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1.
BMC Complement Altern Med ; 19(1): 205, 2019 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-31391093

RESUMO

BACKGROUND: Gastric ulcer is one of the most prevalent diseases worldwide. In Iranian folk medicine, Achillea wilhelmsii (AW) is used as a treatment for gastric ulcer. Previous reports also mentioned Antiulcerogenic properties for this herbal plant. This study investigated the therapeutic effects of Achillea wilhelmsii C. Koch extract on indomethacin-induced gastric lesion in rats, from both proteomic and metabolomic perspectives. METHODS: The rats were divided into 4 groups. Gastric ulceration was induced by a single dose of indomethacin (45 mg/kg) by oral gavage. An amount of 800 mg/kg of AW extract was administered orally. Serum and tissue samples were collected for further investigations. The metabolomic study was performed by 1H-NMR CPMG spectrometry. Proteomic analysis was also executed by using two dimensional gel electrophoresis (2DE) followed by liquid chromatography coupled to tandem mass spectrometry (LC-ESI/MS/MS). Real time PCR was used to confirm some of the genes. RESULTS: The macroscopic and microscopic investigations confirmed the effectiveness of the AW extract. There was a panel of metabolites which showed alteration during gastric lesion development. The levels of some of these metabolite reversed nearly to their control values after the administration of AW extract. There were also changes in the levels of some proteins including Alb, Fabp5, Hspb1, Tagln, Lgals7, Csta and Myl9 which were reversed after AW administration. CONCLUSIONS: Our findings suggested that Achillea wilhelmsii C. Koch extract could be a potential therapy to be used for indomethacin-induced gastric lesion treatment in the future. However, further investigations are needed to confirm the results.


Assuntos
Achillea/química , Antiulcerosos/administração & dosagem , Extratos Vegetais/administração & dosagem , Úlcera Gástrica/tratamento farmacológico , Animais , Antiulcerosos/isolamento & purificação , Humanos , Indometacina/efeitos adversos , Masculino , Metabolômica , Extratos Vegetais/isolamento & purificação , Proteômica , Ratos , Ratos Wistar , Úlcera Gástrica/induzido quimicamente , Úlcera Gástrica/genética , Úlcera Gástrica/metabolismo
2.
Biomed Res Int ; 2019: 4605748, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31111054

RESUMO

Background and Aims: Hydrotalcite plays an important role in the therapy of gastric ulcer induced by nonsteroidal anti-inflammatory drugs (NSAIDs), but little is known about the mechanism. We designed two experiments to study the preventive and curative effects of hydrotalcite on NSAIDs-related gastric injury in rats and to investigate the relationship between the protective and curative mechanism of hydrotalcite and the secretion of epidermal growth factor (EGF)/prostaglandin E2 (PGE2). Methods: Two experiments were separately designed to evaluate the preventive and curative effects of hydrotalcite. A total of 25 male rats and 25 female rats were randomly divided into five groups (vehicle group, model group, omeprazole group, hydrotalcite group, and ranitidine group) in each experiment. Rats were treated with indomethacin by gavage to build the model of acute gastric mucosal injury. The concentrations of EGF and PGE2 in blood specimens and mucosal injury indexes by gross inspection were measured and an immunohistochemical technique was also employed to test the levels of EGF, cyclooxygenase-1 (COX-1), and cyclooxygenase-2 (COX-2) in gastric mucosa. Results: Comparing with model group in both preventive and curative experiments, hydrotalcite decreased the gastric injury in the mucosa of stomach significantly (7±4.5 vs. 16±11.25, 1.5±2 vs. 2.5±6; P<0.01, P<0.05). The levels of EGF and PGE2 in blood serum were markedly higher in hydrotalcite group than that in model group and ranitidine group in preventive experiment (574.39±34.28 vs. 486.22±41.73, 488.07±24.44; P<0.01, P<0.01). The expression levels of COX-2 in gastric mucosa were also higher in hydrotalcite group than that in model group in both preventive and therapeutic experiments (12±4 vs. 9±6, 14±7 vs. 9±4; P<0.01, P<0.05). Conclusions: Hydrotalcite promotes gastric protection and healing via several mechanisms, including increased levels of PGE2 in blood serum, activation of EGF, and antagonising the inhibition of cyclooxygenase (COX) caused by NSAIDs.


Assuntos
Hidróxido de Alumínio/farmacologia , Mucosa Gástrica/efeitos dos fármacos , Mucosa Gástrica/lesões , Indometacina/efeitos adversos , Hidróxido de Magnésio/farmacologia , Úlcera Gástrica/tratamento farmacológico , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Ciclo-Oxigenase 1/metabolismo , Ciclo-Oxigenase 2/metabolismo , Dinoprostona/sangue , Dinoprostona/metabolismo , Modelos Animais de Doenças , Fator de Crescimento Epidérmico/sangue , Fator de Crescimento Epidérmico/metabolismo , Feminino , Mucosa Gástrica/metabolismo , Mucosa Gástrica/patologia , Masculino , Proteínas de Membrana/metabolismo , Omeprazol/farmacologia , Ranitidina/farmacologia , Ratos , Ratos Wistar , Estômago/efeitos dos fármacos , Úlcera Gástrica/patologia
3.
Biomed Res Int ; 2019: 9514703, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30949513

