. The therapeutic effects were evaluated using the WOMAC score. Result The control and marked efficacy rate of ozone injection plus electrothermal acupuncture for knee osteoarthritis was higher than that of Western medicine. The WOMAC score decreased in both groups after treatment (P0.05). The physicalfunction score decreased more in the combination group than in the Western medicine group (P<0.05).Conclusion Ozone injection plus electrothermal acupuncture is more effective than Western medicine in treating knee osteoarthritis. It is more effective in improving knee function but not in relieving the pain and joint stiffness in comparison with Western medicine.

Effects of Nimesulide Combined with Oxaliplatin on Microvessel Density and Immune Function of Esopha-geal Cancer Model Rats / 中国药房

OBJECTIVE:To study the effects of nimesulide combined with oxaliplatin on microvessel density and immune func-tion of esophageal cancer model rats. METHODS:48 rats were selected to establish esophageal cancer model and then randomly di-vided into model group,oxaliplatin group,nimesulide group and combination group,with 12 rats in each group. 1 d after model-ing,model group was given 5% Glucose injection 1 mL via tail vein,3 times a week,and constant volume of Sodium carboxy-methylcellulose solution,once a week. Oxaliplatin group was given oxaliplatin 13.6 mg/kg via tail vein,3 times a week. Nimesu-lide group was given nimesulide 20 mg/kg intragastrically,once a week. Combination group was given oxaliplatin and nimesulide with same usage as above. The administration lasted for 8 weeks. The cancer growth,microvessel density of cancer tissue,peripher-al blood immune function index were observed in four groups. RESULTS:Compared with model group,cancer size,cancer weight,integral absorbance of cancer and positive vessel density were all decreased in treatment groups(P<0.05). The number of peripheral blood CD3+,CD4+T cells and CD4+/CD8+were all decreased in oxaliplatin group and combination group,while the num-ber of CD8+T cells was decreased(P<0.05). Compared with nimesulide group,cancer size,cancer weight,integral absorbance of cancer,positive vessel density,the number of peripheral blood CD3+,CD4+T cells and CD4+/CD8+ were all decreased in oxaliplat-in group and combination group,while tumor inhibition rate and the number of CD8+T cells were all increased(P<0.05);combi-nation group was more significant than oxaliplatin group (P<0.05). CONCLUSIONS:Oxaliplatin combined with nimesulide can effectively inhibit cancer growth of esophageal cancer,the mechanism of which may be associated with inhibiting angiogenesis of tumor tissue and strengthening immune function.

Clinical observation of diosmin combined with nimesulide in treatment of traumatic synovitis of knee joint / 药物评价研究

Objective To observe the clinical curative effect of diosmin combined with nimesulide in treatment of drugs for the traumatic synovitis ofin knee joint.Methods Sixty patients the People's Liberation Army 425 Hospital diagnosis standard and the requirements in this study were averagely and randomly divided into combination group,nimesulide group and diosmin group,the patients in combination group were given diosmin and nimesulide treatment,the patients in nimesulide group were given nimesulide treatment,diosmin group were given diosmin treatment.The course of treatment was 14 d.Then score knee joint VAS,AKS rating,and swelling degree in each group before and after the treatment.Results After treatment,the patients with knee joint swelling,pain degree are improved,the difference before and after treatment has statistical significance (P ＜ 0.05),meanwhile differences in the combination group were larger than the other two groups (P ＜ 0.05).Conclusion The drugs of nimesulide and diosmin for the treatment of traumatic synovitis respectively have certain effect,but the combined treatment curative effect is remarkable than used alone.Combination medication can be more obviously relieving the pain of patients and prevent disease progression,reduce inflammation which achieved a satisfactory therapeutic effect.

Clinical Observation of Nimesulide Combined with Ibuprofen in the Treatment of Pain / 中国药房

OBJECTIVE:To observe the short-term efficacy and safety of nimesulide combined with ibuprofen in the treatment of pain. METHODS:84 patients with pain were randomly divided into observation group and control group. Control group was oral-ly given 0.3 g Ibuprofen sustained-release capsule,twice a day. Observation group was additionally given 100 mg Nimesulide cap-sule,twice a day. The treatment course for both groups was 7 d. Clinical efficacy,visual analogue (VAS) score,quality of life (QOL) score,coagulation indexes (prothrombin time,thrombin time,fibrinogen,activated partial thromboplastin time) before and after treatment,and incidence of adverse reactions in 2 groups were observed. RESULTS:The total effective rate in observa-tion group was significantly higher than control group,the differences were statistically significant(P0.05). After treatment,VAS scores in 2 groups were significantly lower than before,and observation group was lower than control group,QOL scores were significantly higher than before,and observation group was higher than control group,the differences were statistically significant(P0.05). CONCLUSIONS:The short-term efficacy of ibuprofen combined with nimesulide is superior to ibuprofen alone in the treatment of pain,with similar short-term safety.

