RESUMO

Biotechnological advancements require the physicochemical alteration of molecules to enhance their biological efficacy for the effective treatment of gastric ulcers. The study aimed to produce a polyelectrolytic compound from red angico gum (AG) by carboxymethylation, evaluate its physicochemical characteristics and investigate gastric protection against ethanol-induced ulcers. AG and carboxymethylated angico gum (CAG) were characterized by Fourier transform infrared spectroscopy, determination of the degree of substitution and gel permeation chromatography (GPC) and 13C NMR techniques. The results demonstrated that the modification of the polymer was satisfactory, presenting conformational changes e improving the interaction with the gastric mucosa. AG and CAG reduced macroscopic and microscopic damage such as edema, hemorrhage and cell loss caused by exposure of the mucosa to alcohol. Both demonstrated antioxidant activity in vitro, and in vivo, pretreatment with gums led to the restoration of superoxide dismutase and glutathione levels compared to the injured group. Concurrently, the levels of malondialdehyde and nitrite decreased. Atomic force microscopy showed that CAG presented better conformational properties of affinity and protection with the gastric mucosa compared to AG in the acidic pH. Based on our findings, it is suggested that this compound holds promise as a prospective product for future biotechnological applications.

Assuntos

Colubrina , Fabaceae , Úlcera Gástrica , Estudos Prospectivos , Estômago , Antioxidantes/efeitos adversos , Mucosa Gástrica , Úlcera Gástrica/induzido quimicamente , Úlcera Gástrica/tratamento farmacológico , Extratos Vegetais/química

RESUMO

Pain represents one of the leading causes of suffering and disability worldwide. Currently available drugs cannot treat all types of pain and may have adverse effects. Hence, the use of pharmacological combinations is an alternative treatment strategy. Therefore, this study aimed to evaluate the combination of resveratrol and ketorolac through isobolographic analysis. CD1 mice were used to study the antinociceptive effect of this combination using the formalin test and the study was divided into two phases. In the first phase, four individual doses of each drug were evaluated, totaling eight testing groups. From these data, the median effective doses (ED50) of each drug were calculated. In the second phase, four testing groups were used to evaluate the combination of sub-doses of both drugs and obtain the experimental ED50. To evaluate gastric damage, five groups were employed, including indomethacin, vehicle, resveratrol, ketorolac, and combined resveratrol and ketorolac groups. Stomach samples from the mice were taken after 5 h of treatment, and the area of the ulcers was determined. Resveratrol plus ketorolac elicited a reduction in nociceptive behavior during both phases of the formalin test, and isobologram analysis revealed that the theoretical and experimental ED50 values of resveratrol and ketorolac did not differ significantly, implying an additive interaction between the drugs. Additionally, the drug combination did not generate gastric ulcers, thus enhancing the desired effects without increasing the adverse effects. Consequently, these findings substantiate the efficacy of the resveratrol and ketorolac combination in the formalin test, thereby highlighting its potential as a viable alternative for alleviating pain.

RESUMO

OBJECTIVES: Helicobacter pylori (H. pylori) is the primary cause of gastric cancer and eradication in healthy adults has proven effective in decreasing cancer incidence. H. pylori is acquired largely in early childhood, however, the benefits of eradication in children are controversial. We aimed to determine the effect of H. pylori eradication on clinical and laboratory markers associated with gastric damage in apparently healthy school-aged children. METHODS: This was a pilot non-blinded trial including 61 children persistently infected with H. pylori who were randomized to eradication/no treatment and followed for at least 12 months, evaluating clinical and blood markers (Pepsinogen I (PGI) and II (PGII) determined by ELISA) associated with gastric damage. The treatment consisted of a sequential scheme including 7 days of omeprazole + amoxicillin followed by 7 days of omeprazole + clarithromycin + metronidazole; adherence and tolerance were surveyed. Eradication rates were assessed by stool antigen detection or urea breath test 1 month following treatment every 4 months thereafter to detect reinfection. RESULTS: Eradication occurred in 30/31 treated children (median age: 8.8, range: 7.9-10.8) and in 0/30 non-treated controls (median age: 8.6, range: 7.9-11) (p < .001). Treatment was associated with mild transient symptoms (altered taste, nocturnal upper abdominal pain, nausea, and diarrhea). Baseline frequency of symptoms was low and eradication did not change symptoms compared to controls. PGI, PGII, and anti-H. pylori seropositivity were similar in both groups at baseline and significantly decreased only in eradicated patients; PGI (92.5 vs. 74.4, p < .001), PGII (15.2 vs. 8.9, p < .001) levels, and frequency of anti-H. pylori seropositivity (100 vs. 68%, p < .001) respectively. Four eradicated children (13%) were reinfected during follow-up. CONCLUSIONS: H. pylori eradication therapy in apparently asymptomatic school-aged children was well tolerated and associated with decreased serum PGI and PGII levels. Future studies should expand on the middle-long-term effect of early H. pylori eradication, especially on preventing gastric cancer.

