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2.
J Gastroenterol Hepatol ; 30 Suppl 1: 60-5, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25827806

RESUMO

BACKGROUND AND AIM: Luminal nutrients stimulate enteroendocrine L cells to release gut hormones, including intestinotrophic glucagon-like peptide-2 (GLP-2). Because L cells express the bile acid receptor TGR5 and dipeptidyl peptidase-IV (DPPIV) rapidly degrades GLPs, we hypothesized that luminal TGR5 activation may attenuate intestinal injury via GLP-2 release, which is enhanced by DPPIV inhibition. METHODS: Intestinal injury was induced in mice by administration of dextran sulfate sodium (DSS) in drinking water (free access to water containing 5% DSS for 7 days). The selective TGR5 agonist betulinic acid (BTA) and the DPPIV inhibitor sitagliptin phosphate monohydrate (STG) were administered orally for 7 days. Male C57BL/6 mice (6-7 weeks old) were divided into five groups: normal control group, disease control group, BTA low group (drinking water containing 15 mg/L BTA), BTA high group (50 mg/L BTA), and BTA high + STG (3 mg/kg, i.g.) group. RESULTS: The selective TGR5 agonist BTA dose-dependently suppressed disease activity index and mRNA expression of the pro-inflammatory cytokines interleukin (IL)-1ß, IL-6, and tumor necrosis factor-α in the colon. Nevertheless, STG administration had little additive effect on BTA-induced protection. Fibroblast activation protein mRNA expression, but not expression of other DPP family members, was increased in the colon of DSS-treated mice with increased mucosal DPPIV. Co-administration of the selective GLP-2 antagonist GLP-2 (3-33) reversed the effect of BTA. CONCLUSION: The selective TGR5 agonist BTA ameliorated DSS-induced colitis in mice via the GLP-2 pathway with no effect of DPPIV inhibition, suggesting that other DPP enzymatic activity is involved in GLP-2 degradation.


Assuntos
Colite/induzido quimicamente , Colite/tratamento farmacológico , Sulfato de Dextrana , Inibidores da Dipeptidil Peptidase IV/administração & dosagem , Inibidores da Dipeptidil Peptidase IV/farmacologia , Receptores Acoplados a Proteínas G/agonistas , Fosfato de Sitagliptina/administração & dosagem , Fosfato de Sitagliptina/farmacologia , Triterpenos/administração & dosagem , Triterpenos/farmacologia , Animais , Colite/metabolismo , Citocinas/metabolismo , Relação Dose-Resposta a Droga , Peptídeo 2 Semelhante ao Glucagon/metabolismo , Peptídeo 2 Semelhante ao Glucagon/farmacologia , Mediadores da Inflamação/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Triterpenos Pentacíclicos , Fragmentos de Peptídeos/farmacologia , Ácido Betulínico
3.
J Clin Biochem Nutr ; 56(2): 155-62, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25759522

RESUMO

The gut incretin glucagon-like peptide-1 (GLP-1) and the intestinotropic hormone GLP-2 are released from enteroendocrine L cells in response to ingested nutrients. Treatment with an exogenous GLP-2 analogue increases intestinal villous mass and prevents intestinal injury. Since GLP-2 is rapidly degraded by dipeptidyl peptidase 4 (DPP4), DPP4 inhibition may be an effective treatment for intestinal ulcers. We measured mRNA expression and DPP enzymatic activity in intestinal segments. Mucosal DPP activity and GLP concentrations were measured after administration of the DPP4 inhibitor sitagliptin (STG). Small intestinal ulcers were induced by indomethacin (IM) injection. STG was given before IM treatment, or orally administered after IM treatment with or without an elemental diet (ED). DPP4 mRNA expression and enzymatic activity were high in the jejunum and ileum. STG dose-dependently suppressed ileal mucosal enzyme activity. Treatment with STG prior to IM reduced small intestinal ulcer scores. Combined treatment with STG and ED accelerated intestinal ulcer healing, accompanied by increased mucosal GLP-2 concentrations. The reduction of ulcers by ED and STG was reversed by co-administration of the GLP-2 receptor antagonist. DPP4 inhibition combined with luminal nutrients, which up-regulate mucosal concentrations of GLP-2, may be an effective therapy for the treatment of small intestinal ulcers.

