Evaluation of the neurotoxic effects of intrathecal administration of (S)-(+)-Ketoprofen on rat spinal cords: randomized controlled experimental study / Avaliação dos efeitos neurotóxicos da administração intratecal do (S)-(+)-cetoprofeno em medula espinhal de rato: estudo experimental randômico e controlado

Abstract Background and objectives Intrathecal administration of non-steroidal anti-inflammatory drugs is more efficacious for post-operative pain management. Cyclooxygenase inhibiting non-steroidal anti-inflammatory drugs like (S)-(+)-Ketoprofen, may be effective at lower intrathecal doses than parenteral ones. Preclinical safety regarding possible neurotoxicity associated with the intrathecal (S)-(+)-Ketoprofen was not evaluated. Here we analysed the neurotoxicity of intrathecally administered (S)-(+)-Ketoprofen in rats. Methods A randomized placebo-controlled experimental study was conducted. Sprague-Dawley rats (250-300 g) aged 12-16 weeks were randomly divided into 2 treatments [100 and 800 µg (S)-(+)-Ketoprofen] and control (sterile water) groups. Intrathecal catheters were placed via the atlantoaxial space in anesthetized rats. Pinch-toe tests, motor function evaluations and histopathological examinations of the spinal cord and nerve roots were performed at days 3, 7 and 21. Spinal cord sections were evaluated by light microscopy for the dorsal axonal funiculus vacuolation, axonal myelin loss, neuronal chromatolysis, neuritis, meningeal inflammation, adhesions, and fibrosis. Results Rats in all the groups exhibited normal pinch-toe testing response (score = 0) and normal gait at each observed time (motor function evaluation score = 1). Neurotoxicity was higher with treatments on days 3 and 7 than that on day 21 (2, 3, 0, p = 0.044; 2, 5, 0, p = 0.029, respectively). On day 7, the total scores reflecting neuronal damage were higher in the 800 µg group than those in the 100 µg and Control Groups (5, 3, 0, p = 0.048, respectively). Conclusion Intrathecal (S)-(+)-Ketoprofen caused dose-dependent neurohistopathological changes in rats on days 3 and 7 after injection, suggesting that (S)-(+)-Ketoprofen should not be intrathecally administered.

Resumo Justificativa e objetivos A administração intratecal de anti-inflamatórios não esteroides é mais eficaz no tratamento da dor pós-operatória. Anti-inflamatórios não esteroides, como o (S)-(+)-cetoprofeno, pode ser eficaz em doses intratecais inferiores às parenterais. A segurança pré-clínica relativa à possível neurotoxicidade associada ao (S)-(+)-cetoprofeno intratecal não foi avaliada. Neste estudo avaliamos a neurotoxicidade do (S)-(+)-cetoprofeno administrado por via intratecal em ratos. Métodos Conduzimos um estudo experimental randomizado e controlado por placebo em ratos Sprague-Dawley (250-300 g) com idades entre 12 e 16 semanas. Eles foram randomicamente divididos em dois grupos de tratamento [100 e 800 µg de (S)-(+)-cetoprofeno] e um de controle (água estéril). Cateteres intratecais foram colocados através do espaço atlantoaxial nos ratos anestesiados. Testes de pinça, avaliações da função motora e exames histopatológicos da medula espinhal e das raízes nervosas foram realizados nos dias 3, 7 e 21 do estudo. Os cortes da medula espinhal foram avaliados por microscopia de luz para vacuolização do funículo axonal dorsal, perda de mielina axonal, cromatólise neuronal, neurite, inflamação, aderências e fibrose das meninges. Resultados Em todos os grupos, os ratos exibiram resposta normal ao teste de pinça (pontuação = 0) e marcha normal em cada tempo observado (escore de avaliação da função motora = 1). A neurotoxicidade foi maior com os tratamentos nos dias 3 e 7 do que no dia 21 (2, 3, 0, p = 0,044; 2, 5, 0, p = 0,029, respectivamente). No dia 7, os escores totais refletindo o dano neuronal foram maiores no grupo com 800 µg que nos grupos com 100 µg e controle (5, 3, 0, p = 0,048, respectivamente). Conclusão A administração intratecal de (S)-(+)-cetoprofeno causou alterações neuro-histopatológicas dose-dependentes em ratos nos dias 3 e 7 após a aplicação e sugerindo que o (S)-(+)-cetoprofeno não deve ser administrado por via intratecal.