Assuntos

Antiulcerosos , Infecções por Helicobacter , Helicobacter pylori , Adulto , Amoxicilina/uso terapêutico , Antibacterianos/uso terapêutico , Antiulcerosos/uso terapêutico , Biomarcadores , Criança , Pré-Escolar , Claritromicina/uso terapêutico , Quimioterapia Combinada , Infecções por Helicobacter/diagnóstico , Infecções por Helicobacter/tratamento farmacológico , Humanos , Laboratórios , Pepsinogênio C , Instituições Acadêmicas

RESUMO

The transient receptor potential vanilloid channel 4 (TRPV4) is associated with the development of several pathologies, particularly gastric disorders. However, there are no studies associating this receptor with the pathophysiology of gastric erosions. The aim of this study was to investigate the role of TRPV4 in the development of ethanol-induced gastric damage in vivo. Gastric lesions were induced by ethanol in Swiss mice pretreated with TRPV4 antagonists, GSK2193874 (0.1; 0.3 and 0.9 mg/kg) or Ruthenium red (0.03; 0.1 or 0.3 mg/kg) or its agonist, GSK1016790A (0.9 mg/kg). Gastric mucosal samples were taken for histopathology, immunohistochemistry, atomic force microscopy and evaluation of antioxidant parameters. The gastric mucus content and TRPV4 mRNA expression were analyzed. Ethanol exposure induced upregulation of gastric mRNA and protein expression of TRPV4. TRPV4 blockade promoted gastroprotection against ethanol-induced injury on macro- and microscopic levels, leading to reduced hemorrhage, cell loss and edema and enhanced gastric mucosal integrity. Moreover, an increase in superoxide dismutase (SOD) and glutathione (GSH) activity was observed, followed by a decrease in malondialdehyde (MDA) levels. TRPV4 blockade during alcohol challenge reestablished gastric mucus content. The combination of TRPV4 agonist and ethanol revealed macroscopic exacerbation of gastric damage area. Our results confirmed the association of TRPV4 with the development of gastric injury, showing the importance of this receptor for further investigations in the field of gastrointestinal pathophysiology and pharmacology.

Assuntos

Úlcera Gástrica/metabolismo , Úlcera Gástrica/fisiopatologia , Canais de Cátion TRPV/agonistas , Canais de Cátion TRPV/metabolismo , Animais , Edema/induzido quimicamente , Edema/metabolismo , Etanol/toxicidade , Mucosa Gástrica/efeitos dos fármacos , Mucosa Gástrica/lesões , Mucosa Gástrica/metabolismo , Glutationa/metabolismo , Leucina/análogos & derivados , Leucina/farmacologia , Leucina/uso terapêutico , Masculino , Malondialdeído/metabolismo , Camundongos , Estresse Oxidativo/efeitos dos fármacos , Piperidinas/farmacologia , Piperidinas/uso terapêutico , Quinolinas/farmacologia , Quinolinas/uso terapêutico , Rutênio Vermelho/farmacologia , Rutênio Vermelho/uso terapêutico , Úlcera Gástrica/induzido quimicamente , Úlcera Gástrica/patologia , Sulfonamidas/farmacologia , Sulfonamidas/uso terapêutico , Superóxido Dismutase/metabolismo , Canais de Cátion TRPV/antagonistas & inibidores , Canais de Cátion TRPV/genética , Regulação para Cima/efeitos dos fármacos

RESUMO

BACKGROUND: Helicobacter pylori is acquired largely in early childhood, but its association with symptoms and indirect biomarkers of gastric damage in apparently healthy children remains controversial. We aimed to relate persistent H. pylori infection in apparently healthy school-aged children with clinical, laboratory, and noninvasive biomarkers suggestive of gastric damage using a case-control design. MATERIALS AND METHODS: We followed up 83 children aged 4-5 years with persistent H. pylori infection determined by stool antigen detection and/or a urea breath test and 80 noninfected matched controls from a low-income to middle-income, periurban city in Chile for at least 3 years. Monitoring included clinical visits every 4 months and annual assessment by a pediatric gastroenterologist. A blood sample was obtained to determine laboratory parameters potentially associated with gastric damage (hemogram and serum iron and ferritin levels), biomarkers of inflammation (cytokines, pepsinogens I and II, and tissue inhibitor metalloproteinase 1), and expression of cancer-related genes KLK1, BTG3, and SLC5A8. RESULTS: Persistently infected children had higher frequency of epigastric pain on physical examination (40% versus 16%; P = 0.001), especially from 8 to 10 years of age. No differences in anthropometric measurements or iron-deficiency parameters were found. Persistent infection was associated with higher levels of pepsinogen II (median 12.7 ng/mL versus 9.0 ng/mL; P < 0.001); no difference was observed in other biomarkers or gene expression profiles. CONCLUSIONS: H. pylori infection in apparently asymptomatic school-aged children is associated with an increase in clinical symptoms and in the level of one significant biomarker, pepsinogen II, suggesting early gastric involvement.