RESUMO

Gastric ulcers are a common problem in upper gastrointestinal tract (GI) disorders. Nonsteroidal anti-inflammatory drugs (NSAIDs) are one of the most aggressive factors leading to inducing gastric ulcers. Natural products with lower toxicity and safety are currently sought as a potential source to minimize the effect of the gastric ulcers. Perilla frutescens or Nga-mon (in Thai) leaves are rich in rosmarinic acid (RA), which has antioxidant, anti-inflammatory, and anticancer effects. This study investigates the protective effect of ethanolic extract (EE) and aqueous fraction (AF) from Perilla frutescens leaves, which are rich in RA, on indomethacin- (IND-) induced gastric ulcer in a rat model. The EE at the doses of 50 and 500 mg/kg body weight, AF at the doses of 50, 250, and 500 mg/kg body weight, or famotidine (a standard drug) were administered for 14 days prior to ulcer induction. The ulceration was performed by intragastric administration of IND. Gross gastric ulcers and biological and histological parameters were examined. The pretreatment with AF had more significant effects than EE, including reduced ulcer index, decreased gastric secretion volume and decreased acidity, but it had an elevated gastric pH relative to the IND-induced gastric ulcer. In a histopathological study, the EE and AF decreased mucosal ulcer, inflammatory infiltration, and degenerative lining cells. The IND-induced expression of inflammatory mediators was significantly attenuated with EE and AF. The experiment also remarkably showed the preservation of mucus and apoptosis protection of EE and AF on a gastric mucosal ulcer. The findings demonstrated that the EE and AF of perilla leaves were capable of protecting the stomach against gastric ulcers induced by IND through anti-inflammatory and antiapoptotic mechanisms that should be further investigated. It is suggested that Perilla frutescens leaf could be a potential alternative source of RA as a therapeutic agent and food supplement for NSAID-induced gastric injuries.


Assuntos
Cinamatos , Depsídeos , Indometacina/efeitos adversos , Perilla frutescens/química , Folhas de Planta/química , Úlcera Gástrica , Animais , Cinamatos/química , Cinamatos/farmacologia , Depsídeos/química , Depsídeos/farmacologia , Relação Dose-Resposta a Droga , Indometacina/farmacologia , Masculino , Ratos , Ratos Wistar , Úlcera Gástrica/induzido quimicamente , Úlcera Gástrica/patologia , Úlcera Gástrica/prevenção & controle
4.
Drug Dev Res ; 80(5): 585-594, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-30957263

RESUMO

The aims of the study were to evaluate the pharmacodynamic interaction between 3α-hydroxymasticadienonic acid and diligustilide (DLG), isolated from the plants Amphiptherygium adstringens and Ligusticum porteri, respectively, using the indomethacin-induced gastric injury model, as well as their individual gastroprotective efficacy in this model. Male Wistar rats were orally administered with 3α-hydroxymasticadienonic acid, DLG or the mixture of 3α-hydroxymasticadienonic acid-DLG (at a fixed-ratio combination of 1:1, 1:3, and 3:1). Thirty minutes later, the gastric damage was induced by a single oral dose of indomethacin (30 mg/kg). Three hours later, the gastric injury (mm2 ) was determined. 3α-hydroxymasticadienonic acid and DLG as individual compounds showed a gastroprotective effect against indomethacin-induced gastric damage (p < .05). The effective dose (ED50 ) values for each compound were 6.96 ± 1.25 mg/kg for 3α-hydroxymasticadienonic acid and 2.63 ± 0.37 mg/kg for DLG. The isobolographic analysis performed showed that the combination exhibited super-additive interaction as the experimental ED50 values (Zexp) were lower than theoretical additive dose values (Zadd; p < .05). Our results identify the super-additive (synergist) interaction between 3α-hydroxymasticadienonic acid and DLG and the gastric safety of both compounds in the indomethacin-induced gastric injury model, suggesting their potential in the future as a strategy to decrease the gastric damage associated to the chronic use of nonsteroidal anti-inflammatory drugs (NSAIDs).


Assuntos
Gastroenteropatias/tratamento farmacológico , Indometacina/efeitos adversos , Ligusticum/química , Extratos Vegetais/administração & dosagem , Triterpenos/administração & dosagem , Administração Oral , Animais , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Combinação de Medicamentos , Sinergismo Farmacológico , Mucosa Gástrica/efeitos dos fármacos , Mucosa Gástrica/lesões , Gastroenteropatias/induzido quimicamente , Gastroenteropatias/patologia , Masculino , Estrutura Molecular , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Ratos , Ratos Wistar , Triterpenos/farmacologia
5.
Biomed Res Int ; 2019: 8759708, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30906783

RESUMO

Rubus crataegifolius (black raspberry, RF), Ulmus macrocarpa (elm, UL), and Gardenia jasminoides (cape jasmine, GJ) are well known for hundreds of years as folk medicines in China and Korea to treat various gastrointestinal disturbance. The present study evaluated the gastroprotective effects of these plants either single or in combination against HCl/EtOH-induced gastritis and indomethacin-induced ulcer in rat model. Stomach ulcer was induced by oral ingestions of HCl/EtOH or indomethacin. Treatment with RF, UL, and GJ separately or in combination was done 1 h before ulcer induction. On HCl/EtOH-induced gastritis RF, UL, and GJ at a dose of 150 mg/kg showed comparable antigastritis effect (less than 50% inhibition) with lesion index of 94.97±8.05, 108.48±11.51, and 79.10±9.77 mm compared to cimetidine (45.33±23.73 mm). However, the combination of RF, UL, and GJ at a dose of 150 mg/kg with a ratio of 50:50:50 showed remarkable antigastritis effect with 77% inhibition. The observed lesion index at a ratio of 50:50:50 was 23.34±9.11 mm similar to cimetidine (18.88±19.88 mm). On indomethacin-induced ulcer, RF and GJ showed 38.28% and 51.8% inhibition whereas UL showed around 17.73% inhibition at 150 mg/kg. Combination of RF, UL, and GJ at 150 mg/kg showed strong antigastritis effect with 83.71% inhibition. These findings suggest strong gastroprotective effect of combined extract. In addition, these plants showed significant antioxidant activity in DPPH scavenging assay and antilipid peroxidation activity. Combination of black raspberry, elm, and cape jasmine might be a significant systemic gastroprotective agent that could be utilized for the treatment and/or protection of gastritis and gastric ulcer.


