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

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

RESUMO Contexto Anti-inflamatórios não esteroidais induzem lesões da mucosa gástrica devido às suas propriedades ácidas. Ranitidina, um antagonista dos receptores H2, revelou-se benéfico em pacientes com úlceras gástricas. Objetivo - O presente estudo foi realizado para avaliar o efeito da administração de ranitidina em gastropatia induzida por anti-inflamatórios não esteroidais (diclofenaco, nimesulida) e seu efeito sobre a histopatologia do estômago, dos rins e fígado. Métodos Diclofenaco, nimesulida e ranitidina foram administradas em doses de 2, 4 e 6 mg/kg, p.o. uma vez diariamente por 14 dias e seu efeito sobre o volume gástrico, acidez, significam o número de úlcera e o pH gástrico. Além disso, o exame histopatológico também foi realizado em seções do estômago, dos rins e fígado. Resultados Após a administração de diclofenaco ou nimesulida, todos os parâmetros gástricos foram significativamente alterados assim como a histopatologia do estômago, fígado e rim. No grupo controle, as seções renais mostraram glomérulos normais sem espessamento da membrana basal glomerular, enquanto em diclofenaco isolado, nimesulida isolado e grupos com ranitidina e nimesulida, foi observado espessamento da membrana basal glomerular. Estas alterações observou-se serem revertidas no grupo ranitidina com diclofenaco. As seções do fígado, o grupo controle mostrou placas e cordões de hepatócitos cuboidais anastomosados com núcleos bem demarcados e citoplasma abundante. Nos grupos ranitidina com diclofenaco e ranitidina com nimesulida, leve dilatação dos sinusoides é vista acoplados com proeminência de veia central. Nos grupos diclofenaco e nimesulida sozinhos, túbulos proximais e distais contorcidos mostram necrose tubular focal leve. Nas secções gástricas, o grupo controle mostrou várias dobras formando vilosidades e a superfície do revestimento epitelial da mucosa. Nos grupos ranitidina com diclofenaco e ranitidina com nimesulida, o duodeno mostrou dispersas células inflamatórias predominantemente compostas por linfócitos. Nos grupos diclofenaco e nimesulida sozinhos, as secções de áreas gástricas mostraram necrose parcial e inflamação crônica moderada respectivamente. Conclusão - O estudo, portanto, forneceu o fundamento terapêutico para administração simultânea de bloqueador de receptor H2 (ranitidina) com diclofenaco, sendo mais benéfica em comparação com ranitidina com nimesulida para minimizar a intolerância gástrica de diclofenaco no tratamento a longo prazo de condições inflamatórias.

Association of terpinolene and diclofenac presents antinociceptive and anti-inflammatory synergistic effects in a model of chronic inflammation

Pharmacological treatment of inflammatory pain is usually done by administration of non-steroidal anti-inflammatory drugs (NSAIDs). These drugs present high efficacy, although side effects are common, especially gastrointestinal lesions. One of the pharmacological strategies to minimize such effects is the combination of drugs and natural products with synergistic analgesic effect. The monoterpene terpinolene (TPL) is a chemical constituent of essential oils present in many plant species, which have pharmacological activities, such as analgesic and anti-inflammatory. The association of ineffective doses of TPL and diclofenac (DCF) (3.125 and 1.25 mg/kg po, respectively) presented antinociceptive and anti-inflammatory effects in the acute (0, 1, 2, 3, 4, 5 and 6 h, after treatment) and chronic (10 days) inflammatory hyperalgesia induced by Freund's complete adjuvant (CFA) in the right hind paw of female Wistar rats (170-230 g, n=6-8). The mechanical hyperalgesia was assessed by the Randall Selitto paw pressure test, which determines the paw withdrawal thresholds. The development of edema was quantified by measuring the volume of the hind paw by plethismography. The TPL/DCF association reduced neutrophils, macrophages and lymphocytes in the histological analysis of the paw, following a standard staining protocol with hematoxylin and eosin and the counts were performed with the aid of optical microscopy after chronic oral administration of these drugs. Moreover, the TPL/DCF association did not induce macroscopic gastric lesions. A possible mechanism of action of the analgesic effect is the involvement of 5-HT2A serotonin receptors, because ketanserin completely reversed the antinociceptive effect of the TPL/DCF association. These results suggest that the TPL/DCF association had a synergistic anti-inflammatory and analgesic effect without causing apparent gastric injury, and that the serotonergic system may be involved in the antinociceptive effect of this association.

Experimental evidence of pharmacological management of anchorage in Orthodontics: A systematic review

Introduction: Orthodontic anchorage is one of the most challenging aspects of Orthodontics. Preventing undesired movement of teeth could result in safer and less complicated orthodontic treatment. Recently, several reviews have been published about the effects of different molecules on bone physiology and the clinical side effects in Orthodontics. However, the effects of local application of these substances on the rate of orthodontic tooth movement have not been assessed.Objectives: The aim of this research was to analyze the scientific evidence published in the literature about the effects of different molecules on orthodontic anchorage.Methods: The literature was systematically reviewed using PubMed/Medline, Scopus and Cochrane databases from 2000 up to July 31st, 2014. Articles were independently selected by two different researchers based on previously established inclusion and exclusion criteria, with a concordance Kappa index of 0.86. The methodological quality of the reviewed papers was performed.Results: Search strategy identified 270 articles. Twenty-five of them were selected after application of inclusion/exclusion criteria, and only 11 qualified for final analysis. Molecules involved in orthodontic anchorage were divided into three main groups: osteoprotegerin (OPG), bisphosphonates (BPs) and other molecules (OMs).Conclusions: Different drugs are able to alter the bone remodeling cycle, influencing osteoclast function and, therefore, tooth movement. Thus, they could be used in order to provide maximal anchorage while preventing undesired movements. OPG was found the most effective molecule in blocking the action of osteoclasts, thereby reducing undesired movements.