Assuntos

Infecções por Helicobacter/complicações , Helicobacter pylori , Pepsinogênio C/sangue , Gastropatias/microbiologia , Idoso , Biomarcadores/sangue , Estudos de Casos e Controles , Criança , Pré-Escolar , Chile/epidemiologia , Fezes/microbiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Pepsinogênio A/sangue , Estômago , Gastropatias/epidemiologia

RESUMO

Blueberry is a polyphenol-rich fruit bearing great bioactive potential. Natural deep eutectic solvents (NADES) emerged as putatively biocompatible solvents that could substitute for toxic organic solvents in the extraction of fruit phenolic compounds for developing nutraceuticals or functional foods. Therefore, the aim of this study was to investigate the gastroprotective effects and the biocompatibility of a blueberry crude extract (CE) obtained using NADES and of the extract fractions (anthocyanin-rich fraction - ARF; non-anthocyanin phenolic fraction - NAPF) in a model of ethanol-induced gastric ulcer in rats. CE was the NADES-containing, ready-to-use extract that was obtained using choline chloride:glycerol:citric acid NADES (0.5:2:0.5 M ratio). ARF and NAPF were the NADES-free fractions obtained by solid phase purification of CE and were investigated to identify the bioactive fraction responsible for the effects of CE. Animals were treated for 14 days with water, NADES vehicle, CE, ARF, NAPF or lansoprazole (intragastric) and then received ethanol to induce gastric ulcer. CE decreased ulcer index and preserved the integrity of gastric mucosa. The pretreatment with CE or ARF reduced glutathione depletion and the inflammatory response. All treatments, including NADES vehicle reduced protein oxidation and nitric oxide overproduction in ethanol-treated rats. Additionally, ARF increased short-chain fatty acids in feces. These findings suggest that NADES can be used to obtain biocompatible extracts of blueberry that exhibit gastroprotective effects with no need of solvent removal. The gastroprotective effects were mainly associated to ARF but NAPF and even NADES vehicle also contributed to some protective effects.

Assuntos

Mirtilos Azuis (Planta) , Úlcera Gástrica , Animais , Etanol , Extratos Vegetais/farmacologia , Ratos , Solventes , Úlcera Gástrica/induzido quimicamente , Úlcera Gástrica/prevenção & controle

RESUMO

Helicobacter pylori (H. pylori) is well-known to be involved in gastric carcinogenesis, associated with deregulation of cell proliferation and epigenetic changes in cancer-related genes. H. pylori infection is largely acquired during childhood, persisting long-term in about half of infected individuals, a subset of whom will go on to develop peptic ulcer disease and eventually gastric cancer, however, the sequence of events leading to disease is not completely understood. Knowledge on carcinogenesis and gastric damage-related biomarkers is abundant in adult populations, but scarce in children. We performed an extensive literature review focusing on gastric cancer related biomarkers identified in adult populations, which have been detected in children infected with H. pylori. Biomarkers were related to expression levels (RNA or protein) and/or methylation levels (DNA) in gastric tissue or blood of infected children as compared to non-infected controls. In this review, we identified 37 biomarkers of which 24 are over expressed, three are under expressed, and ten genes are significantly hypermethylated in H. pylori-infected children compared to healthy controls in at least 1 study. Only four of these biomarkers (pepsinogen I, pepsinogen II, gastrin, and SLC5A8) have been studied in asymptomatically infected children. Importantly, 13 of these biomarkers (ß-catenin, C-MYC, GATA-4, DAPK1, CXCL13, DC-SIGN, TIMP3, EGFR, GRIN2B, PIM2, SLC5A8, CDH1, and VCAM-1.) are consistently deregulated in infected children and in adults with gastric cancer. Future studies should be designed to determine the clinical significance of these changes in infection-associated biomarkers in children and their persistence over time. The effect of eradication therapy over these biomarkers in children if proven significant, could lead to modifications in treatment guidelines for younger populations, and eventually promote the development of preventive strategies, such as vaccination, in the near future.

RESUMO

Preclinical Research & Development The addition of polyunsaturated fatty acids to nonsteroidal anti-inflammatory drugs can increase their antinociceptive activity and produce a gastroprotective effect. The aim of the present study was to examine the effects of the interaction between docosahexaenoic acid (DHA) and diclofenac on inflammation (fixed ratios 1:1, 1:3, and 3:1), nociception (fixed ratio 1:3), and gastric injury in rats. DHA, diclofenac, or combinations of DHA and diclofenac produced anti-inflammatory and antinociceptive effects in rat. The administration of diclofenac produced significant gastric damage, but this effect was not observed with either DHA or the DHA-diclofenac combinations. Effective dose (ED30 ) values were estimated for each individual drug and analyzed isobolographically. The anti-inflammatory experimental ED30 values were 6.97 mg/kg (1:1 fixed ratio), 1.1 mg/kg (1:3 fixed ratio), and 11.34 mg/kg (3:1 fixed ratio). These values were significantly lower (p < .05) than the theoretical ED30 values: 67.94 mg/kg (1:1), 35.37 mg/kg (1:3), and 100.51 mg/kg (3:1). The antinociceptive experimental value was 1.25 mg/kg (1:3 fixed ratio). This value was lower (p < .05) than the theoretical ED30 , which was predicted to be 15.92 mg/kg. These data indicate that the DHA-diclofenac combinations interact at the systemic level, produce minor gastric damage, and potentially have therapeutic advantages for the clinical treatment of inflammatory pain.

