The association between nonsteroidal anti-inflammatory drugs and skin cancer: Different responses in American and European populations.

OBJECTIVE: To conduct a comprehensive systematic meta-analysis investigating the association of nonsteroidal anti-inflammatory drugs (NSAIDs) and their subtypes with skin cancer (SC) and its subclasses (basal cell carcinoma BCC; squamous cell carcinoma SCC; melanoma; nonmelanoma skin cancer NMSC) in general, American and European populations. METHODS: PubMed, Embase, the Cochrane Library, the China National Knowledge Infrastructure and ClinicalTrials.gov were searched up to 24 February 2019. Pooled effect sizes and 95% confidence intervals were used to estimate associations. RESULTS: Results based on 26 original studies including 223,619 cases and 1,398,507 controls showed both NSAIDs and nonselective Cyclooxygenase (COX) inhibitors to be statistically significantly associated with a reduced risk of SC, BCC, SCC and NMSC but not with melanoma. Conversely, no association was observed between selective Cyclooxygenase 2 (COX-2) inhibitors and SC or its subclasses. Further subgroup analysis showed that the results analyzed for American populations were almost the same as those for the general population. For European populations, neither NSAIDs nor its subtypes correlated significantly with susceptibility to SC or its subclasses. CONCLUSIONS: The use of NSAIDs might reduce the risk of SC, but many factors including study population, drug subtype, and disease subclass affect the significance of the association.

Effects of selective versus non-selective cox-2 inhibition on experimental periodontitis

Abstract In the present study we compared the effects of the selective COX-2 inhibitor etoricoxib with those of the classical non-selective NSAID diclofenac on the inflammatory process and alveolar bone loss in an experimental model of periodontitis in rats. Ninety male Holtzman rats (250 g) were randomly sorted into four experimental groups: Sham+CMC and Ligature+CMC (control) groups which received 0.5% carboxymethylcellulose sodium (CMC) solution; Ligature+Diclofenac and Ligature+Etoricoxib groups which received Potassium Diclofenac and Etoricoxib, respectively, suspended in 0.5% CMC (10 mg/kg/day). At 7, 14 and 21 days after placing ligatures in the cervical region of both the lower right and left first molars, the animals were euthanized. At the end of each period, the mandibles were collected for radiographic examination of alveolar bone loss. In addition, alveolar bone and periodontal ligament tissue samples were collected for COX-2 expression analysis and gingival tissues were collected for measurement of PGE2 contents. Animals with ligature-induced periodontal disease showed significant increased COX-2 gene expression at days 7, 14 and 21 (p<0.05) on alveolar bone and periodontal ligament. However, both treatments resulted in significantly reduced alveolar bone loss when compared to the untreated Ligature group (p<0.05), with no statistical difference between Etoricoxib and Diclofenac Potassium groups. This study shows that both drugs were able to reduce alveolar bone loss after periodontal disease induction.

Resumo No presente estudo nós comparamos os efeitos de um inibidor seletivo da COX-2 (etoricoxibe) com um anti-inflamatório não esteroidal não seletivo (AINE) (diclofenaco de potássio) no processo inflamatório e perda óssea alveolar em modelo de periodontite experimental. Noventa ratos Holtzman machos (250 g) foram randomizados em quatro grupos experimentais: Sham+CMC e Ligadura+CMC (controle) que receberam solução de carboximetilcelulose de sódio (CMC) a 0,5%; Ligadura+Diclofenaco e Ligadura+Etoricoxibe que receberam diclofenaco de potássio e etoricoxibe, respectivamente, suspensos em CMC 0,5% (10 mg/kg/dia). 7, 14 e 21 dias após colocação de ligadura bilateral na região cevical dos primeiros molares inferiores, os animais foram submetidos à eutanásia. No fim de cada período, as mandíbulas foram coletadas para exame radiográfico de perda óssea alveolar. Em adição, osso alveolar e ligamento periodontal foram coletados para determinar a expressão da enzima COX-2, e o tecido gengival foi coletado para determinar a expressão de PGE2. Animais submetidos à indução da doença periodontal pela ligadura (Grupo Ligadura) apresentaram um aumento significativo da expressão gênica de COX-2 nos dias 7, 14 e 21 (p<0,05). Todavia, ambos os tratamentos resultaram em uma significativa redução da perda óssea alveolar em comparação ao grupo Ligadura (p<0,05). Esse estudo mostrou que ambos os fármacos foram capazes de reduzir a perda óssea alveolar após indução da doença periodontal.

Diclofenac sodium gel therapy as an alternative to actinic cheilitis.