Assuntos
Mucosa Gástrica/lesões , Gastrite/tratamento farmacológico , Extratos Vegetais/farmacologia , Folhas de Planta/química , Úlcera Gástrica/tratamento farmacológico , Animais , Mucosa Gástrica/metabolismo , Mucosa Gástrica/patologia , Gastrite/metabolismo , Gastrite/patologia , Indometacina/efeitos adversos , Indometacina/farmacologia , Masculino , Fitoterapia/métodos , Extratos Vegetais/química , Ratos , Ratos Sprague-Dawley , Úlcera Gástrica/induzido quimicamente , Úlcera Gástrica/metabolismo , Úlcera Gástrica/patologia
6.
BMC Complement Altern Med ; 19(1): 49, 2019 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-30786935

RESUMO

BACKGROUND: Hordeum vulgare L (barley) contains numerous phenolic substances with proven anticancer, antioxidant and gastroprotective activities. Saccharification increases the functionality and bioavailability of these compounds thus can aid in the development of a natural product based medicine. This study aimed to investigate the possible gastroprotective effects of saccharification on the indomethacin (IND)-induced gastric ulcers in rats using Weissella cibaria- and Saccharomyces cerevisiae-triple fermented H. vulgare extract (FBe). METHODS: In total, 60 healthy male 6-week old Sprague-Dawley SD (SPF/VAF Outbred CrljOri:CD1) rats were commercially purchased. The FBe extract (100, 200, and 300 mg kg- 1) was orally administered 30 min before an oral treatment of IND (25 mg kg- 1). Six hours after IND treatment, variations in the histopathology, myeloperoxidase (MPO) activity, gross lesion scores, lipid peroxidation, and antioxidant defense system component (superoxide dismutase (SOD), catalase (CAT), and glutathione (GSH)) levels were measured. RESULTS: FBe treatment showed significant (p < 0.01 or p < 0.05) and dose-dependent decrease in gastric mucosal damage. In the present study hemorrhagic gross lesions, gastric MPO activity, and histopathological gastric ulcerative lesions were observed in IND-treated rats compared to the IND control rats. In particular, FBe, in a dose-dependent manner, strengthened the antioxidant defense systems, decreased lipid peroxidation and CAT activity by increasing the GSH levels and SOD activity, respectively. The 200 mg kg- 1 dose of FBe was similarly gastroprotective as the 10 mg kg- 1 dose of omeprazole in rats with IND-induced gastric mucosal damage. CONCLUSIONS: The findings of the present study show that an oral administration of FBe had positive gastroprotective effects through strengthening the body antioxidant defense system and anti-inflammatory effects.


Assuntos
Antioxidantes/farmacologia , Mucosa Gástrica/efeitos dos fármacos , Hordeum/química , Indometacina/efeitos adversos , Extratos Vegetais/farmacologia , Animais , Fermentação , Mucosa Gástrica/metabolismo , Mucosa Gástrica/patologia , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Oxirredutases/metabolismo , Ratos , Ratos Sprague-Dawley , Úlcera Gástrica
7.
PLoS One ; 14(2): e0211436, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30785904

RESUMO

Gliadin, a component of wheat gluten known to be an important factor in the etiology of celiac disease, is related to several other diseases through its enhancing effect on intestinal paracellular permeability. We investigated the significance of gliadin in non-steroidal anti-inflammatory drug (NSAID)-induced small-intestinal damage in mice. 7-week-old C57BL/6 male mice were divided into the following groups: standard diet group, in which mice were fed with wheat-containing standard rodent diet (CE-2); gluten-free diet group, in which mice were fed with gluten-free diet (AIN-76A); and gliadin-administered group, in which mice fed with gluten-free diet were administered with gliadin (~250 mg/kg BW). Each group was subdivided into negative, healthy control group and NSAID-treated group. To some mice fed with gluten-free diet and administered with gliadin, epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor was administered for clarification of the significance of EGFR in NSAID-induced small intestinal damage and intestinal permeability. In mice fed with a gluten-free diet, indomethacin or diclofenac induced very mild mucosal damage in the small intestine compared with that in mice fed with a wheat-containing standard diet. Gliadin exacerbated the NSAID-induced small-intestinal damage in mice fed with a gluten-free diet. With the administration of indomethacin, MPO activity, a marker of neutrophil infiltration into the mucosa and mRNA expression level of tumor necrosis factor α and interleukin-1ß in the small intestine were higher in the gliadin-administered mice. Gliadin increased the intestinal paracellular permeability without indomethacin administration (4.3-fold) and further increased the permeability after indomethacin administration (2.1-fold). Gliadin induced phosphorylation of epidermal growth factor receptor (EGFR) in small-intestinal tissues, and erlotinib (an EGFR tyrosine kinase inhibitor) attenuated the indomethacin-induced intestinal damage and permeability exacerbated by gliadin, accompanied by inhibition of EGFR phosphorylation. These results suggest that gliadin plays an important role in the induction and exacerbation of NSAID-induced small-intestinal damage, and that increase in intestinal permeability via the EGFR signalling pathway is involved in its mechanism.


Assuntos
Gliadina/efeitos adversos , Intestino Delgado/efeitos dos fármacos , Intestino Delgado/fisiopatologia , Triticum/efeitos adversos , Animais , Anti-Inflamatórios não Esteroides/efeitos adversos , Doença Celíaca/etiologia , Diclofenaco/efeitos adversos , Dieta Livre de Glúten , Modelos Animais de Doenças , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/fisiologia , Cloridrato de Erlotinib/farmacologia , Glutens/efeitos adversos , Indometacina/efeitos adversos , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/patologia , Mucosa Intestinal/fisiopatologia , Intestino Delgado/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Permeabilidade/efeitos dos fármacos , Fosforilação , Inibidores de Proteínas Quinases/farmacologia
8.
mBio ; 10(1)2019 01 08.
Artigo em Inglês | MEDLINE | ID: mdl-30622186

