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1.
Chem Biol Interact ; 339: 109445, 2021 Apr 25.
Artigo em Inglês | MEDLINE | ID: mdl-33741339

RESUMO

Taxifolin (3,5,7,3,4-pentahydroxy flavanone or dihydroquercetin, Tax) was identified as a gastroprotective compound and a gastroadhesive formulation was recently developed to prolong its residence time and release in the stomach. So, the gastric healing effectiveness of Tax and gastro-mucoadhesive microparticles containing Tax (MPTax) against the acetic acid induced-gastric ulcer in rats was investigated in this study. Moreover, the interactions between Tax and H+/K+-ATPase were investigated in silico, and its anti- H. pylori activity was determined in vitro. The oral treatment with MPTax (81.37 mg/kg, containing 12.29% of Tax) twice a day for seven days reduced the ulcer area by 63%, compared to vehicle-treated group (Veh: 91.9 ± 10.3 mm2). Tax (10 mg/kg, p.o) reduced the ulcer by 40% but with a p = 0.07 versus Veh group. Histological analysis confirmed these effects. Tax and MPTax increased the gastric mucin amount, reduced the myeloperoxidase activity, and increased the glutathione reduced content at ulcer site. However, only MPTax decreased the lipoperoxide accumulation at ulcer site. Besides, Tax and MPTax normalize the catalase and glutathione S-transferase activity. Tax showed reversible interaction with H+/K+-ATPase in silico and its anti-H. pylori effects was confirmed (MIC = 625 µg/mL). These results suggest that the antiulcer property of Tax involves the strengthening of the gastric protective factors in parallel to its inhibitory interaction with H+/K+-ATPase and H. pylori. Considering that ulcer healing action displayed by Tax was favored by gastroadhesive microparticles, this approach seems to be promising for its oral delivery to treat acid-peptic diseases.


Assuntos
Adesivos/farmacologia , Helicobacter pylori/efeitos dos fármacos , Bombas de Próton/fisiologia , Quercetina/análogos & derivados , Estômago/efeitos dos fármacos , Cicatrização/efeitos dos fármacos , Ácido Acético/farmacologia , Animais , Antiulcerosos/farmacologia , Antioxidantes/metabolismo , Catalase/metabolismo , Simulação por Computador , Feminino , Mucinas Gástricas/metabolismo , Mucosa Gástrica/efeitos dos fármacos , Mucosa Gástrica/metabolismo , ATPase Trocadora de Hidrogênio-Potássio/metabolismo , Infecções por Helicobacter/tratamento farmacológico , Infecções por Helicobacter/metabolismo , Infecções por Helicobacter/microbiologia , Fitoterapia/métodos , Extratos Vegetais/farmacologia , Quercetina/fisiologia , Ratos , Ratos Wistar , Úlcera Gástrica/induzido quimicamente , Úlcera Gástrica/tratamento farmacológico , Úlcera Gástrica/metabolismo , Úlcera Gástrica/microbiologia
2.
Int J Nanomedicine ; 15: 10099-10112, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33363369

RESUMO

Background: Gastric ulcer is a prevalent disease with various etiologies, including non-steroidal anti-inflammatory drugs and alcohol consumption. This study aimed to explore the dual gastric protection effect of tadalafil and limonene as a self-nanoemulsifying system (SNES)-based orodispersible tablets. Methods: Tadalafil-loaded limonene-based SNES was prepared, and the optimum formula was characterized in terms of particle size (PS), polydispersity index (PDI), and zeta potential (ZP) then loaded on various porous carriers to formulate lyophilized orodispersible tablets (ODTs). The ODTs were evaluated via determining hardness, friability, content uniformity, wetting, and disintegration time. The selected ODT was examined for its gastric ulcer protective effect against alcohol-induced ulcers in rat model. Ulcer score and ulcer index were computed for rats stomachs that were inspected macroscopically and histopathologically. Results: The prepared SNES had droplet size of 104 nm, polydispersity index of 0.2, and zeta potential of -15.4 mV. From the different ODTs formulated, the formula with superior wetting time: 23.67 s, outstanding disintegration time: 28 s, accepted hardness value: 3.11 kg/cm2 and friability: 0.6% was designated. A significant gastroprotective effect of the unloaded and tadalafil-loaded ODTs was recognized compared to the omeprazole pre-treated group. Moreover, the histopathological analysis displayed very mild inflammation in the limonene-based ODTs group and intact structure in the tadalafil-loaded pre-treated animals. Conclusion: Limonene gastroprotective effect functioned along with tadalafil in the form of SNES-incorporated ODTs could serve as a promising revenue for better efficacy in gastric ulcer prevention.


Assuntos
Composição de Medicamentos , Limoneno/química , Substâncias Protetoras/farmacologia , Estômago/efeitos dos fármacos , Tadalafila/administração & dosagem , Tadalafila/farmacologia , Administração Oral , Animais , Sistemas de Liberação de Medicamentos , Emulsões/química , Liofilização , Dureza , Masculino , Porosidade , Ratos Wistar , Solubilidade , Estômago/patologia , Úlcera Gástrica/tratamento farmacológico , Úlcera Gástrica/patologia , Comprimidos , Tadalafila/uso terapêutico , Termodinâmica , Água/química
3.
Anticancer Res ; 40(10): 5393-5397, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32988858

RESUMO

BACKGROUND/AIM: We established a new patient-derived orthotopic xenograft (PDOX) model of gastric cancer liver metastasis and evaluated the efficacy of a novel combination chemotherapy, gemcitabine (GEM) plus 5-fluorouracil (5-FU), compared to a standard regimen of oxaliplatinum (L-OHP) plus 5-FU on the liver metastasis. MATERIALS AND METHODS: Patient-derived gastric cancer was established in nude mice from the patient' s surgical tumor specimen. A single tumor fragment was implanted in the liver of nude mice. The mice with tumors were treated by GEM plus 5-FU or L-OHP plus 5-FU. RESULTS: GEM plus 5-FU or L-OHP plus 5-FU significantly and similarly inhibited tumor growth on the liver compared to the untreated control (p=0.007, p=0.02, respectively). CONCLUSION: GEM plus 5-FU could be a novel future clinical alternative to L-OHP plus 5-FU in gastric cancer patients who cannot tolerate platinum drugs.