4.
World J Gastroenterol ; 21(6): 1880-6, 2015 Feb 14.
Artigo em Inglês | MEDLINE | ID: mdl-25684955

RESUMO

AIM: To determine the efficacy and safety of rapid induction therapy with oral tacrolimus without a meal in steroid-refractory ulcerative colitis (UC) patients. METHODS: This was a prospective, multicenter, observational study. Between May 2010 and August 2012, 49 steroid-refractory UC patients (55 flare-ups) were consecutively enrolled. All patients were treated with oral tacrolimus without a meal at an initial dose of 0.1 mg/kg per day. The dose was adjusted to maintain trough whole-blood levels of 10-15 ng/mL for the first 2 wk. Induction of remission at 2 and 4 wk after tacrolimus treatment initiation was evaluated using Lichtiger's clinical activity index (CAI). RESULTS: The mean CAI was 12.6 ± 3.6 at onset. Within the first 7 d, 93.5% of patients maintained high trough levels (10-15 ng/mL). The CAI significantly decreased beginning 2 d after treatment initiation. At 2 wk, 73.1% of patients experienced clinical responses. After tacrolimus initiation, 31.4% and 75.6% of patients achieved clinical remission at 2 and 4 wk, respectively. Treatment was well tolerated. CONCLUSION: Rapid induction therapy with oral tacrolimus shortened the time to achievement of appropriate trough levels and demonstrated a high remission rate 28 d after treatment initiation. Rapid induction therapy with oral tacrolimus appears to be a useful therapy for the treatment of refractory UC.


Assuntos
Colite Ulcerativa/tratamento farmacológico , Imunossupressores/administração & dosagem , Tacrolimo/administração & dosagem , Administração Oral , Adulto , Colite Ulcerativa/diagnóstico , Monitoramento de Medicamentos , Feminino , Humanos , Imunossupressores/efeitos adversos , Imunossupressores/sangue , Quimioterapia de Indução , Japão , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Indução de Remissão , Tacrolimo/efeitos adversos , Tacrolimo/sangue , Fatores de Tempo , Resultado do Tratamento
5.
Intern Med ; 53(16): 1755-8, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25130105

RESUMO

Toxic megacolon is an infrequent but life-threatening complication that occurs most commonly in patients with severe ulcerative colitis. Intravenous steroids are often recommended for patients with toxic megacolon secondary to ulcerative colitis. However, steroid dependency may mask the presence of intra-abdominal sepsis and is associated with refractoriness, during which cytomegalovirus reactivation may occur. In this report, we present two rare cases of megacolon accompanying pancolonic severe ulcerative colitis that were successfully treated with oral tacrolimus, including one steroid-naïve patient. In cases of ulcerative colitis with megacolon, treatment with oral tacrolimus is recommended, thereby avoiding steroid dependency and improving the long-term prognosis.


Assuntos
Colite Ulcerativa/complicações , Imunossupressores/uso terapêutico , Megacolo Tóxico/tratamento farmacológico , Tacrolimo/administração & dosagem , Administração Oral , Feminino , Humanos , Masculino , Megacolo Tóxico/diagnóstico , Megacolo Tóxico/etiologia , Pessoa de Meia-Idade , Prognóstico , Resultado do Tratamento
6.
Intern Med ; 53(4): 283-90, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24531083

RESUMO

OBJECTIVE: A treatment strategy to inhibit nonsteroidal anti-inflammatory drug (NSAID)-induced small intestinal lesions has not yet been established. To clarify whether monotherapy with a gastromucoprotective drug, geranylgeranylacetone (GGA), inhibits NSAID-induced acute mucosal injury of the upper digestive tract and small intestine. METHODS: A prospective, randomized, comparative study. All procedures were performed at Osaka Medical College. The subjects, thirty healthy adult volunteers, were randomly divided into two groups. In the NSAID-GGA group, 75 mg/day of diclofenac sodium and 150 mg/day of GGA were orally administered for two weeks. In the NSAID-FAM group, 75 mg/day of diclofenac sodium and 20 mg/day of famotidine (FAM) were orally administered for two weeks. esophagogastroduodenoscopy (EGD) and video capsule endoscopy (VCE) were performed before and two weeks after drug administration. In addition, we measured fecal occult blood reactions and the fecal calprotectin levels. RESULTS: No significant differences were observed between the groups in the mean increase in esophageal/gastroduodenal lesions. The mean increases in the scores in the NSAID-FAM group (NSAID-GGA group) of small bowel lesions were as follows: erythema: 1.93 ± 0.67 (0.30 ± 0.60), erosions: 1.13 ± 0.54 (0.38 ± 0.35), ulcers: 0.73 ± 0.33 (0.07 ± 0.07) and edema: 0.53 ± 0.44 (0.07 ± 0.07). The scores for erythema and ulcers were significantly lower in the NSAID-GGA group than in the NSAID-FAM group (p=0.032 and 0.0165, respectively). CONCLUSION: We compared the prophylactic effects of a mucoprotective drug, GGA, and an H2RA, famotidine, on mucosal injury involving the esophagus to the small intestine related to the two-week oral administration of diclofenac sodium in healthy volunteers. In the upper digestive tract, the prophylactic effects were similar between the two drugs. However, in the small intestine, GGA more markedly inhibited the development of lesions compared to famotidine.