OBJECTIVE: Actinic cheilitis (AC) is a potentially malignant lesion caused by prolonged exposure to ultraviolet light. The aim of this research was to analyze the efficacy of diclofenac sodium 3% gel in the treatment of this condition, through clinical follow-up. METHODS: Thirty-one patients diagnosed with AC were instructed to perform a topical application of the gel three times a day for a period of 90 days. In each visit, a digital photography was obtained for verified progress and response to treatment. Two researchers evaluated all images after treatment was completed and assigned the following scores regarding clinical aspect of the lip: 1, complete improvement; 2, partial improvement; 3, no changes; 4, worsening of the clinical condition. In addition, the patients' tolerability to the drug and their satisfaction after treatment were evaluated. RESULTS: Twelve cases abandoned the treatment for reasons unrelated to the study. Ten participants showed total remission of all clinical features of the lesion and three had partial improvement of the characteristics. One participant presented worsening of clinical condition, and in five cases, treatment was discontinued due to development of mild adverse effects at the site of gel application. Regarding satisfaction analyses and tolerability to the drug, from 14 patients who completed treatment without adverse effects or complications, most agreed fully that they were satisfied with the therapy (n = 11) and that the drug was not irritating to the mouth (n = 9). Patients are being monitored without clinical signs of recurrence and/or progression of the lesions. CONCLUSION: Topical application of the drug has provided a convenient and well tolerated in most cases. CLINICAL RELEVANCE: Diclofenac sodium gel (3%) may be a promising alternative for treatment of actinic cheilitis.

Pulmonary Arterial Hypertension after Ibuprofen Treatment for Patent Ductus Arteriosus in Very Low Birth Weight Infants.

OBJECTIVE: To describe the clinical course and risk factors for pulmonary arterial hypertension (PAH) after ibuprofen treatment to close patent ductus arteriosus. STUDY DESIGN: All neonates weighing < 1500 g at birth who received ibuprofen to close patent ductus arteriosus and were admitted to Seoul National University Children's Hospital's neonatal intensive care unit in 2010-2014 were eligible for this study. The study population was divided into the PAH and non-PAH groups, and medical records were retrospectively reviewed. RESULTS: Of the 144 eligible infants, 10 developed PAH (6.9%). Relative to the non-PAH group, the PAH group exhibited greater respiratory severity and more frequent severe bronchopulmonary dysplasia or death before 36 weeks postmenstrual age. Multivariable analysis demonstrated that lower gestational age, birth weight in less than the third percentile for age, maternal hypertension of pregnancy, and oligohydramnios were risk factors for developing PAH after ibuprofen treatment. CONCLUSION: A high incidence of PAH after ibuprofen treatment was observed in the study population. Furthermore, younger gestational age and several prenatal conditions were identified as risk factors for developing PAH after ibuprofen treatment. Additional large cohort studies are necessary to confirm our results.

Queilite actínica: expressão imuno-histoquímica da cox-2 e avaliação do diclofenaco sódico gel como uma terapia alternativa / Actinic cheilitis: Immunohistochemical expression of cox-2 and evaluation of diclofenac sodium gel as an alternative therapy

A queilite actínica (QA) é uma lesão potencialmente maligna que acomete o vermelhão do lábio e resulta da exposição crônica aos raios solares. Atualmente, não é possível predizer quais os casos de QA progredirão para o carcinoma de células escamosas e, portanto, alguns marcadores biomoleculares têm sido estudados. A ciclo-oxigenase 2 (COX-2) é uma enzima associada com a resposta inflamatória e superexpressa no câncer oral; no entanto, pouco se sabe sobre o papel desta proteína em queilites actínicas. Além disso, as modalidades terapêuticas atualmente disponíveis para QA podem ocasionar efeitos deletérios e citotóxicos aos pacientes. Portanto, o objetivo desse trabalho foi avaliar a expressão imuno-histoquímica da COX-2 em QAs de diferentes riscos de transformação maligna e analisar, através de acompanhamento clínico, a eficácia do gel de diclofenaco sódico a 3% no tratamento dessa lesão. A imunoexpressão da COX-2 foi analisada semi-quantitativamente em 90 casos de QAs graduadas em baixo risco (n = 55) e alto risco (n = 35) de transformação maligna. O teste Qui-quadrado de Pearson foi realizado para verificar possíveis associações entre a imunoexpressão da COX-2 e a gradação histológica das queilites actínicas. O coeficiente ponderado de Kappa denotou uma boa concordância interobservador (0.677). Para o estudo clínico, dezenove pacientes diagnosticados com QA foram orientados a realizar aplicação tópica do gel de diclofenaco, três vezes por dia, durante 90 dias. A cada visita, os casos foram documentados através de fotografia digital e, ao final do tratamento, dois pesquisadores analisaram todas as imagens para avaliar o aspecto clínico do lábio. Também foi avaliada a tolerabilidade ao fármaco e satisfação do paciente ao final do tratamento. A COX-2 esteve superexpressa em 74.4% dos casos de queilites actínicas.