RESUMO

Clostridium difficile infection (CDI) is a major public health threat worldwide. The use of nonsteroidal anti-inflammatory drugs (NSAIDs) is associated with enhanced susceptibility to and severity of CDI; however, the mechanisms driving this phenomenon have not been elucidated. NSAIDs alter prostaglandin (PG) metabolism by inhibiting cyclooxygenase (COX) enzymes. Here, we found that treatment with the NSAID indomethacin prior to infection altered the microbiota and dramatically increased mortality and the intestinal pathology associated with CDI in mice. We demonstrated that in C. difficile-infected animals, indomethacin treatment led to PG deregulation, an altered proinflammatory transcriptional and protein profile, and perturbed epithelial cell junctions. These effects were paralleled by increased recruitment of intestinal neutrophils and CD4+ cells and also by a perturbation of the gut microbiota. Together, these data implicate NSAIDs in the disruption of protective COX-mediated PG production during CDI, resulting in altered epithelial integrity and associated immune responses.IMPORTANCE Clostridium difficile infection (CDI) is a spore-forming anaerobic bacterium and leading cause of antibiotic-associated colitis. Epidemiological data suggest that use of nonsteroidal anti-inflammatory drugs (NSAIDs) increases the risk for CDI in humans, a potentially important observation given the widespread use of NSAIDs. Prior studies in rodent models of CDI found that NSAID exposure following infection increases the severity of CDI, but mechanisms to explain this are lacking. Here we present new data from a mouse model of antibiotic-associated CDI suggesting that brief NSAID exposure prior to CDI increases the severity of the infectious colitis. These data shed new light on potential mechanisms linking NSAID use to worsened CDI, including drug-induced disturbances to the gut microbiome and colonic epithelial integrity. Studies were limited to a single NSAID (indomethacin), so future studies are needed to assess the generalizability of our findings and to establish a direct link to the human condition.


Assuntos
Anti-Inflamatórios não Esteroides/efeitos adversos , Infecções por Clostridium/mortalidade , Infecções por Clostridium/patologia , Microbioma Gastrointestinal/efeitos dos fármacos , Indometacina/efeitos adversos , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/patologia , Animais , Anti-Inflamatórios não Esteroides/administração & dosagem , Linfócitos T CD4-Positivos/imunologia , Indometacina/administração & dosagem , Camundongos , Neutrófilos/imunologia , Prostaglandinas/análise , Análise de Sobrevida
9.
Environ Toxicol ; 34(1): 67-72, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30259636

RESUMO

Indomethacin is generally used in clinical therapeutics as a non-steroidal anti-inflammatory drug. However, its use has been limited due to the gastrointestinal and renal toxic effects of this drug. These toxic effects were associated with not only the inhibition of prostaglandin synthesis but also drug-elevated oxidative stress. To ameliorate these toxicities, natural antioxidants can be used as an alternative and/or combination therapies. Therefore, the current study was conducted to assess the renoprotective effects of oleuropein against indomethacin-induced renal damages. Male Sprague-Dawley rats were pretreated with oleuropein (75, 150, and 300 mg/kg), and then treated with indomethacin (25 mg/kg). To evaluate kidney function, serum blood urea nitrogen, uric acid, and creatinine were measured. In addition, prostaglandin E2 , tumor necrosis factor-alpha, endothelial nitric oxide synthase, caspase-3, oxidant/antioxidant status, and 8-Oxo-2'-deoxyguanosine levels were determined for the antioxidative and anti-inflammatory effects of oleuropein. Tissue sections were also histopathologically assessed. The biochemical and histopathological analysis proved the toxic effects of indomethacin on kidney. However, the pretreatment with oleuropein (300 mg/kg) protects kidney from indomethacin-induced damages. Our study proved that prior administration of oleuropein has renoprotective activity against indomethacin-associated toxicities.


Assuntos
Anti-Inflamatórios não Esteroides/efeitos adversos , Iridoides/uso terapêutico , Nefropatias/induzido quimicamente , Nefropatias/prevenção & controle , Substâncias Protetoras/uso terapêutico , Animais , Antioxidantes/farmacologia , Antioxidantes/uso terapêutico , Indometacina/efeitos adversos , Iridoides/farmacologia , Rim/efeitos dos fármacos , Masculino , Estresse Oxidativo/efeitos dos fármacos , Substâncias Protetoras/farmacologia , Ratos , Ratos Sprague-Dawley , Resultado do Tratamento
10.
Australas J Dermatol ; 60(1): 50-52, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30039854

RESUMO

We report a case of long-standing inexplicable perianal ulcers. After exclusion of an inflammatory, infectious or neoplastic origin, a thorough personal history revealed that for many years the patient had been using analgesic suppositories containing indomethacin, caffeine, and prochlorperazine dimaleate, four to five times a week, for migraine. On stopping the suppositories, there was complete healing within 12 weeks. We hypothesize that vasoconstriction and vascular damage were the pathogenetic mechanisms behind the perianal ulcers.


Assuntos
Anti-Inflamatórios não Esteroides/efeitos adversos , Doenças do Ânus/induzido quimicamente , Estimulantes do Sistema Nervoso Central/efeitos adversos , Indometacina/efeitos adversos , Úlcera Cutânea/induzido quimicamente , Idoso , Cafeína/efeitos adversos , Doença Crônica , Antagonistas de Dopamina/efeitos adversos , Combinação de Medicamentos , Feminino , Humanos , Proclorperazina , Supositórios
11.
PLoS One ; 13(11): e0204746, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30383755

RESUMO

BACKGROUND: Use of selective COX-2 non-steroidal anti-inflammatory drugs (NSAIDs) (coxibs) has been associated with an increased risk of acute myocardial infarction (AMI). However, the risk of AMI has only been studied for very few NSAIDs that are frequently used. OBJECTIVES: To estimate the risk of AMI for individual NSAIDs. METHODS: A nested case-control study was performed from a cohort of new NSAID users ≥18 years (1999-2011) matching cases to a maximum of 100 controls on database, sex, age, and calendar time. Data were retrieved from six healthcare databases. Adjusted odds ratios (ORs) of current use of individual NSAIDs compared to past use were estimated per database. Pooling was done by two-stage pooling using a random effects model (ORmeta) and by one-stage pooling (ORpool). RESULTS: Among 8.5 million new NSAID users, 79,553 AMI cases were identified. The risk was elevated for current use of ketorolac (ORmeta 2.06;95%CI 1.83-2.32, ORpool 1.80; 1.49-2.18) followed, in descending order of point estimate, by indometacin, etoricoxib, rofecoxib, diclofenac, fixed combination of diclofenac with misoprostol, piroxicam, ibuprofen, naproxen, celecoxib, meloxicam, nimesulide and ketoprofen (ORmeta 1.12; 1.03-1.22, ORpool 1.00;0.86-1.16). Higher doses showed higher risk estimates than lower doses. CONCLUSIONS: The relative risk estimates of AMI differed slightly between 28 individual NSAIDs. The relative risk was highest for ketorolac and was correlated with COX-2 potency, but not restricted to coxibs.