Introdução: a ancoragem ortodôntica é um dos aspectos mais desafiadores da Ortodontia. A prevenção de movimentos dentários indesejados poderia resultar em um tratamento ortodôntico mais seguro e menos complexo. Recentemente, foram publicadas várias revisões de literatura sobre os efeitos de diferentes substâncias na fisiologia do tecido ósseo e os efeitos colaterais clínicos na Ortodontia. Porém, os efeitos da aplicação local dessas substâncias no grau de movimentação dentária ortodôntica não foram avaliados.Objetivos: o objetivo da presente pesquisa foi analisar a evidência científica publicada na literatura sobre os efeitos de diferentes substâncias na ancoragem ortodôntica.Métodos: a literatura foi sistematicamente revisada utilizando-se as bases de dados PubMed/Medline, Scopus e Cochrane, de 2000 a 31 de julho de 2014. Os artigos foram selecionados, de maneira independente, por dois pesquisadores diferentes, tendo como base critérios de inclusão e exclusão previamente estabelecidos, com um índice Kappa de concordância de 0,86. A qualidade metodológica dos artigos revisados foi analisada.Resultados: a estratégia de pesquisa identificou 270 artigos; 25 artigos foram selecionados após a aplicação dos critérios de inclusão e exclusão, mas apenas 11 foram qualificados para a análise final. As substâncias envolvidas na ancoragem ortodôntica foram divididas em três grupos principais: osteoprotegerina (OPG), bisfosfonatos (BFs) e outras substâncias (OSs).Conclusões: diferentes substâncias são capazes de alterar o ciclo de remodelação óssea, influenciando na função dos osteoclastos e, portanto, na movimentação dentária. Sendo assim, essas substâncias podem ser utilizadas para promover o máximo de ancoragem e prevenir movimentos indesejados. A OPG foi a substância mais eficaz no bloqueio da ação dos osteoclastos, reduzindo os movimentos indesejados.

Differential pulse voltammetric determination of diclofenac in pharmaceutical preparations and human serum / Pulso diferencial determinação voltamétrica de diclofenaco em preparações farmacêuticas e em soro humano

This article describes a differential pulse voltammetric (DPV) method for the determination of diclofenac in pharmaceutical preparations and human serum. The proposed method was based on electro-oxidation of diclofenac at platinum electrode in 0.1 M TBAClO₄/acetonitrile solution. The well-defined two oxidation peaks were observed at 0.87 and 1.27 V, respectively. Calibration curves that obtained by using current values measured for second peak were linear over the concentration range of 1.5-17.5 μg mL^-1and 2-20 μg mL^-1 in supporting electrolyte and serum, respectively. Precision and accuracy were also checked in all media. Intra- and inter-day precision values for diclofenac were less than 3.87, and accuracy (relative error) was better than 4.12%. The method developed in this study is accurate, precise and can be easily applied to Diclomec, Dicloflam and Voltaren tablets as pharmaceutical preparation. In addition, the proposed technique was successfully applied to spiked human serum samples. No electro-active interferences from the endogenous substances were found in human serum...

Este artigo descreve um método de voltametria de pulso diferencial (VPD) para a determinação de diclofenaco em preparações farmacêuticas e em soro humano. O método proposto foi baseado em eletroxidação de diclofenaco no eléctrodo de platina em solução 0,1 M TBAClO₄/acetonitrila. Dois picos de oxidação bem definidos foram observados em 0,87 e 1,27 V, respectivamente. As curvas de calibração obtidas utilizando-se valores de corrente medidos por segundo pico foram lineares no intervalo de concentração de 1,5-17,5 μg mL^-1e 2-20 μg mL^-1em eletrólito suporte e soro, respectivamente. Precisão e exatidão também foram verificadas em todos os meios. Valores de precisão intra- e inter-dia para o diclofenaco foram inferiores a 3.87 e a precisão (erro relativo) foi melhor do que 4,12%. O método desenvolvido neste estudo é exato, preciso e pode ser facilmente aplicado a Diclomec, Dicloflam e comprimidos Voltaren, como preparação farmacêutica. Além disso, a técnica proposta foi aplicada com sucesso em amostras de soro humano. Não se observaram interferências das substâncias endógenas no soro humano...

Novel approach of aceclofenac fast dissolving tablet

Fast disintegrating tablets [FDTs] have received ever increasing demand during the last decade, and the field has become a hastily growing area in the pharmaceutical industry. Upon introduction into the mouth, these tablets dissolve or disintegrate in the mouth in the absence of additional water for easy administration of active pharmaceutical ingredients. Aceclofenac, an NSAID, has been recommended orally for the treatment of bone and connective tissue disorder and thus the formulation of the same resulted in development of several FDT technologies. The present aim is to formulate a tablet which disintegrate and dissolve rapidly and give its rapid onset of action: analgesic, antipyretic and anti-inflammatory action. Besides, the conventional tablets also show poor patient compliance an attempt had been made to formulate for FDT of aceclofenac by using various super disintegrants like sodium starch glycolate, croscarmellose sodium and crosspovidone [polyplasdone XL] and PEG 6000 followed by novel technique. The tablets were evaluated for friability, hardness, weight variation, disintegration time, wetting time, in vitro dissolution studies and drug content studies. It was concluded that the batch which was prepared by using combination of crosspovidone and sodium starch glycolate as a super disintegrant shows excellent disintegration time, enhance dissolution rate, taste masking and hence lead to improve efficacy and bioavailability of drug

Treatment with some anti-inflammatory drugs reduces germ tube formation in Candida albicans strains