Ambos os grupos, de baixo e alto risco, revelaram predominância do escore 3 (elevada imunoexpressão), seguida dos escores 2 e 1 (baixa expressão e ausência de expressão, respectivamente). Não foi observada associação significativa (p = 0.283) entre a expressão de COX-2 e a gradação histológica das QAs analisadas. Dos indivíduos que participaram do estudo clínico, dez apresentaram remissão total das características clínicas da lesão (escore 1), e em três pacientes, a melhora foi considerada parcial (escore 2). Um participante apresentou piora do quadro clínico (escore 4). Em cinco casos, o tratamento foi descontinuado devido ao desenvolvimento de leves efeitos adversos no local de aplicação do gel. Quanto à análise de satisfação e tolerabilidade ao fármaco, a maioria dos pacientes mostrou-se plenamente satisfeita com a terapia (n = 11) e relatou que o fármaco não era irritante para os lábios (n = 9). Os resultados desse estudo demonstram que a elevada imunoexpressão da COX-2 é frequente em QAs; no entanto, essa proteína não esteve associada ao risco de transformação maligna nos casos analisados. A aplicação tópica do gel de diclofenaco sódico a 3% forneceu uma abordagem conveniente, não invasiva e bem tolerada na maioria dos casos, podendo constituir uma alternativa promissora no tratamento da queilite actínica. (AU)

Actinic cheilitis (AC) is a potentially malignant disorder which affects the lip vermilion and results from chronic exposure to sunlight. Currently, it is not possible to predict which cases of AC may progress to squamous cell carcinoma, and therefore, some biomolecular markers have been researched. Cyclooxygenase 2 (COX-2) is an enzyme associated with inflammatory response which is overexpressed in oral cancer; however, little is known about the role of this protein in actinic cheilitis. About the treatment of this lesion, currently available therapeutic modalities to AC may cause cytotoxic effects and deleterious results to patients. Therefore, the aim of this study was to evaluate the immunoexpression of COX-2 in AC of different risks of malignant transformation and analyse, through clinical follow-up, the efficacy of diclofenac sodium 3% gel in the treatment of this condition. Epithelial immunoexpression of COX-2 was analysed semi-quantitatively in 90 cases of AC classified as low risk (n = 55) and high risk (n = 35) of malignant transformation, in which the scores were assigned: (0) 0 to 5% of positive cells - Negative; (1) 6 to 30% of positive cells - Low expression; (2) 31 to 100% of positive cells - High expression. The chi-square test of Pearson was conducted to verify possible associations between immunoexpression of COX-2 and histologic grade of actinic cheilitis. The weighted kappa coefficient denoted a good interobserver agreement (0.677). Nineteen patients diagnosed with AC were instructed to perform topical application of the gel three times a day for a period of 90 days. In each biweekly visit, a follow-up record was accomplished through digital photographs and after treatment was completed, two researchers analysed all the images to assess clinical aspects of the lip. Furthermore, tolerability to the drug and patient satisfaction after treatment were evaluated. COX-2 was overexpressed in 74.4% of AC cases. Both low and high-risk groups revealed predominance of score 3, followed by scores 2 and 1. There was no significant association (p = 0.315) between COX-2 expression and histological grading. Among the total number of participants of this clinical study, ten showed total remission of all clinical features of the lesion and three had partial improvement of these characteristics. One participant presented worsening of the clinical condition. In five cases, the treatment was discontinued due to development of mild adverse effects at the site of gel application. Regarding analysis of satisfaction and tolerability to the drug, most patients were fully satisfied with the therapy (n = 11) and reported that the drug was not irritating to the lips (n = 9). Our study demonstrates that high expression of COX-2 is common in AC; however, this protein was not associated with malignant transformation risk of the analysed cases. Topical application of diclofenac sodium 3% gel provided a convenient and well tolerated approach in most cases, and may be a promising alternative for the treatment of actinic cheilitis. (AU)

Effects of Different Therapeutic Ultrasound Waveforms on Endothelial Function in Healthy Volunteers: A Randomized Clinical Trial.

The purpose of this study was to determine the effects of different therapeutic 1-MHz ultrasound waveforms on endothelial function before and after cyclooxygenase (COX) inhibition. Forty-two healthy volunteers aged 27.2 ± 3.8 y underwent interventions and an evaluation for endothelial function (n = 15; with COX inhibition, n = 15; duration of the vasodilator effect, n = 12) by technique flow-mediated dilation. Continuous ultrasound therapy (0.4 W/cm(2 SATA)), pulsed ultrasound therapy (20% duty cycle, 0.08 W/cm(2 SATA)) or placebo (equipment power off) was randomly applied over the brachial artery for 5 min. COX inhibition (aspirin) was carried out 30 min before treatments. In relation to the placebo, flow-mediated dilation increased by 4.8% using continuous ultrasound and by 3.4% using pulsed ultrasound. After COX, flow-mediated dilation was enhanced by 2.1% by continuous ultrasound and 2.6% by pulsed ultrasound. This vasodilation persisted for 20 min. Continuous and pulsed therapeutic 1-MHz ultrasound waveforms improved endothelial function in humans, which provided them with anti-inflammatory vascular effects.

