RESUMO
BACKGROUND: We previously demonstrated that Helicobacter pylori colonization evokes gastric mucosal inflammation and an extensive increase in lipid peroxides and glutathione in Mongolian gerbils. Zinc and its derivative, polaprezinc, have been reported to be potent antioxidants in gastric mucosa. AIM: To examine the effect of polaprezinc on gastric mucosal oxidative inflammation in H. pylori-colonized Mongolian gerbils. METHODS: Sixty-eight male Mongolian gerbils were orally inoculated with H. pylori (ATCC43504, 5 x 10(8) CFUs/gerbil; H. pylori group) and 35 gerbils were inoculated with the culture media (control group). Twenty-two gerbils in the H. pylori and 13 gerbils in the control group were fed with diets containing polaprezinc (0.06%, 100 mg/kg, 10 times the usual clinical dose) (H. pylori + polaprezinc group, polaprezinc group). The remaining gerbils were fed a standard laboratory chow diet. Neutrophil infiltration, assessed histologically and by the activity of myeloperoxidase, the contents of CXC-chemokine (GRO/CINC-1-like protein) and the contents of thiobarbituric acid-reactive substances, was evaluated in each group 12 weeks after the inoculation. Separately, gastric mucosal leucocyte activation and capillary perfusion were also assessed using intravital microscopy 2, 4, 8 and 12 weeks after the inoculation. RESULTS: In all H. pylori-inoculated animals, the bacterial infection persisted throughout the experimental period. Gastric mucosal lesion formation in the H. pylori group was significantly inhibited in the H. pylori + polaprezinc group. Elevated levels of myeloperoxidase activity, GRO/CINC-1 and thiobarbituric acid-reactive substances in the H. pylori group at 12 weeks were attenuated significantly by polaprezinc treatment. Enhanced levels of venular leucocyte activation observed in the H. pylori group were attenuated significantly in the H. pylori + polaprezinc group during both the early phase (2 weeks) and late phase (12 weeks). CONCLUSION: Polaprezinc inhibited H. pylori-associated gastric mucosal oxidative inflammation, including initial micro-vascular leucocyte activation, in Mongolian gerbils.
Assuntos
Antiulcerosos/farmacologia , Carnosina/análogos & derivados , Carnosina/farmacologia , Mucosa Gástrica/imunologia , Infecções por Helicobacter/imunologia , Helicobacter pylori/patogenicidade , Leucócitos/imunologia , Compostos Organometálicos/farmacologia , Animais , Modelos Animais de Doenças , Mucosa Gástrica/patologia , Gerbillinae , Infecções por Helicobacter/patologia , Infecções por Helicobacter/veterinária , Inflamação , Masculino , Oxirredução , Compostos de ZincoRESUMO
We examined the roles of lipid peroxidation, neutrophil accumulation, and inflammatory cytokines in the protective effect of polaprezinc against aspirin-induced gastric mucosal injury in rats. The intragastric administration of acidified aspirin induced hyperemia and hemorrhagic erosions in rat stomachs. The increase in the total gastric erosive area after aspirin administration was significantly inhibited in a dose-dependent manner by treatment with polaprezinc. The increases in thiobarbituric acid-reactive substances and tissue-associated myeloperoxidase activity 3 hr after aspirin administration were significantly inhibited by pretreatment with polaprezinc. The gastric concentration of TNF-alpha increased after aspirin administration, and the increase was also inhibited in a dose-dependent manner by treatment with polaprezinc. The peak expression of TNF-alpha mRNA 1 hr after aspirin administration was inhibited by 30 mg/kg of polaprezinc. Based on these data, the beneficial effects of polaprezinc on aspirin-induced gastric mucosal injury may be attributed to its antioxidative and antiinflammatory properties.
Assuntos
Anti-Inflamatórios não Esteroides/efeitos adversos , Antiulcerosos/farmacologia , Aspirina/efeitos adversos , Carnosina/análogos & derivados , Carnosina/farmacologia , Peroxidação de Lipídeos/efeitos dos fármacos , Neutrófilos/efeitos dos fármacos , Compostos Organometálicos/farmacologia , Gastropatias/induzido quimicamente , Gastropatias/prevenção & controle , Fator de Necrose Tumoral alfa/biossíntese , Fator de Necrose Tumoral alfa/efeitos dos fármacos , Animais , Mucosa Gástrica , Masculino , Ratos , Ratos Sprague-Dawley , Gastropatias/imunologia , Gastropatias/metabolismo , Compostos de ZincoRESUMO
1. The relationship between plasma levels of a new H2-receptor antagonist, Z-300, and an active sulphoxide metabolite, and inhibitory effects on gastric acid secretion after intravenous or oral administration to dog have been examined. After both routes of administration, Z-300 in plasma eliminated with two phases, and the terminal half-lives were approximately 2 h. The level of sulphoxide in plasma reached a maximum at 0.6-0.7 h after administration, then subsequently eliminated with a half-life of approximately 6 h. 2. The maximal pharmacological effect of inhibition of gastric acid secretion (90-91%) was observed at 2 h (i.v.) and 6 h (p.o.), and the action persisted until 7 h after administration. 3. Since there was no correlation between plasma levels of Z-300 and pharmacological effects, the pharmacological effects were calculated by pharmacodynamic model including the effect compartment. The inhibition of acid output could be calculated by the amounts of Z-300 and sulphoxide corrected by pharmacological efficacy in the effect compartment. 4. These findings suggest that Z-300 contributes to the rapid appearance of the pharmacological effects in dog, whereas the sulphoxide, which eliminates slowly in plasma, contributes to duration.