Difficult Establishment of a Chronic Nonsteroidal Anti-inflammatory Drugs Induced Gastric Inflammation Rat Model due to Gastric Adaptation and Small Bowel Damage / 대한소화기학회지

BACKGROUND/AIMS: The prevalence of peptic ulcer disease has not decreased mainly due to an increase in the use of NSAIDs. This study was conducted in order to determine whether a chronic NSAID-induced gastric inflammation model could be established by repeated administration of NSAID. METHODS: Indomethacin (10 mg/kg) was administered once per week for six weeks in 8- and 26-week rats and animals were sacrificed every week after administration. Gross ulcer index, histologic damage index, myeloperoxidase (MPO) activity, and mucus (glucosamine) levels were measured. Small bowel damage was also evaluated. RESULTS: Gross gastric damage index showed a peak level at three weeks and then decreased slowly in the 26-week indomethacin group. Gastric mucosal glucosamine level increased in both the 8-week (p=0.038) and 26-week groups (p=0.007). In addition, gastric mucosal MPO level decreased in the 8-week group (p=0.018) but did not show a decrease in the 26-week group. Small bowel damage began to occur at three weeks during the schedule and eight of 36 rats (22.2%) died due to perforation or peritonitis of the small bowel in the 8- and 26-week indomethacin groups, respectively. CONCLUSIONS: Due to gastric adaptation and small bowel damage, repeated administration of NSAID to experimental animals may not be an adequate method for establishment of the chronic gastric inflammation model.

Difficult Establishment of a Chronic Nonsteroidal Anti-inflammatory Drugs Induced Gastric Inflammation Rat Model due to Gastric Adaptation and Small Bowel Damage / 대한소화기학회지

BACKGROUND/AIMS: The prevalence of peptic ulcer disease has not decreased mainly due to an increase in the use of NSAIDs. This study was conducted in order to determine whether a chronic NSAID-induced gastric inflammation model could be established by repeated administration of NSAID. METHODS: Indomethacin (10 mg/kg) was administered once per week for six weeks in 8- and 26-week rats and animals were sacrificed every week after administration. Gross ulcer index, histologic damage index, myeloperoxidase (MPO) activity, and mucus (glucosamine) levels were measured. Small bowel damage was also evaluated. RESULTS: Gross gastric damage index showed a peak level at three weeks and then decreased slowly in the 26-week indomethacin group. Gastric mucosal glucosamine level increased in both the 8-week (p=0.038) and 26-week groups (p=0.007). In addition, gastric mucosal MPO level decreased in the 8-week group (p=0.018) but did not show a decrease in the 26-week group. Small bowel damage began to occur at three weeks during the schedule and eight of 36 rats (22.2%) died due to perforation or peritonitis of the small bowel in the 8- and 26-week indomethacin groups, respectively. CONCLUSIONS: Due to gastric adaptation and small bowel damage, repeated administration of NSAID to experimental animals may not be an adequate method for establishment of the chronic gastric inflammation model.

Guidelines of Treatment for Non-bleeding Peptic Ulcer Disease / 대한소화기학회지

Over the past century, since the introduction of non steroidal anti-inflammatory drugs (NSAID), antacid, histamine H2-receptor antagonists (H2RA), proton pump inhibitors (PPI), and discovery of Helicobacter pylori infection, the paradigm of peptic ulcer disease has changed with marked decrease in morbidity and mortality. However, peptic ulcer disease still occupies a position as a major health problem with increase of aged population and NSAIDs usage. In daily general practice, the management of peptic ulcer disease is directed according to the presence of bleeding or not. For non-bleeding peptic ulcer disease, proper acid suppression and the correction of underlying causes such as Helicobacter pylori infection and NSAID use is the main stay of treatment. Though a complete understanding of pathophysiology and a perfect treatment strategy are still a challenge, this guideline aims to provide practical recommendations based on evidences or consensus of experts through in-depth literature review and expert meeting.