Assuntos
Desoxicitidina/análogos & derivados , Fluoruracila/farmacologia , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Gástricas/tratamento farmacológico , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Desoxicitidina/farmacologia , Modelos Animais de Doenças , Humanos , Neoplasias Hepáticas/patologia , Camundongos , Oxaliplatina/farmacologia , Estômago/efeitos dos fármacos , Estômago/patologia , Neoplasias Gástricas/patologia , Ensaios Antitumorais Modelo de Xenoenxerto
4.
Int. j. morphol ; 38(4): 940-946, Aug. 2020. tab, graf
Artigo em Inglês | LILACS | ID: biblio-1124880

RESUMO

Solanum nigrum (SLN), commonly known as African nightshade, is used as a vegetable as well as in the management and treatment of various ailments including gastric ulcers. We analyzed, both grossly and microscopically using H&E, Masson's trichrome and PSA staining methods, the protective effects of aqueous leaf extracts of three Kenyan SLN genotypes namely S. scabrum (SSB), S. sarrachoides (SSR) and S. villosum (SVL) on ethanol-induced gastric lesions in rats. There was evidence of gastro-protection by all the three genotypes with the SSB showing the highest ulcer inhibition score (76.37 %) followed by SSR (72.51 %) and SVL (63.30 %). SLN-pretreated rats showed less areas of gastric mucosal surface erosion. Additionally in the pretreated animals, the depth of the ulcers were markedly reduced, reaching only the gastric pit region except in those treated with SVL where the ulcers penetrated slightly more deeply to affect the gastric glands. Compared with controls, the mean microscopic ulcer index decreased 5.07, 3.55 and 2.37-fold in rats pretreated with SSB, SSR and SVL extracts respectively. Results of this work show extracts of the three SLN genotypes to have antiulcerogenic potential but at varied strengths, thus confirming earlier reports that phytoconstituents and hence the efficacy of a medicinal plant may be influenced by genetic factors.


Solanum nigrum (SLN), comúnmente conocida como la solanácea africana, se usa como vegetal, para el tratamiento de diversas dolencias incluyendo las úlceras gástricas. Analizamos de forma macro y microscópica, de forma macroscópica y microscópica, utilizando para ello tinciones de H&E, tricrómico de Masson y PSA los efectos protectores de extractos acuosos de hojas de tres genotipos SLN de Kenia: S. scabrum (SSB), S. sarrachoides (SSR) and S. villosum (SVL) en lesiones gástricas inducidas por etanol en ratas. Hubo evidencia de gastroprotección por parte de los tres genotipos con el SSB mostrando el puntaje más alto de inhibición de la úlcera (76,37 %) seguido de SSR (72,51 %) y SVL (63,30 %). Las ratas tratadas previamente con SLN mostraron menos áreas de erosión de la superficie de la mucosa gástrica. Además, en los animales pretratados, la profundidad de las úlceras se redujo notablemente, llegando solo a la región del fondo gástrico, excepto en aquellos tratados con SVL donde las úlceras penetraron un poco más profundamente para afectar las glándulas gástricas. En comparación con los controles, el índice medio de úlcera microscópica disminuyó 5,07, 3,55 y 2,37 veces en ratas pretratadas con extractos de SSB, SSR y SVL, respectivamente. Los resultados de este trabajo muestran que los extractos de los tres genotipos de SLN tienen potencial antiulcerogénico en diferentes concentraciones, lo que confirma informes anteriores que los fitoconstituyentes y la eficacia de una planta medicinal pueden estar influenciados por factores genéticos.


Assuntos
Animais , Ratos , Úlcera Gástrica/tratamento farmacológico , Extratos Vegetais/uso terapêutico , Solanum nigrum/química , Antiulcerosos/uso terapêutico , Estômago/efeitos dos fármacos , Ratos Wistar , Substâncias Protetoras , Preparações de Plantas/farmacologia , Quênia , Antiulcerosos/farmacologia
5.
Mutat Res ; 854-855: 503201, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32660825

RESUMO

Oxidative stress is a critical factor in the pathogenesis of several gastrointestinal diseases. Sulforaphane (SFN), a bioactive compound found in cruciferous vegetables, activates the redox-sensitive nuclear erythroid 2-related factor 2 (NRF2). In addition to its protective role, SFN exerts cytotoxic effects on cancer cells. However, there is a lack of information concerning the toxicity of SFN in normal cells. We investigated the effects of SFN on cell viability, antioxidant defenses, and gene expression in human stomach mucosa cells (MNP01). SFN reduced ROS formation and protected the cells against induced oxidative stress but high concentrations increased apoptosis. An intermediate SFN concentration (8 µM) was chosen for RNA sequencing studies. We observed upregulation of genes of the NRF2 (antioxidant) pathway, the DNA damage response, and apoptosis signaling; whereas SFN downregulated cell cycle and DNA repair pathway genes. SFN may be cytoprotective at low concentrations and cytotoxic at high concentrations.