Assuntos
Acetamidas/farmacologia , Antagonistas dos Receptores H2 da Histamina/farmacologia , Piperidinas/farmacologia , Acetamidas/farmacocinética , Animais , Cães , Ácido Gástrico/metabolismo , Antagonistas dos Receptores H2 da Histamina/farmacocinética , Masculino , Estrutura Molecular , Piperidinas/farmacocinética , Estômago/efeitos dos fármacos , Sulfóxidos/sangue , Fatores de TempoRESUMO
The present study was undertaken to clarify a prokinetic activity of nizatidine (CAS 76963-41-2) during the digestive state as well as gastric emptying of a solid test meal in comparison with cimetidine (CAS 51481-61-9), famotidine (CAS 76842-35-6) and cisapride (CAS 81098-60-4). Intravenous administration of nizatidine (0.3-3 mg/kg) enhanced the motility of the gastric antrum and duodenum during the digestive state. With cimetidine (1-10 mg/kg) and famotidine (0.1-1 mg/kg) enhancement of gastric motility was observed only with the highest dose of cimetidine, and famotidine had no effect. Marked enhancement of gastric motility was observed with cisapride (0.1-0.5 mg/kg). After intraduodenal administration of nizatidine (10 and 20 mg/kg) and cisapride (0.25 and 0.5 mg/kg), they also amplified the contractile activity of the gastric antrum. Gastric emptying of a solid test meal was accelerated by intraperitoneal administration of nizatidine (1-10 mg/kg) to the same extent as cisapride (0.1-1 mg/kg). In addition, even in a model of delayed gastric emptying induced by clonidine, nizatidine, like cisapride, improved the rate of gastric emptying. Neither cimetidine (3-30 mg/kg) nor famotidine (0.3-3 mg/kg) affected the gastric emptying of a solid meal or delayed gastric emptying. These results suggest that nizatidine enhanced gastric motility even during the digestive state, and accelerated gastric emptying of a solid meal, similar to cisapride. Furthermore, nizatidine improved clonidine-induced delayed gastric emptying. These prokinetic activities of nizatidine may by useful for the treatment of abdominal symptoms due to dysmotility and delayed gastric emptying in patients with gastritis and non-ulcer dyspepsia (NUD). In comparison with famotidine and cimetidine, nizatidine may be different from other histamine H2-receptor antagonists and has unique properties other than its gastric antisecretory activity.
Assuntos
Antiulcerosos/farmacologia , Digestão/efeitos dos fármacos , Esvaziamento Gástrico/efeitos dos fármacos , Nizatidina/farmacologia , Estômago/efeitos dos fármacos , Animais , Antiulcerosos/administração & dosagem , Cimetidina/farmacologia , Cisaprida/farmacologia , Cães , Duodeno/metabolismo , Famotidina/farmacologia , Motilidade Gastrointestinal/efeitos dos fármacos , Injeções Intravenosas , Intubação Gastrointestinal , Masculino , Nizatidina/administração & dosagem , Ratos , Ratos Sprague-Dawley , Estimulação QuímicaRESUMO
The effect of polaprezinc (N-(3-aminopropionyl)-L-histidinato zinc), a novel antiulcer drug containing zinc, on cellular proliferation was studied using cultured cells. In human umbilical vein endothelial cells (HUVEC) or human foreskin fibroblast cells, bromodeoxyuridine (BrdU) uptake and the number of cells were increased by polaprezinc under low serum conditions, but polaprezinc had no effect on guinea pig gastric mucosal epithelial cells. In addition, L-carnosine (a component of polaprezinc) had no effect on cultured HUVEC, while zinc sulfate, a representative zinc compound, increased BrdU uptake by about 2-fold at 10(-9) M. However, the action of zinc sulfate was weaker than that of polaprezinc. The insulin-like growth factor I (IGF-I) mRNA level was increased in HUVEC by polaprezinc at 10(-9) M approximately 3 x 10(-8) M concentrations, causing stimulation of BrdU uptake. When an anti-IGF-I antibody was added to cultures, the effects of polaprezinc on BrdU uptake was suppressed. These results suggest that although polaprezinc, a novel antiulcer agent, does not have proliferative effects on epithelial cells, it does promote the proliferation of non-parenchymal cells, and IGF-I is involved in this action.