Assuntos
Anti-Inflamatórios não Esteroides/efeitos adversos , Diterpenos/uso terapêutico , Esôfago/efeitos dos fármacos , Esôfago/lesões , Famotidina/uso terapêutico , Mucosa Gástrica/efeitos dos fármacos , Mucosa Gástrica/lesões , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/lesões , Adulto , Antiulcerosos/uso terapêutico , Endoscopia por Cápsula , Diclofenaco/efeitos adversos , Endoscopia do Sistema Digestório , Esôfago/patologia , Mucosa Gástrica/patologia , Humanos , Mucosa Intestinal/patologia , Complexo Antígeno L1 Leucocitário/metabolismo , Masculino , Estudos Prospectivos , Adulto Jovem
7.
BMC Gastroenterol ; 13: 85, 2013 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-23672202

RESUMO

BACKGROUND: Proton-pump inhibitors such as omeprazole are a standard treatment to prevent non-steroidal anti-inflammatory drug-induced upper gastrointestinal mucosal injuries. However, it is unclear which drugs may protect against all NSAID-induced digestive-tract injuries. Here, we compare the efficacy of the gastromucoprotective drug irsogladine with omeprazole in preventing NSAID-induced esophagitis, peptic ulcers, and small-intestinal mucosal injury in healthy subjects. METHODS: Thirty-two healthy volunteers were assigned to an irsogladine group (Group I; n = 16) receiving diclofenac sodium 75 mg and irsogladine 4 mg daily for 14 days, or an omeprazole group (Group O; n = 16) receiving diclofenac sodium 75 mg and omeprazole 10 mg daily for 14 days. Esophagitis and peptic ulcers were evaluated by esophagogastroduodenoscopy and small-intestinal injuries by capsule endoscopy, fecal calprotectin, and fecal occult blood before and after treatment. RESULTS: There was no significant difference between Group I and Group O with respect to the change in lesion score in the esophagus, stomach, and duodenum before and after treatment.NSAID treatment significantly increased the number of small intestinal mucosal breaks per subject by capsule endoscopic evaluation, from a basal level of 0.1 ± 0.3 up to 1.9 ± 2.0 lesions in Group O (p = 0.0002). In contrast, there were no significant changes in the mean number of mucosal breaks before and after co-treatment in Group I (0.3 ± 0.8 to 0.5 ± 0.7, p = 0.62), and the between-group difference was significant (p = 0.0040). Fecal calprotectin concentration, when the concentration before treatment was defined as 1, was significantly increased both in Group O (from 1.0 ± 0.0 to 18.1 ± 37.1, p = 0.0002) and Group I (from 1.0 ± 0.0 to 6.0 ± 11.1, p = 0.0280); the degree of increase in Group O was significantly higher compared with that in Group I (p<0.05). In addition, fecal occult blood levels increased significantly in Group O (p = 0.0018), but there was no change in Group I (p = 1.0), and the between-group difference was significant (p = 0.0031). CONCLUSION: Irsogladine protected against NSAID-induced mucosal injuries throughout the gastrointestinal tract, from esophagus to small intestine, significantly better than omeprazole. TRIAL REGISTRATION: This study was registered in the UMIN Clinical Trials Registry (Registry ID number; UMIN000008114).