Assuntos
Anti-Inflamatórios não Esteroides/efeitos adversos , Infarto do Miocárdio/induzido quimicamente , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Diclofenaco/efeitos adversos , Etoricoxib/efeitos adversos , Feminino , Humanos , Indometacina/efeitos adversos , Cetorolaco/efeitos adversos , Lactonas/efeitos adversos , Masculino , Pessoa de Meia-Idade , Razão de Chances , Fatores de Risco , Sulfonas/efeitos adversos
12.
Cochrane Database Syst Rev ; 9: CD003481, 2018 09 28.
Artigo em Inglês | MEDLINE | ID: mdl-30264852

RESUMO

BACKGROUND: Indomethacin is used as standard therapy to close a patent ductus arteriosus (PDA) but is associated with reduced blood flow to several organs. Ibuprofen, another cyclo-oxygenase inhibitor, may be as effective as indomethacin with fewer adverse effects. OBJECTIVES: To determine the effectiveness and safety of ibuprofen compared with indomethacin, other cyclo-oxygenase inhibitor(s), placebo, or no intervention for closing a patent ductus arteriosus in preterm, low-birth-weight, or preterm and low-birth-weight infants. SEARCH METHODS: We used the standard search strategy of Cochrane Neonatal to search the Cochrane Central Register of Controlled Trials (CENTRAL 2017, Issue 10), MEDLINE via PubMed (1966 to 30 November 2017), Embase (1980 to 30 November 2017), and CINAHL (1982 to 30 November 2017). We searched clinical trials databases, conference proceedings, and the reference lists of retrieved articles for randomised controlled trials and quasi-randomised trials. SELECTION CRITERIA: Randomised or quasi-randomised controlled trials of ibuprofen for the treatment of a PDA in preterm, low birth weight, or both preterm and low-birth-weight newborn infants. DATA COLLECTION AND ANALYSIS: Data collection and analysis conformed to the methods of the Cochrane Neonatal Review Group. We used the GRADE approach to assess the quality of evidence. MAIN RESULTS: We included 39 studies enrolling 2843 infants.Ibuprofen (IV) versus placebo: IV Ibuprofen (3 doses) reduced the failure to close a PDA compared with placebo (typical relative risk (RR); 0.62 (95% CI 0.44 to 0.86); typical risk difference (RD); -0.18 (95% CI -0.30 to -0.06); NNTB 6 (95% CI 3 to 17); I2 = 65% for RR and I2 = 0% for RD; 2 studies, 206 infants; moderate-quality the evidence). One study reported decreased failure to close a PDA after single or three doses of oral ibuprofen compared with placebo (64 infants; RR 0.26, 95% CI 0.11 to 0.62; RD -0.44, 95% CI -0.65 to -0.23; NNTB 2, 95% CI 2 to 4; I2 test not applicable).Ibuprofen (IV or oral) compared with indomethacin (IV or oral): Twenty-four studies (1590 infants) comparing ibuprofen (IV or oral) with indomethacin (IV or oral) found no significant differences in failure rates for PDA closure (typical RR 1.07, 95% CI 0.92 to 1.24; typical RD 0.02, 95% CI -0.02 to 0.06; I2 = 0% for both RR and RD; moderate-quality evidence). A reduction in NEC (necrotising enterocolitis) was noted in the ibuprofen (IV or oral) group (18 studies, 1292 infants; typical RR 0.68, 95% CI 0.49 to 0.94; typical RD -0.04, 95% CI -0.07 to -0.01; NNTB 25, 95% CI 14 to 100; I2 = 0% for both RR and RD; moderate-quality evidence). There was a statistically significant reduction in the proportion of infants with oliguria in the ibuprofen group (6 studies, 576 infants; typical RR 0.28, 95% CI 0.14 to 0.54; typical RD -0.09, 95% CI -0.14 to -0.05; NNTB 11, 95% CI 7 to 20; I2 = 24% for RR and I2 = 69% for RD; moderate-quality evidence). The serum/plasma creatinine levels 72 hours after initiation of treatment were statistically significantly lower in the ibuprofen group (11 studies, 918 infants; MD -8.12 µmol/L, 95% CI -10.81 to -5.43). For this comparison, there was high between-study heterogeneity (I2 = 83%) and low-quality evidence.Ibuprofen (oral) compared with indomethacin (IV or oral): Eight studies (272 infants) reported on failure rates for PDA closure in a subgroup of the above studies comparing oral ibuprofen with indomethacin (IV or oral). There was no significant difference between the groups (typical RR 0.96, 95% CI 0.73 to 1.27; typical RD -0.01, 95% CI -0.12 to 0.09; I2 = 0% for both RR and RD). The risk of NEC was reduced with oral ibuprofen compared with indomethacin (IV or oral) (7 studies, 249 infants; typical RR 0.41, 95% CI 0.23 to 0.73; typical RD -0.13, 95% CI -0.22 to -0.05; NNTB 8, 95% CI 5 to 20; I2 = 0% for both RR and RD). There was low-quality evidence for these two outcomes. There was a decreased risk of failure to close a PDA with oral ibuprofen compared with IV ibuprofen (5 studies, 406 infants; typical RR 0.38, 95% CI 0.26 to 0.56; typical RD -0.22, 95% CI -0.31 to -0.14; NNTB 5, 95% CI 3 to 7; moderate-quality evidence). There was a decreased risk of failure to close a PDA with high-dose versus standard-dose of IV ibuprofen (3 studies 190 infants; typical RR 0.37, 95% CI 0.22 to 0.61; typical RD - 0.26, 95% CI -0.38 to -0.15; NNTB 4, 95% CI 3 to 7); I2 = 4% for RR and 0% for RD); moderate-quality evidence).Early versus expectant administration of IV ibuprofen, echocardiographically-guided IV ibuprofen treatment versus standard IV ibuprofen treatment, continuous infusion of ibuprofen versus intermittent boluses of ibuprofen, and rectal ibuprofen versus oral ibuprofen were studied in too few trials to allow for precise estimates of any clinical outcomes. AUTHORS' CONCLUSIONS: Ibuprofen is as effective as indomethacin in closing a PDA. Ibuprofen reduces the risk of NEC and transient renal insufficiency. Therefore, of these two drugs, ibuprofen appears to be the drug of choice. The effectiveness of ibuprofen versus paracetamol is assessed in a separate review. Oro-gastric administration of ibuprofen appears as effective as IV administration. To make further recommendations, studies are needed to assess the effectiveness of high-dose versus standard-dose ibuprofen, early versus expectant administration of ibuprofen, echocardiographically-guided versus standard IV ibuprofen, and continuous infusion versus intermittent boluses of ibuprofen. Studies are lacking evaluating the effect of ibuprofen on longer-term outcomes in infants with PDA.