Efeito antimicrobiano da indometacina no biofilme periodontal: estudo em ratos / Antimicrobial effect of indomethacin on periodontal biofilm: study in rats

Introdução: A doença periodontal é uma doença de caráter multifatorial que se desenvolve em decorrência da interação do biofilme bacteriano com a resposta imuno-inflamatória do hospedeiro que pode ser modulada por fatores sistêmicos e ambientais. Objetivo: o presente estudo teve como objetivo avaliar a ação antimicrobiana do anti-inflamatório não esteroidal indometacina sobre o biofilme retido em ligaduras inseridas subgengivalmente para indução de periodontite experimental em ratos. Método: assim, 20 animais foram divididos aleatoriamente em um dos grupos: grupo Indometacina (n=10); grupo água destilada (n=10). Os animais receberam gavagem diária da medicação (5 mg/kg indometacina) ou de água destilada (2 ml), durante 7 dias. As ligaduras ao redor dos dentes foram coletadas e o biofilme foi dispersado, diluído em 10-1, 10-2 e 10-3, semeado em ágar sangue e as placas foram cultivadas em anaerobiose durante 4 dias. As quantificações foram realizadas a partir da contagem das unidades formadoras de colônias (UFC) totais pelo programa Colony counter aplicativo para androide, caracterizadas pela presença de bactérias aeróbias e aeróbias facultativas relacionadas ao processo de saúde, e pela contagem manual de UFC grandes, que melhor caracterizam as bactérias anaeróbias relacionadas ao processo de doença. Resultado: constatou-se um número significativamente maior de UFC grandes no grupo indometacina quando comparado ao grupo água (p=0,004) e um número significativamente menor de UFC totais no grupo indometacina quando comparado ao grupo água (p=0,0013). Conclusão: dentro dos limites do presente estudo pôde-se concluir que a indometaciana agrava o processo infeccioso periodontal devido ao crescimento de UFC anaeróbias e redução de UFC facultativas.

Introduction: Periodontal disease is a multifactorial disease the develop as a result of the interaction of the bacterial biofilm and the immune-inflammatory response of the individual, which, in its turn, is modulate by systemic and environmental factors. Objective: This study aimed to evaluate the antimicrobial effect of indomethacin, a non-steroidal anti-inflammatory, on the biofilm retained in ligatures inserted in the subgingival region to induce experimental periodontitis in rats. Method: 20 animals were randomly assigned to one of the groups: Indomethacin (n = 10); distilled water (n = 10). The animals received daily gavage of drugs (5 mg / kg indomethacin) or distilled water (2 ml) for 7 days. The ligatures around the teeth were collected and the biofilm was dispersed, diluted 10-1, 10-2 and 10-3, seeded in blood agar and the plates were grown anaerobically for 4 days. The measurements were carried out from the counting of total colony forming units (CFU) by Colony counter application program for android, characterized by the presence of facultative aerobic and aerobic bacteria related health process, and the manual counting of large CFU, which better characterized the anaerobic bacteria-related disease process. Result: it was found a significantly higher number of large CFU in indomethacin group compared to the water group (p = 0.004) and a significantly lower number of total CFU in the indomethacin group compared to the water group (p = 0.0 013). Conclusion: within the limits of this study it was concluded that the indomethacin worsens periodontal infectious process due to the growth of anaerobic CFU and the reduction of facultative CFU.

Beneficial effects of methanolic extract of Indigofera linnaei Ali. on the inflammatory and nociceptive responses in rodent models

ABSTRACT Indigofera linnaei Ali. (Tamil Name: Cheppu Nerinjil) belongs to the family Fabaceae, used for the treatment of various ailments in the traditional system of medicine. In the present study, the beneficial effects of methanol extract of whole plant of I. linnaei (MEIL) were evaluated on inflammation and nociception responses in rodent models. In vitro nitric oxide (NO), lipoxygenase (LOX) and cyclooxygense (COX) inhibitory activities were also performed to understand the mode of action. MEIL at the dose of 200 & 400 mg/kg, p.o. significantly inhibited carrageenan induced rat paw volume and reduced the weight of granuloma in cotton pellet granuloma model. The results obtained were comparable with the standard drug aceclofenac. The anti-nociceptive effect of MEIL in mice was evaluated in hot plate and acetic acid induced writhing model. The plant extract significantly reduced the number of writhes and the analgesic effect was higher than that of the standard drug aspirin. However, the extract fails to increase the latency period in hot plate method suggesting that the extract produce nociception by peripheral activity. The extract produced inhibitory effect on NO, LOX and COX in concentration dependent manner. The extract exhibited pronounced and selective COX-2 inhibition. Altogether, these results suggested that the methanol extract of Indigofera linnaei could be considered as a potential anti-inflammatory and analgesic agent.

