Formulation and evaluation of Buccal mucoadhesive tablets of diclofenac sodium using 23 factorial designs

Buccal tablets

Diclofenac sodium

Drug release

Mucoadhesion

Mucoadhesive tablets

Release kinetics

Narrative Review of Nimesulide in Adults: Current Scenario

Nimesulide, a nonsteroidal anti-inflammatory drug (NSAID), has been used as an effective treatment regimen for patients aged >12 years for fever, acute pain, acute tendinitis, osteoarthritis and dysmenorrhea. It is reported to be a superior antipyretic and anti-inflammatory drug than paracetamol and aspirin, respectively, and is equal to any of the NSAIDs alone in terms of analgesia. This paper reviews the current scenario of nimesulide in adult patients, concerning clinical evidence, use in special population and expert opinion. Overall, in comparison to other NSAIDs, including coxibs, nimesulide has a promising overall efficacy, safety and tolerability profile, as well as a satisfactory benefit/risk evaluation.

Anti-inflammatories for delayed onset muscle soreness: systematic review and meta-analysis / Antiinflamatorios para el dolor muscular de inicio tardío: revisión sistemática y metanálisis / Anti-inflamatórios para dor muscular de início tardio: revisão sistemática e metanálise

ABSTRACT Objective: To investigate the effectiveness of pharmacological interventions in the treatment of delayed onset muscle soreness (DOMS). Design: A systematic review and meta-analysis of randomized controlled clinical trials (RCTs). Data sources: The PubMed/MEDLINE, EMBASE, SPORTDiscus, Scielo and Cochrane Central Register of Controlled Trials (CENTRAL) databases were searched for RCTs published prior to August 3, 2020. Eligibility criteria for selecting studies: Studies that 1) used an RCT design; 2) evaluated the effectiveness of steroidal or nonsteroidal anti-inflammatory drugs (NSAIDs) in treating DOMS; and 3) therapeutically used drugs after exercise were included. Results: In total, 26 studies (patients = 934) were eligible for inclusion in the qualitative analysis on the treatment of DOMS. The results of the meta-analysis showed no superiority between the use and non-use of NSAIDs in the improvement of late muscle pain, as no statistically significant differences were verified (21 studies, n= 955; standard mean difference (SMD)= 0.02; 95% confidence interval (CI) −0.58, 0.63; p=0.94; I2=93%). The quality of the synthesized evidence was very low according to the Grading of Recommendations Assessment, Development and Evaluation (GRADE) criteria, and there was significant heterogeneity among the included studies. Conclusion: The results demonstrate that NSAIDs are not superior to controls/placebos in treating DOMS. The inclusion of both studies with dose-response protocols and those with exercise protocols may have influenced the results. In addition, the high risk of bias identified reveals that limitations need to be considered when interpreting the results. Level of evidence I; ystematic review of RCT (Randomized and Controlled Clinical Trials).

RESUMEN Objetivo: Investigar la efectividad de las intervenciones farmacológicas en el tratamiento del dolor muscular de aparición tardía (DOMS). Metodología: Revisión sistemática y metanálisis de ensayos clínicos controlados aleatorios (RCT). Fuentes de datos: Se realizaron búsquedas en las bases de datos de PubMed/MEDLINE, EMBASE, SPORTDiscus, Scielo y Cochrane Central Register of Controlled Trials (CENTRAL) para ECA publicados antes del 3 de agosto de 2020. Criterios de elegibilidad para la selección de estudios: Estudios en los que 1) se utilizó un diseño de RCT; 2) se evaluó la eficacia de los fármacos antiinflamatorios no esteroideos (AINE) y esteroideos en el tratamiento de DOMS; y 3) se incluyó el uso terapéutico de medicamentos para dolor después del ejercicio. Resultados: En total, 26 estudios (pacientes = 934) fueron elegibles para su inclusión en el análisis cualitativo sobre el tratamiento de DOMS. Los resultados encontrados en el metanálisis no demostraron superioridad entre el uso y no uso de AINE para mejorar el dolor muscular tardío cuando se comparó con una condición de control, ya que no hubo diferencias estadísticamente significativas (21 estudios, n = 955; media estándar diferencia = 0,02; intervalo de confianza (IC) del 95% −0,58, 0,63; p = 0,94; I2 = 93%). La calidad de la evidencia encontrada se clasificó como muy baja según los criterios del "Grading of Recommendations Assessment, Development and Evaluation" (GRADE), principalmente porque existe una heterogeneidad significativa entre los estudios incluidos. Conclusión: Los resultados demuestran que los AINE no son superiores a los controles o placebos en el tratamiento de DOMS. La inclusión de ambos modelos de estudio con protocolos de dosis-respuesta y protocolos de ejercicio puede haber influido en los resultados. Además, el alto riesgo de sesgo identificado revela que la interpretación de los resultados debe verse con limitaciones. Nivel de evidencia: I; Revisión sistemática de ECRC (Ensayos clínicos aleatorizados y controlados).