Assuntos
Inibidores de Ciclo-Oxigenase/uso terapêutico , Permeabilidade do Canal Arterial/tratamento farmacológico , Ibuprofeno/uso terapêutico , Recém-Nascido de Baixo Peso , Recém-Nascido Prematuro , Administração Oral , Inibidores de Ciclo-Oxigenase/efeitos adversos , Enterocolite Necrosante/prevenção & controle , Humanos , Ibuprofeno/efeitos adversos , Indometacina/efeitos adversos , Indometacina/uso terapêutico , Recém-Nascido , Injeções Intravenosas , Ensaios Clínicos Controlados Aleatórios como Assunto , Falha de Tratamento
13.
Future Microbiol ; 13: 1271-1281, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-30238771

RESUMO

AIM: To evaluate the effect on the nonsteroidal anti-inflammatory drug indomethacin on Clostridium difficile infection (CDI) severity. MATERIALS & METHODS: Indomethacin was administered in two different mouse models of antibiotic-associated CDI in two different facilities, using a low and high dose of indomethacin. RESULTS: Indomethacin administration caused weight loss, increased the signs of severe infection and worsened histopathological damage, leading to 100% mortality during CDI. Indomethacin-treated, antibiotic-exposed mice infected with C. difficile had enhanced intestinal inflammation with increased expression of KC, IL-1ß and IL-22 compared with infected mice unexposed to indomethacin. CONCLUSION: These results demonstrate a negative impact of nonsteroidal anti-inflammatory drugs on antibiotic-associated CDI in mice and suggest that targeting the synthesis or signaling of prostaglandins might be an approach to ameliorating the severity of CDI.


Assuntos
Anti-Inflamatórios não Esteroides/efeitos adversos , Infecções por Clostridium/tratamento farmacológico , Infecções por Clostridium/patologia , Clostridium difficile , Indometacina/efeitos adversos , Intestinos/patologia , Índice de Gravidade de Doença , Animais , Antibacterianos/efeitos adversos , Anti-Inflamatórios não Esteroides/administração & dosagem , Modelos Animais de Doenças , Indometacina/administração & dosagem , Interleucina-1beta/metabolismo , Interleucinas/metabolismo , Intestinos/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Antagonistas de Prostaglandina/efeitos adversos , Prostaglandinas/biossíntese , Fatores de Risco , Perda de Peso
14.
Curr Pain Headache Rep ; 22(11): 71, 2018 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-30151604

RESUMO

PURPOSE OF REVIEW: The aim is twofold. First, to give an insight on the role exerted by different classes of drugs in favouring migraine chronification. Second, to explore the relationship between type and amount of overused medications and history of previous withdrawal treatment and of frequent relapses. RECENT FINDINGS: All drug classes were found to favour migraine chronification. No data are available for the association with relapses into CM-MOH. Our clinical study shows that patients who underwent previous withdrawal treatments were more likely to be overusers of multiple drug classes and overuse higher amounts of symptomatic medications, particularly, indomethacin, eletriptan and tramadol. Frequent relapsers were more likely to be overusers of opioids or ergotamine and caffeine derivates or of multiple classes, particularly acetylsalicylic acid and ergotamine/caffeine derivates. The joint results our review and clinical study do not seem to support the idea that MOH is drug-specific: rather, it points out that all drug classes may induce migraine chronification. Those drugs which are at higher risk of overuse are among those preferred by the "worst" patients, i.e. those who needed one or more withdrawal treatments for MOH. Our results reinforce the clinical impression that patients with CM and MOH, and particularly the most difficult to treat for their poor response to withdrawal treatments, are characterised by a particular drive towards the consumption of "whatever is likely to be perceived to provide some relief", despite these drugs that are perceived as "more powerful", are often indicated as second- or third-line medications.


Assuntos
Transtornos da Cefaleia Secundários/epidemiologia , Adulto , Analgésicos não Entorpecentes/efeitos adversos , Analgésicos Opioides/efeitos adversos , Anti-Inflamatórios não Esteroides/efeitos adversos , Aspirina/efeitos adversos , Avaliação da Deficiência , Feminino , Humanos , Indometacina/efeitos adversos , Itália/epidemiologia , Masculino , Pessoa de Meia-Idade , Transtornos de Enxaqueca/epidemiologia , Recidiva , Tramadol/efeitos adversos , Triptaminas/efeitos adversos
15.
Pharmacoepidemiol Drug Saf ; 27(9): 1019-1028, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29992656

RESUMO

PURPOSE: Existing knowledge of medicines that increase the risk of an adverse event may be corroborated and augmented by population studies specifically assessing the risk associated with the concurrent use of these medicines and use by patients with existing comorbidity. An American Heart Association review recently identified a variety of medicines that may cause or exacerbate heart failure (HF), many with evidence from limited evaluation of population data. We assessed the risk of first-time HF associated with the use of 50 of these medicines by New Zealand's primary care population. METHODS: Case-control study utilising national pharmaceutical use and hospital admissions data 2007-2015; 22,989 patients with first-time HF 2008-2015 were matched with 114 498 control patients. The primary outcome was first-time HF and its association with medicine exposure in the prior 90 days, estimated using conditional logistic regression. We also assessed the risk associated with new use of medicines in the prior month, concurrent use, and in patients with existing comorbidity. RESULTS: Eleven medicines were significantly associated with HF with several other infrequently used medicines providing signals of increased risk. A high risk was associated with the use of salbutamol (adjusted odds ratio 2.63; 95% CI, 2.48-2.78), clozapine (2.70; 2.46-4.98), diltiazem (1.52; 1.44-1.60), indomethacin (2.51; 1.54-4.10), pioglitazone (1.50; 1.16-1.95), and antifungal medicines. New use of medicines and use of medicine combinations increased this risk in many cases. CONCLUSIONS: Our study provides further evidence to inform cautious use of these medicines in patients with HF or at risk of developing HF.