Assuntos

Analgésicos/farmacologia , Anti-Inflamatórios não Esteroides/farmacologia , Diclofenaco/farmacologia , Ácidos Docosa-Hexaenoicos/farmacologia , Nociceptividade/efeitos dos fármacos , Estômago/efeitos dos fármacos , Analgésicos/efeitos adversos , Analgésicos/uso terapêutico , Animais , Anti-Inflamatórios não Esteroides/efeitos adversos , Anti-Inflamatórios não Esteroides/uso terapêutico , Diclofenaco/efeitos adversos , Diclofenaco/uso terapêutico , Ácidos Docosa-Hexaenoicos/efeitos adversos , Ácidos Docosa-Hexaenoicos/uso terapêutico , Relação Dose-Resposta a Droga , Sinergismo Farmacológico , Quimioterapia Combinada , Feminino , Humanos , Inflamação/tratamento farmacológico , Ratos Wistar , Estômago/patologia

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Barks of Ximenia americana are used by the population to treat gastrointestinal inflammatory disorders. Indomethacin is a non-selective non-steroidal anti-inflammatory drug that induces marked gastrointestinal damage. AIMS OF THE STUDIES: To evaluate the gastroprotective activity of total polysaccharides contained in the extract (TPL-Xa) or tea (Tea-Xa) of Ximenia americana barks in the mice gastric damage induced by indomethacin. MATERIALS AND METHODS: TPL-Xa was obtained by a combination of NaOH extraction and ethanol precipitation. Tea-Xa was prepared in distilled water boiled during 5 min. Animals received p.o. 0.9% NaCl (saline - control group), TPL-Xa (1-90 mg/kg) or Tea-Xa 1 h before gastritis induction by indomethacin (20 mg/kg). Mice were sacrificed 7 h after gastritis induction and analyzed for the following parameters: stomach lesions measurement; histological evaluation; myeloperoxidase (MPO) activity; nitrate/nitrite and cytokine levels; leukocyte adhesion and rolling by intravital microscopy. RESULTS: TPL-Xa reduced macroscopic and microscopic damage, MPO activity (59%), leukocyte rolling (86%) and adhesion (84%), nitrite/nitrate ratio (100%) and IL-8 (69%), but increased IL-4 (50%). Tea-Xa (12.8 yield; 39.3% carbohydrate, including 25.8% uronic acid; 4% protein) reduced macroscopic damage (62%) and MPO activity (50%). CONCLUSION: TPL and Tea of Ximenia americana barks ameliorate the gastric injury induced by indomethacin in mice, an effect that was dependent on the reduction of neutrophil infiltration.

Assuntos

Bebidas , Gastrite/tratamento farmacológico , Olacaceae , Extratos Vegetais , Polissacarídeos , Substâncias Protetoras , Animais , Anti-Inflamatórios não Esteroides , Adesão Celular/efeitos dos fármacos , Feminino , Mucosa Gástrica/efeitos dos fármacos , Mucosa Gástrica/imunologia , Mucosa Gástrica/metabolismo , Mucosa Gástrica/patologia , Gastrite/induzido quimicamente , Gastrite/imunologia , Gastrite/metabolismo , Indometacina , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/imunologia , Mucosa Intestinal/metabolismo , Migração e Rolagem de Leucócitos/efeitos dos fármacos , Leucócitos/efeitos dos fármacos , Leucócitos/fisiologia , Camundongos , Infiltração de Neutrófilos/efeitos dos fármacos , Nitratos/metabolismo , Nitritos/metabolismo , Peroxidase/metabolismo , Fitoterapia , Casca de Planta , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico , Polissacarídeos/farmacologia , Polissacarídeos/uso terapêutico , Substâncias Protetoras/farmacologia , Substâncias Protetoras/uso terapêutico

RESUMO

Preclinical Research & Development The combination of nonsteroidal anti-inflammatory drugs (NSAIDs) with herbal products having analgesic and anti-inflammatory effects may increase their beneficial effects and limit their side effects. In this study, the effects of an interaction between α-bisabolol and the NSAID, diclofenac on nociception (formalin test), inflammation (paw inflammation produced by carrageenan) and gastric injury in rat was assessed. Diclofenac, α-bisabolol, or diclofenac-α-bisabolol combinations produced antinociceptive and anti-inflammatory effects in rat (p < .05). The systemic administration of diclofenac, but not α-bisabolol, produced gastric damage while the diclofenac-α-bisabolol combinations produced limited gastric damage. Effective dose (ED40 ) values were determined for each individual drug and analyzed isobolographically. The theoretical ED40 values for the antinociceptive (98.89 mg/kg) and the anti-inflammatory (41.2 mg/kg) effects differed from the experimental ED40 values (antinociception: 38.7 mg/kg and anti-inflammation: 13.4 mg/kg). We concluded that the interactions between diclofenac and α-bisabolol are synergistic. These data suggest that the diclofenac-α-bisabolol combinations can interact to produce minor gastric damage, thereby offering a safer therapeutic alternative for the clinical management of inflammation and/or inflammatory pain.