Assuntos
Antiulcerosos/farmacologia , Carnosina/análogos & derivados , Divisão Celular/efeitos dos fármacos , Fator de Crescimento Insulin-Like I/fisiologia , Compostos Organometálicos/farmacologia , Carnosina/farmacologia , Células Cultivadas , Expressão Gênica/efeitos dos fármacos , Humanos , Fator de Crescimento Insulin-Like I/genética , Cicatrização/efeitos dos fármacos , Zinco/química , Compostos de ZincoRESUMO
Effects of a novel zinc compound (polaprezinc), N-(3-aminopropionyl)-L-histidinato zinc, on the mucosal ulcerogenic and healing impairing responses induced by monochloramine (NH2Cl) were examined in rat stomach. Oral administration of NH2Cl (> 60 mM) produced severe hemorrhagic lesions in unanesthetized rat stomachs with a marked increase of thiobarbituric acid reactants (TBAR). Pretreatment of the animals with polaprezinc (3 approximately 30 mg/kg, p.o.) showed a dose-dependent inhibition against gastric ulcerogenic and TBAR responses induced by NH2Cl (120 mM). Likewise, mucosal exposure to NH4OH (60 mM) in urethane anesthetized stomachs made ischemic by bleeding from the carotid artery (1 ml per 100 g body w.t.) resulted in severe gastric lesions. This ulcerogenic response caused NH4OH plus ischemia was also attenuated by prior application of polaprezinc as well as taurine (25 mg/ml, 1 ml). On the other hand, the healing of gastric mucosal lesions induced by NH2Cl occurred more slowly than of ethanol-induced lesions, and the latter was significantly delayed by the repeated administration of NH2Cl. Polaprezinc (> 10 mg/kg, p.o.) given twice daily for 7 days not only accelerated the healing of NH2Cl-induced gastric lesions but also antagonized the delayed healing of ethanol-induced lesions in the presence of NH2Cl as well. Polaprezinc showed a scavenging action against NH2Cl in vitro. These results suggest that NH2Cl caused deleterious action on the healing of pre-existing acute lesions as well as irritating action to the mucosa in the rat stomach. Polaprezinc not only protects the stomach against injury caused by NH2Cl but also promotes healing of NH2Cl-induced gastric lesions as well as the delayed healing of ethanol-induced lesions caused by NH2Cl. Although the detailed mechanisms underlying these actions of polaprezinc remain unknown, they may be partly attributable to a scavenging action of this agent against NH2Cl.
Assuntos
Antiulcerosos/uso terapêutico , Carnosina/análogos & derivados , Cloraminas/farmacologia , Citotoxinas/fisiologia , Compostos Organometálicos/uso terapêutico , Úlcera Gástrica/tratamento farmacológico , Cicatrização/efeitos dos fármacos , Administração Oral , Animais , Carnosina/uso terapêutico , Cloraminas/administração & dosagem , Citotoxinas/farmacologia , Etanol , Mucosa Gástrica/efeitos dos fármacos , Masculino , Ratos , Solventes , Úlcera Gástrica/induzido quimicamente , Compostos de ZincoRESUMO
Helicobacter pylori colonized gastric mucosa is manifest in a significant neutrophil infiltration with an extensive level of oxyradical formation. Mongolian gerbil is one of the excellent models for H. pylori-infection. The present study was designed to investigate pro- and antioxidant formation in the stomach of H. pylori-positive gerbils. Fourteen male Mongolian gerbils (MGS/Sea) were orally inoculated with H. pylori (ATCC43504) (Hp group) and 15 gerbils were inoculated with the culture media (Control). H. pylori infection was confirmed by the serum anti-H. pylori IgG test. Each gerbil was evaluated 6 or 12 weeks after the inoculation. Neutrophil infiltration was assessed by the tissue MPO activity. Mucosal oxidative stress was evaluated by thiobarbituric acid-reactive substances (TBARS), total glutathione contents, glutathione peroxidase (GSHPx) activity and Cu-, Zn-superoxide dismutase (SOD) activity. In Hp group, the H. pylori was persistently infected until 12 weeks. The level of MPO activity was significantly higher in Hp group at 6 and 12 weeks. Although the levels of TBARS and total glutathione were within the same range as controls at 6 weeks, they were significantly increased at 12 weeks. However, GSHPx activity was significantly increased at 6 weeks, but became the same range with the controls at 12 weeks. SOD activity showed no significant increase in Hp group at 6 and 12 weeks. In conclusion, H. pylori inoculation induced gastric mucosal neutrophil activation and pro-oxidant formation and also increased total glutathione contents, one of the mucosal antioxidants in gerbils.