Assuntos
Antiulcerosos/uso terapêutico , Esofagite/prevenção & controle , Mucosa Intestinal/patologia , Omeprazol/uso terapêutico , Úlcera Péptica/prevenção & controle , Triazinas/uso terapêutico , Adulto , Anti-Inflamatórios não Esteroides/efeitos adversos , Diclofenaco/efeitos adversos , Endoscopia Gastrointestinal , Esofagite/induzido quimicamente , Fezes/química , Feminino , Humanos , Intestino Delgado/patologia , Complexo Antígeno L1 Leucocitário/análise , Masculino , Sangue Oculto , Úlcera Péptica/induzido quimicamente , Adulto Jovem
8.
World J Gastroenterol ; 19(17): 2676-82, 2013 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-23674875

RESUMO

AIM: To assess adalimumab's efficacy with concomitant azathioprine (AZA) for induction and maintenance of clinical remission in Japanese Crohn's disease (CD) patients. METHODS: This retrospective, observational, single-center study enrolled 28 consecutive CD patients treated with adalimumab (ADA). Mean age and mean disease duration were 38.1 ± 11.8 years and 11.8 ± 10.1 years, respectively. The baseline mean Crohn's disease activity index (CDAI) and C-reactive protein were 177.8 ± 82.0 and 0.70 ± 0.83 mg/dL, respectively. Twelve of these patients also received a concomitant stable dose of AZA. ADA was subcutaneously administered: 160 mg at week 0, 80 mg at week 2, followed by 40 mg every other week. Clinical response and remission rates were assessed via CDAI and C-reactive protein for 24 wk. RESULTS: The mean CDAI at weeks 2, 4, 8, and 24 was 124.4, 120.2, 123.6, and 135.1, respectively. The CDAI was significantly decreased at weeks 2 and 4 with ADA and was significantly suppressed at 24 wk with ADA/AZA. Overall clinical remission rates at weeks 4 and 24 were 66.7% and 63.2%, respectively. Although no statistically significant difference in C-reactive protein was demonstrated, ADA with AZA resulted in a greater statistically significant improvement in CDAI at 24 wk, compared to ADA alone. CONCLUSION: Scheduled ADA with concomitant AZA may be more effective for clinical remission achievement at 24 wk in Japanese Crohn's disease patients.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Azatioprina/uso terapêutico , Doença de Crohn/tratamento farmacológico , Imunossupressores/uso terapêutico , Adalimumab , Adulto , Povo Asiático , Distribuição de Qui-Quadrado , Doença de Crohn/diagnóstico , Doença de Crohn/etnologia , Quimioterapia Combinada , Feminino , Humanos , Japão/epidemiologia , Masculino , Pessoa de Meia-Idade , Indução de Remissão , Estudos Retrospectivos , Fatores de Tempo , Resultado do Tratamento
9.
Intern Med ; 52(1): 15-20, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23291669

RESUMO

OBJECTIVE: The calcineurin inhibitor tacrolimus has been shown to be safe and effective as salvage therapy for steroid-refractory ulcerative colitis (UC). Since differences in the onset of action between various agents are thought to influence the achievement and maintenance of disease remission, top-down or accelerated step-up therapy with tacrolimus may be useful. However, the efficacy of tacrolimus in moderate to severe UC patients not receiving concomitant steroids remains unknown. METHODS: Ten patients (11 attacks) with active, moderate to severe UC were treated with oral tacrolimus at a dose of 0.1 mg/kg body weight daily. The dosages were adapted to maintain trough whole-blood levels of 10 to 15 ng/mL to induce remission and 5 to 10 ng/mL to maintain remission. Lichtiger scores, the incidence of adverse effects (serum creatinine and glucose) and long-term outcomes were assessed. RESULTS: At four weeks after the initiation of tacrolimus therapy, clinical remissions were observed for eight attacks (72.7%) and clinical responses were demonstrated for three attacks. At 12 weeks after the initiation of tacrolimus treatment, clinical remissions were achieved for nine attacks (90%). After a mean follow-up of 10.4 months, clinical remissions were maintained for eight of 11 attacks. During the tacrolimus treatment, the serum creatinine and glucose levels were not significantly elevated. CONCLUSION: Oral tacrolimus is a safe and effective therapy for the treatment of moderate to severe UC in patients not receiving concomitant treatment with systemic steroids. Although further studies are required to establish the efficacy and safety of oral tacrolimus therapy in patients with UC, oral tacrolimus may represent a top-down or accelerated step-up treatment option for patients with moderate to severe UC.