Assuntos
Apoptose/efeitos dos fármacos , Isotiocianatos/farmacologia , Membrana Mucosa/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Estômago/efeitos dos fármacos , Transcrição Genética/efeitos dos fármacos , Anticarcinógenos/farmacologia , Antioxidantes/farmacologia , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Humanos , Membrana Mucosa/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Oxirredução/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos , Regulação para Cima/efeitos dos fármacos
6.
Life Sci ; 256: 117915, 2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32504752

RESUMO

AIMS: Autonomic dysfunction in arterial hypertension affects cardiorespiratory control and gastric motility and has been characterized by increased sympathetic and reduced parasympathetic activity. In the present work we investigated the effects of anticholinesterase drugs [donepezil (DON) or pyridostigmine (PYR)] on cardiovascular, autonomic, and gastric parameters in L-NAME-induced hypertensive rats. MATERIALS AND METHODS: Daily oral gavage of L-NAME (70 mg/kg/day) was performed over 14 days in male Wistar rats (180-220 g), whereas daily oral gavage of DON or PYR (1.6 and 22 mg/kg/day, respectively) started 2 days after the L-NAME treatment initiation and lasted 12 days. The development of hypertension was verified by tail plethysmography technique. After the end of treatments, the animals were subjected to experimental protocols (6-12 animals per group; total number of animals used: 78). KEY FINDINGS: L-NAME hypertensive animals had no alterations in heart rate (HR) and intrinsic HR, but showed reduction in baroreflex sensitivity, parasympathetic tone, and gastric motility; and the sympathetic tone, chemoreflex sensitivity, and the LF (low frequency) band of systolic arterial pressure (SAP) variability were increased. DON or PYR attenuated the increase in mean arterial pressure (MAP) induced by L-NAME. Both anticholinesterase drugs were effective in preventing the decrease in baroreflex sensitivity, parasympathetic tone and gastric motility, and also prevented the increases in peripheral chemoreflex response and cardiac sympathetic tone. SIGNIFICANCE: Acetylcholinesterase inhibition with DON or PYR is a promising pharmacological approach to increase parasympathetic function, thus preventing the hypertension-induced alterations in the cardiovascular, gastrointestinal and autonomic systems.


Assuntos
Acetilcolinesterase/metabolismo , Inibidores da Colinesterase/farmacologia , Hipertensão/prevenção & controle , NG-Nitroarginina Metil Éster/efeitos adversos , Substâncias Protetoras/farmacologia , Brometo de Piridostigmina/farmacologia , Animais , Pressão Arterial/efeitos dos fármacos , Sistema Nervoso Autônomo/efeitos dos fármacos , Barorreflexo/efeitos dos fármacos , Sistema Cardiovascular/efeitos dos fármacos , Inibidores da Colinesterase/metabolismo , Modelos Animais de Doenças , Donepezila/metabolismo , Donepezila/farmacologia , Frequência Cardíaca , Hipertensão/metabolismo , Masculino , Substâncias Protetoras/metabolismo , Brometo de Piridostigmina/metabolismo , Ratos , Ratos Wistar , Estômago/efeitos dos fármacos , Volume Sistólico
7.
Int J Nanomedicine ; 15: 2529-2539, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32346290

RESUMO

Background: Peptic ulcer disease, a painful lesion of the gastric mucosa, is considered one of the most common gastrointestinal disorders. This study aims to investigate the formulation of pumpkin seed oil (PSO)-based nanostructured lipid carriers (NLCs) to utilize PSO as the liquid lipid component of NLCs and to achieve oil dispersion in the nano-range in the stomach. Methods: Box-Behnken design was utilized to deduce the optimum formula with minimum particle size. The optimized PSO-NLCs formula was investigated for gastric ulcer protective effects in Wistar rats by evaluating ulcer index and determination of gastric mucosa oxidative stress parameters. Results: PSO was successfully incorporated as the liquid lipid (LL) component of NLCs. The prepared optimum PSO-NLCs formula showed a size of 64.3 nm. Pretreatment of animals using the optimized PSO-NLCs formula showed significantly (p< 0.001) lower ulcer index compared to indomethacin alone group and significantly (p<0.05) less mucosal lesions compared to the raw oil. Conclusion: These results indicated great potential for future application of optimized PSO-NLCs formula for antiulcer effect in non-steroidal anti-inflammatory drug (NSAID)-induced gastric ulcer.


Assuntos
Anti-Inflamatórios não Esteroides/uso terapêutico , Cucurbita/química , Portadores de Fármacos/química , Lipídeos/química , Nanoestruturas/química , Óleos Vegetais/química , Úlcera Gástrica/tratamento farmacológico , Animais , Modelos Animais de Doenças , Mucosa Gástrica/efeitos dos fármacos , Mucosa Gástrica/patologia , Indometacina/uso terapêutico , Masculino , Estresse Oxidativo/efeitos dos fármacos , Tamanho da Partícula , Ratos Wistar , Reprodutibilidade dos Testes , Espectroscopia de Infravermelho com Transformada de Fourier , Estômago/efeitos dos fármacos , Estômago/patologia , Úlcera Gástrica/patologia
8.
Anticancer Res ; 40(4): 1897-1904, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32234878