Effect of nimesulide on the levels of IL-8 and TNF-αin gingival cervical fluid in patients with chronic periodontitis and its clinical efficacy / 中国生化药物杂志

Objective To investigate the clinical efficacy of nimesulide in the treatment of chronic periodontitis patients,and analyze the effect of IL-8 and TNF-αlevels in the gingival sulcus fluid.Methods 88 patients with chronic periodontitis in our hospital between June 2014 to December 2015 were divided into control group and observation group by the random number method, 44 cases in each group, the control group patients were given metronidazole treatment, observation group patients were given nimesulide treatment,two groups therapeutic effect and the incidence of adverse reactions were observed, compared two groups of patients before and after treatment in gingival sulcus fluid IL-8 and TNF-αlevel, compared sulcus bleeding index (SBI), plaque index (PLI) and clinical attachment level (CAL),before and after treatment two weeks and four weeks of probing depth (PD) of two groups.Results The total effective rate of observation group patients was 95.55%, significantly higher than the control group patients’total efficiency (81.82%) (χ2 =4.06, P=0.04), after treatment in the observation group gingival sulcus fluid IL-8 factor and TNF-αlevels were significantly lower than the control group (P<0.05), After 2 weeks and 4 weeks of treatment, PD, SBI and CAL indicators observation group were significantly lower than the control group ( P <0.05 ) , the incidence of adverse reactions of observation group patients was 4.55%, significantly lower than the incidence of adverse reactions in control group patients(22.73%)(χ2 =6.18, P=0.01).Conclusion Nimesulide in the treatment of chronic periodontitis with a highly efficient clinical efficacy, while reducing gastrointestinal side effects, etc., can effectively reduce the gingival sulcus fluid IL-8 and TNF-αlevels, ease clinical symptoms, is a highly effective treatment.

Proliferation inhibition induced by Nimesulide through PPARγpathway in human colon cancer cell / 重庆医学

Objective To study PPARγ inhibitor(GW9662) ,on colon cancer SW480 cell proliferation and apoptosis intervened by Nimesulide(N) in vitro ,in order to investigate the role of PPARγpathway in colon cancer cell proliferation inhibition and apop‐tosis promotion induced by Nimesulide .Methods Cells were divided into 4 groups ,namely :the control group ,GW9662 group (GW9662 0 .1 ,0 .5 ,1 .0 ,5 .0μmol/L) ,N group ,GW9662+N group .MTT assay and FCM were used to determine proliferation ,ap‐optosis and cell cycle of SW480 cells .And the expression of PPARγ,p21Waf1 ,p27Kip1 ,Bcl‐2 ,Bax ,VEGF proteins were measured by Western‐blot .Results N inhibited SW480 cells proliferation in a time‐dependent manner (P0 .05) . Cell apoptosis rate of group N increased significantly ,compared with control group(P<0 .01) .The apoptosis rates of SW480 cells incubated with Nimesulide and GW9662 dropped significantly compared with Nimesulide alone (P<0 .01) .Above results showed that GW9662 could attenuate the effect of nimesulide on cell apoptosis and cell cycle .The results of Western‐blot :Compared with the control group ,the expression of PPARγ,p21Waf1 ,p27Kip1 ,Bax protein were up‐regulated significantly in nimesulide group(P<0 .05 or P<0 .01) ,but Bcl‐2 and VEGF were down‐regulated significantly(P<0 .01) .Compared with the nimesulide group ,the expres‐sion of PPARγ,p21Waf1 , p27Kip1 and Bax protein were down‐regulated obviously in GW9662+N group(P<0 .05 or P<0 .01) .Corre‐spondingly ,Bcl‐2 and VEGF were up‐regulated obviously(P<0 .05) .Conclusion N could effectively inhibit SW480 cell prolifera‐tion and induce its apoptosis .PPARγpathway may play an important role in proliferation inhibition and apoptosis induced by Nime‐sulide in colon cancer cell .

Determination of the Related Substances in Nimesulide Granules by HPLC / 中国药师

Objective:To establish an HPLC method for the determination of the related substances in nimesulide granules. Meth-ods:An Agilent HC-C18(250 mm ×4.6 mm,5 μm)column was used, the mobile phase was composed of acetonitrile-0.01 mol ·L-1 ammonium dihydrogen phosphate (adjusting pH to 7. 0 with ammonia) (40:60) and the detection wavelength was 230 nm, the flow rate was 1. 0 ml·min-1 ,the column temperature was 30℃, and the injection volume was 20μl. Results:The linear range of nimesu-lide was 0. 10-0. 30 mg·ml-1(r=0. 999 9). Nimesulide and its related substances could be well separated with the peak separation degree above 2. 0. The limit of detection and the limit of quantification was 0. 3 ng and 1. 0 ng, respectively. Conclusion:The method is simple, accurate and reproducible, which can be used for the quality control of nimesulide granules.