Assuntos
Antioxidantes/metabolismo , Mucosa Gástrica/microbiologia , Infecções por Helicobacter/fisiopatologia , Helicobacter pylori/fisiologia , Oxidantes/metabolismo , Animais , Anticorpos Antibacterianos/sangue , Mucosa Gástrica/fisiologia , Mucosa Gástrica/fisiopatologia , Gerbillinae , Glutationa/metabolismo , Dissulfeto de Glutationa/metabolismo , Glutationa Peroxidase/metabolismo , Imunoglobulina G/sangue , Masculino , Neutrófilos/fisiologia , Peroxidase/metabolismo , Superóxido Dismutase/metabolismo , Substâncias Reativas com Ácido Tiobarbitúrico/análise , Fatores de TempoRESUMO
We previously reported that NH2Cl induced extensive DNA fragmentation in gastric cells. Polaprezinc, a zinc-carnosine chelate compound, is reported to be a potent antioxidant in gastric mucosa. The present study was designed to examine whether polaprezinc could attenuate the NH3Cl-induced DNA damage. Gastric cell lines, MKN45, were exposed to NH2Cl in Ca(2+)-containing Hanks' balanced salt solution. DNA fragmentation was evaluated by photometric enzyme immunoassay for in vitro determination of cytoplasmic mono- and oligonucleosomes. Polaprezinc, L-carnosine, and zinc sulfate (ZnSO4) were added to the cell incubation medium to evaluate the inhibitory effect on the formation of cytoplasmic mono- and oligonucleosomes. Separately, the bleaching level of beta-carotene with the addition of each test solution was evaluated to confirm the inhibitory effect against hypochlorous acid. Polaprezinc or L-carnosine, but not ZnSO4, at a concentration of 0.001 mM, significantly attenuated the increased levels of cytoplasmic mono- and oligonucleosomes evoked by 0.001 mM NH2Cl. Polaprezinc and L-carnosine, but not ZnSO4, also inhibited NH2Cl-induced beta-carotene bleaching in the cell-free system. In conclusion, polaprezinc, especially its subportion L-carnosine, inhibited NH2Cl-evoked gastric epithelial DNA fragmentation, suggesting a role for this agent in preventing the progression of gastric epithelial injury induced by NH2Cl.
Assuntos
Antiulcerosos/farmacologia , Carnosina/análogos & derivados , Fragmentação do DNA/efeitos dos fármacos , Mucosa Gástrica/efeitos dos fármacos , Compostos Organometálicos/farmacologia , Análise de Variância , Antiulcerosos/uso terapêutico , Carnosina/farmacologia , Carnosina/uso terapêutico , Linhagem Celular , Cloraminas , Dano ao DNA , Infecções por Helicobacter/tratamento farmacológico , Helicobacter pylori , Humanos , Compostos Organometálicos/uso terapêutico , Taurina/farmacologia , Compostos de Zinco , Sulfato de Zinco/farmacologiaRESUMO
BACKGROUND: Although the detailed mechanism is unclear, zinc and its derivative, polaprezinc, have been reported to accelerate gastric ulcer healing in vivo. AIM: To investigate the detailed cellular mechanism of polaprezinc on gastric epithelial cells and fibroblasts with special attention to insulin-like growth factor I (IGF-I). METHODS: Isolated rabbit gastric epithelial cells formed a complete monolayer, from which a circular artificial wound with constant size was made. The restoration process was monitored by measuring wound size up to 48 h. Either polaprezinc, IGF-I, fibroblast conditioned medium or neutralized medium conditioned by anti-IGF-I antibody was added at the time of wounding. The expression of mRNA of IGF-I, hepatocyte growth factor (HGF) and transforming growth factor alpha (TGF-alpha) in fibroblasts with or without polaprezinc treatment was tested using reverse transcription polymerase chain reaction (RT-PCR). Gastric epithelial cell proliferation was also examined by bromodeoxyuridine (BrdU) staining. RESULTS: IGF-I and fibroblast conditioned medium treatment accelerated gastric epithelial restoration which included cell migration and proliferation. However, polaprezinc and neutralized conditioned medium treatment did not accelerate epithelial repair. RT-PCR for growth factor mRNA revealed the IGF-I mRNA expression in fibroblasts was increased after treatment with polaprezinc. CONCLUSION: Polaprezinc induced IGF-I production from mesenchymal cells, resulting in stimulation of epithelial cell restoration through a paracrine pathway. IGF-I may play an important role in gastric wound repair.