RESUMO Objetivo: Investigar a eficácia das intervenções farmacológicas no tratamento da dor muscular de início tardio (DOMS). Desenho: Revisão sistemática e metanálise de estudos clínicos randomizados e controlados (RCTs). Fontes de dados: Os bancos de dados PubMed/MEDLINE, EMBASE, SPORTDiscus, Scielo e Cochrane Central Register of Controlled Trials (CENTRAL) foram pesquisados em busca de RCTs publicados antes de 3 de agosto de 2020. Critérios de elegibilidade para selecionar estudos: Estudos que 1) usaram um desenho de RCT; 2) avaliaram a eficácia de anti-inflamatórios esteroides ou não esteroides (AINEs) no tratamento de DOMS e 3) incluíram tratamento medicamentoso depois de exercício. Resultados: No total, 26 estudos (pacientes = 934) foram elegíveis para inclusão na análise qualitativa do tratamento de DOMS. Os resultados da metanálise não mostraram superioridade entre o uso e não uso de AINEs na melhora da dor muscular tardia, pois não foram verificadas diferenças estatisticamente significativas (21 estudos, n = 955; diferença média padronizada (SMD) = 0,02; Intervalo de confiança (IC) de 95% −0,58, 0,63; p = 0,94; I2 = 93%). A qualidade da evidência encontrada foi muito baixa de acordo com os critérios da Grading of Recommendations Assessment, Development and Evaluation (GRADE), e verificou-se heterogeneidade significante entre os estudos incluídos. Conclusão: Os resultados demonstram que os AINEs não são superiores aos controles ou placebos no tratamento de DOMS. A inclusão de estudos com protocolos de dose-resposta e com protocolos de exercícios podem ter influenciado os resultados. Além disso, o alto risco de viés identificado revela que as limitações devem ser consideradas na interpretação dos resultados. Nível de evidência I; Revisão sistemática de ECRC (Estudos clínicos randomizados e controlados).

Profilaxia da pancreatite pós-colangiopancreatografia retrógrada endoscópica: avaliação de dois regimes com AINEs diferentes / Post endoscopic retrograde cholangiopancreatography pancreatitis prophylaxis: evaluation of two different nsaid regimens

ABSTRACT BACKGROUND: Endoscopic retrograde cholangiopancreatography is a widely used therapeutic modality for the pancreaticobiliary tree. However, it is responsible for the highest rates of complications among the endoscopic procedures, especially post-endoscopic retrograde cholangiopancreatography pancreatitis. The preventive methods include mechanical and pharmacological approaches, such as the use of non-steroidal anti-inflammatory drugs. OBJECTIVE: To compare the efficacy of two different strategies using non-steroidal anti-inflammatory drugs for the prevention of post-endoscopic retrograde cholangiopancreatography pancreatitis, and to clarify the uncertainty about the route of administration of non-steroidal anti-inflammatory drugs in the prevention of this complication. METHODS: This was a prospective trial. Two therapeutic groups were compared with a control group that was composed of patients who underwent endoscopic retrograde cholangiopancreatography, performed in the same service and by the same team in the period preceding the study (historical series), without the administration of any type of prophylaxis. The first group received 100 mg rectal diclofenac. The second group received 100 mg intravenous ketoprofen. Both groups were compared, separately and jointly, with the control group. RESULTS: Post-endoscopic retrograde cholangiopancreatography pancreatitis occurred in 4.39% (12/273) of the participants. In the group without prophylaxis, the incidence was 6.89% (10/145). Among those who received intravenous ketoprofen, the incidence was 2.56% (2/78). No cases of acute post-procedural pancreatitis were observed in the group that received rectal diclofenac (0/52). Although there was no statistical difference between the therapeutic groups when they were separately analyzed, a statistical difference in the prevention of post-procedural pancreatitis was observed when they were analyzed together (P=0.037). CONCLUSION: This study provides evidence for the efficacy of non-steroidal anti-inflammatory drugs in the prophylaxis of post-endoscopic retrograde cholangiopancreatography pancreatitis.