Assuntos

Analgésicos/uso terapêutico , Anti-Inflamatórios não Esteroides/uso terapêutico , Diclofenaco/uso terapêutico , Edema/tratamento farmacológico , Nociceptividade/efeitos dos fármacos , Sesquiterpenos/uso terapêutico , Animais , Carragenina , Sinergismo Farmacológico , Edema/induzido quimicamente , Formaldeído , Masculino , Sesquiterpenos Monocíclicos , Ratos Wistar , Estômago/efeitos dos fármacos , Estômago/patologia

RESUMO

Preclinical Research The coadministration of non-steroidal anti-inflammatory drugs (NSAIDs) with medicinal plant extracts may increase anti-inflammatory activity, thus permitting the use of lower NSAID doses and limiting the side effects. The aim of this study was to explore the interactions between an ethanolic extract of M. chamomilla extract (MCE) with two NSAIDs, diclofenac and indomethacin on carrageenan-induced paw inflammation and gastric injury in rats. Diclofenac, indomethacin and MCE, or combinations with MCE produced an anti-inflammatory effect. Effective dose (ED) values were estimated for the individual drugs, and isobolograms were constructed. The final experimental ED values were 483.7 mg/kg for diclofenac + MCE combination, and 212.6 mg/kg for indomethacin + MCE. These values were lower (p < 0.05) than the theoretical ED values (1186.9 mg/kg for diclofenac + MCE combination, and 1183.8 mg/kg for indomethacin + MCE). These data suggest that the interactions between NSAIDs and MCE that mediate the anti-inflammatory effects at the systemic level are synergistic and may have therapeutic advantages for the clinical treatment of inflammatory processes. Drug Dev Res 78 : 360-367, 2017. © 2017 Wiley Periodicals, Inc.

Assuntos

Carragenina/efeitos adversos , Diclofenaco/administração & dosagem , Indometacina/administração & dosagem , Inflamação/tratamento farmacológico , Matricaria/química , Extratos Vegetais/administração & dosagem , Animais , Diclofenaco/uso terapêutico , Relação Dose-Resposta a Droga , Sinergismo Farmacológico , Indometacina/uso terapêutico , Inflamação/induzido quimicamente , Masculino , Extratos Vegetais/uso terapêutico , Ratos , Ratos Wistar , Resultado do Tratamento

RESUMO

(-)-Linalool is a monoterpene constituent of many essential oils. This particular monoterpene has both anti-inflammatory and antimicrobial activity. Moreover, this compound has been shown to be antinociceptive. However, the poor chemical stability and short half-life prevents the clinical application of (-)-linalool and many other essential oils. Important to the topic of this study, ß-cyclodextrin (ß-CD) has been used to increase the solubility, stability, and pharmacological effects of numerous lipophilic compounds in vivo. In this study, the gastroprotective activities of (-)-linalool (LIN) and linalool incorporated into inclusion complex containing ß-cyclodextrin (LIN-ßCD) were evaluated using models of acute and chronic gastric ulcers in rodents. LIN and LIN-ßCD showed strong gastroprotective activity (p < 0.001). The LIN-ßCD complex revealed that the gastroprotective effect was significantly improved compared with LIN uncomplexed, suggesting that this improvement is related to increased solubility and stability. Taking together the potentiation of the antioxidant profile of this monoterpene, our results suggest that ß-CD may represent an important tool for improved gastroprotective activity of (-)-linalool and other water-insoluble compounds.

Assuntos

Antiulcerosos/farmacologia , Magnoliopsida , Monoterpenos/farmacologia , Óleos Voláteis/farmacologia , Óleos de Plantas/farmacologia , Úlcera Gástrica/prevenção & controle , Estômago/efeitos dos fármacos , beta-Ciclodextrinas/farmacologia , Ácido Acético , Monoterpenos Acíclicos , Animais , Antiulcerosos/química , Antiulcerosos/isolamento & purificação , Antioxidantes/isolamento & purificação , Antioxidantes/farmacologia , Citoproteção , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Estabilidade de Medicamentos , Quimioterapia Combinada , Etanol , Feminino , Mucosa Gástrica/metabolismo , Peroxidação de Lipídeos/efeitos dos fármacos , Magnoliopsida/química , Masculino , Camundongos , Monoterpenos/química , Monoterpenos/isolamento & purificação , Óleos Voláteis/isolamento & purificação , Peroxidase/metabolismo , Fitoterapia , Óleos de Plantas/isolamento & purificação , Plantas Medicinais , Ratos Wistar , Solubilidade , Estômago/patologia , Úlcera Gástrica/induzido quimicamente , Úlcera Gástrica/metabolismo , Úlcera Gástrica/patologia , Compostos de Sulfidrila/metabolismo

RESUMO

Novel complexes consisting of Eudragit E100-risedronate are presented. The oral bioavailability of risedronate in rats was determined through its percentage excreted in urine after administration of complexed or free risedronate in fed and fasted conditions. The evaluation of the risedronate gastro-duodenal irritation potential was carried out by macroscopic and histological analyses in an experimental rat model. The degree of counterionic condensation between Eudragit E100 and risedronate was assessed by dialysis with, mechanistic information about the interaction with calcium and the release of risedronate from the complexes being obtained using physiological solution and simulated gastric fluid without pepsin. Non-significant differences were observed in the urinary excretion of risedronate when the complex or free risedronate was administered to fasted rats. However, the urinary excretion of risedronate in the complex group was 4-times higher than in the free risedronate group when animals were concomitantly administered with food. This behavior was related to the high degree of counterionic condensation in the complex (86.5%), which led to a reduction in the calcium induced rate and magnitude of risedronate precipitation and resulted in a decrease in the gastroduodenal damage from the complex, as evidenced by a lower frequency of gastric mucosae hemorrhage. A sustained release of risedronate from the complex was observed toward water, simulated gastric fluid or physiological solution, through an ionic-exchange mechanism. In conclusion, complexation with Eudragit E100 could be a useful strategy to overcome the unfavorable properties of risedronate.