Assuntos
Carnosina/análogos & derivados , Mucosa Gástrica/efeitos dos fármacos , Fator de Crescimento Insulin-Like I/farmacologia , Compostos Organometálicos/farmacologia , Cicatrização/efeitos dos fármacos , Animais , Southern Blotting , Carnosina/farmacologia , Divisão Celular/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Células Cultivadas , Fibroblastos/metabolismo , Mucosa Gástrica/citologia , Expressão Gênica , Substâncias de Crescimento/análise , Fator de Crescimento Insulin-Like I/genética , Masculino , Mesoderma , RNA Mensageiro/metabolismo , Coelhos , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Compostos de ZincoRESUMO
The bacterial toxin VacA produced by H. pylori induces large vacuoles in several types of cultured cells such as HeLa cells or gastric cells. To determine the mechanism of vacuolation induced by this toxin we employed several inhibitors of membrane trafficking and endocytosis. The development of vacuolation induced by VacA in HeLa cells were prevented by bafilomycin A1 and low temperature conditions that inhibited vesicle transport or endocytosis. Formation of large vacuoles was also inhibited by an antibody against EGF receptor, which was previously shown to be internalized by endocytosis, but not by an anti-transferrin receptor antibody. Moreover, proteins of 58 and 37 kDa, corresponding to fragments of VacA, were recognized by an anti-H. pylori antibody after immunoprecipitation with anti-EGF receptor of cell extracts from HeLa cells treated with VacA, but not from untreated HeLa cells. We suggest that VacA may enter cells by endocytosis mediated by the EGF receptor. These are the first data indicating that the EGF receptor may be significant in the development of vacuolation caused by VacA.
Assuntos
Proteínas de Bactérias/farmacologia , Toxinas Bacterianas/farmacologia , Receptores ErbB/fisiologia , Helicobacter pylori/metabolismo , Macrolídeos , Vacúolos/efeitos dos fármacos , Antibacterianos/farmacologia , Anticorpos/imunologia , Proteínas de Bactérias/metabolismo , Toxinas Bacterianas/metabolismo , Temperatura Baixa , Endocitose , Células HeLa , Humanos , Ligação Proteica , Receptores de Superfície Celular/imunologia , Vacúolos/metabolismoRESUMO
OBJECTIVE: To determine the role of plasma insulin concentration in regulating glucose and lipid metabolism in insulin-resistant obese Zucker rats and to compare obese rats with lean controls with respect to changes in insulin sensitivity. DESIGN: Animal study of lean and obese rats with or without insulin sensitizer, YM268. ANIMALS: Nine week old male lean (Fa/-) and obese (fa/fa) Zucker rats. MEASUREMENTS: Plasma glucose, insulin, triglyceride (TG), non-esterified fatty acid (NEFA), cholesterol at baseline and after 14 d, the dose of YM268 for exhibiting a 30% decrease in each parameter (ED30). RESULTS: Insulin, TG, and NEFA concentrations were approximately 2-6 times higher in obese rats. YM268 had no effect on glucose but decreased insulin in lean and obese rats with ED30 of 3.0 and 2.9 mg/kg. YM268 also reduced TG and NEFA in lean and obese rats (ED30 (mg/kg): lean; 4.1 (TG), 5.0 (NEFA), obese; 2.1, 3.0]. A significant correlation of either TG or NEFA level to insulin was established in lean and obese rats. CONCLUSION: Plasma TG and NEFA, but not cholesterol concentration, are dependent on plasma insulin in lean and obese Zucker rats, and insulin sensitivity with respect to TG and NEFA metabolism in obese rats may not be different from that in lean rats.
Assuntos
Glicemia/metabolismo , Hipoglicemiantes/farmacologia , Insulina/sangue , Metabolismo dos Lipídeos , Obesidade/metabolismo , Tiazóis/farmacologia , Administração Oral , Animais , Glicemia/análise , Glicemia/efeitos dos fármacos , Colesterol/sangue , Colesterol/metabolismo , HDL-Colesterol/sangue , HDL-Colesterol/metabolismo , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Ácidos Graxos não Esterificados/sangue , Ácidos Graxos não Esterificados/metabolismo , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/química , Insulina/metabolismo , Lipídeos/sangue , Masculino , Camundongos , Camundongos Endogâmicos , Ratos , Ratos Zucker , Tiazóis/administração & dosagem , Tiazóis/química , Tiazolidinas , Fatores de Tempo , Triglicerídeos/sangue , Triglicerídeos/metabolismoRESUMO
Genetically obese Zucker rats exhibit mild hyperglycaemia and hyperinsulinaemia suggesting the existence of peripheral insulin resistance. We have examined the effects of YM268, an analogue of thiazolidinedione, on the content and translocation of a glucose transporter (GLUT4) in epididymal adipose tissue in 11-week-old obese and lean Zucker rats. The administration of YM268 at a dose of 10 mg/kg for 2 weeks ameliorated hyperglycaemia, hyperinsulinaemia, and impaired glucose tolerance after glucose load in obese rats. The GLUT4 content per fat pad in obese rats was reduced to 36% of that in lean littermates. Obese rats treated with YM268 increased GLUT4 concentrations in their fat pads from a basal value of 36% up to 191% of the level in lean rats. Furthermore, in adipocytes prepared from obese rats, an increase in the ratio of GLUT4 in plasma membrane to the total amount of GLUT4 (PM-GLUT4 ratio) induced by the submaximal concentration of insulin (0.3 nmol/l) was significantly attenuated compared with that in lean rats. But the maximum effect of insulin (3 nmol/l) was not attenuated. Meanwhile, YM268 had no significant effect on the attenuated PM-GLUT4 ratio in response to insulin in obese rats. These data suggested that one of the mechanisms by which YM268 improved insulin resistance in obese Zucker rats was to normalize the decreased GLUT4 content in the adipose tissue.