RESUMO CONTEXTO: A colangiopancreatografia retrógrada endoscópica (CPRE) é uma modalidade terapêutica amplamente utilizada para vias biliopancreáticas, responsável pelas taxas mais elevadas de complicações entre os procedimentos endoscópicos, especialmente a pancreatite pós-CPRE (PPC). Os métodos preventivos incluem abordagens mecânicas e farmacológicas, entre elas, a utilização de antinflamatórios não esteroidais (AINEs). OBJETIVO: Comparar a eficácia de duas estratégias diferentes utilizando AINEs para a prevenção de PPC. Elucidar o cenário incerto sobre a via de administração do AINEs na prevenção da PPC. MÉTODOS - Ensaio clínico prospectivo. Duas estratégias terapêuticas foram comparadas a um grupo controle, composto por pacientes submetidos a CPRE no mesmo serviço e com a mesma equipe no período anterior ao estudo (série histórica), que não recebeu qualquer tipo de profilaxia. O primeiro grupo experimental recebeu 100 mg de diclofenaco via retal, o segundo grupo recebeu 100 mg de cetoprofeno endovenoso. Ambos os grupos foram comparados separadamente e em associação com o grupo de controle. RESULTADOS: A PPC ocorreu em 4,39% (12/273) dos participantes. No grupo sem profilaxia, esta incidência foi de 6,89% (10/145); entre os que receberam cetoprofeno endovenoso foi de 2,56% (2/78). Não houve casos de pancreatite aguda após o procedimento no grupo que recebeu diclofenaco via retal (0/52). Apesar de não haver diferença estatística entre estes grupos analisados separadamente, quando os dois grupos terapêuticos são analisados em conjunto estes apresentam diferenças estatísticas na prevenção da PPC (P=0,037). CONCLUSÃO: Este estudo foi capaz de corroborar a eficácia da utilização de AINEs para a profilaxia de pancreatite pós-CPRE.

Pharmacogenetic and pharmacokinetic assays from saliva samples can guarantee personalized drug prescription

Abstract Saliva is widely used for clinical and laboratory analysis. This study proposed to use DNA extracted from saliva for genotyping and pharmacokinetics of piroxicam. A fast and efficient genotyping method was used to determine relevant allelic variants of CYP2C9 (*2 and *3), since genetic factors can influence in non-steroidal anti-inflammatory drugs (NSAIDs) metabolization. DNA Extract All Reagents Kit® was used for DNA extraction and genotyping was performed using TaqMan® GTXpress™ Master Mix, SNP genotyping assays and a Viia7 Real-Time PCR system. Volunteers performed sequential collections of saliva samples before and after taking a single dose of piroxicam (0.25 to 72 h) which were used for pharmacokinetics assays. Piroxicam concentrations were analyzed using LC-MS/MS. Sixty-six percent of volunteers were ancestral homozygous (CYP2C9*1/*1), and 34% showed one or both polymorphisms. Of these 34%, 22 individuals showed CYP2C9*2 polymorphism, 8 CYP2C9*3, and 4 CYP2C9*2/*3. Piroxicam pharmacokinetics were performed in 5 subjects. Areas under the curve (AUC0-t(h*ng/mL)) for CYP2C9*1/*1, *1/*2 and *1/*3 were, respectively, 194.33±70.93, 166 and 303. Maximum concentrations (Cmax(ng/mL)) for these genotypes were respectively 6.46±2.56, 4.3 and 10.2. Saliva sampling was a very effective matrix for both pharmacogenetic and pharmacokinetic tests, ensuring the speed of the procedure and the well-being and agreement of the participants. Once having the knowledge about the slow and fast metabolizers, it is possible to make an adequate prescription in order to avoid the adverse effects of the medication and to guarantee greater analgesic comfort to the patients respectively.

Resumo Saliva é amplamente utilizada para análises clínicas e laboratoriais. Este estudo propôs o uso de DNA extraído da saliva para genotipagem e farmacocinética do piroxicam. Um método de genotipagem rápido e eficiente foi usado para determinar as variantes alélicas clinicamente relevantes de CYP2C9 (* 2 e * 3), uma vez que fatores genéticos podem influenciar nas respostas metabólicas individuais a medicamentos como anti-inflamatórios não esteroides (AINEs). DNA Extract All Reagents Kit® foi usado para extração de DNA e a genotipagem foi realizada usando TaqMan® GTXpress ™ Master Mix, ensaios de genotipagem SNP e um sistema Viia7 Real-Time PCR. Os voluntários realizaram coletas sequenciais de amostras de saliva antes e após a ingestão de uma única dose de piroxicam (0,25 a 72 h) que foram utilizadas para ensaios farmacocinéticos. As concentrações de piroxicam foram analisadas usando LC - MS / MS. Sessenta e seis por cento dos voluntários eram homozigotos ancestrais (CYP2C9 * 1 / * 1) e 34% apresentaram um ou ambos os polimorfismos. Destes 34%, 22 indivíduos apresentaram polimorfismo CYP2C9 * 2, 8 CYP2C9 * 3 e 4 CYP2C9 * 2 / * 3. A farmacocinética do piroxicam foi realizada em 5 indivíduos. As áreas sob a curva (AUC0-t (h * ng / mL)) para CYP2C9 * 1 / * 1, * 1 / * 2 e * 1 / * 3 foram, respectivamente, 194,33±70,93, 166 e 303. Concentrações máximas (Cmax (ng / mL)) para esses genótipos foram, respectivamente, 6,46±2,56, 4,3 e 10,2. A amostra de saliva foi uma matriz muito eficaz tanto para os testes farmacogenéticos quanto para os farmacocinéticos, garantindo a agilidade do procedimento e o bem-estar e concordância dos participantes. Com o conhecimento dos metabolizadores lentos e rápidos, é possível fazer uma prescrição adequada para evitar os efeitos adversos da medicação e garantir maior conforto analgésico aos pacientes respectivamente.