RESUMO

BACKGROUND/AIM: We investigated the clinical role of the molecular targets, APEX1 and Jagged-1, and the Apex1 - Jagged-1 cascade in gastric cancer cells. MATERIALS AND METHODS: We used 6 human gastric cancer cell lines (SNU-1, SNU-5, SNU-16, NCI-N87, KATO- III and AGS), and demonstrated the chemosensitivity of APEX1 and Jagged-1 through the MTT assay and immunoblotting. Tumor growth was assayed following cisplatin and 5-FU treatment using a xenograft model injected with KATO-III cells. Moreover, gastric tumor samples from 9 patients, divided in 2 groups according to chemotherapy response, were examined by immunocytochemical (IHC) staining, and protein expression levels were scored. RESULTS: Following APEX1 knockdown, the MTT assay revealed that the IC50 of cisplatin and 5-FU in AGS cells was decreased approximately 7% and 15%, respectively, however, their decrease in chemoresistant KATO-III cells was decreased by approximately 21% and 67% for cisplatin and 5-FU, respectively. The tumor volume of KATO-III/sicontrol mice treated with cisplatin and 5-FU was affected less, compared with KATO-III/siAPEX1 mice treated with cisplatin and 5-FU. Also, the expression levels of APEX1, Jagged-1 and CD133, assayed by IHC staining, were higher in the chemorefractory group than in the chemoresponsive group. CONCLUSION: Jagged-1-activated signaling by APEX1 plays a role in advanced gastric cancer.


Assuntos
DNA Liase (Sítios Apurínicos ou Apirimidínicos)/genética , Resistencia a Medicamentos Antineoplásicos/genética , Proteína Jagged-1/genética , Neoplasias Gástricas/tratamento farmacológico , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cisplatino/farmacologia , Fluoruracila/farmacologia , Humanos , Camundongos , Estadiamento de Neoplasias , Estômago/efeitos dos fármacos , Estômago/patologia , Neoplasias Gástricas/genética , Neoplasias Gástricas/patologia , Ensaios Antitumorais Modelo de Xenoenxerto
9.
Food Funct ; 11(1): 722-729, 2020 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-31912082

RESUMO

The objective of this study was to evaluate the benefits of a new extraction process, the ipowder® technology, applied to Melissa officinalis L. Compared to M. officinalis ground dry leaves, the ipowder® had a similar phytochemical fingerprint but contained twice the concentration of rosmarinic acid (by HPTLC and HPLC) and had a two-fold greater antioxidant activity (DPPH* method). In vitro digestion experiments (TIM-1 model) showed better availability of rosmarinic acid for intestinal absorption with the ipowder® than with ground dry leaves, manifested by a three-fold reduction in the quantity of ingested product needed for delivery of the same amount of rosmarinic acid into the upper gastro-intestinal tract. This study shows that the ipowder® technology preserves all the original plant compounds intact while making some active ingredients more accessible and available to exert their effects. To obtain a given effect, the amount of ipowder® extract to ingest will therefore be lower; a reduction in the daily dosage will be more convenient for the patient and will improve patient compliance with supplementation.


Assuntos
Antioxidantes/química , Cinamatos/química , Depsídeos/química , Intestinos/efeitos dos fármacos , Melissa , Extratos Vegetais/química , Estômago/efeitos dos fármacos , Antioxidantes/farmacologia , Cinamatos/farmacologia , Depsídeos/farmacologia , Composição de Medicamentos , Humanos , Técnicas In Vitro , Modelos Anatômicos , Fitoterapia , Folhas de Planta/química
10.
Food Chem Toxicol ; 136: 111080, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31891755

RESUMO

Fumonisin B1 (FB1) is a mycotoxin, produced by Fusarium verticillioides and Fusarium proliferatum, and a common fungal contaminant of maize worldwide. Its potential health hazard as a natural toxin is well documented in human and domestic animals. However, the molecular mechanism and the key factors responsible for FB1-induced cytotoxicity have not been elucidated. In this study, we first examined the cytotoxicity induced by FB1 in human gastric epithelial cell line (GES-1). We found that FB1 notably decreased cell viability and induced apoptotic cell death. Furthermore, the levels of ER stress markers were significantly increased after FB1 exposure and the ER stress inhibitor 4-phenylbutyric acid strongly suppressed FB1-induced cytotoxicity. Interestingly, the inhibition of PERK activity by GSK2606414 or shPERK3 blocked FB1-induced apoptotic cell death and cell proliferation suppression, which indicated that the cytotoxicity induced by FB1 was dependent on this signalling pathway. Moreover, myriocin could relieve FB1-induced ER stress and prevent cell death, which implied that the disruption of sphingolipid metabolism is an apical event for FB1-induced cytotoxicity. In the present study, we demonstrated that the ER stress-related PERK-CHOP signalling pathway is a novel mechanism for FB1-induced cytotoxicity and the gastrointestinal injury caused by FB1 should be concerned in the future.


Assuntos
Células Epiteliais/efeitos dos fármacos , Fumonisinas/toxicidade , Fator de Transcrição CHOP/metabolismo , eIF-2 Quinase/metabolismo , Linhagem Celular , Células Epiteliais/metabolismo , Humanos , Transdução de Sinais/efeitos dos fármacos , Estômago/citologia , Estômago/efeitos dos fármacos , Fator de Transcrição CHOP/genética , eIF-2 Quinase/genética
11.
Drug Dev Ind Pharm ; 46(2): 253-263, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31937139