Candida albicans is an opportunistic dimorphic fungus that inhabits various host mucosal sites. It can cause both superficial and serious systemic disease. Conversion from the yeast to the hyphal form has been associated with increased virulence and mucosal invasiveness. The aim of this study was to investigate the effect of sodium diclofenac and aspirin on germs tube formation of different Candida albicans strains. Prostaglandins may play an important role in fungal colonization. Nonsteroidal anti-inflammatory drugs are inhibitors of the cyclooxygenase isoenzymes. These drugs specifically block the biosynthesis of mammalian prostaglandins by inhibiting one or both of cyclooxygenase isoenzymes. In tests for germ tube formation sodium diclofenac reduced the filamentation to the 12.5%- 5.1%. In the presence of aspirin the filamentation was reduced up to 85-45% depending on the tested strain. Our results suggest that cyclooxygenase-depending synthesis of fungal prostaglandins is important for morphogenesis and fungal virulence. Inhibitors of cyclooxygenase isoensymes (aspirin and diclofenac) are effective in decreasing germ tube formation of Candida albicans.

Análise de Resíduos de Diclofenaco Sódico Veterinário em Leite por Espectroscopia no Infravermelho Próximo / Analisys Of Residues Of Veterinary Sodium Diclofenac in Milk through Near Infrared Spectroscopy

O leite é um dos alimentos mais consumidos no mundo,principalmente por crianças e idosos. Em 2007, a Polícia Federal realizou uma operação que apontou um gigantesco esquema de fraudes em leites comercializados no Brasil, constatou-se ainda que 1/3 do leite consumido no Brasil não passava por fiscalização. Muitas são as adulterações: adição de água, soda cáustica, cloreto de sódio, entre outros. No entanto, ainda há outro problema, o da contaminação por fármacos veterinários. Estes podem estar presentes em altas concentrações no leite caso este tenha sido ordenhado dentro do período de carência da vaca. O leite contaminado pode causar sérios dados à saúde do consumidor ou então causar prejuízos para a produção de seus derivados. Objetivo: Desenvolver uma técnica complementar para detectar a presença de resíduos de medicamentosveterinários em amostras de leites. Material e Métodos: Atualmente,com o desenvolvimento tecnológico há muitas técnicas de análisemultielementar que permitem estudar os componentes químicos dedeterminadas amostras. O presente trabalho utiliza a técnica deEspectroscopia no Infravermelho Próximo por Transformada de FourierFT-NIR e a Análise de Componentes Principais PCA para detectar apresença de resíduos do medicamento veterinário em leites. Paraisto, simulou-se adulteração do leite com percentuais de (0,1; 0,5 e10)% de fármaco no leite. Resultados: Crioscopia: 0,539 ºH com0,18% de água; leite não ácido pelo teste do Alizarol; pH 6,71; Gordura:3,25%; Proteína: 3,01%; Lactose: 4,55%; Sólidos: 10,80%. Resíduosdo fármaco foram observados via derivada primeira de espectros derefletância, e análise de PCA em níveis inferiores a 1%. Conclusão:o sistema FT-NIR pôde detectar os resíduos dos fármacos estudadosdentro dos percentuais simulados...

Milk is one of most consumed food by human beings,especially children and elderly. In 2007, the Federal Police conductedan operation that showed an enormous fraud scheme in industrializedmilk in Brazil. In addition, they found out that 1/3 of the milk consumedin Brazil did not pass by inspection. There are several ways to adulteratemilk, such as with addition of water, caustic soda, sodium chlorideand others. However, there is another issue, that is, milk contaminationwith veterinary drugs. These drugs may be present in highconcentrations in milk, in case the cow was milked in the clearanceperiod. Contaminated milk can cause damages to consumers’ healthor injury to the production of derivates. Objective: To develop acomplementary technique to detect the presence of residues ofveterinary drugs in milk samples. Material and Methods: currently,given the technological development, there are many techniquesbased on multielement analysis for studying the chemical componentsof different samples. This paper uses the technique of FourierTransform Near Infrared Spectroscopy and the Principal ComponentsAnalysis (PCA) to detect the evidence of residues of veterinarydrugs in milk. To this end, we simulated adulteration in milk withpercentages of 0.1%, 0.5% and 10% drugs in milk. Results: cryoscopy:0.539 ºH with 0.18% water; non-acid milk according to Alizarol test; pH6.71; Fat: 3.25%; Protein: 3.01%; Lactose: 4.55%; Solids: 10.80%.Drug residues were observed via the first derivative of reflectancespectra and PCA analysis at levels below 1%. Conclusion: The resultwas positive indicating that the FT-NIR system can detected theresidues of studied drugs within the simulated percentage...

Utilização do diclofenaco na prática clínica: revisão das evidências terapêuticas e ações farmacológicas / Use of diclofenac in clinical practice: review of the therapeutic evidence and pharmacologic actions

JUSTIFICATIVA E OBJETIVOS: Os anti-inflamatórios não esteroides (AINES) apresentam atividade farmacológica de inibição das isoenzimas ciclo-oxigenase-1 (COX-1) e ciclo-oxigenase-2 (COX-2) em graus diversos, cujos perfis de segurança variam individualmente.A eficácia é semelhante, porém os possíveis eventos adversos são relevantes nas decisões do tratamento prescrito. O diclofenaco está disponível internacionalmente há mais de 40 anos, tendo seu perfil farmacológico e de segurança documentados em diversos estudos básicos e clínicos. O objetivo desta revisão da literatura foi de apresentar aspectos da dor e do uso de diclofenaco na prática clínica, incluindo as indicações as questões de segurança e a eficácia do medicamento. CONTEÚDO: Esta revisão da literatura apresentará a farmacologia básica do diclofenaco, bem como evidências terapêuticas com o uso deste fármaco em diversas condições dolorosas e suas implicações na prática clínica. CONCLUSÃO: O diclofenaco tem demonstrado eficácia clínica no tratamento de diversas condições dolorosas, entre estas lombalgias, artrites, dores pós-traumáticas e pós-cirúrgicas, dismenorreias,bem como cólica renal e biliar. Vale ressaltar que, na avaliação de um paciente apresentando dor e ao decidir um plano de tratamento e na prescrição de qualquer medicamento, cabe ao médico avaliar cuidadosamente o paciente para determinar o melhor curso de ação no individuo, levando-se em consideração o histórico médico do paciente, comorbidades e uso de medicamentos concomitantes, a fim de proporcionar a melhor alternativa terapêutica, com redução máxima da dor e inflamação e a restauração da funcionalidade de forma mais segura.