Organic carbon monoxide prodrug, BW-CO-111, in protection against chemically-induced gastric mucosal damage

Metal-based carbon monoxide (CO)-releasing molecules have been shown to exert anti-inflammatory and anti-oxidative properties maintaining gastric mucosal integrity. We are interested in further development of metal-free CO-based therapeutics for oral administration. Thus, we examine the protective effect of representative CO prodrug, BW-CO-111, in rat models of gastric damage induced by necrotic ethanol or aspirin, a representative non-steroidal anti-inflammatory drug. Treatment effectiveness was assessed by measuring the microscopic/macroscopic gastric damage area and gastric blood flow by laser flowmetry. Gastric mucosal mRNA and/or protein expressions of HMOX1, HMOX2, nuclear factor erythroid 2-related factor 2, COX1, COX2,

Clinical management of dogs with presumptive diagnosis of thoracolumbar intervertebral disc disease: 164 cases (2006-2017) / Tratamento clínico de cães com diagnóstico presuntivo de doença do disco intervertebral toracolombar: 164 casos (2006-2017)

This study aimed to identify dogs with presumptive diagnosis of cervical intervertebral disc disease (IVDD) submitted to clinical management and to evaluate the outcomes. Data were obtained from the medical records of patients with neurological dysfunction assisted at a University Veterinary Hospital from 2006 to 2017. In addition to the patients' records, dog owners responded to a questionnaire on the success of therapy. Four hundred and thirteen neurological records were evaluated, and 164 met the inclusion criteria of the study. The most common breed was Dachshund, followed by mongrels. Classification of neurological dysfunction in the study sample was as follows: 15.9% with grade I, 25.6% with grade II, 26.8% with grade III, 8.5% with grade IV, and 23.2% with grade V. Outcome was satisfactory in 71.6% of the dogs and unsatisfactory in 28.4% of them. Recurrence was observed in 27.7% of those with satisfactory outcomes. The clinical treatment of dogs with thoracolumbar IVDD is satisfactory, particularly for animals with milder disease grades (I, II, and III). There is possibility of recurrence with conservative therapy and clinical signs may be more severe.(AU)

O objetivo desse estudo foi identificar cães com diagnóstico presuntivo de DDIV toracolombar submetidos ao tratamento clínico, a fim de avaliar a resposta à terapia instituída. Foram revisados os registros neurológicos de cães atendidos pelo Serviço de Neurologia e Neurocirurgia Veterinária no período de 2006 a 2017 de um Hospital Veterinário Universitário. Foi realizada coleta de dados a partir dos registros e por meio de um questionário respondido pelos tutores. Foram avaliadas 413 fichas neurológicas de cães e obtidas informações para inclusão no estudo em 164 delas. As raças mais frequentes foram dachshunds, seguido de cães sem raça definida. Quanto ao grau de disfunção neurológica foi definido como grau I para 15,9% dos cães, grau II para 25,6%, grau III para 26,8%, grau IV para 8,5% e grau V para 23,2%. A recuperação foi satisfatória em 71,6% dos cães e insatisfatória em 28,4%. Dos que se recuperaram satisfatoriamente, 27,7% tiveram recidivas. Com base nos resultados obtidos pode-se concluir que o tratamento clínico em repouso absoluto e administração de anti-inflamatórios e analgésicos opióides para cães com DDIV toracolombar é efetivo, principalmente para cães em graus mais leves da doença (grau I, II e III). Há possibilidade de recidiva com esse tipo de terapia cujos sinais clínicos poderão ser mais graves.(AU)

Update on the Management of Nonsteroidal Anti-Inflammatory Drug Hypersensitivity

Eficacia y seguridad de los AINE tópicos / Efficacy and safety of topical NSAIDs / Eficácia e segurança dos AINEs tópicos

Resumen: Introducción: los antiinflamatorios no esteroideos (AINE) constituyen uno de los grupos farmacológicos más prescritos a nivel mundial. En los últimos años ha aumentado el uso de AINE de administración tópica, con una prevalencia de prescripción creciente. Objetivo: revisar la eficacia y seguridad de AINE tópicos comparados con los administrados por vía oral en el tratamiento del dolor. Material y método: se realizó una revisión narrativa utilizando la base de datos Pubmed. La búsqueda arrojó un total de 141 artículos de los cuales 4 cumplían con los criterios de inclusión propuestos. Discusión: la evidencia que respalda el uso de AINE tópicos en cuanto a eficacia está comparada con placebo, incluyen escaso número de pacientes y utilizan variables primarias blandas, lo que constituye una limitante metodológica para determinar su beneficio, por lo que no se pudo analizar la evidencia disponible según el objetivo planteado. En cuanto a la seguridad, la incidencia de efectos adversos más frecuentemente reportados son los gastrointestinales, siendo menos frecuente con la administración tópica, sin embargo, ésta vía agrega efectos adversos cutáneos en el sitio de administración. Conclusión: la facilidad de acceso a estos medicamentos, la percepción de menor riesgo por tratarse de una vía no sistémica y la escasa evidencia disponible favorecen el uso irracional de los AINE tópicos.