Assuntos
Necessidades e Demandas de Serviços de Saúde/estatística & dados numéricos , Insuficiência Cardíaca/induzido quimicamente , Hospitalização/estatística & dados numéricos , Atenção Primária à Saúde/estatística & dados numéricos , Idoso , Idoso de 80 Anos ou mais , Albuterol/administração & dosagem , Albuterol/efeitos adversos , Antifúngicos/administração & dosagem , Antifúngicos/efeitos adversos , Estudos de Casos e Controles , Clozapina/administração & dosagem , Clozapina/efeitos adversos , Diltiazem/administração & dosagem , Diltiazem/efeitos adversos , Quimioterapia Combinada/efeitos adversos , Quimioterapia Combinada/métodos , Feminino , Seguimentos , Insuficiência Cardíaca/epidemiologia , Humanos , Indometacina/administração & dosagem , Indometacina/efeitos adversos , Masculino , Pessoa de Meia-Idade , Nova Zelândia/epidemiologia , Pioglitazona/administração & dosagem , Pioglitazona/efeitos adversos , Pontuação de Propensão , Fatores de Risco
16.
Can J Physiol Pharmacol ; 96(11): 1161-1170, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30011378

RESUMO

The protective effect of N-acetylcysteine (NAC) and genistein (GEN) on an experimental model of indomethacin (IND)-induced gastric injury was investigated. A total of 50 male rats were divided into 5 groups: (1) control, (2) IND, (3) NAC pretreated, (4) GEN pretreated, and (5) NAC+GEN pretreated. Rats in groups 3-5 were orally administered NAC (500 mg/kg), GEN (10 mg/kg), or both, respectively, once daily for 7 days before the induction of gastric injury by IND (50 mg/kg). The stomach was removed for biochemical analysis and histopathological examination. Pretreatment with NAC, GEN, or both significantly improved ulcer indices and increased nitric oxide level and superoxide dismutase activity. They also significantly decreased malondialdehyde, tumour necrosis factor α levels, and myeloperoxidase activity, and downregulated matrix metalloproteinase 9 (MMP-9) gene expression compared to the IND group. NAC alone ameliorated IND-induced apoptosis, whereas GEN only significantly increased prostaglandin E2 level. Further, coadministration of both resulted in a significantly better gastroprotective effect versus solo administration. Coadministration of NAC and GEN has an additive gastroprotective effect in IND-induced gastric injury, which may be through interaction of their potential cytoprotective, antioxidant, anti-inflammatory, and antiapoptotic mechanisms together with regulation of MMP-9 expression.


Assuntos
Acetilcisteína/farmacologia , Anti-Inflamatórios não Esteroides/efeitos adversos , Antiulcerosos/farmacologia , Genisteína/farmacologia , Indometacina/efeitos adversos , Úlcera Gástrica/prevenção & controle , Acetilcisteína/uso terapêutico , Animais , Antiulcerosos/uso terapêutico , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Quimioterapia Combinada , Mucosa Gástrica/efeitos dos fármacos , Mucosa Gástrica/patologia , Genisteína/uso terapêutico , Humanos , Masculino , Metaloproteinase 9 da Matriz/metabolismo , Ratos , Ratos Wistar , Úlcera Gástrica/induzido quimicamente , Úlcera Gástrica/patologia
17.
Acta Paediatr ; 107(12): 2092-2098, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-29873414

RESUMO

AIM: This study aimed to determine whether neonatal intensive care therapies increase the risk of carcinogenesis in childhood. METHODS: This study used population-based data on 1 072 957 infants born in New South Wales, Australia, between 2000 and 2011 and multivariate logistic regression to examine any associations between therapies used in the neonatal intensive care unit and diagnoses of cancer until mid 2012. RESULTS: A total of 1126 of 1 072 957 (0.1%) children were diagnosed with cancer. Cancer risk was significantly increased by preterm birth (gestation <37 weeks; adjusted odds ratio (aOR) 1.3 (95% confidence interval: 1.0-1.6), birth weight ≥4 kg (aOR 1.4, 1.2-1.6) and caesarean delivery (aOR 1.2, 1.1-1.4). Extremely preterm (<28 weeks of gestation) infants were more likely to develop hepatic tumours (aOR 12.7, 3.3-48.3) than term infants. The only therapy used in the neonatal intensive care that was independently associated with an increased risk of cancer was nitric oxide (aOR 8.6, 4.3-17.4). Eight of the 790 (1%) infants treated with nitric oxide developed cancer (gestation range 30-41 weeks, age of cancer diagnosis: four months-five years). CONCLUSION: Treatment with nitric oxide was associated with a higher risk of childhood cancer. These findings require further research.


Assuntos
Broncodilatadores/efeitos adversos , Terapia Intensiva Neonatal/métodos , Neoplasias/induzido quimicamente , Óxido Nítrico/efeitos adversos , Feminino , Glucocorticoides/efeitos adversos , Humanos , Indometacina/efeitos adversos , Recém-Nascido , Recém-Nascido Prematuro , Unidades de Terapia Intensiva Neonatal , Masculino , Surfactantes Pulmonares/efeitos adversos , Estudos Retrospectivos
18.
Semin Perinatol ; 42(4): 228-234, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29907397

RESUMO

The use of prophylactic indomethacin in very preterm infants is controversial. The last randomized controlled trial (RCT) to study this therapy enrolled infants over 20 years ago. More recently, observational studies have investigated the association between exposure to prophylactic indomethacin and neonatal morbidities and mortality. We performed a systematic review and meta-analysis of these studies for the outcomes of death and bronchopulmonary dysplasia (BPD). Two observational studies involving a total of 11,289 very preterm infants were suitable for meta-analysis. The pooled data showed that prophylactic indomethacin was not associated with higher or lower risk-adjusted odds of death or BPD (0.93, 95% CI: 0.76-1.13) and of BPD among survivors (0.94, 95% CI: 0.78-1.12). However, there was a weak association between indomethacin prophylaxis and decreased risk-adjusted odds of mortality (0.81, 95% CI: 0.66-0.98). It is unknown whether this finding resulted from unmeasured confounding, chance, or represents a true benefit. To confirm the hypothesis that prophylactic indomethacin has a small effect on mortality in the current era, a contemporary RCT would need to enroll over 3500 very immature infants at high risk of death.