RESUMO Indigofera linnaei Ali pertence à família Leguminosae e é utilizada para o tratamento de várias doenças na medicina tradicional. No presente estudo, os efeitos benéficos do extrato metanólico da planta inteira de I. linnaei (MEIL) foram avaliados em respostas inflamatórias e nocicepção em modelos de roedores. Testes in vitro de atividade inibitória do óxido nítrico (NO), lipoxigenase (LOX) e ciclooxigenase (COX) também foram realizados para compreender o modo de ação. MEIL nas doses de 200 e 400 mg/kg, p.o. inibiu significativamente o volume da pata de rato induzido por carragenana e reduziu o peso do granuloma no modelo de pélete de algodão. Os resultados obtidos foram comparáveis ao do fármaco padrão, aceclofenaco. O efeito anti-nociceptivo de MEIL foi avaliado em camundongos no modelo de placa quente e de contorção induzida por ácido acético. O extrato da planta reduziu significativamente o número de contorções e o efeito analgésico foi maior do que o do fármaco padrão, ácido acetilsalicílico. Porém, o extrato não conseguiu aumentar o período de latência no método da placa quente, sugerindo que este produz nocicepção por atividade periférica. O extrato produziu efeito inibitório sobre o NO, LOX e COX dependente da concentração. O extrato exibiu inibição acentuada e seletiva da COX-2. No seu conjunto, estes resultados sugerem que o extrato metanólico de Indigofera linnaei poderia ser considerado como agente anti-inflamatório e analgésico potencial.

[Safety nonsteroidal antiinflammatory drugs]. / Seguridad de los antiinflamatorios no esteroideos.

The choice of a specific medication belonging to a drug class is under the criteria of efficacy, safety, cost and suitability. NSAIDs currently constitute one of the most consumed drug in the world, so it is very important review of the safety aspects of this drug class. This review has the objective of analyze the safety of NSAIDs on 3 main criteria: gastrolesivity, cardiotoxicity and nephrotoxicity.

La selección de un medicamento específico perteneciente a una clase farmacológica debe ser bajo los criterios de eficacia, seguridad, costo y conveniencia. Actualmente, los aintiinflamatorios no esteroideos (AINE) constituyen uno de los grupos de medicamentos más consumidos en el mundo, por lo tanto es de gran importancia la revisión de los aspectos de seguridad de estos fármacos. El presente trabajo tiene el objetivo de analizar bajo las evidencias disponibles hasta ahora, la seguridad de los AINE bajo 3 criterios principales: gastrolesividad, cardiotoxicidad y nefrotoxicidad.

Late administration of a specific COX-2 inhibitor does not treat and/or prevent progression of gastric tumors in rats submitted to duodenogastric reflux procedure

PURPOSE:To assess whether late introduction of a specific COX-2 inhibitor (Meloxicam) can treat and/or prevent the progression of tumors in the stomach of rats submitted to duodenogastric reflux. METHODS: Seventy five male Wistar rats, weighing 150 grams, were submitted to the induction of duodenogastric reflux through the pylorus. At 36 weeks of follow-up were established three experimental groups: DGR36 sacrificed immediately, DGR54 and DGR54MLX both sacrificed at 54th week of follow-up . The animals of the latter group were fed with a rat chow premixed with Meloxicam (2.0 mg/ kg feed; 0.3 mg / kg bw / day) and the other two with standard rat chow. The lesions found in the pyloric mucosa and gastrojejunal anastomosis were analyzed macroscopically and histologically. For statistical analysis was adjusted a generalized linear model assuming a binomial distribution with LOGIT link function. RESULTS: No significant differences were found when comparing the incidences of benign tumor lesions (Adenomatous Hyperplasia), p=0.4915, or malignant (Mucinous Adenocarcinoma), p=0.2731, among groups. CONCLUSION: Late introduction of specific COX-2 inhibitor (Meloxicam) did not treat and was not able to prevent the progression of tumoral lesions induced by duodenogastric reflux in the rat stomachs.

Late administration of a specific COX-2 inhibitor does not treat and/or prevent progression of gastric tumors in rats submitted to duodenogastric reflux procedure

PURPOSE:To assess whether late introduction of a specific COX-2 inhibitor (Meloxicam) can treat and/or prevent the progression of tumors in the stomach of rats submitted to duodenogastric reflux. METHODS: Seventy five male Wistar rats, weighing 150 grams, were submitted to the induction of duodenogastric reflux through the pylorus. At 36 weeks of follow-up were established three experimental groups: DGR36 sacrificed immediately, DGR54 and DGR54MLX both sacrificed at 54th week of follow-up . The animals of the latter group were fed with a rat chow premixed with Meloxicam (2.0 mg/ kg feed; 0.3 mg / kg bw / day) and the other two with standard rat chow. The lesions found in the pyloric mucosa and gastrojejunal anastomosis were analyzed macroscopically and histologically. For statistical analysis was adjusted a generalized linear model assuming a binomial distribution with LOGIT link function. RESULTS: No significant differences were found when comparing the incidences of benign tumor lesions (Adenomatous Hyperplasia), p=0.4915, or malignant (Mucinous Adenocarcinoma), p=0.2731, among groups. CONCLUSION: Late introduction of specific COX-2 inhibitor (Meloxicam) did not treat and was not able to prevent the progression of tumoral lesions induced by duodenogastric reflux in the rat stomachs.(AU)