Assuntos
Tecido Adiposo/metabolismo , Hipoglicemiantes/farmacologia , Resistência à Insulina , Proteínas de Transporte de Monossacarídeos/metabolismo , Proteínas Musculares , Ratos Zucker/metabolismo , Tiazóis/farmacologia , Animais , Glicemia/metabolismo , Transportador de Glucose Tipo 4 , Insulina/sangue , Masculino , Ratos , TiazolidinasRESUMO
Polaprezinc, an insoluble zinc complex of L-carnosine, exhibits anti-ulcer effects by acting directly on mucosal lesions. The disposition of polaprezinc in the stomach was studied to clarify the usefulness of its structure as an insoluble complex. The time courses of 14C-radioactivity in the gastric contents and gastric tissues were parallel to those of 65Zn after oral administration of a mixture of 14C-polaprezinc and 65Zn-polaprezinc (14C-, 65Zn-polaprezinc) to rats. The gastric contents of 14C-polaprezinc and 65Zn-polaprezinc were greater than those of 14C-L-carnosine and 65ZnSO4. Mean residence times (MRT) of 14C-polaprezinc and 65Zn-polaprezinc in the stomach were almost the same (ca. 2 hr), and they were double those of 14C-L-carnosine and 65ZnSO4. In gastric tissues, the area under the concentration curves (AUC0-8 hr) of 14C-polaprezinc and 65Zn-polaprezinc were 1.7 times greater than those of 14C-L-carnosine and 65ZnSO4, respectively. After administration of 14C-, 65Zn-polaprezinc to rats with acetic acid-induced ulcers, 14C and 65Zn-radioactivities in the ulcerous sites were very similar and greater than those of 14C-, 65Zn-polaprezinc dissolved in acid. In conclusion, polaprezinc is retained in the stomach longer and adheres to the ulcerous sites more than zinc or L-carnosine. The characteristics of this compound may arise from its insolubility and contribute to its strong pharmacological action.
Assuntos
Antiulcerosos/uso terapêutico , Carnosina/análogos & derivados , Mucosa Gástrica/efeitos dos fármacos , Compostos Organometálicos/uso terapêutico , Úlcera Gástrica/metabolismo , Animais , Antiulcerosos/administração & dosagem , Antiulcerosos/sangue , Antiulcerosos/metabolismo , Antiulcerosos/farmacologia , Sítios de Ligação , Isótopos de Carbono , Carnosina/administração & dosagem , Carnosina/sangue , Carnosina/metabolismo , Carnosina/farmacologia , Carnosina/uso terapêutico , Modelos Animais de Doenças , Esvaziamento Gástrico/efeitos dos fármacos , Mucosa Gástrica/metabolismo , Conteúdo Gastrointestinal/química , Marcação por Isótopo , Masculino , Compostos Organometálicos/administração & dosagem , Compostos Organometálicos/sangue , Compostos Organometálicos/metabolismo , Compostos Organometálicos/farmacologia , Ratos , Ratos Sprague-Dawley , Organismos Livres de Patógenos Específicos , Úlcera Gástrica/tratamento farmacológico , Sulfatos/sangue , Sulfatos/metabolismo , Zinco/metabolismo , Compostos de Zinco/sangue , Compostos de Zinco/metabolismo , Radioisótopos de Zinco , Sulfato de ZincoRESUMO
We developed a new gastric ulcer model in which the ulcers are induced by the local injection of a ferrous iron and ascorbic acid (Fe/ASA) solution into the gastric wall. These ulcers resemble human gastric ulcers that penetrate the muscularis mucosa. The involvement of oxygen radical-mediated lipid peroxidation as the cause of these ulcers was investigated. With ferrous iron or ascorbic acid alone, gastric ulcers did not form, whereas penetrating ulcers were produced by the simultaneous injection of the Fe/ASA solution in a dose-dependent manner. Lipid peroxides significantly accumulated in the gastric mucosa from 1 to 24 h after the injection of the Fe/ASA solution. This increase in lipid peroxides preceded grossly evident gastric ulcer. Treatment with superoxide dismutase (SOD, recombinant human CuZnSOD) significantly reduced the size of the ulcers and inhibited the accumulation in lipid peroxides in the gastric mucosa, while treatment with apo-SOD or heat-inactivated SOD did not. These results suggest that lipid peroxidation mediated by oxygen radicals plays a crucial role in the pathogenesis of the gastric ulceration induced by the Fe/ASA solution.