Assuntos

Acrilatos/química , Bloqueadores dos Canais de Cálcio/farmacologia , Química Farmacêutica , Interações Alimento-Droga , Polímeros/química , Ácido Risedrônico/farmacologia , Estômago/efeitos dos fármacos , Administração Oral , Animais , Bloqueadores dos Canais de Cálcio/química , Bloqueadores dos Canais de Cálcio/farmacocinética , Ingestão de Alimentos , Jejum , Técnicas In Vitro , Masculino , Ratos , Ratos Wistar , Ácido Risedrônico/química , Ácido Risedrônico/farmacocinética

RESUMO

OBJECTIVES: (-)-Myrtenol is a natural fragrance monoterpenoid structurally related to α-pinene found in diverse plant essential oils. This study was aimed to assess the anti-ulcerogenic potential of (-)-myrtenol against ethanol-induced gastric lesions and to elucidate the underlying mechanism(s). METHODS: Gastroprotective activity of (-)-myrtenol was evaluated using the mouse model of ethanol-induced gastric damage. To elucidate the gastroprotective mechanism(s), the roles of GABA, prostaglandins, nitric oxide and KATP channels were assessed. Besides, the oxidative stress-related parameters and the mucus content in gastric tissues were analysed. KEY FINDINGS: (-)-Myrtenol at oral doses of 25, 50 and 100 mg/kg significantly decreased the severity of ethanol-induced gastric lesions affording gastroprotection that was accompanied by a decrease in the activity of myeloperoxidase and malondialdehyde, an increase in GPx, SOD, and catalase activity in gastric tissues, and with well-maintained normal levels of nitrite/nitrate, gastric mucus and NP-SHs. Pretreatment with GABA-A receptor antagonist flumazenil, the COX inhibitor indomethacin, and NO synthesis inhibitor L-NAME but not with KATP channel blocker glibenclamide significantly blocked the (-)-myrtenol gastroprotection. CONCLUSION: These results provide first-time evidence for the gastroprotective effect of (-)-myrtenol that could be related to GABAA -receptor activation and antioxidant activity.

Assuntos

Antiulcerosos/farmacologia , Antioxidantes/farmacologia , Monoterpenos/farmacologia , Fitoterapia , Receptores de GABA-A/metabolismo , Úlcera Gástrica/metabolismo , Estômago/efeitos dos fármacos , Animais , Antiulcerosos/uso terapêutico , Antioxidantes/metabolismo , Antioxidantes/uso terapêutico , Monoterpenos Bicíclicos , Mucosa Gástrica/metabolismo , Masculino , Camundongos , Monoterpenos/uso terapêutico , Muco/metabolismo , Myrtus/química , Óleos Voláteis/química , Peroxidase/metabolismo , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico , Estômago/patologia , Úlcera Gástrica/prevenção & controle , Ácido gama-Aminobutírico/metabolismo

RESUMO

Chamomile (Matricaria chamomilla L., Asteraceae) is a medicinal plant widely used as remedy for pain and gastric disorders. The association of non-steroidal anti-inflammatory drugs (NSAIDs) with medicinal plant extracts may increase its antinociceptive activity, permit the use of lower doses and limit side effects. The aim was to isolate and identify the main chemical constituents of Matricaria chamomilla ethanolic extract (MCE) as well as to explore their activity as cyclooxygenase (COX) inhibitors in silico; besides, to examine the interaction between MCE and diclofenac on nociception in the formalin test by isobolographic analysis, and to determine the level of gastric injury in rats. Three terpenoids, α-bisabolol, bisabolol oxide A, and guaiazulene, were isolated and identified by (1)H NMR. Docking simulation predicted COX inhibitory activity for those terpenoids. Diclofenac, MCE, or their combinations produced an antinociceptive effect. The sole administration of diclofenac and the highest combined dose diclofenac-MCE produced significant a gastric damage, but that effect was not seen with MCE alone. An isobologram was constructed and the derived theoretical ED35 for the antinociceptive effect was significantly different from the experimental ED35; hence, the interaction between diclofenac and MCE that mediates the antinociceptive effect is synergist. The MCE contains three major terpenoids with plausible COX inhibitory activity in silico, but α-bisabolol showed the highest affinity. Data suggest that the diclofenac-MCE combination can interact at the systemic level in a synergic manner and may have therapeutic advantages for the clinical treatment of inflammatory pain.