Lethal effect of high concentrations of Parecoxib and Flunixin meglumine on the in vitro culture of bovine embryos

Since cyclooxygenase (COX) inhibitors have been pointed out as potent ial treatments to increase pregnancy rates after embryo transfer, the present experiment aimed to evaluate the effects of flunixin meglumine (FM) and parecoxib (P), a COX-1 and 2 or COX-2 specific inhibitor, respectively, on the development of bovine embryos until the hatched blastocyst stage. In vitro produced bovine embryos were cultured in media with different concentrations of FM (0.14; 1.4; 14; 140 or 1400 μg/ml) or P (0.09; 0.9; 9; 90 or 900 μg/ml) and the production rates were evaluated. Concentrations of FM ≤ 14 μg/ml and P ≤ 90 μg/ml did not impair embryo development, although compiled data from non-lethal FM concentrations ( ≤ 14 μg/ml) indicated a toxic effect enough to decrease the hatching rate of blastocysts. Concentrations of FM at 140 and 1400 μg/ml and P at 900 μg/ml were lethal as no cleavage was detected on presumptive zygotes.(AU)

Lethal effect of high concentrations of Parecoxib and Flunixin meglumine on the in vitro culture of bovine embryos

Since cyclooxygenase (COX) inhibitors have been pointed out as potent ial treatments to increase pregnancy rates after embryo transfer, the present experiment aimed to evaluate the effects of flunixin meglumine (FM) and parecoxib (P), a COX-1 and 2 or COX-2 specific inhibitor, respectively, on the development of bovine embryos until the hatched blastocyst stage. In vitro produced bovine embryos were cultured in media with different concentrations of FM (0.14; 1.4; 14; 140 or 1400 μg/ml) or P (0.09; 0.9; 9; 90 or 900 μg/ml) and the production rates were evaluated. Concentrations of FM ≤ 14 μg/ml and P ≤ 90 μg/ml did not impair embryo development, although compiled data from non-lethal FM concentrations ( ≤ 14 μg/ml) indicated a toxic effect enough to decrease the hatching rate of blastocysts. Concentrations of FM at 140 and 1400 μg/ml and P at 900 μg/ml were lethal as no cleavage was detected on presumptive zygotes.

Celecoxib reduces symptoms in men with difficult chronic pelvic pain syndrome (Category IIIA)

We investigated the effectiveness of celecoxib in reducing symptoms in patients with difficult chronic pelvic pain syndrome (CPPS), NIH category IIIA. Sixty-four patients with category IIIA CPPS were randomized into two groups of 32 subjects each. One group was treated with celecoxib (200 mg daily) and the other with placebo. All patients underwent treatment for 6 weeks and were evaluated clinically before (baseline) and after 1, 2, 4, 6, and 8 weeks of treatment. The evaluation included the NIH Chronic Prostatitis Symptom Index (NIH-CPSI) and a subjective global assessment (SGA). Repeated measures analysis of variance was used to evaluate treatment and time effects and their interaction. A decrease (means ± SD) in total NIH-CPSI score from 23.91 ± 5.27 to 15.88 ± 2.51 in the celecoxib group and from 24.25 ± 5.09 to 19.50 ± 2.50 in the placebo group was observed during treatment (0 to 6 weeks). A statistically significant decrease was observed in pain subscore (P < 0.006), quality of life subscore (P < 0.032) and total NIH-CPSI score (P < 0.015) after 2, 4 and 6 weeks, but not in urinary subscore. In addition, 38 percent of the celecoxib and 13 percent of the placebo subjects had at least a moderate improvement in SGA. The trend was similar for the NIH-CPSI scores. However, the response to treatment in terms of total NIH-CPSI score or subscore was not significantly different from placebo after interruption of treatment for 2 weeks. Our results show that celecoxib provides significant symptomatic improvement limited to the duration of the therapy in patients with difficult category IIIA CPPS compared to placebo.

Chemoprevention by celecoxib in reflux-induced gastric adenocarcinoma in Wistar rats that underwent gastrojejunostomy / Quimioprevenção pelo celecoxibe no adenocarcinoma gástrico induzido por refluxo em ratos Wistar submetidos à gastrojejunostomia

PURPOSE: To evaluate chemoprevention by celecoxib in cases of reflux-induced gastric adenocarcinoma, in Wistar rats that underwent gastrojejunostomy. METHODS: Sixty male Wistar rats of average age three months underwent surgery and were distributed into three groups: group 1, exploratory laparotomy; group 2, gastrojejunostomy; and group 3, gastrojejunostomy and daily celecoxib administration. After 53 weeks, the animals were sacrificed. Changes in the mucosa of the gastric body of group 1 and in the gastrojejunal anastomosis of groups 2 and 3, observed in histopathological and immunohistochemical examinations, were compared. All statistical analyses were performed using Epi-Info®, version 3.4.3. RESULTS: Comparison between groups 2 and 3 relative to the presence of adenocarcinoma showed a statistically significant difference (p=0.0023). Analysis of the association between groups 2 and 3 relative to COX-2 expression also showed a statistically significant difference (p=0.0018). CONCLUSION: Celecoxib had an inhibiting effect on gastric carcinogenesis induced by enterogastric reflux in an animal model.(AU)