Assuntos
Ácido Ascórbico/administração & dosagem , Modelos Animais de Doenças , Compostos Ferrosos/administração & dosagem , Ratos Sprague-Dawley , Úlcera Gástrica/induzido quimicamente , Animais , Relação Dose-Resposta a Droga , Mucosa Gástrica/metabolismo , Mucosa Gástrica/patologia , Injeções , Peróxidos Lipídicos/metabolismo , Masculino , Ratos , Úlcera Gástrica/metabolismo , Úlcera Gástrica/patologia , Superóxido Dismutase/farmacologia , Substâncias Reativas com Ácido Tiobarbitúrico/metabolismoRESUMO
We studied the anti-acetylcholinesterase (AChE) activity of a new H2-antagonist, nizatidine, in in vitro experiments and its gastroprokinetic action in the dog and rat in comparison with other H2-antagonists, neostigmine and cisapride. The IC50 of nizatidine for AChE was 6.7 x 10(-6) M, and this activity was reversible. The relative anti-AChE potency was in the following order: neostigmine > nizatidine > cimetidine >> famotidine. The inhibition of AChE by nizatidine was noncompetitive, with a Ki value of 7.4 x 10(-6) M. Gastrointestinal (GI) motility was examined during the interdigestive state in dogs with chronically implanted force transducers. Nizatidine (0.3-3 mg/kg, i.v.) significantly increased the motor index in a dose-dependent manner. It was of interest that the contractile response of the GI tract to nizatidine was similar to the interdigestive migrating contractions-like activity. At the doses used in this study, neither cimetidine nor famotidine had a significant effect on the motor index. Neostigmine at a higher dose of 0.06 mg/kg and cisapride at 0.3 mg/kg were found to stimulate GI contractions. Gastric emptying was determined in rats given phenol red as a liquid test meal. Nizatidine (3 mg/kg, i.p., or above) significantly increased gastric emptying, whereas the other H2-antagonists had no such effect. The ED50 and ED90 values of nizatidine for inhibition of gastric acid secretion were 0.18 and 3.22 mg/kg in dogs, and 2.94 and 19.6 mg/kg in rats, respectively. These findings suggest that nizatidine stimulates GI contractions and accelerates gastric emptying at gastric antisecretory doses.(ABSTRACT TRUNCATED AT 250 WORDS)
Assuntos
Motilidade Gastrointestinal/efeitos dos fármacos , Nizatidina/farmacologia , Animais , Inibidores da Colinesterase/farmacologia , Cimetidina/farmacologia , Sistema Digestório/efeitos dos fármacos , Fenômenos Fisiológicos do Sistema Digestório , Cães , Relação Dose-Resposta a Droga , Famotidina/farmacologia , Jejum/fisiologia , Ácido Gástrico/metabolismo , Esvaziamento Gástrico/efeitos dos fármacos , Antagonistas dos Receptores H2 da Histamina/farmacologia , Humanos , Masculino , Atividade Motora/efeitos dos fármacos , Piloro/fisiologia , Ratos , Ratos Sprague-DawleyRESUMO
We investigated the effects of Z-103, ZnSO4, L-carnosine and solcoseryl on wound healing by dermal incision in guinea pigs. The tensile strength, hydroxyproline contents and the value of angiogenesis (carmine contents) at the wounded site of dorsal skin were used as indices of wound healing. Z-103, given daily s.c., increased the tensile strength and hydroxyproline contents on day 4 after operation in a dose-dependent manner; in particular, the effect of 10 mg/kg of Z-103 was nearly equal to that of solcoseryl at 0.5 ml/animal. Moreover, Z-103 10 mg/kg increased the value of angiogenesis on day 3 after the operation. On the other hand, ZnSO4 and L-carnosine, components of Z-103, also similarly increased the tensile strength and hydroxyproline contents. These results suggest that Z-103 possessed an accelerative action on wound healing, and these effects may be due to the activity of its components, ZnSO4 and L-carnosine.