Assuntos
Colite Ulcerativa/diagnóstico , Colite Ulcerativa/tratamento farmacológico , Imunossupressores/uso terapêutico , Tacrolimo/uso terapêutico , Administração Oral , Corticosteroides , Adulto , Estudos de Coortes , Relação Dose-Resposta a Droga , Esquema de Medicação , Endoscopia Gastrointestinal , Feminino , Seguimentos , Humanos , Mucosa Intestinal/efeitos dos fármacos , Masculino , Pessoa de Meia-Idade , Segurança do Paciente , Estudos Retrospectivos , Índice de Gravidade de Doença , Fatores de Tempo , Resultado do Tratamento , Adulto Jovem
10.
Intern Med ; 51(18): 2545-9, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22989824

RESUMO

Yersinia enterocolitica (YE) infection is a rare cause of intestinal intussusception, especially in adults. We herein, report a case of adult intussusception due to YE enterocolitis. A 24-year-old woman was admitted because of severe abdominal pain. She was clinically diagnosed with ileocolic intussusception on the basis of the findings of computed tomography (CT) and a gastrografin enema. Manual surgical reduction was sufficient to alleviate the intussusception. A histological examination of the lymph nodes around the ileocecum excluded lymphoma. Serological testing revealed that the cause of the intussusception was a YE infection. The patient's postoperative course was good and no recurrence was seen during the follow-up.


Assuntos
Enterocolite/complicações , Enterocolite/microbiologia , Intussuscepção/diagnóstico por imagem , Intussuscepção/etiologia , Yersiniose/complicações , Yersinia enterocolitica , Feminino , Humanos , Intussuscepção/cirurgia , Tomografia Computadorizada por Raios X , Resultado do Tratamento , Adulto Jovem
11.
Digestion ; 85(2): 136-40, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22269295

RESUMO

Collagenous colitis (CC) is a well-known cause of chronic non-bloody diarrhea, especially in elderly women. CC is characterized histopathologically by an increase in the thickness of the subepithelial collagen layer to at least 10 µm, epithelial damage, and chronic inflammation of the lamina propria. Generally, the colonic mucosa in CC is macroscopically normal, although minor, non-specific abnormalities may be found. Due to the recent advancement of endoscopic and diagnostic technologies, however, microscopic mucosal abnormalities and specific longitudinal linear lacerations of the mucosa characteristic of CC have been identified. The association of CC with non-steroidal anti-inflammatory drugs and proton pump inhibitors has also been reported. Since definitive diagnosis of CC has to rely on pathologically documented collagen bands and mononuclear infiltration, the efficiency and precision of colonic biopsy need to be improved. Of the 29 CC patients that we have encountered at our institution, it was in 15 of 29 cases that the endoscopic finding that we performed a biopsy on was apparent. Our comparison of the endoscopic and histopathological findings of CC in the 15 patients showed that the mucosa frequently appeared coarse and nodular on the surface of the mucosa, which was also significantly thicker in collagen bands, demonstrating a strong correlation between collagen band formation and CC. Also, the coarse and nodular surface of the mucosa was most frequently seen affecting the proximal colon. The results suggest that endoscopic observation and biopsy of the proximal colon, where a coarse and nodular surface of the mucosa is often found, may be useful for confirmation of the diagnosis in patients with suspected CC.


Assuntos
Colite Colagenosa/patologia , Colo/patologia , Mucosa Intestinal/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Colite Colagenosa/complicações , Colonoscopia , Diarreia/etiologia , Endoscopia Gastrointestinal/métodos , Feminino , Humanos , Pessoa de Meia-Idade
12.
Dig Dis Sci ; 57(2): 335-44, 2012 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-21909991