BACKGROUND AND OBJECTIVES: The nonsteroidal antiinflammatory-drugs (NSAIDs) exhibit pharmacological activity inhibiting the isoenzymes cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) in varying degrees, and their safety profiles vary individually. Their efficacy is similar, but the possible adverse effects are relevant in deciding treatment prescriptions. Diclofenac has been available internationally for over 40 years, and its pharmacological and safety profile has been documented in numerous preclinical and clinical studies. The objective of this literature review was to present aspects of pain and the use of diclofenac in clinical practice, including indications, safety issues, and efficacy of the drug. CONTENTS: This literature review will present the basic pharmacology of diclofenac, as well as evidence for the therapeutic use of this drug in several painful conditions and the implications for clinical practice. CONCLUSION: Diclofenac has shown clinical efficacy in the treatment of a variety of painful conditions, including lumbagos,arthritis, post-traumatic and post-surgical pain, dysmenorrhea,as well as renal and biliary colic. It is important to note that in the evaluation of a patient presenting pain and when deciding a treatment plan and the prescription of any medication, it is upto the physician to carefully assess the patient to determine the best course of action in that individual, taking into account thepatients' medical history, co-morbidities, and use of concomitant medications, in order to provide the best therapeutic alternative,with a maximum reduction of pain and inflammation and restoration of functionality in the safest possible way.

Analgesic activity of various extracts of Holoptelea integrifolia [Roxb] Planch leaves

The various extracts of leaves Holoptelea integrifolia [Ulmaceae] were investigated for analgesic activity in mice by tail flick method. The fresh plant leaves of H. integrifolia were collected, dried, cleaned, weighed and chopped into small pieces and percolated in ethanol. The fractionation of crude extract, followed by the addition of distilled water, ethyl acetate and n-butanol to an aqueous portion of each solvent, to obtain the dried masses of each four layers. Qualitative chemical examination indicates the presence of secondary metabolites such as alkaloids, flavones, phenol, steroids, tannins and triterpenoids. No acute oral toxicity was observed and extracts considered being safe at the dose of 50-2000 mg/kg body weight. At the dose of 500 mg/kg various extracts of leaves of H. integrifolia were found statistically significant [P<0.05]. A maximum effect was established at 150 min, after drug administration. Diclofenace sodium used as a standard

Diseño de estrategias para controlar la resistencia a los antimicrobianos utilizando herramientas de bioinformática y modelado molecular / Design of strategies to control antimicrobial resistance using bioinformatics tools and molecular modeling

El éxito del tratamiento de las enfermedades infecciosas se ha visto comprometido en los últimos años debido a la diseminación de genes de resistencia a antibióticos entre las bacterias patógenas. Estos genes de resistencia a antibióticos son transportados por plásmidos, los cuáles son transferidos de una bacteria a otra mediante el proceso de conjugación. La reducción del uso inadecuado de los antibióticos y la búsqueda de inhibidores de la conjugación bacteriana son estrategias que podrían contribuir a la solución de este grave problema de salud pública. Basándose en la primera de esta estrategias, en enero de 2006 se regulo la dispensación de un grupo de antibióticos a fin de controlar su consumo. El análisis realizado en este trabajo seǹala que esta medida ha resultado ineficaz, puesto que el consumo y la resistencia bacteriana total a estos antimicrobianos se incrementó significativamente durante el periodo posterior a su promulgación. La resistencia bacteriana a muchas de las familias de antibióticos estudiadas esta solo parcialmente influenciada por su consumo, destacando la participación de otros factores, como la transferencia de genes de resistencia a antibióticos, en la prevalencia de cepas bacterianas resistentes. La identificación de proteínas del cito-cromo P450 de estructura y ligados conocidos, que tenían una similitud significativa en su secuencia de aminoácidos con la proteína de acoplamiento TRAG de los plásmidos R27 y R478, permitió identificar a los medicamentos diclofenac y ketoprofeno como potenciales inhibidores de la transferencia por conjugación de estos plásmidos. El modelado por homología de TRAG revelo que su dominio de solo hélices alfa podría ser el blanco de estos medicamentos. El ingreso de diclofenac o ketoprofeno a una cavidad en este dominio podría interferir en la interacción con el DNA portador de genes de resistencia a antibióticos que esta siendo transferido mediante el proceso de conjugación.