OBJETIVO: Avaliar a quimioprevenção pelo celecoxibe no adenocarcinoma gástrico induzido por refluxo, em ratos Wistar, submetidos a gastrojejunostomia. MÉTODOS: Sessenta ratos machos Wistar, com média de idade de três meses foram operados e distribuídos em 03 grupos: Grupo 1 - Os animais foram submetidos a laparotomia exploradora. Grupo 2 - Os animais foram submetidos a gastrojejunostomia. Grupo 3 - Os animais foram submetidos a gastrojejunostomia e tomaram celecoxib, diariamente. Após um período de 53 semanas, os animais foram sacrificados. As alterações da mucosa do corpo gástrico dos animais do grupo 1 e da anastomose gastrojejunal dos animais dos grupos 2 e 3 foram analisadas no exame histopatológico e imuno-histoquímica e foram comparadas. Todas as análises estatísticas foram realizadas pelo programa Epi Info®, versão 3.4.3. RESULTADOS: No cotejo entre os animais dos grupos 2 e 3 com relação à presença de adenocarcinoma observou-se uma diferença estatística significante (p=0,0023). A análise de associação entre os grupos 2 e 3 com relação à expressão da COX-2, também evidenciou uma diferença estatística significante (p=0,0018). CONCLUSÃO: O celecoxib teve efeito inibidor da carcinogênese gástrica, induzida pelo refluxo em ratos.(AU)

Chemoprevention by celecoxib in reflux-induced gastric adenocarcinoma in Wistar rats that underwent gastrojejunostomy / Quimioprevenção pelo celecoxibe no adenocarcinoma gástrico induzido por refluxo em ratos Wistar submetidos à gastrojejunostomia

PURPOSE: To evaluate chemoprevention by celecoxib in cases of reflux-induced gastric adenocarcinoma, in Wistar rats that underwent gastrojejunostomy. METHODS: Sixty male Wistar rats of average age three months underwent surgery and were distributed into three groups: group 1, exploratory laparotomy; group 2, gastrojejunostomy; and group 3, gastrojejunostomy and daily celecoxib administration. After 53 weeks, the animals were sacrificed. Changes in the mucosa of the gastric body of group 1 and in the gastrojejunal anastomosis of groups 2 and 3, observed in histopathological and immunohistochemical examinations, were compared. All statistical analyses were performed using Epi-Info®, version 3.4.3. RESULTS: Comparison between groups 2 and 3 relative to the presence of adenocarcinoma showed a statistically significant difference (p=0.0023). Analysis of the association between groups 2 and 3 relative to COX-2 expression also showed a statistically significant difference (p=0.0018). CONCLUSION: Celecoxib had an inhibiting effect on gastric carcinogenesis induced by enterogastric reflux in an animal model.

OBJETIVO: Avaliar a quimioprevenção pelo celecoxibe no adenocarcinoma gástrico induzido por refluxo, em ratos Wistar, submetidos a gastrojejunostomia. MÉTODOS: Sessenta ratos machos Wistar, com média de idade de três meses foram operados e distribuídos em 03 grupos: Grupo 1 - Os animais foram submetidos a laparotomia exploradora. Grupo 2 - Os animais foram submetidos a gastrojejunostomia. Grupo 3 - Os animais foram submetidos a gastrojejunostomia e tomaram celecoxib, diariamente. Após um período de 53 semanas, os animais foram sacrificados. As alterações da mucosa do corpo gástrico dos animais do grupo 1 e da anastomose gastrojejunal dos animais dos grupos 2 e 3 foram analisadas no exame histopatológico e imuno-histoquímica e foram comparadas. Todas as análises estatísticas foram realizadas pelo programa Epi Info®, versão 3.4.3. RESULTADOS: No cotejo entre os animais dos grupos 2 e 3 com relação à presença de adenocarcinoma observou-se uma diferença estatística significante (p=0,0023). A análise de associação entre os grupos 2 e 3 com relação à expressão da COX-2, também evidenciou uma diferença estatística significante (p=0,0018). CONCLUSÃO: O celecoxib teve efeito inibidor da carcinogênese gástrica, induzida pelo refluxo em ratos.

A doença de Alzheimer: aspectos fisiopatológicos e farmacológicos: [revisão] / Alzheimer's disease: pathophysiological and pharmacological features: [revision]

A doença de Alzheimer é a patologia neurodegenerativa mais freqüente associada à idade, cujas manifestações cognitivas e neuropsiquiátricas resultam em deficiência progressiva e incapacitação. A doença afeta aproximadamente 10% dos indivíduos com idade superior a 65 anos e 40% acima de 80 anos. Estima-se que, em 2050, mais de 25% da população mundial será idosa, aumentando, assim, a prevalência da doença. O sintoma inicial da doença é caracterizado pela perda progressiva da memória recente. Com a evolução da patologia, outrasalterações ocorrem na memória e na cognição, entre elas as deficiências de linguagem e nas funções vísuo-espaciais. Esses sintomas são freqüentemente acompanhados por distúrbios comportamentais, incluindo agressividade, depressão e alucinações. O objetivo deste trabalho foi revisar, na literatura médica, os principais aspectos que envolvem a doença de Alzheimer,como as características istopatológicas, a neuroinflamação e a farmacoterapia atual.