healing effects of Teucrium polium in the repair of indomethacin-induced gastric ulcer in rats

To determine the healing effect of Teucrium polium [T. polium] in indomethacin-induced gastric ulcer in rats. In the fall of 2007, 250 Sprague-Dawley rats provided by the Shiraz University Laboratory Animal Center were divided into 4 equal groups including control [70 rats], and 3 experimental groups [60 rats each], and each group received different doses of T. polium. Ten rats were used to study the induction of gastric ulcer by indomethacin [25 mg/kg/stat]. After 24 hours, their stomachs were evaluated for any mucosal ulcer. The T. polium extract was administered orally, 24 hours after indomethacin administration. In the experimental group, 10 animals were sacrificed after 24, 48, and 72 hours, after administration of T. polium, and at one, 2, and 4 weeks, and in the control group identically after the administration of distilled water. In rats treated with indomethacin, multiple ulcers were evident. After 4 weeks of treatment with T. polium, more re-epithelialization, proliferation, mucosal hyperplasia, migration of the gastric epithelial cells, and decrease in inflammatory cells were observed. The T. polium reduced the ulcer indices by >50% after one week, >80% after 2 weeks, and >90% after 4 weeks. The healing effect of T. polium may be due to antioxidant activity along with the ability to modulate the mucin secretion, prostaglandin synthesis, and epidermal growth factor receptor expression. These results along with the non-toxicity properties of T. polium suggests it as a promising anti-ulcer compound

The cytoprotective effect of a nitric oxide donor drug on gastric mucous membrane of rats treated with ketoprofen, a non-steroidal anti-inflammatory drug / Efeito citoprotetor de uma droga doadora de óxido nítrico na membrana da mucosa gástrica de ratos tratados com o antiinflamatório não-esteróide - o cetoprofeno

BACKGROUND: Non-steroidal anti-inflammatory drugs are considered today a very important group of medication, with a wide variety of therapeutic use, in different areas of modern medicine. Despite their beneficial effects on the patient, these drugs show a high incidence of side effects, mainly in the gastrointestinal tract. The physiopathological mechanisms of non-steroidal anti-inflammatory drugs induced lesions and the gastric mucosa defense mechanism became an important source for medical research, especially those which try to evaluate the role of nitric oxide as a cytoprotective agent. AIM: To define a possible cytoprotective effect of a nitric oxide donor, isosorbide dinitrate, on the gastric mucous of rats submitted to non-steroidal anti-inflammatory drugs ketoprofen treatment. METHODS: Adult male Wistar rats, previously submitted to starvation for 24 hours and divided in three groups: group I (standard): animals that received isotonic saline solution intragastric by gavage and intravenous. Group II (control-ketoprofen): animals that received isotonic saline solution intragastric by gavage and ketoprofen intravenous. Group III (nitrate/ketoprofen): animals that received 2mM solution of isosorbide dinitrate intragastric by gavage and ketoprofen intravenous. Later on, these animals were sacrificed and had their stomach removed and submitted to macroscopical, microscopical and biochemical studies. The evaluated parameters were: a) gastric lesion index; b) gastric mucous layer thickness; c) gastric tissue nitrate/nitrite (NOx) concentration and d) gastric tissue malondialdehyde concentration. RESULTS: a) Gastric lesion index evaluation showed a smaller statistically significant incidence on the animals of group III; b) group III showed a thicker mucous layer, which also was statistically significant, when compared to group II; c) the variation on tissue nitrate/nitrite concentration was similar in all three groups, without statistical significance when compared...