RESUMO

Famotidine (FM) is considered among the first-line therapy for treatment of gastric ulcers; however, its poor aqueous solubility resulted in low bioavailability and limited therapeutic efficacy. Therefore, fast disintegrating tablet (FDT) incorporating FM solid dispersion was developed in a combined formulation approach for efficient treatment of ulcers. Within the investigated polymers, solid dispersions were prepared using the novel copolymer, Soluplus® (SP) by kneading and freeze-drying techniques at various FM:SP ratios. FM solid dispersion prepared at 1:10 ratio using freeze drying (FM-SP10) manifested the highest saturation solubility, having smooth porous surface with the complete conversion of FM to the amorphous form. FDTs of FM-SP10 was produced by direct compression using three ready-to-use excipients; F-melt, Pearlitol Flash, and Fujicalin. All tablets showed adequate thickness, diameter, weight variation, drug content, and friability (<1%). Fujicalin-FDTs (FM-FDT-FU) exhibited the shortest disintegration time with almost complete dissolution of the drug (>95%) within 30 min. It also revealed remarkable antiulcerogenic effect on ethanol induced gastric ulcers in terms of ulcer and protection indices compared to the market product. Pretreated rats with FM-FDT-FU demonstrated normal gastric area with the absence of edema and leucocytes infiltration, supported by the histological examination. FM-FDT-FU administration protected the stomach from oxidative damage and severe inflammatory response via the significant increase of glutathione level and the decreased levels of nitric oxide, interleukin and cyclooxygenase. Thus, the present study provides a promising dosage form of FM characterized by superior antiulcerogenic potential with desired tableting properties.


Assuntos
Famotidina/química , Famotidina/farmacologia , Polietilenoglicóis/química , Polivinil/química , Solubilidade/efeitos dos fármacos , Úlcera Gástrica/tratamento farmacológico , Comprimidos/química , Comprimidos/farmacologia , Animais , Química Farmacêutica/métodos , Composição de Medicamentos/métodos , Excipientes/química , Inflamação/dietoterapia , Masculino , Polímeros/química , Ratos , Ratos Wistar , Estômago/efeitos dos fármacos
12.
PLoS One ; 15(1): e0227781, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31978146

RESUMO

BACKGROUND: Memantine, currently available for the treatment of Alzheimer's disease, is an uncompetitive antagonist of the N-methyl-D-aspartate type of glutamate receptors. Under normal physiologic conditions, these unstimulated receptor ion channels are blocked by magnesium ions, which are displaced after agonist-induced depolarization. In humans, memantine administration is associated with different gastrointestinal dysmotility side effects (vomiting, diarrhoea, constipation, motor-mediated abdominal pain), thus limiting its clinical use. Mechanism of these motility disorders has not been clarified yet. Pigs can be used in various preclinical experiments due to their relatively very similar gastrointestinal functions compared to humans. The aim of this study was to evaluate the impact of a single and repeated doses of memantine on porcine gastric myoelectric activity evaluated by means of electrogastrography (EGG). METHODS: Six adult female experimental pigs (Sus scrofa f. domestica, mean weight 41.7±5.0 kg) entered the study for two times. The first EGG was recorded after a single intragastric dose of memantine (20 mg). In the second part, EGG was accomplished after 7-day intragastric administration (20 mg per day). All EGG recordings were performed under general anaesthesia. Basal (15 minutes) and study recordings (120 minutes) were accomplished using an EGG stand (MMS, Enschede, the Netherlands). Running spectral analysis based on Fourier transform was used. Results were expressed as dominant frequency of gastric slow waves (DF) and power analysis (areas of amplitudes). RESULTS: Single dose of memantine significantly increased DF, from basic values (1.65±1.05 cycles per min.) to 2.86 cpm after 30 min. (p = 0.008), lasting till 75 min. (p = 0.014). Basal power (median 452; inter-quartile range 280-1312 µV^2) raised after 15 min. (median 827; IQR 224-2769; p = 0.386; NS), lasting next 30 min. Repetitively administrated memantine caused important gastric arrhythmia. Basal DF after single and repeated administration was not different, however, a DF increase in the second part was more prominent (up to 3.18±2.16 after 15 and 30 min., p<0.001). In comparison with a single dose, basal power was significantly higher after repetitively administrated memantine (median 3940; IQR 695-15023 µV^2; p<0.001). Next dose of 20 mg memantine in the second part induced a prominent drop of power after 15 min. (median 541; IQR 328-2280 µV^2; p<0.001), lasting till 120 min. (p<0.001). CONCLUSIONS: Both single and repeated doses of memantine increased DF. Severe gastric arrhythmia and long-lasting low power after repeated administration might explain possible gastric dysmotility side effects in the chronic use of memantine.


Assuntos
Antagonistas de Aminoácidos Excitatórios/efeitos adversos , Gastroenteropatias/induzido quimicamente , Motilidade Gastrointestinal/efeitos dos fármacos , Memantina/efeitos adversos , Estômago/efeitos dos fármacos , Administração Oral , Doença de Alzheimer/tratamento farmacológico , Animais , Modelos Animais de Doenças , Eletromiografia , Antagonistas de Aminoácidos Excitatórios/administração & dosagem , Feminino , Gastroenteropatias/diagnóstico , Gastroenteropatias/fisiopatologia , Motilidade Gastrointestinal/fisiologia , Humanos , Memantina/administração & dosagem , Estômago/fisiopatologia , Sus scrofa
13.
Int J Pharm ; 574: 118885, 2020 Jan 25.
Artigo em Inglês | MEDLINE | ID: mdl-31765775