Effect of a cholesterol rich diet, recurrent infection and possible treatment modalities on the pulmonary vascular system: an experimental study / Efecto de la dieta rica en colesterol, la infección recurrente, y las posibles modalidades de tratamiento sobre el sistema vascular pulmonar: un estudio experimental

OBJECTIVE: Infection may lead to inflammation, atherosclerosis and thrombotic vascular events. The atherosclerotic effect of hypercholesterolaemia on the vascular system is well-known. However, limited studies were done on the therapeutic and preventative agents. The aim of this study was to investigate the effects of infection and cholesterol rich diet combined with an antibiotic, anti-inflammatory agent and red wine on the pulmonary vascular system. METHODS: Fifty-nine rats were evaluated. Six groups were created: Control-Group I (n = 10); infection - Group II (n = 9), infection-cholesterol rich diet - Group III (n = 12), infection-cholesterol rich dietcefepime - Group IV (n = 11); infection-cholesterol rich diet-diclofenac potassium - Group V (n = 9); infection-cholesterol rich diet and red wine - Group VI (n = 8). Blood samples of rats were collected for cholesterol analysis every month. Sections of central pulmonary arteries were examined for thickness of the intima and medial wall by computerised image analysis. RESULTS: There was a statistically significant difference in serum cholesterol levels and in thickness of the intima between the groups (p = 0.000). The rest of the groups had more intimal thickening than Group I (p = 0.000). Group III had thicker intima than Groups IV and V (p = 0.009, p = 0.011 respectively). There was no significant difference between the groups in thickness of media (p = 0.432). CONCLUSION: Infection and cholesterol rich diet have a synergistic effect on atherosclerosis in pulmonary arteries. However, antibiotics and anti-inflammatory agents could be useful in prevention.

OBJETIVO: La infección puede conducir a inflamación, ateroesclerosis y eventos vasculares trombóticos. El efecto aterosclerótico de la hipercolesterolemia en el sistema vascular es bien conocido. Sin embargo, se hicieron estudios limitados sobre los agentes preventivos y terapéuticos. El objetivo de este estudio fue investigar los efectos de la infección y la dieta rica en colesterol, combinados con agentes antibióticos, anti-inflamatorios, y vino tinto, sobre el sistema vascular pulmonar. MÉTODOS: Cincuenta y nueve ratas fueron evaluadas. Se hicieron seis grupos: grupo-control I (n = 10), grupo-infección II (n = 9), grupo infección-dieta rica en colesterol III (n = 12), grupo-infección-dieta rica en colesterol-cefepima IV (n = 11), grupo-infección-dieta rica en colesterol-diclofenaco potásico V (n = 9), grupo-infección-dieta rica en -vino tinto VI (n = 8). Se tomaron muestras de sangre de ratas para analizar el colesterol cada mes. Se examinaron secciones de las arterias pulmonares centrales para determinar el grosor de la pared íntima y media mediante análisis computarizado de imágenes. RESULTADOS: Hubo una diferencia estadísticamente significativa en los niveles de colesterol en suero y el grosor de la íntima entre los grupos (p = 0.000). El resto de los grupos tenía más engrosamiento de la íntima que el grupo I (p = 0.000). El grupo III tenía una íntima más gruesa que los grupos IV y V (p = 0,009, p = 0.011 respectivamente). No hubo ninguna diferencia significativa entre los grupos en cuanto al espesor de la media (p = 0.432). CONCLUSIÓN: La infección y la dieta rica en colesterol tienen un efecto sinérgico sobre la aterosclerosis en las arterias pulmonares. Sin embargo, los antibióticos y los agentes antiinflamatorios podrían ser útiles para la prevención.

Correlação in vitro-in vivo para formas farmacêuticas sólidas de liberação modificada contendo diclofenaco de sódio / In vitro-in vivo correlation for sodium diclofenac modified release tablet formulations

A correlação in vitro-in vivo (CIVIV) refere-se ao estabelecimento de uma relação racional entre as propriedades biológicas, ou parâmetros derivados destas, produzidos por uma forma farmacêutica e suas propriedades ou características físico-químicas. O estabelecimento desse tipo de correlação de dados pode possibilitar a substituição dos estudos in vivo, necessários à demonstração da bioequivalência, pelos estudos in vitro, no caso de alterações no processo de fabricação pós-registro. Os sistemas matriciais apresentam, como principal exemplo de material controlador da liberação, substâncias poliméricas formadoras de matrizes hidrofílicas. Hidroxipropilmetilcelulose (HPMC) é um excipiente de escolha para o preparo de matrizes hidrofílicas, devido à capacidade de formação de gel e controle da liberação. O diclofenaco de sódio (DCL) é um antiinflamatório não esteroidal com ação analgésica e antipirética. Considerando suas características físico-químicas e farmacológicas, é objetivo deste trabalho o estabelecimento de uma CIVIV para DCL incorporado em sistemas matriciais. Os comprimidos de DCL com HPMC foram desenvolvidos e submetidos aos ensaios de dissolução utilizando os aparatos 1, 2, 3 e 4 conforme as especificações farmacopeicas. Foi realizado o estudo de biodisponibilidade, seguindo as normas éticas, com as formulações selecionadas. A partir dos dados de absorção obtidos pela técnica de deconvolução e dos dados de dissolução foi estabelecida a correlação. Os resultados demonstraram que o aumento da concentração de HPMC produziu a redução da velocidade de dissolução e, dependendo da condição de estudo, estas diferenças foram mais ou menos significativas. Os comprimidos com concentração intermediária de HPMC (15 a 20%) foram mais sensíveis às alterações de formulação e das condições do ensaio de dissolução. As formulações contendo 30% de HPMC praticamente não modificaram o perfil de dissolução, mesmo com alterações na formulação e condições de estudo. No...