RACIONAL: Drogas antiinflamatórias não-esteróides são consideradas, atualmente, importante grupo de medicamentos, com ampla variedade de uso terapêutico, em diferentes áreas da medicina moderna. Apesar de seus efeitos benéficos para o paciente, apresentam grande incidência de efeitos colaterais, principalmente no trato gastrointestinal. Os mecanismos fisiopatológicos de lesões induzidas por essas drogas e os mecanismos de defesa da mucosa gástrica tornaram-se uma importante linha de pesquisa médica, especialmente procurando avaliar o papel de óxido nítrico como agente citoprotetor. OBJETIVO: Estudar uma droga doadora de ácido nítrico - o dinitrato de isossorbida - e sua ação citoprotetora da mucosa gástrica de ratos submetidos ao tratamento com uma droga antiinflamatória - o cetoprofeno. MÉTODOS: Ratos machos adultos previamente submetidos a jejum de 24 horas, foram divididos em três grupos: a) grupo I (controle): animais, que receberam apenas solução salina isotônica via intragástrica, por gavagem e via endovenosa; b) grupo II (cetoprofeno-controle): animais que receberam solução salina via intragástrica por gavagem e cetoprofeno via endovenosa, e c) grupo III (nitrato/cetoprofeno): animais que receberam solução de 2 mM de dinitrato de isossorbida a via intragástrica por gavagem e cetoprofeno via endovenosa. Esses grupos foram, posteriormente, submetidos a exames macroscópico, microscópico e bioquímico, avaliando-se os seguintes parâmetros: a) determinação do índice de lesão gástrica; b) determinação da espessura da camada do muco secretor; c) determinação da concentração de ácido nítrico x tecidual, e d) determinação da concentração do malondialdeído tecidual. RESULTADOS: Encontrou-se menor índice de lesão gástrica nos animais do grupo III (nitrato), assim como maior espessura da camada do muco secretor nos animais deste grupo, do que nos animais do grupo II (cetoprofeno). A variação da concentração do ácido nítrico x tecidual foi semelhante nos três grupos. A taxa...

Effect of therapeutic plasma concentrations of non-steroidal anti-inflammatory drugs on the production of reactive oxygen species by activated rat neutrophils

The release of reactive oxygen specie (ROS) by activated neutrophil is involved in both the antimicrobial and deleterious effects in chronic inflammation. The objective of the present investigation was to determine the effect of therapeutic plasma concentrations of non-steroidal anti-inflammatory drugs (NSAIDs) on the production of ROS by stimulated rat neutrophils. Diclofenac (3.6 µM), indomethacin (12 µM), naproxen (160 µM), piroxicam (13 µM), and tenoxicam (30 µM) were incubated at 37°C in PBS (10 mM), pH 7.4, for 30 min with rat neutrophils (1 x 10(6) cells/ml) stimulated by phorbol-12-myristate-13-acetate (100 nM). The ROS production was measured by luminol and lucigenin-dependent chemiluminescence. Except for naproxen, NSAIDs reduced ROS production: 58 ± 2 percent diclofenac, 90 ± 2 percent indomethacin, 33 ± 3 percent piroxicam, and 45 ± 6 percent tenoxicam (N = 6). For the lucigenin assay, naproxen, piroxicam and tenoxicam were ineffective. For indomethacin the inhibition was 52 ± 5 percent and diclofenac showed amplification in the light emission of 181 ± 60 percent (N = 6). Using the myeloperoxidase (MPO)/H2O2/luminol system, the effects of NSAIDs on MPO activity were also screened. We found that NSAIDs inhibited both the peroxidation and chlorinating activity of MPO as follows: diclofenac (36 ± 10, 45 ± 3 percent), indomethacin (97 ± 2, 100 ± 1 percent), naproxen (56 ± 8, 76 ± 3 percent), piroxicam (77 ± 5, 99 ± 1 percent), and tenoxicam (90 ± 2, 100 ± 1 percent), respectively (N = 3). These results show that therapeutic levels of NSAIDs are able to suppress the oxygen-dependent antimicrobial or oxidative functions of neutrophils by inhibiting the generation of hypochlorous acid.

Evaluation of Pongamia pinnata root extract on gastric ulcers and mucosal offensive and defensive factors in rats.

Effect of methanolic extract of P. Pinnata roots (PPRM) was studied against various experimental gastric ulcer models and offensive and defensive gastric mucosal factors in rats. An initial dose-response study using 12.5-50 mg/kg P. Pinnata root extract, when given orally in two divided dose for 4 days + 5th full dose on the day of experiment 60 min before the experiment, indicated 25 mg/kg as an optimal regimen and was used for further study. PPRM showed significant protection against aspirin and 4 hr PL, but not against ethanol-induced gastric ulceration. It showed tendency to decrease acetic acid-induced ulcer after 10 days treatment. Ulcer protective effect of PPRM was due to augmentation of mucosal defensive factors like mucin secretion, life span of mucosal cells, mucosal cell glycoproteins, cell proliferation and prevention of lipid per oxidation rather than on the offensive acid-pepsin secretion.