RESUMO

The relatively simple technique of coaxial electrospraying allows to produce core-shell microparticles with potentially high encapsulation efficiencies. In this study, amorphous solid dispersions of a hydroxypropyl methylcellulose or polyvinlypyrrolidone based polymer matrix containing the active pharmaceutical ingredient darunavir were coated with a gastro-resistant shell polymer that does not dissolve at lower pH present in the stomach, but only later at a higher pH in the small intestine. A multitude of shell polymers were tested with the aim to identify a material that limits the drug release to less than 10% after two hours at a pH of 1 to comply with the European Pharmacopoeia regarding gastro-resistant formulations. In parallel, the core-shell structure of the particles was determined with confocal imaging and their surface morphology with SEM imaging. While the structural analysis revealed significant differences between the different formulations, all investigated shell polymers exhibited a burst drug release followed by a slow release for the remainder of a two hour period. Ultimately, the shell copolymer poly(methacrylic acid-co-methyl methacrylate), in particular for a monomer ratio 1/2, resulted consistently in darunavir release below the 10% upper limit compared to the other tested polymers, where such low releases were inaccessible. Further investigation of this shell polymer revealed that both the monomer ratio of methacrylic acid to methyl methacrylate in the copolymer and the utilized solvent are determining factors in the release performance of the final particles.


Assuntos
Darunavir/química , Mucosa Gástrica/metabolismo , Estômago/efeitos dos fármacos , Química Farmacêutica/métodos , Liberação Controlada de Fármacos , Derivados da Hipromelose/química , Metacrilatos/química , Tamanho da Partícula , Polímeros/química , Solventes/química
14.
Hum Exp Toxicol ; 39(4): 492-499, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31868530

RESUMO

The current study was undertaken to evaluate the effect of combined therapy of gabapentin and pantoprazole against forestomach and pylorus ligation-induced gastric esophageal reflux disease (GERD) in albino Wistar rats. Rats were randomly divided into five groups, each group consisting of six rats, fasted for 24 h, underwent forestomach and pylorus ligation, received normal saline (3 ml/kg, p.o.), normal control, toxic control, pantoprazole (30 mg/kg, p.o.), gabapentin (50 mg/kg, p.o.), or their combination. After 10 h, animals were killed by cervical dislocation and evaluated for pH of gastric content, volume of gastric juice, total acidity, and esophagitis index. Esophageal tissues were further analyzed for biochemical parameters such as superoxide dismutase, glutathione, catalase, thiobarbituric acid reactive substances, and protein carbonyl, and scanning electron microscopy (SEM) and histopathology were used for morphological evaluation. The results show the combination therapy of gabapentin and pantoprazole significantly inhibited the volume of gastric juice and total acidity esophagitis index and significantly increased the pH of gastric juice. Treatment with gabapentin and pantoprazole exhibited maximum antioxidant effect in comparison with monotherapy. Marked protection and restoration of normal morphology was observed through SEM and histopathology in the combination therapy as compared to monotherapy. Finally, it was concluded that combination therapy of pantoprazole and gabapentin has beneficial effect against GERD.


Assuntos
Gabapentina/uso terapêutico , Refluxo Gastroesofágico/prevenção & controle , Pantoprazol/uso terapêutico , Inibidores da Bomba de Prótons/uso terapêutico , Estômago/efeitos dos fármacos , Vias Aferentes/efeitos dos fármacos , Animais , Modelos Animais de Doenças , Quimioterapia Combinada , Gabapentina/administração & dosagem , Esvaziamento Gástrico/efeitos dos fármacos , Refluxo Gastroesofágico/patologia , Pantoprazol/administração & dosagem , Inibidores da Bomba de Prótons/administração & dosagem , Ratos Wistar , Estômago/inervação , Estômago/patologia
15.
Endocr J ; 67(1): 73-80, 2020 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-31611477

RESUMO

Those who smoke nicotine-based cigarettes have elevated plasma levels of ghrelin, a hormone secreted from the stomach. Ghrelin has various physiological functions and has recently been shown to be involved in regulating biological rhythms. Therefore, in this study, in order to clarify the significance of the plasma ghrelin increase in smokers, we sought to clarify how nicotine and ghrelin affect the expression dynamics of clock genes using a mouse model. A single dose of nicotine administered intraperitoneally increased plasma ghrelin concentrations transiently, whereas continuous administration of nicotine with an osmotic minipump did not induce any change in the plasma ghrelin concentration. Single administration of nicotine resulted in a transient increase in ghrelin gene expression in the pancreas but not in the stomach, which is the major producer of ghrelin. In addition, in the pancreas, the expression of clock genes was also increased temporarily. Therefore, in order to clarify the interaction between nicotine-induced ghrelin gene expression and clock gene expression in the pancreas, nicotine was administered to ghrelin gene-deficient mice. Administration of nicotine to ghrelin-gene deficient mice increased clock gene expression in the pancreas. However, upon nicotine administration to mice pretreated with octanoate to upregulate ghrelin activity, expression levels of nicotine-inducible clock genes in the pancreas were virtually the same as those in mice not administered nicotine. Thus, our findings indicate that pancreatic ghrelin may suppress nicotine-induced clock gene expression in the pancreas.