Abstract: Introduction: Nonsteroidal anti-inflammatory drugs (NSAID) are one of the most prescribed pharmacological groups worldwide. In recent years the use of topical NSAID has increased, with a growing prevalence of prescription. Objective: The aim of the present work was to review the efficacy and safety of topical NSAID compared to oral administration for the treatment of pain. Material and method: A narrative review was made using the Pubmed database. The evidence that supports the use of topical NSAID in terms of efficacy is compared with placebo, include a small number of patients and use soft primary outcomes, which constitutes a methodological limitation to asses their benefit, not allowing to analyze the available evidence according to the aim set. Regarding safety, the incidence of adverse effects most frequently reported are gastrointestinal, which are less frequent with topical administration, however, this route adds adverse cutaneous effects at the administration site. Conclusion: The ease of access to these medications, the low risk perception due to it is a non-systemic route and the limited available evidence stimulate the irrational use of topical NSAID.

Resumo: Introdução: Os medicamentos anti-inflamatórios não esteroides (AINE) são um dos grupos farmacológicos mais prescritos em todo o mundo. Nos últimos anos, o uso de AINE tópicos aumentou, com uma crescente prevalência de prescrição. Objetivos: O objetivo do presente trabalho foi revisar a eficácia e segurança dos AINE tópicos em comparação com a via oral no tratamento da dor. Materiais e métodos: Uma revisão narrativa foi feita usando o banco de dados Pubmed. A evidência que suporta o uso de AINE tópicos em termos de eficácia é comparada com placebo, inclui um pequeno número de pacientes e usa variáveis ​​primárias moles, o que constitui uma limitação metodológica para determinar seu benefício, portanto, a evidência disponível não pôde ser analisada de acordo com o objetivo. Em relação à segurança, a incidência de efeitos adversos mais frequentemente relatados é gastrointestinal, sendo menos freqüente com a administração tópica, porém, esta via acrescenta efeitos cutâneos adversos no local de administração. Conclusões: A facilidade de acesso a esses medicamentos, a percepção de menor risco, por ser uma via não sistêmica e a limitada evidência disponível, favorecem o uso irracional de AINE tópicos.

Systemic absortion and adverse effects of topical ocular use of ketorolac tromethamine and sodium diclofenac in New Zealand rabbits for 90 days / Absorção sistêmica e efeitos adversos do uso tópico ocular por 90 dias de cetorolaco de trometamina e diclofenacode sódio em coelhos da raça Nova Zelândia

The effect of the systemic absorption of 0.1% diclofenac sodium (DS) eyedrop was compared to that of 0.5% ketorolac tromethamine (KT) in female New Zealand white rabbits treated on both eyes three times a day for 90 days. The rabbits were divided in three groups of six animals (n= 18): KT group, DS group, and control (Co) group, in which saline (0.9% NaCl) solution was instilled. Water and food consumption were measured daily, clinical examination was performed weekly, and blood samples were collected every 30 days for laboratory examination. The plasma was analyzed for the presence of KT and DS by solid-phase extraction (SPE) associated with mass spectrometry (MS). Systemic absorption of these drugs was confirmed by SPE-MS, allowing their separation and identification in the plasma. At the end of the treatment, the animals were euthanized and necropsied, and no macroscopic or microscopic changes were found. This observation confirmed the laboratory results, which were within normal reference standards for the species. According to the results obtained, it can be concluded that treatment with eyedrops containing KT and DS for 90 days in healthy rabbits does not cause adverse systemic effects.(AU)

Comparou-se o efeito da absorção sistêmica do colírio de diclofenaco de sódio 0,1% (DS) em relação ao de cetorolaco de trometamina 0,5% (CT) em coelhas da raça Nova Zelândia, tratadas nos dois olhos, três vezes ao dia, por 90 dias. As coelhas foram separadas em três grupos de seis animais (n=18): grupo CT, grupo DS e grupo controle (Co), no qual foi instilada solução fisiológica (NaCl 0,9%). Os consumos de água e ração foram mensurados diariamente, os exames clínicos foram realizados semanalmente e o sangue foi coletado a cada 30 dias para realização de exames laboratoriais. O plasma foi analisado para detectar a presença de CT e DS por extração em fase sólida (SPE) associada à espectrometria de massas (MS). A absorção sistêmica desses fármacos foi confirmada por SPE-MS, permitindo sua separação e identificação no plasma. Ao final do tratamento, os animais foram eutanasiados e necropsiados, e não foram encontradas alterações macroscópicas ou microscópicas. Essa observação confirmou os resultados laboratoriais, que estavam dentro dos padrões de referência para a espécie. De acordo com os resultados obtidos, pode-se concluir que o tratamento com colírio contendo KT e DS, por 90 dias, em coelhos saudáveis, não causa efeitos adversos sistêmicos.(AU)