The term in vitro-in vivo correlation (IVIVC) refers to the establishment of a rational relationship between the biological properties, or a parameter derived from a biological property produced by a dosage form, and a physicochemical characteristic or property of the same dosage form. The establishment of IVIVC enables the substitution of in vivo studies for in vitro studies to evaluate bioequivalence, e.g. in case of post-approval changes. Matrix tablets employ mainly hydrophilic polymers to control drug release. Hydroxypropylmethylcellulose (HPMC) is an excipient of choice for preparation of hydrophilic matrices, due to its gel formation and controlled drug release capacities. Sodium diclofenac (SD) is a non-steroidal anti-inflammatory drug with analgesic and antipyretic effects. Considering its physicochemical and pharmacological characteristics, the objective of this work is to establish an IVIVC for HPMC matrix tablets containing SD. HPMC matrix tablets with SD were formulated and submitted to dissolution testing using apparatus 1, 2, 3 and 4 in accordance with pharmacopoeial specifications. The bioavailability study was carried out under ethical guidelines, using the selected formulations. The correlation was obtained by plotting absorption data, obtained from diclofenac plasmatic curves through a deconvolution technique, against dissolution data. The results showed that the increase of HPMC concentration produces a decrease of the drug dissolution rate and these differences were more or less significant, depending on the study conditions. Tablets with intermediate HPMC concentrations (15 to 20%) were more sensitive to changes in dissolution conditions. Formulations containing 30% HPMC do not present changes in dissolution profiles, even when the formulation or the study conditions change. Formulations F1, F2A, F3 and Voltaren® 50 mg as reference product were used in the bioavailability study to establish IVIVC. The linear correlation between...

[Effects of plasticizers and surfactants on the film forming properties of hydroxypropyl methylcellulose for the coating of diclofenac sodium tablets]

Hydroxy Propyl Methyl Cellulose [HPMC] 5cPs, an aqueous soluble polymer was employed for coating diclofenac sodium [DFS] tablets 25mg for protecting the integrity of the drug yet rendering the drug to release at a faster rate on contact with the gastric environment. Proper optimization for the aqueous based film coating formulation was undertaken primarily employing plasticizers like polyethylene glycol [PEG] 400 and propylene glycol [PG]. The defect free selected formulations were further subjected for studying the effects of surfactants like Sodium Lauryl Sulphate [SLS] and Tween-80 along with the plasticizers. The quality of the aqueous film coats or the plasticizer efficiency in case of PEG-400 is in the order 1.5%>0.5%>1.0% and for PG 1%> 4%> 3% which can be stated on the basis of less incidence of major coat defects like chipping, cracking, orange peel, roughness, blistering, blooming, picking. The quality of aqueous film coat or the surfactant efficiency in case of SLS+PEG-400 is in the order 0.3%< 0.5%< 0.1% and SLS+PG is in the order 0.5%< 0.1%< 0.3%. In case of Tween-80+PEG-400 the order is 0.3%< 0.5%< 0.1% and Tween-80+PG is in the order 0.3%< 0.1%< 0.5%. Elegant film formation can be stated from fewer incidences of coat defects. The obtained coated tablets eventually satisfied all the normal physical parameters like thickness, weights, and weight gain, drug content, crushing strength, percent friability, disintegration time, dissolution profile and possible drug-polymer interactions. ANOVA was undertaken followed by Dunnet multiple comparison for the dissolution profile considering uncoated as the standard. The difference was considered significant at p

effect of chlorpromazine, diclofenac and their combination on four models of induced pain in mice

Adjuvant or co-analgesic drugs, such as antipsychotics are commonly administered in combination with one of the primary analgesics. The present study is carried out to investigate the effects of the antipsychotic drug; chlorpromazine in four animal models of induced pain and to compare its effects with diclofenac sodium and with their combination. All experiments were performed on albino mice [Balb/C] strain. Mice were evaluated for their responsiveness to noxious stimuli using four tests: tail-flick test, hot-plate test, formalin test and acetic acid-induced writhing test. These effects were measured before and one hour after intraperitoneal drug administration. In some experiments, they were followed for 6 and 24 hours. In general,chlorpromazine,on its own, showed a significant analgesic activity in heat-induced pain models [tail-flick and hot-plate tests] increasing latency by around 34% and 80% in the two tests respectively. This is compared to 83% and 88% increase by diclofenac sodium. In the early phase of chemically-induced somatic type of pain [formalin test] and visceral-type of pain [writhing test], chlorpromazine had similar effect to diclofenac sodium. When chlorpromazine was given in combination with diclofenac sodium in writhing test, it did not enhance diclofenac effect. In the other three models, chlorpromazine resulted in a significant enhancement of diclofenac effect in at least two of the remaining three pain models to an extent, ranging from 46% to 55% more than that of the diclofenac effect. Chlorpromazine showed different analgesic activity according to the type of pain model utilized. The analgesic activities were either similar to diclofenac [in writhing and formalin tests], or less than diclofenac effect in tail-flick and hot-plate tests. Chlorpromazine increased the analgesic effect of diclofenac when used in combination in tail-flick, hot-plate and formalin tests

Evaluation of in vitro percutaneous enhancement effect of papain and pequi oil on diclofenac sodium permeation through human skin / Avaliação in vitro da papaína e do óleo de pequi como promotores de permeação cutânea para diclofenaco de sódio em pele humana

The purpose of this research was to determine the potential of papain and pequi oil as penetration enhancers for diclofenac sodium (DS) across human skin in vitro. The permeation studies were conducted with vertical diffusion cells. The enhancers were associated or not in gels in different concentrations. In vitro studies reveled that papain 0.2 percent (w/v) presented an elevated enhancer property for diclofenac sodium (J = 0.3369 mg/cm²x h). Pequi oil 10 percent (w/v) generated a reduced flux value (J = 0.1848 mg/cm²x h) and a combination of both enhancers presented a medium value of J = 0.2187 mg/cm²x h. Papain was found to be better enhancer than pequi oil.

O objetivo desta pesquisa foi determinar in vitro o potencial da papaína e do óleo de pequi como promotores de penetração cutânea para o diclofenaco de sódio (DS) através de pele humana. Os estudos de penetração foram conduzidos em células de difusão vertical. Os promotores foram associados ou não em géis em concentrações distintas. A avaliação in vitro revelou que a papaína 0,2 por cento p/p apresentou propriedade promotora maior para o diclofenaco de sódio (J = 0,3369 mg/cm²x h). O óleo de pequi 10,0 por cento p/v promoveu redução do fluxo (J = 0,1848 mg/cm²x h) e a combinação de ambos os promotores apresentou valor mediano de fluxo de J = 0,2187 mg/cm²x h. A partir dos resultados, verificou-se que a papaína exerceu ação promotora de penetração cutânea melhor que o óleo de pequi.