Assuntos
Peptídeos e Proteínas de Sinalização do Ritmo Circadiano/efeitos dos fármacos , Grelina/efeitos dos fármacos , Hipotálamo/efeitos dos fármacos , Nicotina/farmacologia , Agonistas Nicotínicos/farmacologia , Pâncreas/efeitos dos fármacos , RNA Mensageiro/efeitos dos fármacos , Estômago/efeitos dos fármacos , Fatores de Transcrição ARNTL/efeitos dos fármacos , Fatores de Transcrição ARNTL/genética , Animais , Proteínas CLOCK/efeitos dos fármacos , Proteínas CLOCK/genética , Caprilatos/farmacologia , Peptídeos e Proteínas de Sinalização do Ritmo Circadiano/genética , Criptocromos/efeitos dos fármacos , Criptocromos/genética , Mucosa Gástrica/efeitos dos fármacos , Mucosa Gástrica/metabolismo , Regulação da Expressão Gênica , Grelina/genética , Grelina/metabolismo , Transportador de Glucose Tipo 2/efeitos dos fármacos , Transportador de Glucose Tipo 2/genética , Hipotálamo/metabolismo , Camundongos , Nicotina/administração & dosagem , Agonistas Nicotínicos/administração & dosagem , Pâncreas/metabolismo , Proteínas Circadianas Period/efeitos dos fármacos , Proteínas Circadianas Period/genética
16.
Eur J Pharm Sci ; 142: 105117, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31682976

RESUMO

In fasting conditions, the gastrointestinal system contracts according to the interdigestive migrating motor complex (MMC), in which phases of quiescence (MMC phase I) alternate with phases of medium (MMC phase II) to very strong (MMC phase III) contractions. The time of drug intake relative to this cyclic motility pattern may cause variations in formulation behavior. To explore this hypothesis, a cross-over study was performed in healthy volunteers with an immediate release tablet of fosamprenavir (Telzir) which was administered in either MMC phase I or MMC phase II, as determined by high-resolution manometry. In the intestinal tract, fosamprenavir is rapidly hydrolyzed to the active compound amprenavir by alkaline phosphatases. Drug concentrations of both prodrug and drug were determined in the stomach and duodenum and linked to simultaneously assessed systemic concentrations. In 5 out of 6 healthy volunteers, the gastric release of fosamprenavir and the systemic uptake of amprenavir were affected by the MMC phase in which the tablet was administered. The intragastric disintegration of the tablet was faster and less variable after administration in MMC phase II, resulting in faster and less variable uptake of amprenavir in the systemic circulation. Mean plasma tmax values were 157 (±72.0) and 73.3 (±27.3) min after administration in MMC phase I and MMC phase II, respectively. The study clearly identified the time of oral drug intake relative to the interdigestive motility pattern as a possible source of variation in gastrointestinal drug behavior and absorption.


Assuntos
Carbamatos/uso terapêutico , Fármacos Gastrointestinais/uso terapêutico , Motilidade Gastrointestinal/efeitos dos fármacos , Organofosfatos/uso terapêutico , Estômago/efeitos dos fármacos , Sulfonamidas/uso terapêutico , Adulto , Estudos Cross-Over , Digestão/efeitos dos fármacos , Duodeno/efeitos dos fármacos , Feminino , Furanos , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem
17.
J Invest Surg ; 33(1): 97-105, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29842839

RESUMO

Background: The aim of this study was to evaluate the effect of acellular amniotic membrane matrix patch on healing cut surface after sleeve gastrectomy in rats. Methods: Thirty male Wistar albino rats were divided into three groups: control (n = 10), Experiment-1 (n = 10), and Experiment-2 (n = 10) groups. Control group rats underwent only sleeve gastrectomy with primary gastrorrhaphy. Experiment-1 group rats underwent sleeve gastrectomy, primary gastrorrhaphy and covered with acellular amniotic membrane matrix patch. Experiment-2 group rats underwent sleeve gastrectomy, incomplete primary gastrorrhaphy and covered with acellular amniotic membrane matrix patch. All rats were sacrificed on the fifth postoperative day. Macroscopic findings and histopathologic alterations were evaluated and compared. Results: There was a statistically significant difference between levels of PMNs, granulation formation and vascularization, distributions of edema, type of mucosal epithelium, and fibroblastic proliferation according to groups (p < 0.05). The PMNs level in the Experiment-1 group was significantly lower than the control group (p < 0.05). In experiment groups, the level of granulation tissue, vascularization and fibroblastic proliferation was significantly higher than the control group (p < 0.05). The levels of edema and type of mucosal epithelium of the experiment groups were significantly lower than the control group (p < 0.05). Conclusion: Covering sleeve gastrectomy cut surface area with acellular amniotic membrane matrix results better healing. Moreover, acellular amniotic membrane matrix provides safe healing even in incomplete sutured area.


Assuntos
Âmnio , Fístula Anastomótica/prevenção & controle , Cirurgia Bariátrica/efeitos adversos , Produtos Biológicos/administração & dosagem , Gastrectomia/efeitos adversos , Cicatrização/efeitos dos fármacos , Fístula Anastomótica/etiologia , Animais , Cirurgia Bariátrica/métodos , Modelos Animais de Doenças , Matriz Extracelular , Gastrectomia/métodos , Humanos , Masculino , Teste de Materiais , Obesidade Mórbida/cirurgia , Ratos , Ratos Wistar , Estômago/efeitos dos fármacos , Estômago/cirurgia , Técnicas de Sutura/efeitos adversos , Adesivos Teciduais/administração & dosagem , Extratos de Tecidos
18.
Anaesthesia ; 75(3): 323-330, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31802485