Investigation into the Possible Risk Effects Associated with Drug and Alcohol-induced Gastrointestinal Ulcer in Wistar Albino Rats

Aim: The study investigated the possible risks associated with gastrointestinal ulcer disease by evaluating the biochemical response of three body organs; heart, kidney and liver, in gastric ulcerated rats. Methodology: Twenty male wistar albino rats were used in the study. Gastric ulcer was induced in rats with single oral dose of 400 mg/kg body weight (b.w.) aspirin, 80 mg/kg b.w. indomethacin and 5 ml/kg b.w. acidified ethanol (40:60 v/v). Blood samples were collected into heparinized bottle and centrifuged at 4000 rpm for 10 mins to obtain the plasma. Gastric tissue, liver, kidney and heart were also collected. Results: Oral administration of 400 mg/kg b.w. aspirin, 80 mg/kg b.w. indomethacin and 5 ml/kg b.w. acidified ethanol caused a remarkable increase in ulcer index. There was observed a significant (p<0.05) reduction in AST and ALT activities in gastric ulceration caused by aspirin (Asp), with no significant (p<0.05) change in total protein (TP) concentration, lactate dehydrogenase and creatine kinase activity. However, there was increase in creatinine and urea concentration. Acidified ethanol and Indomethacin-induced ulcerated rats showed significant (p<0.05) reduction in all other parameters except ALT and lactate dehydrogenase activities which did not show any significant (p<0.05) change. There was also observed a significant (p<0.05) increase in creatine kinase activity in indomethacin-induced ulcerated rats. Conclusion: Overall, the result indicates a link between gastric ulcer and organ toxicity. The use of NSAIDs above the therapeutic doses in the treatment of pains and related illness as well as excess consumption of alcohol is shown to negatively impact the stomach and cause serious damage to different body organs of wistar rats.

The impact of non-steroidal anti-inflammatory drugs use in elderly cardiovascular patients: an observational study from tertiary care in South India

Background: Long-term use of NSAIDs, by patients having cardiovascular conditions, has shown to increase the risk of cardiovascular events and increased risk of death. Hence, the study was conducted to determine the complications related to NSAID use by the elderly patients with cardiovascular disease (CVD).Methods: The study was a single-center prospective observational study conducted November 2017 to October 2018. Elderly patients (>60 years) suffering from various CVDs and reported NSAID intake daily for at least one month were included. A questionnaire included demographic, treatment related history and complete details of NSAIDs intake including nature, dose, indication, source etc. The same questionnaire was again filled at the end of one-year follow-up.Results: A total of 100 participants were included in the study. The mean age was 72±8.6 years. Majority of the patients (93%) had hypertension, and 69% of the patient had previous MI.  Five NSAIDs (diclofenac, ibuprofen, mefenamic acid, naproxen, and ketorolac) were used routinely. At least one over the counter NSAID used was reported by 86%, 57% were prescribed at least one NSAIDs by their orthopaedics and physicians. At the end of 1-year follow-up, authors found that 71% had MI (2% increase), 4% developed reinfarction, 20% had severe left ventricular failure (4% increase), 7% had atrial fibrillation (1% increase), and 2% patients died and 63% patients reported raise in systolic blood pressure by 5mmHg.Conclusions: High prevalence of concomitant NSAID use among elderly CVD patients, which might be contributing towards increase in CVS morbidity and mortality.

Virtual screening of natural and synthetic inhibitors of cyclooxygenase COX-2 enzyme using docking-scoring functions

In this paper, theoretical elucidation of cyclooxygenase interaction with synthetic and natural bioactive moleculesusing molecular docking is studied with molecular docking implicating solvation parameters. Obtained results showthat synthetics and natural inhibitors of thym interact differently with cyclooxygenase inflammation enzyme afterincluding solvatation parameter and confirm primary studies concerning the anti-inflammatory effect. We concludethat the solvatation parameter must be taken into account in all molecular docking studies because of different resultswhich permits a better comprehension of the inhibition process and more clear ideas to develop new drugs. Resultsallow us to propose chlorogenique as a novel molecule to be developed into a new novel drug

Formulation And Evaluation Of Solid Dispersion Incorporated Fast Disintegrating Tablets Of Tenoxicam Using Design Of Experiment