Assuntos
Anti-Inflamatórios não Esteroides/uso terapêutico , Displasia Broncopulmonar/mortalidade , Displasia Broncopulmonar/prevenção & controle , Permeabilidade do Canal Arterial/tratamento farmacológico , Permeabilidade do Canal Arterial/mortalidade , Indometacina/uso terapêutico , Lactente Extremamente Prematuro , Fatores Etários , Anti-Inflamatórios não Esteroides/efeitos adversos , Displasia Broncopulmonar/fisiopatologia , Permeabilidade do Canal Arterial/fisiopatologia , Humanos , Indometacina/efeitos adversos , Recém-Nascido , Estudos Observacionais como Assunto , Resultado do Tratamento
19.
Int J Mol Sci ; 19(5)2018 Apr 24.
Artigo em Inglês | MEDLINE | ID: mdl-29695040

RESUMO

Kalanchoe brasiliensis and Kalanchoe pinnata are used interchangeably in traditional medicine for treating peptic ulcers and inflammatory problems. In this context, this study aims to characterize the chemical constituents and evaluate the gastroprotective activity of the leaf juices of the two species in acute gastric lesions models. Thin Layer Chromatography (TLC) and Ultra High Performance Liquid Chromatography coupled to Mass Spectrometer (UHPLC-MS) were performed for chemical characterization. Wistar rats were pre-treated orally with leaf juices (125, 250 and 500 mg/kg) or ranitidine (50 mg/kg). The peaks observed in the chromatogram of K. brasiliensis showed similar mass spectra to flavonoid glycosides derived from patuletin and eupafolin, while K. pinnata showed mass spectra similar to compounds derived from quercetin, patuletin, eupafolin and kaempferol. K. brasiliensis at all doses and K. pinnata at doses of 250 mg/kg and 500 mg/kg significantly reduced the lesions in the ethanol induction model. In the indomethacin induction model, both species showed significant results at doses of 250 and 500 mg/kg. Also, the pre-treatment with leaf juices increased the antioxidant defense system, glutathione (GSH), whereas malondialdehyde (MDA), myeloperoxidase (MPO), interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α) levels were significantly decreased. Treatment with leaf juices led to the upregulation of zone occludes-1 (ZO-1) and the downregulation of inducible nitric oxide synthase (iNOS) and factor nuclear-κβ transcription (NF-κB-p65), while also showing a cytoprotective effect and maintaining mucus production. These findings show that the leaf juices of the two species showed gastroprotective effects on ethanol and gastric indomethacin injury which were a consequence of gastric inflammation suppression, antioxidant activity and the maintenance of cytoprotective defenses and mucosal structure architecture.


Assuntos
Antioxidantes/farmacologia , Etanol/efeitos adversos , Gastrite/etiologia , Gastrite/patologia , Indometacina/efeitos adversos , Kalanchoe/química , Extratos Vegetais/farmacologia , Folhas de Planta/química , Substâncias Protetoras/farmacologia , Animais , Antioxidantes/química , Cromatografia Líquida de Alta Pressão , Cromatografia em Camada Delgada , Citocinas/metabolismo , Modelos Animais de Doenças , Feminino , Mucosa Gástrica/efeitos dos fármacos , Mucosa Gástrica/patologia , Gastrite/tratamento farmacológico , Gastrite/metabolismo , Glutationa/metabolismo , Glicoproteínas/metabolismo , Imuno-Histoquímica , Mediadores da Inflamação/metabolismo , Malondialdeído/metabolismo , Espectrometria de Massas , Peroxidase/metabolismo , Extratos Vegetais/química , Substâncias Protetoras/química , Ratos , Úlcera Gástrica/tratamento farmacológico , Úlcera Gástrica/etiologia , Úlcera Gástrica/patologia
20.
Artigo em Inglês | MEDLINE | ID: mdl-29462674

RESUMO

Lysophosphatidic acid (LPA) is a bioactive phospholipid that induces diverse biological responses. Recently, we found that LPA ameliorates NSAIDs-induced gastric ulcer in mice. Here, we quantified LPA in 21 medicinal herbs used for treatment of gastrointestinal (GI) disorders. We found that half of them contained LPA at relatively high levels (40-240 µg/g) compared to soybean seed powder (4.6 µg/g), which we previously identified as an LPA-rich food. The LPA in peony (Paeonia lactiflora) root powder is highly concentrated in the lipid fraction that ameliorates indomethacin-induced gastric ulcer in mice. Synthetic 18:1 LPA, peony root LPA and peony root lipid enhanced prostaglandin E2 production in a gastric cancer cell line, MKN74 cells that express LPA2 abundantly. These materials also prevented indomethacin-induced cell death and stimulated the proliferation of MKN74 cells. We found that LPA was present in stomach fluids at 2.4 µM, which is an effective LPA concentration for inducing a cellular response in vitro. These results indicated that LPA is one of the active components of medicinal herbs for the treatment of GI disorder and that orally administered LPA-rich herbs may augment the protective actions of endogenous LPA on gastric mucosa.


Assuntos
Dinoprostona/metabolismo , Indometacina/efeitos adversos , Lisofosfolipídeos/uso terapêutico , Plantas Medicinais/química , Animais , Morte Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Camundongos , Transdução de Sinais/efeitos dos fármacos , Úlcera Gástrica/induzido quimicamente , Úlcera Gástrica/tratamento farmacológico , Úlcera Gástrica/metabolismo
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