Effect of anti-inflammatory agents on the integration of autogenous bone graft and bovine bone devitalized matrix in rats

PURPOSE: To study the repair of bone defect filled with autograft or bovine bone devitalized matrix in rats under anti-inflammatory action. METHODS: Two hundred and forty Wistar rats were distributed to two groups of 120 animals each. A 2mm-diameter defect was created in the femoral diaphysis. Animals of Group I had the bone defect filled with autograft and those of Group II, with bovine bone devitalized matrix. Animals of each group were redistributed to four subgroups according to the intramuscular administration of anti-inflammatory drug or saline solution: A - diclofenac sodium; B - dexamethasone; C - meloxicam; D - saline solution. Evaluation periods were 7, 14 and 30 days. Histological evaluation consisted of quantifying the inflammatory process, the bone neoformation, the collagen formation and the presence of macrophages. RESULTS: Animals of Group I did not show significant difference considering inflammatory reaction. Significant and progressive increase of bone neoformation was observed in both groups. The animals that received meloxicam and autograft showed less collagen formation at 14 and 30 days. The number of macrophages was higher in Group II than in Group I. The animals treated with dexamethasone and saline solution did not show statistically significant difference. CONCLUSIONS: Diclofenac sodium and meloxicam delayed bone graft repair and dexamethasone did not interfere in it.

OBJETIVO: Estudar o reparo do defeito ósseo preenchido com enxerto ósseo autógeno ou matriz óssea bovina desvitalizada sob ação de antiinflamatórios em ratos. MÉTODOS: 240 ratos Wistar, distribuídos em dois grupos de 120 animais. Confeccionou-se defeito de 2 mm de diâmetro na diáfise femoral. Os animais do Grupo I tiveram o defeito ósseo preenchido com enxerto ósseo autógeno e os do Grupo II com matriz óssea bovina desvitalizada. Cada grupo foi redistribuído em quatro subgrupos segundo a administração intramuscular de antiinflamatório ou solução salina: A - diclofenaco de sódio; B - dexametasona; C - meloxicam; D - solução salina. Os períodos de avaliação foram de 7, 14 e 30 dias. A avaliação histológica constou da quantificação do processo inflamatório, osso neoformado, formação de colágeno e macrófagos. RESULTADOS: Os animais do Grupo I não mostraram diferença significante em relação à reação inflamatória. Observou-se aumento significante e progressivo da neoformação óssea nos Grupos I e II. Os animais que receberam meloxicam e enxerto autógeno mostraram menor aporte de colágeno aos 14 e 30 dias de observação. Os macrófagos apresentaram-se em maior quantidade no Grupo II que no Grupo I. Os animais tratados com dexametasona e solução salina não demonstraram diferença estatisticamente significante entre os Grupos I e II. CONCLUSÕES: O diclofenaco de sódio e o meloxicam retardam a reparação do enxerto ósseo. A dexametasona não interfere na reparação do enxerto ósseo.

Comparing the effect of intramuscular injection of pethidine and diclofenac suppository in relief of pain following laminectomy surgery

Pain, particularly after surgery, can create a variety of side effects including delay in wound healing. Different drugs such as pethidine and non-steroidal anti-inflammatory drugs are used for relieving patient's pain after surgery. The purpose of this research was to compare effect of pethidine vs. diclofenac suppository in relief of pain after laminectomy. A total of 100 patients who underwent laminectomy entered this study. They were divided into pethidine and diclofenac groups. The patients' pain score was measured with visual analog scale [VAS] method. The mean pain score 24 hours after surgery was 2.8 +/- 2.0 in pethidine group and 4.46 +/- 2.30 in diclofenac group. There was a significant statistical difference between pain score after surgery in two groups [P < 0.05]. Nausea was the most common side effect observed in pethidine group [20%] and epigastric pain was the most common one in diclofenac group [18%]. There wasn't any statistical significant difference between side effects in these two groups. It seems that pethidine injection is more effective than diclofenac suppository in relieving pain after laminectomy

Polyamines in inflammation and their modulation by conventional anti-inflammatory drugs.

Significant increase in polyamines levels in inflamed tissue was observed in the experimental animal models of inflammation. Treatment with dexamethasone positively modulated the levels of polyamines whereas non-steroidal drugs, diclofenac and valdecoxib negatively modulated their levels.

Efectos de Diclofenac, Celecoxib y sulfato de glucosamina sobre marcadores inflamatorios en cultivo de condrocitos de pacientes con osteoartritis / Articular cartilage in osteoarthritic patients: effects of diclofenac, celecoxib and glucosamine sulfate on inflammatory markers