The aim of the present work is to develop fast dissolving tablets from the solid dispersion of Tenoxicam for enhancement of solubility. The solid dispersions of Tenoxicam were prepared with Kollidon CL, PVP K30 and Poloxamer 127, in 1:1:1, 1:2:1 and 1:3:1 by using solvent evaporation method. The prepared solid dispersions were analyzed for all the physical parameters, drug: carrier interactions like FTIR, SEM, XRD. Solid dispersions showed a better dissolution compared to the pure drugs and among all the other formulations SD9 shows high percentage drug release i.e. 99.11 ± 5.17% for 90 min and selected as an optimized formulation for the preparation of fast disintegrating tablets of Tenoxicam. Gellan Gum, Fenugreek Seed Mucilage and L-HPC (low, middle and high concentrations) used in the preparation of fast disintegrating tablets prepared by direct compression method using 33 Response surface method. The post compression parameters of all the prepared tablets were within the limits. TF13 was selected as optimized formulation based on its highest disintegration time 36 sec and drug release 99.68 ± 1.52% for 10 min. Drug-excipients characterization also revealed that there is no interaction. Hence it concluded that solid dispersions incorporated fast disintegrating tablets is very useful approach for immediate release of Tenoxicam in the efficient management of inflammation and pain.

Complementary Participation of Genetics and Epigenetics in Development of NSAID-exacerbated Respiratory Disease

Nonsteroidal anti-inflammatory drug (NSAID)-exacerbated respiratory disease (NERD) has attracted a great deal of attention because of its association with severe asthma. However, it remains widely underdiagnosed in asthmatics as well as the general population. Upon pharmacological inhibition of cyclooxygenase 1 by NSAIDs, production of anti-inflammatory prostaglandin E2 and lipoxins ceases, while release of proinflammatory cysteinyl leukotrienes increases. To determine the underlying mechanisms, many studies have attempted to elucidate the genetic variants, such as single nucleotide polymorphisms, responsible for alterations of prostaglandins and leukotrienes, but the results of these genetic studies could not explain the whole genetic pathogenesis of NERD. Accordingly, the field of epigenetics has been introduced as an additional contributor to genomic alteration underlying the development of NERD. Recently, changes in CpG methylation, as one of the epigenetic components, have been identified in target tissues of NERD. This review discusses in silico analyses of both genetic and epigenetic components to gain a better understanding of their complementary roles in the development of NERD. Although the molecular mechanisms underlying NERD pathogenesis remain poorly understood, genetic and epigenetic variations play significant roles. Our results enhance the understanding of the genetic and epigenetic mechanisms involved in the development of NERD and suggest new approaches toward better diagnosis and management.

Are COX-2 Selective NSAIDs Associated with Less GI, Renal, and Cardiovascular Side Effects: Evidence from Animals Treated with NSAIDs

Aims: Nonsteroidal anti-inflammatory drugs (NSAIDs) are frequently used to treat both acute and chronic pain in animals, especially when the pain is resulted from inflammatory conditions. NSAIDs work by inhibition of cyclooxygenases (COX) enzymes and reduce the production of key inflammatory mediators prostaglandins and associated chemicals. Prostaglandins have important roles in pain signalling and haemostasis, including platelet aggregation and gastric mucosal protection. There are two known isoforms of cyclooxygenases enzymes, namely COX-1 and COX-2. Notable adverse effects commonly resulted from NSAIDs uses include gastrointestinal ulceration, compromised haemostasis and renal toxicity, which are due to inhibition of COX-1 isoform. Despite the development of COX-2 selective medicines and continuing effort to improve the safety of NSAIDs in routine veterinary practice, adverse effects of NSAIDs still exist and require closed monitoring. This study aims to summarise and evaluate the current literature on reported adverse effects of NSAIDs used in animals and to compare COX-2 selective versus non-selective agents. Methodology: Literature on reported adverse effects of NSAIDs used in animals over the last decade has been systematically reviewed. Some older sources from the primary literature search have also been included to determine the background information leading to current rationale behind NSAIDs’ therapeutic uses, dosage and route of administration, observed adverse effects and COX-2 selective versus non-selective agents. The primary focus of this study is NSAIDs administered to animals in prospective randomised placebo-controlled blinded trials. Results: A total of 12 studies that met the inclusion criteria were included in the review, with total 13 NSAIDs being discussed, including meloxicam, phenylbutazone, deracoxib, carprofen, aspirin, firocoxib, vedaprofen, etorolac, ketoprofen, tepoxalin, rofecoxib, licofelone and flunixin. It was found that there were variable findings in comparing the adverse effects associated with COX-2 selective NSAIDs and non-selective NSAIDs. COX-2 selective NSAIDs have been found associated with no adverse effects in some studies and minimal adverse effects in other studies. Severe adverse effects were reported for COX-2 selective NSAID administered at higher than recommended doses or for a long duration and some studies reported reduced adverse effects in COX-2 selective NSAIDs when compared to non-selective NSAIDs. Overall, gastrointestinal adverse effects were predominantly reported, followed by adverse findings relating to haemostasis and renal function. Conclusion: Collectively, the findings suggest COX-2 selective NSAIDs provide a clinically useful improvement over non-selective NSAIDs as well as reduce adverse effects when given at recommended dose.