RESUMO

We aimed to compare the reliability of aspiration via a nasogastric tube with ultrasound for assessment of residual gastric volume. Sixty-one adult patients who were mechanically ventilated and received continuous enteral feeding through a nasogastric tube for > 48 h were included. A first qualitative and quantitative ultrasound examination of the gastric antrum was followed by gastric suctioning, performed by an operator blinded to the result of the ultrasound examination. A second ultrasound examination was performed thereafter, followed by re-injection of the aspirated gastric contents (≤ 250 ml) into the stomach. A third ultrasound assessment was then immediately performed. If the suctioned volume was ≥ 250 ml, 250 mg erythromycin was infused over 30 min. A fourth ultrasound was performed 90 min after the third. Sixty (98%) patients had a qualitatively assessed full stomach at first ultrasound examination vs. 52 (85%) after gastric suctioning (p = 0.016). The calculated gastric volume significantly decreased after gastric suctioning, without a significant decrease in the number of patients with volume ≥ 250 ml. Four of the nine patients with calculated gastric volume ≥ 250 ml had vomiting within the last 24 h (p = 0.013). The antral cross-sectional area significantly decreased between the third and the fourth ultrasound examination (p = 0.015). Erythromycin infusion did not make a significant difference to gastric volume (n = 10). Our results demonstrate that gastric suctioning is not a reliable tool for monitoring residual gastric volume. Gastric ultrasound is a feasible and promising tool for gastric volume monitoring in clinical practice.


Assuntos
Aspiração Respiratória de Conteúdos Gástricos/diagnóstico por imagem , Estômago/diagnóstico por imagem , Sucção/métodos , Adulto , Idoso , Antibacterianos/efeitos adversos , Estudos de Coortes , Eritromicina/efeitos adversos , Feminino , Esvaziamento Gástrico , Conteúdo Gastrointestinal , Humanos , Intubação Gastrointestinal , Masculino , Pessoa de Meia-Idade , Monitorização Intraoperatória , Estudos Prospectivos , Reprodutibilidade dos Testes , Estômago/anatomia & histologia , Estômago/efeitos dos fármacos , Ultrassonografia , Vômito/etiologia
19.
Environ Pollut ; 258: 113758, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31881510

RESUMO

Natural halloysite nanotubes (HNTs) with a hollow lumen are already applied in numerous fields and enter the environment in increasing quantities, which may have effects on animal and human health. However their in vivo toxicity in mammals is still largely unclear. The aim of this study is to assess acute oral toxicity of HNTs in the stomach of mice and recovery. Oral HNTs at low dose (5 mg HNTs/kg BW) for 30 days increased in daily food and water intake and promoted mouse growth with no obvious adverse effect on the stomach. The promotive effect on mouse growth disappeared after cessation of oral administration of the nanotubes. Oral HNTs for 30 days at high dose (50 mg HNTs/kg BW) induced Si and Al accumulation in the stomach, which caused oxidative stress, inflammation and iNOS-mediated damage in the organ. The damage in the stomach led to slight atrophic gastritis and reduced mouse growth. Oral HNTs-induced changes at high dose were not observed after a 30-days recovery period. The findings provided the evidence that oral HNTs-induced acute toxicity in the stomach was reversible. More importantly, this research showed that Al and Si were cleared out of the mice by hepatic excretion and renal excretion, respectively, during the recovery period. The results suggest that HNTs at low concentration in environments have no adverse effect on mice, while there are health risks to mice under severe contamination by HNTs.


Assuntos
Argila , Nanotubos/toxicidade , Óxido Nítrico Sintase Tipo II/metabolismo , Estômago/enzimologia , Administração Oral , Alumínio , Animais , Camundongos , Estresse Oxidativo , Silício , Estômago/efeitos dos fármacos , Testes de Toxicidade Aguda
20.
BMC Complement Altern Med ; 19(1): 345, 2019 Dec 02.
Artigo em Inglês | MEDLINE | ID: mdl-31791313

RESUMO

BACKGROUND: Cuphea ignea is one of the herbal resources belonging to Lythraceae family. Some species of this family have been used traditionally in South and Central America's folk medicine for treating stomach disorders. Therefore, the present study was performed to evaluate the gastropreventive effect of aqueous ethanolic extract of C. ignea aerial parts on ethanol-induced gastric ulcer. METHODS: Gastric ulcers were induced in Sprague Dawley rats using one oral dose of absolute ethanol (1.5 mL/rat). The C. ignea aerial parts extract at doses of 250 and 500 mg/kg body weight and ranitidine (a reference drug) at a dose of 30 mg/kg body weight were orally administrated daily for 7 days before ulcer induction. One hour after ethanol administration blood samples were collected and then stomachs of sacrificed rats were subjected to biochemical, macroscopic and microscopic studies. RESULTS: Oral administration of C. ignea extract significantly attenuated gastric ulcer as revealed by significant reduction in the gastric ulcer index and volume of gastric juice while significantly increased preventive percentage, gastric pH value and pepsin activity. Pre-treatment of C. ignea extract markedly improved the serum level of TNF-α, the gastric MPO activity and NO content. Furthermore, C. ignea pre-treatment significantly increased the gastric levels of enzymatic and non- enzymatic antioxidants namely CAT, SOD, GSH-Px, and GSH with concomitant reduction in MDA level compared with those in the ethanol group. These results were further supported by histopathological findings which revealed the curing effect of C. ignea on the hemorrhagic shock induced by ethanol toxicity. CONCLUSIONS: C. ignea extract showed a potential gastroprotective effect on ethanol-induced gastric ulcer, and its effect may be mediated through suppression of oxidative stress and gastric inflammation.


Assuntos
Antiulcerosos/farmacologia , Antioxidantes/farmacologia , Cuphea , Extratos Vegetais/farmacologia , Úlcera Gástrica , Animais , Etanol/efeitos adversos , Feminino , Ratos , Ratos Sprague-Dawley , Estômago/efeitos dos fármacos , Estômago/patologia , Úlcera Gástrica/induzido quimicamente , Úlcera Gástrica/metabolismo , Úlcera Gástrica/patologia
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