Effect of ethanol extract of Piper betle Linn leaf on healing of NSAID-induced experimental ulcer--a novel role of free radical scavenging action.

Treatment with ethanol extract of leaf of P. betle at a dose of 150 mg/kg body weight daily for 10 days, after induction of peptic ulcer by NSAID in albino rats, produced significant healing effect. During healing process, on treatment with the extractive, antioxidative factor, e.g. superoxide dismutase and catalase activity, mucus and total gastric tissue sulfhydryl group were increased. In contrast, oxidised lipid and oxidatively modified proteins were reduced to near normalcy, within 7 to 10 days, however, change in the untreated group was not significant. The extract also showed significant in vitro free radical scavenging action. The results suggest that the antioxidant or free radical scavenging activity of the plant extract, may be responsible for its healing action.

Influence of intragastric perfusion of aqueous spice extracts on acid secretion in anesthetized albino rats.

BACKGROUND: The effect of spices on gastric acid secretion is variable. Their mechanism of action is also not well established. AIM: To study the effect of spices on gastric acid secretion in anesthetized rats. METHODS: Aqueous extracts (10% w/v) of red pepper (Capsicum annuum), fennel (Foeniculum vulgare), omum/ajwan (Carum copticum), cardamom (Elettaria cardamomum), black pepper (Piper nigrum), cumin (Cuminum cyminum) and coriander (Coriandrum sativum) were prepared. The stomach of pentobarbitone-anesthetized rats was perfused at 0.15 mL/min with aqueous extracts of spice or acetylcholine (1 microgram/mL or 10 micrograms/mL solutions, in 40 min blocks, twice in each experiment bracketed by saline perfusions. The acid content in the samples was estimated by titration with 0.1N NaOH with phenolphthalein as indicator. Atropine 1 microgram/mL was added to the perfusion fluid in 28 experiments. In 32, acute gastric mucosal injury was induced by leaving aspirin 125 mg/Kg in the stomach for 2 h before perfusion. RESULTS: All the spices tested increased acid secretion in the following declining order: red pepper, fennel, omum, cardamom, black pepper, cumin, coriander. Red pepper increased acid secretion (mean [SEM] 0.93 [0.16] mL 0.1N HCl) to about 7 times the basal secretion (0.14 [0.05]; p < 0.005). The increase in acid secretion by the other spices was as follows: fennel 0.42 (0.11) mL 0.1 N HCl from basal secretion (0.12 [0.03]) (p < 0.02); omum 0.33 (0.05) from 0.09 (0.02) (p < 0.01); cardamom 0.28 (0.04) from 0.10 (0.03) (p < 0.005); black pepper 0.19 (0.03) from 0.04 (0.01) (p < 0.005); cumin 0.12 (0.02) from 0.08 (0.01) (p < 0.05); coriander 0.18 (0.03) from 0.09 (0.02) (p < 0.005). Atropine abolished the acid secretion induced by acetylcholine and significantly reduced acid induction by red pepper, omum and coriander, but not that by fennel. In experiments with aspirin-induced mucosal injury the basal acid secretion was low; acid secretion by red pepper and fennel was reduced significantly, but not that by acetylcholine. Cumin and coriander increased acid secretion in injured stomachs. CONCLUSION: The spices tested increased gastric acid secretion, in some by a cholinergic mechanism but by other mechanism(s) as well. Red pepper produced maximum increase in acid secretion, but this was significantly reduced in injured stomachs. Cumin and coriander increased gastric secretion in injured stomachs.

Gastric mucosal cellular changes induced by indomethacin (NSAID) in male albino rats.

Indomethacin (2 mg/100 g body weight), induces haemorrhagic gastric ulcers in albino rats. The incidence and severity of ulceration increased with starvation period. Indomethacin caused little or no effect on the cellular and the nuclear diameter of parietal and chief cells while reduction was observed in mucus and endocrine cells. The effect was enhanced with increased duration of starvation. Both mucous and endocrine cells decreased in their number after 72 hr of starvation. Thus prolonged starvation enhanced the gastric mucosal damage induced by indomethacin.