La osteoartritis (OA) es una enfermedad articular crónica, progresiva que se instala como consecuencia de un proceso complejo que involcra alteraciones mecánicas y biológicas del sistema músculo-esquelético, siendo resultante de múltiples interacciones entre factores genéticos e injurias extrínsecas. La patogenia de esta enfermedad se ralaciona con alta y desviada producción de citokinas flogógenas y de enzimas proteolíticas, que degradan y destruyen la matriz extracelular en tejidos articulares y peri-articulares. Se estudiaron 20 casos con OA, de los cuales se obtuvo cartílago durante intervenciones quirúrgicas programadas. El cartílago se cultivó en medio Dulbecco-Eagle, con o sin agregado de AINEs o condromodulares. En los sobrenadantes se determinaron óxido nítrico por reacción de Giess y la medición espectrofotométrica; y colagenasa por ELISA doble sándwich en presencia de anticuerpos monoclonales. En ausencia de AINEs, los cultivos de condrocitos produjeron 1950 ± 665ng/ml de MMP-1, La adición de Diclofenac redujo esa cifra a 1140 ± 155 ng/ml, aunque esta diferencia no fue estadisticamente significativa, (p<0.60). Por el contrario, Celecoxib redujo el nivel de la enzima a 760 ± 75ng/ml (p<0,01) y la Glucosamina también provocó un descenso (950 ± 89 ng/ml) significativo (p<0.05). Los niveles de ON en ausencia de AINEs llegaron a 47,3 ± 4,9 µM. Su producción no varió significativamente con la adición de Diclofenac, Ceecoxib o Glucosamina (p=ns). Los resultados indicarían la incapacidad de Diclofenac para modificar la generación de enzimas proteolíticas, mientras que Celecoxib y Glucosamina disminuyen su producción significativamente. Ninguno de los fármacos utilizados en nuestro trabajo ha logrado alterar la concentración de ON. Muchos integrantes quedan aún sin resolver y todavía se carece de fármacos de eficacia comprobada para alterar el curso natural de la enfermedad.

Osteoarthritis is a chronic and progressive joint disease. It is established by a complex process involving mechanical and biological alterations of the musculoskeletal system, which are generated by a great variety of interactions between genetic factors and extrinsic injuries. The pathogenesis of this disease is related to an increased and divergent production of inflammatory markers and proteolytic enzymes that promote the degradation and destruction of the extracellular matrix of articular and periarticular tissues. Cartilage samples were taken from 20 osteoarthritic patients during programmed surgical interventions. The cartilage samples were cultured in Dulbecco-Eagle medium, with or without the addition of NSAIDs or modulators of chondrocyte metabolism. The content of nitric oxide in the supernatant was quantified using the Griess reaction; the concentration of MMP-1 was quantified via double-sandwich ELISA. Untreated chondrocyte cultures produced 1950 +/- 665 ng/ml MMP-1. With the addition of Diclofenac this value decreased to 1140 +/- 155 ng/ml, although this difference was not statistically significant (p < 0.06). However, in the presence of Celecoxib the level significantly dropped to 760 +/- 75 ng/ml (p < 0.01). Although the addition ofglucosamine did not produce such a noticeable reduction in the level of MMP-1 (950 +/- 89 ng/ml), it was statistically significant (p < 0.05). On the contrary, none of the drugs (Diclofenac, Celecoxib, Glucosamine) modified the level of nitric oxide which had a mean value of 47.3 +/- 4.9 microM in the control samples. This investigation evidenced the inability of Diclofenac to significantly modify the production of proteolytic enzymes in osteoarthritic chondrocyte cultures. However, both Celecoxib and Glucosamine significantly reduced the production of MMP-1. On the contrary, none of the drugs used in this study managed to modify the concentration of nitric oxide. To the present day, no drugs have been found to be...

Utilização prévia de antiinflamatórios não-esteróides por pacientes encaminhados para endoscopia em um hospital universitário brasileiro / Use of nonsteroidal anti-inflammatory drugs by patients before undergoing to endoscopy in a Brazilian university hospital

O estudo teve como objetivo descrever o padrão de uso de antiinflamatórios não-esteróides (AINE) por pacientes encaminhados para endoscopia digestiva alta no Hospital das Clínicas/UFMG, Belo Horizonte/MG. Trata-se de um estudo transversal de uma amostra de 533 pacientes com idade igual ou superior a 17 anos, com endoscopia previamente marcada. Os dados foram coletados por meio de questionário padronizado. As variáveis estudadas foram relativas aos antiinflamatórios não-esteróidese ao seu modo de uso. Cerca de 34% dos entrevistados relatou uso de AINE no período de um mês anterior à endoscopia. Os AINE mais utilizados foram o ácido acetilsalicílico e o diclofenaco e o uso caracterizou-se, principalmente, pela forma esporádica e por período inferior a sete dias. Entre os AINE que foram utilizados por período prolongado, foram mais frequentes o uso em dose diária elevada e o uso de mais de uma especialidade. Evidenciou-se um cenário de utilização inadequada destes medicamentos entre os pacientes estudados, caracterizado pelo uso de especialidades desaconselhadas, uso de AINE em indicações inadequadas, uso de associações medicamentos as questionáveis e uso desnecessário de especialidades dispendiosas em detrimento daquelas seguras e mais acessíveis. Os resultados apontam para a necessidade de estudos adicionais, a fim de maior aprofundamento no conhecimento dessa questão no Brasil.

The objective of this study was to describe the pattern of use of nonsteroidal anti-inflammatory drugs (NSAIDs) among patients referred for upper endoscopy at the Teaching Hospital of the Federal University of Minas Gerais, Belo Horizonte, Brazil. This cross-sectional survey included 533 patients, aged 17 or older, whose endoscopies had been previously scheduled. A standardized questionnaire was used to collect the data, which related to the nonsteroidal anti-inflammatory drugs taken and the way in which they were used. Almost 34% of the interviewed subjects reported having taken NSAIDs during the month prior to the endoscopy. The NSAIDs used most were acetylsalicylic acid and diclofenac and their pattern of use was characterized, in the main, by sporadic use over a period of less than seven days. Among the NSAIDs taken for long periods of time (> 30 dias), a commonly observed pattern was high daily doses and more than one kind of drug. The general picture that emerged was of inappropriate use of these medicines among the studied patients, typically the use of non-recommended types of drug, inappropriate use of NSAIDs for certain conditions, use of questionable drug combinations and the unnecessary use of expensive drugs despite the availability of safer and cheaper alternatives. The results point to the need to carry out more research, to improve our understanding of this question in Brazil.