Selection of surfactants and dissolution profiles of nimesulide sustained-release tablets / 军事医学

Objective To study the effect of surfactants on the dissolution profiles of poorly water-soluble acidic drug nimesulide from sustained-release tablets.Methods The anionic surfactant sodium dodecyl sulfate (SDS), cationic sur-factant cetyltrimethyl ammonium bromide (CTAB) and nonionic surfactant polysorbate 80 (Tween 80) were used to prepare nimesulide micelles .The effect of the buffer , surfactant and ionic strength on the equilibrium solubility of the drug and the in vitro release of sustained-release tablets was studied .Results and Conclusion In pH 1.2 HCl solution, water and pH 6.8 phosphate buffer, the solubilization capacity of CTAB was the highest.However, in pH 9.0 Tris buffer, when CTAB concen-tration was at about 1%, the equilibrium solubility of nimesulide was at the trough value .The in vitro release results were similar to those of equilibrium solubility and the kinetic pattern conformed to the first order equation according to the coefficient R .

Determination and Stability of Nimesulide in Thermo-sensitive Hydrogels / 中国药师

Objective:To establish the method for determining nimesulide in thermo-sensitive hydrogels and study the stability of the preparation. Methods:An HPLC method was adopted with a Shim-Pack C18-ODS (150 mm × 4. 6 mm,5 μm) column, the mobile phase was composed of menthol-water-acetic acid (65∶35∶0. 8) with the flow rate of 1. 0 ml·min-1 at 30℃, the detection wavelength was at 299 nm, and the injection volume was 10 μl. Results:The separation of nimesulide, impurities and degradation products was good. The linear range of nimesulide was 2. 43-24. 37μg·ml-1(r=0. 999 8), the average recovery was 100. 02%(RSD=1. 12%, n=5). The lowest detectable limit and the lowest quantitation limit was 0. 098μg·ml-1 and 0. 25μg·ml-1, respectively. The stabil-ity results of hard-light exposure, destructive testing and long-term testing showed that the preparation was basically stable at room tem-perature, while under high temperature with hard light, strong basicity, acidicity or oxidation solution, the preparation was unstable. Conclusion:The method is accurate and reliable in the determination and stability study of nimesulide thermo-sensitive hydrogels. The hydrogels should be stored in shady, cool and dark place.

Determination of substances in 4 nimesulide preparations by ultra-fast liquid chromatography / 第二军医大学学报

Objective: To establish an ultra-fast liquid chromatography (UFLC) method for detecting the substances in different preparations of nimesulide. Methods: Ultra-fast liquid chromatography instruments Shimadzu and Syncronis C18 column (100 mm×2.1 mm×1.7 μm) were used. The mobile phase was a mixture solvent of methanol-acetonitrile-0.1% solution of orthophosphoric acid (adjusted to pH 6.5 with ammonia) (45:15:40). The flowing rate was 0.3 mL/min, and the detection wavelength was 230 nm. The system suitability solutions of European Pharmacopoeia and Chinese Pharmacopoeia, the damaging samples and the accessories of different preparations of different manufacturers were used to investigate the method applicability. Results: The method had high resolution, strong specificity and can efficiently and quickly detect the related substances in nimesulide preparations. Various degradation products of damaging tests and the accessories of different preparations from different manufacturers had no effect on the determination results. Conclusion: The method is efficient, fast, widely applicable and can be used for detecting the substances in different preparations of nimesulide by different manufacturers.

Bioequivalence of Nimesulide Granules in Healthy Volunteers / 中国药师

Objective:To evaluate the bioequivalence of two kinds of domestic nimesulide granules in healthy volunteers. Meth-ods:In self-control and two-way crossover design, 18 healthy male volunteers were divided into two groups randomly. Each subject was given 100 mg test or reference nimesulide granules with single dose. The concentration of nimesulide in plasma was determined by HPLC. The concentration of nimesulide in plasma was calculated and compared statistically to evaluate the bioequivalence between the two kinds of granules by DAS 2. 1 software. Results:The main pharmacokinetic parameters of test and reference preparations were as follows:Cmax was(9. 28 ± 2. 05) and(9. 41 ± 2. 31)μg·ml-1;Tmax was(3. 50 ± 1. 86)and(3. 56 ± 1. 65)h;T1/2 was (3. 43 ± 0. 85) and(3.38 ±0.68)h;AUC0-24 was(77.78 ±18.42)and(81.69 ±23.50)μg·ml·h-1;AUC(0-∞) was (79.07 ±19.21)and(82.92 ± 24. 11)μg·ml·h-1, respectively. The 90% confidential interval of ln(AUC0-24), ln(AUC0-∞) and ln(Cmax) of the test preparation was 90. 7%-107. 9%,90. 6%-111. 2% and 90. 7%-103. 0%, respectively. The relative bioavailability was (96. 7 ± 37. 6)%. Con-clusion:The two nimesulide granules are bioequivalent.