Assuntos

Inibidores de Ciclo-Oxigenase 2/isolamento & purificação , Inibidores de Ciclo-Oxigenase 2/farmacologia , Diclofenaco/farmacologia , Matricaria/química , Simulação de Acoplamento Molecular , Nociceptividade/efeitos dos fármacos , Extratos Vegetais/farmacologia , Estômago/patologia , Animais , Inibidores de Ciclo-Oxigenase 2/química , Interações Medicamentosas , Sinergismo Farmacológico , Masculino , Atividade Motora/efeitos dos fármacos , Extratos Vegetais/química , Espectroscopia de Prótons por Ressonância Magnética , Ratos Wistar , Padrões de Referência , Estômago/efeitos dos fármacos , Termodinâmica

RESUMO

BACKGROUND: It has been reported that simvastatin, a statin commonly prescribed for its anti-inflammatory and antioxidant effects, has gastroprotective effects in indomethacin and ethanol-induced gastric ulcers. However, the effects of simvastatin on alendronate-induced gastric mucosal injury remain unexplored. AIM: This study investigated the use of simvastatin for the treatment of alendronate-induced gastric ulcers in rats. METHODS: Female rats were pretreated with vehicle or simvastatin (20 and 60 mg/kg p.o.). After 1 h, the rats received alendronate (50 mg/kg p.o.). Simvastatin was administered once daily for 7 days, and from the fourth day of simvastatin treatment, alendronate was administered once daily for 4 days. On the final day of treatment, 4 h after alendronate administration, animals were euthanized, their stomachs were removed, and gastric damage was measured. Samples of the stomach were fixed in 10 % formalin immediately after their removal for subsequent histopathological assessment. Unfixed samples were weighed, frozen at -80 °C until assayed for glutathione (GSH), malondialdehyde (MDA), and cytokine levels and myeloperoxidase (MPO) activity. A third group was used to measure mucus and gastric secretion. RESULTS: Pretreatment with simvastatin prevented alendronate-induced macroscopic gastric damage and reduced the levels of MDA and GSH, TNF-α and IL-1ß, MPO activity, and mucus levels, in the stomach. CONCLUSIONS: This study demonstrates the protective effects of simvastatin against alendronate-induced gastric ulceration. Maintenance of mucosal integrity, inhibition of neutrophil activity, and reduced oxidative stress associated with decreased gastric acidity may explain the gastroprotective effects of simvastatin.

Assuntos

Alendronato/toxicidade , Mucosa Gástrica/efeitos dos fármacos , Sinvastatina/farmacologia , Úlcera Gástrica/induzido quimicamente , Úlcera Gástrica/prevenção & controle , Animais , Conservadores da Densidade Óssea/toxicidade , Relação Dose-Resposta a Droga , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Glutationa/metabolismo , Inibidores de Hidroximetilglutaril-CoA Redutases/administração & dosagem , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Malondialdeído/metabolismo , Peroxidase/genética , Peroxidase/metabolismo , Ratos , Ratos Wistar , Sinvastatina/administração & dosagem , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo

RESUMO

Chronic use of alendronate has been linked to gastrointestinal tract problems. Our objective was to evaluate the role of the NO/cGMP/KATP signaling pathway and nitric oxide synthase expression in alendronate-induced gastric damage. Rats were either treated with the NO donor, sodium nitroprusside (SNP; 1, 3, and 10 mg/kg), or the NO synthase (NOS) substrate, L-arginine (L-Arg; 50, 100, and 200 mg/kg). Some rats were pretreated with either ODQ (a guanylate cyclase inhibitor; 10 mg/kg) or glibenclamide (KATP channels blocker; 10 mg/kg). In other experiments, rats were pretreated with L-NAME (non-selective NOS inhibitor; 10 mg/kg), 1400 W (selective inducible NOS [iNOS] inhibitor; 10 mg/kg), or L-NIO (a selective endothelial NOS [eNOS] inhibitor; 30 mg/kg). After 1 h, the rats were treated with alendronate (30 mg/kg) by gavage for 4 days. SNP and L-Arg prevented alendronate-induced gastric damage in a dose-dependent manner. Alendronate reduced nitrite/nitrate levels, an effect that was reversed with SNP or L-Arg treatment. Pretreatment with ODQ or glibenclamide reversed the protective effects of SNP and L-Arg. L-NAME, 1400 W, or L-NIO aggravated the severity of alendronate-induced lesions. In addition, alendronate reduced the expression of iNOS and eNOS in the gastric mucosa. Gastric ulcerogenic responses induced by alendronate were mediated by a decrease in NO derived from both eNOS and iNOS. In addition, our findings support the hypothesis that activation of the NO/cGMP/KATP pathway is of primary importance for protection against alendronate-induced gastric damage.

Assuntos

Alendronato/farmacologia , GMP Cíclico/metabolismo , Canais KATP/metabolismo , Óxido Nítrico Sintase/antagonistas & inibidores , Óxido Nítrico/metabolismo , Úlcera Gástrica/induzido quimicamente , Administração Oral , Alendronato/administração & dosagem , Animais , Relação Dose-Resposta a Droga , Feminino , Óxido Nítrico Sintase/biossíntese , Óxido Nítrico Sintase/metabolismo , Ratos , Ratos Wistar , Transdução de Sinais , Úlcera Gástrica/enzimologia , Úlcera Gástrica/metabolismo , Relação Estrutura-Atividade

RESUMO

Ethnobotanical claims regarding Kigelia africana reported antiulcer properties as part of its medicinal application. In this work, aqueous leaf extract from K. africana was investigated for its phytochemical constituents and antiulcer potential against ethanol-induced ulcer in rats. The participation of oxidative stress on ethanol-induced ulcer and the potential protective antioxidant activity of K. africana extracts were investigated by determining vitamin C and thiobarbituric acid reactive species (TBARS) contents in the gastric mucosa of rats. The HPLC analysis showed the presence of gallic acid, chlorogenic acid, caffeic acid and also the flavonoids rutin, quercetin and kaempferol in the aqueous plant extract. Oral treatment with K. africana extract (1.75; 3.5; 7 and 14 mg/kg) one hour after ulcer induction with ethanol decreased in a dose dependent manner the ulcer index. Ethanol increased significantly stomachal TBARS levels and decreased vitamin C content when compared to the control animals. K. africana blunted the ethanol-induced oxidative stress and restored vitamin C content to the control levels. The present results indicate that the aqueous leaf extract from K. africana possesses antiulcer potential. The presence of flavonoids in plant extract suggests that its antiulcerogenic potential is associated with antioxidant activity. Of particular therapeutic potential, K. africana was effective against ethanol even after the induction of ulcer, indicating that it can have protective and curative effects against gastric lesion.