Alzheimer's disease is the most frequent age-associated neurodegenerative disease. Its cognitive and neuropsychiatric manifestations result in progressive disorder and disability.Alzheimer's disease affects approximately 10% of patients more than 65 years old and 40% of patients more than 80 years old. It is estimated that, in 2050, 25% of the global population will be elderly, thus increasing the disease prevalence. The initial symptom is characterized byprogressive loss of recent memory. The progressive impairment in cognitive faculties such as memory, verbal and visuospatial ability is often accompanied by behavioral disorders, such asaggressiveness, depression and hallucinations. This article aims at reviewing the main aspects in Alzheimer's disease, such as histopathologic features, neuroinflammation and current pharmacotherapy.

Comparison of etoricoxib and indomethacin for the treatment of experimental periodontitis in rats

We investigated the effect of etoricoxib, a selective cyclooxygenase-2 inhibitor, and indomethacin, a non-selective cyclooxygenase inhibitor, on experimental periodontitis, and compared their gastrointestinal side effects. A ligature was placed around the second upper left molars of female Wistar rats (160 to 200 g). Animals (6 per group) were treated daily with oral doses of 3 or 9 mg/kg etoricoxib, 5 mg/kg indomethacin, or 0.2 mL saline, starting 5 days after the induction of periodontitis, when bone resorption was detected, until the sacrifice on the 11th day. The weight and survival rate were monitored. Alveolar bone loss (ABL) was measured as the sum of distances between the cusp tips and the alveolar bone. The gastric mucosa was examined macroscopically and the periodontium and gastric and intestinal mucosa were examined by histopathology. The ongoing ABL was significantly inhibited (P < 0.05) by 3 and 9 mg/kg etoricoxib and by indomethacin: control = 4.08 ± 0.47 mm; etoricoxib (3 mg/kg) = 1.89 ± 0.26 mm; etoricoxib (9 mg/kg) = 1.02 ± 0.14 mm; indomethacin = 0.64 ± 0.15 mm. Histopathology of periodontium showed that etoricoxib and indomethacin reduced inflammatory cell infiltration, ABL, and cementum and collagen fiber destruction. Macroscopic and histopathological analysis of gastric and intestinal mucosa demonstrated that etoricoxib induces less damage than indomethacin. Animals that received indomethacin presented weight loss starting on the 7th day, and higher mortality rate (58.3 percent) compared to etoricoxib (0 percent). Treatment with etoricoxib, even starting when ABL is detected, reduces inflammation and cementum and bone resorption, with fewer gastrointestinal side effects.

Toxicidade renal de inibidores seletivos da Ciclooxigenase-2: Celecoxib e Rofecoxib / Renal toxicity of the selective Cyclooxygenase-2 inhibitors: Celecoxib and Rofecoxib

Os antiinflamatórios não esteróides inibidores seletivos da ciclooxigenase-2 foram desenvolvidos com a perspectiva de evitar os efeitos colaterais dos inibidores não seletivos, especialmente para o trato gastrintestinal e rins. Contudo, recentes estudos têm demonstrado que a ciclooxigenase-2 é constitutivamente expressada nos rins, e altamente regulada em resposta a alterações no volume intravascular. Quando o volume sangüíneo está comprometido, as prostaglandinas derivadas da ciclooxigenase-2 desempenham um importante papel na circulação renal. Supõe-se que os fármacos que a inibem seletivamente possam interferir na função renal de maneira semelhante aos não seletivos. Esta revisão tem por objetivo averiguar o perfil de nefrotoxicidade dos inibidores seletivos da ciclooxigenase-2 de gerações mais recentes, os coxibs, enfatizando celecoxib e rofecoxib, quando administrados a indivíduos sem doença renal, e àqueles com comprometimento renal prévio. As publicações pertinentes, contidas em periódicos nacionais e internacionais entre 1999 e 2004, constituíram o objeto de análise. Os resultados mostraram que os coxibs, assim como os antiinflamatórios não esteróides não seletivos, reduzem a excreção de sódio, potássio e água, podendo elevar a pressão arterial, causar edema e falência renal aguda em pacientes em que a manutenção da perfusão renal adequada é dependente de prostaglandina. Em indivíduosonde tal manutenção acontece por outros mecanismos, as alterações nos parâmetros citados, quando ocorrem, são, em geral, transitórias. Concluiu-se que os inibidores seletivos da ciclooxigenase-2 não apresentam maior segurança renal que os não seletivos e, como estes, devem ser empregados com cautela ou não ser administrados a pacientes predispostos a doenças renais