Inversión quiral de profenos: consecuencias terapéuticas y toxicológicas / Chiral inversion of profens: therapeutic and toxicological consequences

El presente trabajo tiene como objetivo describir las características farmacocinéticas, metabólicas y toxicológicas de los ácidos asimétricos aril-2-propiónicos y mostrar la importante variabilidad inter-especies existentes. Además se explican las derivaciones metabólicas del proceso de inversión quiral (camino metabólico de crucial importancia para estos compuestos) y las consecuencias toxicológicas relacionadas con su naturaleza quiral

Subacute toxicity study of the combination of ginseng (Panax ginseng) and ashwagandha (Withania somnifera) in rats: a safety assessment.

Ginseng (Panax ginseng) and Ashwagandha (Withania somnifera) are widely used as geriatric tonics. Both individually have not shown any toxicity on long term administration. Study was planned to assess the safety of the combination by doing subacute toxicity study in rats with 90 days oral administration using three doses. Food consumption, body weight, haematological, biochemical and histopathological parameters were studied. There was significant increase in body weight, food consumption and liver weight, and improved hematopoiesis was observed. Brain, heart, lung, liver, spleen, kidneys, stomach, testis and ovaries were normal on gross examination and histopathologically. Subacute toxicity studies in rats did not reveal any toxicity.

Hepatotoxicidad asociada a la nimesulida: revisión de 5 casos / Hepatotoxicity associated to Nimesulida: revision of 5 cases

Se presentan 5 pacientes de sexo femenino, entre 32 y 8O años que han sufrido hepatitis tóxica por Nimesulida, nueva droga antinflamatoria no esteroidea derivada del ácido arilantranílico, 2 de las cuales fallecieron por falla hepática fulminante (FHF). La duración de la administración de Nimesulida previo al inicio de la hepatitis fue menor a 1 mes en 2 pacientes y mayor de 1 mes en las 3 restantes. La hepatitis fue acompañada de manifestaciones biológicas de hipersensibilidad (eosinofilia > 4 por ciento) en las pacientes con menor latencia. Las 2 pacientes con FHF fallecieron como consecuencia de la Insuficiencia hepatocelular, mientras que las otras 3 normalizaron el funcional y enzimograma hepático a los 20-30 días de la suspensión de la administración de Nimesulida. La lesión hepática, obtenida por necropsia de 1 de las pacientes fallecidas, se correspondió con una necrosis hepática masiva, con pérdida total de la arquitectura del mismo. Se plantea como mecanismos probables de injuria, el idiosincrático metabólico para las pacientes con mayor latencia e inmunológico idiosincrático para las 2 pacientes con latencia menor a 1 mes y con manifestaciones de hipersensibilidad. El patrón bioquímico de lesión hepática fue mixto a predominio citolítico en las 3 pacientes con exposición prolongada a la nimesulida y colestático canalicular en las 2 pacientes con menor exposición a la misma y con elementos de hipersensibilidad

Antipyretic activity of diacetyl para-amino phenol.

Diacetyl para-amino phenol (DAPAP) was generated by interaction between aspirin and paracetamol in a mechanical shaker. It revealed antipyretic activity in albino rats. The antipyretic action was found to be having the same onset of action and duration as that of aspirin. This compound lacked ulcerogenic and analgesic activity. DAPAP therefore may have safety as an antipyretic drug in patients with history of peptic ulcer.

Pharmacological study of ulcerogenic action of antipyretic analgesic agents and their interaction with sodium salicylate.

The present work was undertaken to study and compare the gastric ulcerogenic action of analgesic antipyretic agents in guinea pigs. Their interaction with sodium salicylate was also studied. It was observed that aspirin, both microfined and ordinary, phenylbutazone, indomethacin and sodium salicylate were highly ulcerogenic in guinea pigs, while paracetamol and ibuprofen did not exhibit this action. It was also observed that sodium salicylate did not modify the ulcerogenic action of aspirin (both ordinary and microfined), phenylbutazone, ibuprofen and paracetamol but antagonized significantly the ulcerogenic action of indomethacin.