RESUMO

Our objective was to investigate the protective effect of Lawesson's reagent, an H2S donor, against alendronate (ALD)-induced gastric damage in rats. Rats were pretreated with saline or Lawesson's reagent (3, 9, or 27 µmol/kg, po) once daily for 4 days. After 30 min, gastric damage was induced by ALD (30 mg/kg) administration by gavage. On the last day of treatment, the animals were killed 4 h after ALD administration. Gastric lesions were measured using a computer planimetry program, and gastric corpus pieces were assayed for malondialdehyde (MDA), glutathione (GSH), proinflammatory cytokines [tumor necrosis factor (TNF)-α and interleukin (IL)-1β], and myeloperoxidase (MPO). Other groups were pretreated with glibenclamide (5 mg/kg, ip) or with glibenclamide (5 mg/kg, ip)+diazoxide (3 mg/kg, ip). After 1 h, 27 µmol/kg Lawesson's reagent was administered. After 30 min, 30 mg/kg ALD was administered. ALD caused gastric damage (63.35±9.8 mm2); increased levels of TNF-α, IL-1β, and MDA (2311±302.3 pg/mL, 901.9±106.2 pg/mL, 121.1±4.3 nmol/g, respectively); increased MPO activity (26.1±3.8 U/mg); and reduced GSH levels (180.3±21.9 µg/g). ALD also increased cystathionine-γ-lyase immunoreactivity in the gastric mucosa. Pretreatment with Lawesson's reagent (27 µmol/kg) attenuated ALD-mediated gastric damage (15.77±5.3 mm2); reduced TNF-α, IL-1β, and MDA formation (1502±150.2 pg/mL, 632.3±43.4 pg/mL, 78.4±7.6 nmol/g, respectively); lowered MPO activity (11.7±2.8 U/mg); and increased the level of GSH in the gastric tissue (397.9±40.2 µg/g). Glibenclamide alone reversed the gastric protective effect of Lawesson's reagent. However, glibenclamide plus diazoxide did not alter the effects of Lawesson's reagent. Our results suggest that Lawesson's reagent plays a protective role against ALD-induced gastric damage through mechanisms that depend at least in part on activation of ATP-sensitive potassium (KATP) channels.

Assuntos

Animais , Feminino , Ratos , Alendronato/antagonistas & inibidores , Mucosa Gástrica/efeitos dos fármacos , Sulfeto de Hidrogênio/farmacologia , Indicadores e Reagentes/farmacologia , Compostos Organotiofosforados/farmacologia , Gastropatias/induzido quimicamente , Análise de Variância , Cistationina gama-Liase/análise , Diagnóstico por Computador , Diazóxido/administração & dosagem , Mucosa Gástrica/patologia , Glutationa/análise , Glibureto/administração & dosagem , Interleucina-1beta/análise , Canais KATP/farmacologia , Malondialdeído/análise , Peroxidase/análise , Peroxidase/metabolismo , Ratos Wistar , Gastropatias/enzimologia , Gastropatias/patologia , Fator de Necrose Tumoral alfa/análise

RESUMO

Seaweeds are the most abundant source of polysaccharides such as alginates and agar, as well as carrageenans. This study aimed to investigate the gastroprotective activity and the mechanism underlying this activity of a sulfated-polysaccharide fraction extracted from the algae Hypnea musciformis (Wulfen) J.V. Lamour. (Gigartinales-Rhodophyta). Mice were treated with sulfated-polysaccharide fraction (3, 10, 30, and 90 mg/kg, p.o.) and, after 30 min, they were administered 50% ethanol (0.5 mL/25 g, p.o.). After 1 h, gastric damage was measured using a planimeter. In addition, samples of the stomach tissue were obtained for histopathological examination and for assays to determine the glutathione and malondialdehyde levels. Other groups of mice were pretreated with N G-nitro-L-arginine methyl ester (L-NAME, 10 mg/kg, i.p.), aminoguanidine (100 mg/kg, i.p.), or glibenclamide (10 mg/kg, i.p.). After 30 min to the aminoguanidine group and 1 h to the other groups, sulfated-polysaccharide fraction (30 mg/kg, p.o.) was administered and gastric damage was induced as described above. Sulfated-polysaccharide fraction prevented ethanol-induced gastric injury in a dose-dependent manner. However, treatment with L-NAME or glibenclamide reversed this gastroprotective effect. Administration of aminoguanidine did not influence the effect of sulfated-polysaccharide fraction. Our results suggest that sulfated-polysaccharide fraction exerts a protective effect against ethanol-induced gastric damage via activation of the NO/K ATP pathway.