Curcumin and Piperine: A novel therapy in the management of osteoarthritis in Indian patients

@#To evaluate the efficacy and tolerability of fixed dose combination of curcumin and piperine in osteoarthritis (OA), a non-randomized, open labeled, non-comparative, single-centric, and post marketing surveillance (PMS) study was conducted in 166 osteoarthritic patients (73 men and 93 women, mean age: 54.5 ± 12.45 years). Each patient was administered a combination of curcumin 500 mg and piperine 5 mg twice daily for 12 weeks. The Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) was used as a tool to assess the efficacy of the fixe dose combination during the 12 weeks therapy. At the end of 12 weeks of therapy, WOMAC score improved significantly (p<0.0001) from 65.82 ± 18.10 to 25.12 ± 21.26. Also a significant reduction (p<0.0001) was found in scores for pain, stiffness and physical function from 15.03 ± 3.74 to 5.83 ± 4.42, 5.43 ± 1.95 to 1.52 ± 1.56 and 45.57 ± 13.72 to 17.76 ± 16.23 respectively at the end of 12 weeks. Combination of Curcumin and Piperine was effective and safe for the management of osteoarthritis in Indian patients.

Opposite Interplay Between the Canonical WNT/β-Catenin Pathway and PPAR Gamma: A Potential Therapeutic Target in Gliomas / 神经科学通报·英文版

In gliomas, the canonical Wingless/Int (WNT)/β-catenin pathway is increased while peroxisome proliferator-activated receptor gamma (PPAR-γ) is downregulated. The two systems act in an opposite manner. This review focuses on the interplay between WNT/β-catenin signaling and PPAR-γ and their metabolic implications as potential therapeutic target in gliomas. Activation of the WNT/β-catenin pathway stimulates the transcription of genes involved in proliferation, invasion, nucleotide synthesis, tumor growth, and angiogenesis. Activation of PPAR-γ agonists inhibits various signaling pathways such as the JAK/STAT, WNT/β-catenin, and PI3K/Akt pathways, which reduces tumor growth, cell proliferation, cell invasiveness, and angiogenesis. Nonsteroidal anti-inflammatory drugs, curcumin, antipsychotic drugs, adiponectin, and sulforaphane downregulate the WNT/β-catenin pathway through the upregulation of PPAR-γ and thus appear to provide an interesting therapeutic approach for gliomas. Temozolomide (TMZ) is an antiangiogenic agent. The downstream action of this opposite interplay may explain the TMZ-resistance often reported in gliomas.

COX2 Inhibitors as Anti-Inflammatory Agents

Pain and inflammation are common problems in clinical practice. Anti-inflammatory drugs are one of the most often prescribed groups of medications. The issue is that they carry gastrointestinal (GI) and cardiovascular (CV) risks. Therefore, anti-inflammatory drugs should be used mostly in the setting of inflammation. Non inflammatory pain can be managed with other groups of drugs and therapies. For patients who do need anti-inflammatory agents, the choice is dependent on the GI and CV risk profile of the patient. Where possible, efforts should be directed to the underlying cause of the pain and inflammation.

Patterns of Ketorolac dosing by emergency physicians / 世界急诊医学杂志（英文）

@#BACKGROUND: Ketorolac tromethamine is a non-steroidal anti-inflammatory drug (NSAIDs) that is widely used in the emergency department (ED) for the treatment of moderate-to-severe pain. Ketorolac, like other NSAIDs, exhibits an analgesic ceiling effect and previous research suggests that 10 mg is possibly the ceiling dose. Do the patterns of ketorolac dosing by emergency physicians follow its analgesic ceiling dose? METHODS: This was a single center retrospective, descriptive study to characterize patterns of ketorolac administration in ED patients. Data for all patients who received ketorolac during the ten year study period from January 1, 2003 to January 1, 2013 were collected from the electronic medical record of an urban community ED with an annual volume of 116935 patients. RESULTS: There were 49605 ketorolac administrations during the study period; 38687 (78%) were given intravenously, 9916 (20%) intramuscularly, and 1002 (2%) orally. Through the intravenous route, 5288 (13.7%) were 15 mg, 32715 (84.6%) were 30 mg, 15 (0.03%) were 60 mg, and 669 (1.7%) were other varying doses. Through the intramuscular route, 102 (1.0%) were 15 mg, 4916 (49.6%) were 30 mg, 4553 (45.9%) were 60 mg, and 345 (3.5%) were other varying doses. The most common diagnoses at discharge were renal colic (21%), low back pain (17%) and abdominal pain (11%). CONCLUSION: The data show that ketorolac was prescribed above its ceiling dose of 10 mg in 97% of patients who received intravenous doses and in 96% of patients receiving intramuscular doses.