Assuntos
Antiulcerosos/farmacologia , Carnosina/análogos & derivados , Dipeptídeos/farmacologia , Compostos Organometálicos/farmacologia , Pele/fisiopatologia , Cicatrização/efeitos dos fármacos , Animais , Modelos Animais de Doenças , Cobaias , Hidroxiprolina/metabolismo , Masculino , Neovascularização Patológica , Pele/irrigação sanguínea , Pele/metabolismo , Resistência à Tração/efeitos dos fármacos , Compostos de ZincoRESUMO
We studied the healing promoting action of Z-103 on the chronic gastric ulcer induced by acetic acid (AAU) or Fe-ascorbic acid (FAU) in rats. The area of the gastric ulcers, hydroxyproline (Hyp) and DNA contents in the ulcer region were measured as an index of ulcer healing. The area of gastric ulcers was the largest on day 4 and thereafter gradually decreased, but the ulcers still remained at the 14th day. Hyp contents in the ulcer region decreased until the 7th day in both models, and then this level increased. Significant decrease in DNA contents in the ulcer region was observed on the 7th day only in FAU. In AAU and FAU, administration of Z-103 (3 mg/kg/day x 2, p.o.) resulted in a significant decrease in the area of gastric ulcers on the 14th day and a significant increase in Hyp contents in the ulcer region on the 7th day as compared with the control group. Z-103 increased the DNA contents in the ulcer region on the 4th day in AAU and on the 7th day in FAU. These results suggest that tissue destruction surrounding the ulcer region in AAU and FAU models might occur until the 4th or 7th day after operation, and that the acceleration of ulcer healing by Z-103 on these models may be facilitated by the wound healing action of this drug.
Assuntos
Antiulcerosos/farmacologia , Carnosina/análogos & derivados , Dipeptídeos/farmacologia , Compostos Organometálicos/farmacologia , Úlcera Gástrica/tratamento farmacológico , Zinco/farmacologia , Animais , Antiulcerosos/uso terapêutico , DNA/análise , Dipeptídeos/uso terapêutico , Modelos Animais de Doenças , Hidroxiprolina/análise , Masculino , Compostos Organometálicos/uso terapêutico , Ratos , Ratos Endogâmicos , Cicatrização/efeitos dos fármacos , Zinco/uso terapêutico , Compostos de ZincoRESUMO
The gastric mucosal adhesiveness of Z-103 in rats with acetic acid ulcer was studied macroscopically, histologically, and biochemically. From macroscopical observations, when Z-103 was orally administered to an acetic acid ulcer model, there was adhesion of Zn to the normal mucosa as well as the ulcerous site under both the fasting condition and after feeding. It was also proven that the strength and duration of adhesiveness were increased dose-dependently under fasting conditions. In addition, histological localization of Zn was noted from the covering epithelial cell layer to the gastric lamina propria mucosae in the normal tissue and in the most superficial ulcerous layer and the granulous layer of the ulcerous site. Measurement of the gastric tissue Zn content after oral administration of 100 mg/kg of Zn showed that the Zn content was significantly increased for 6 hr at the normal site and for 24 hr at the ulcerous site. On the other hand, although ZnSO4 and ZnSO4+carnosine combination macroscopically produced generally the same level of adhesiveness as Z-103, when the gastric tissue Zn content for Z-103 and ZnSO4 were compared, the Zn content of ZnSO4 was lower than that for Z-103 at both the normal and ulcerous site. In summary, Z-103 shows a long-term adhesive and permeable action on the gastric mucosa in acetic acid ulcer rats, and it has a comparable high affinity at the ulcerous site.
Assuntos
Antiulcerosos/farmacocinética , Carnosina/análogos & derivados , Dipeptídeos/farmacocinética , Mucosa Gástrica/metabolismo , Compostos Organometálicos/farmacocinética , Úlcera Gástrica/metabolismo , Acetatos , Ácido Acético , Adesividade , Animais , Doença Crônica , Jejum/metabolismo , Masculino , Ratos , Ratos Endogâmicos , Úlcera Gástrica/induzido quimicamente , Zinco/farmacocinética , Compostos de ZincoRESUMO
A zinc-carnosine chelate compound, Z-103, attenuates gastric mucosal injuries and inhibits the increase of lipid peroxide in the gastric mucosa induced by burn shock or ischemia-reperfusion. However, the exact mechanism of the antioxidative effect of Z-103 is not clear. The antioxidant properties of a novel anti-peptic ulcer agent Z-103 in vitro were compared with those of zinc ion and L-carnosine. Z-103 scavenged superoxide anion radicals. Z-103 and ZnSO4, but not L-carnosine, inhibited the superoxide generation from polymorphonuclear leukocytes stimulated by opsonized zymosan, and also inhibited the generation of hydroxyl radicals by the Fenton reaction. The increase of lipid peroxides produced by rat brain homogenates and liver microsomes was also inhibited by Z-103 and ZnSO4. These findings indicate that the strong anti-ulcer and antioxidative actions of Z-103 in vivo are due to a combination of these antioxidant actions in vitro.