RESUMO

BACKGROUND: Intestinal deformity and stenosis are induced by fibrosis during the process healing of intestinal chronic inflammation in inflammatory bowel disease (IBD). Potent anti-inflammatory treatment of patients with Crohn's disease (CD) may induce fibrous stenosis, and this is often difficult to treat in clinical practice. Therefore, it is necessary to develop a treatment strategy that concomitantly exhibits repair/regenerative and anti-fibrotic effects, in addition to the current anti-inflammatory effect, for the treatment of inflammatory bowel diseases. However, the relationship between the course of inflammatory activity and the healing process and fibrogenesis has not been elucidated; although the complex involvement of various factors in the mechanism of biological fibrosis has been investigated. Simvastatin (SIMV), an HMG-CoA reductase inhibitor, exhibits anti-inflammatory and anti-fibrotic effects. The current study established a model of the regeneration/healing process from TNBS-induced colitis and investigated the anti-inflammatory and anti-fibrotic effects of SIMV. SUBJECTS AND METHODS: Four groups of TNBS-induced colitis model were prepared using male SJL/J mice: A: Normal control group, B: control group, and C and D: treatment groups. The mucosal healing process was classified into three phases (an early phase: inflammation period, a mid-phase: regeneration promoting period, and a late phase: regeneration-converging period), and inflammation, the expression of fibrosis-related growth factors, and induction of apoptosis of fibrosis-related cells were compared in each period. RESULTS: (1) The clinical findings showed that SIMV showed anti-inflammatory effects with body weight gain and improvement of epithelial injury in the late phase. Histological (macroscopic/microscopic) improvement was noted in the mid- and late phases. The inflammatory cytokine (TNF-α) level significantly decreased in the mid- and late phases in the high-dose treatment group. (2) SIMV also had anti-fibrotic effects characterized by a dose-dependent decrease in the level of a fibrosis-related growth factor (CTGF) in the early and mid-phases, irrespective of inflammation or changes in the TGF-ß(1) level. Dose-dependent induction of apoptosis was noted in both fibroblasts and myofibroblasts from a relatively early stage. CONCLUSIONS: The results suggested that SIMV induces anti-fibrotic activity that is not directly involved in the anti-inflammatory effect from a relatively early stage the healing process of TNBS-induced colitis.


Assuntos
Apoptose/efeitos dos fármacos , Colite/fisiopatologia , Modelos Animais de Doenças , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Intestinos/patologia , Sinvastatina/farmacologia , Cicatrização/fisiologia , Animais , Peso Corporal/fisiologia , Cicatriz Hipertrófica/fisiopatologia , Colite/induzido quimicamente , Colite/patologia , Fibroblastos/fisiologia , Fibrose , Marcação In Situ das Extremidades Cortadas , Intestinos/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos , Miofibroblastos/fisiologia , Cicatrização/efeitos dos fármacos
13.
Oncol Rep ; 24(6): 1487-92, 2010 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-21042743

RESUMO

Colorectal cancer is one of the most serious complications of ulcerative colitis (UC), and the risk of UC-associated neoplasia increases as the region and duration of the disease increase. Selective cyclooxygenase (COX)-2 inhibitors effectively diminish carcinogenesis in a murine UC model. However, this may exacerbate colitis. The selective COX-2 inhibitor etodolac is marketed as a racemic mixture of the R- and S-enantiomers. The biochemical and pharmacological effects of etodolac are caused by the S-enantiomer, while the R-enantiomer lacks COX-inhibitory activity. In this study, we evaluated the effect of R-etodolac on colitis-related mouse colon tumorigenesis. The mice received 1,2-dimethlhydrazine (DMH), and then chronic colitis was induced by administration of two cycles of DSS (each cycle: 3% DSS for 7 days followed by distilled water for 14 days). The mice were sacrificed 28 days after the completion of both cycles. Mice were divided into the following groups: group A served as a disease control; group B received a low (2-mg/kg) dose of R-etodolac every 3 days during the entire period; group C received a high (10-mg/kg) dose of R-etodolac on the same schedule as group B; and group D served as a normal control. Administration of R-etodolac decreased the disease activity index during the DSS administration cycle. The mean number of tumors was 17.8, 15.2, 6.0, and 0 in groups A-D, respectively. In group C, R-etodolac significantly suppressed the occurrence of neoplasia (p<0.05). Although R-etodolac treatment did not affect COX-2 expression, it significantly enhanced expression of E-cadherin in both neoplastic lesions and background mucosa (i.e., lesion-free colon). Thus, administration of R-etodolac exerts a suppressive effect on the development of neoplasia in a murine model of DSS-induced colitis without exacerbation of the colitis. These results suggest that R-etodolac could be useful in the prevention of UC-associated neoplasia.


Assuntos
Caderinas/genética , Carcinoma/etiologia , Carcinoma/prevenção & controle , Colite/complicações , Neoplasias do Colo/etiologia , Neoplasias do Colo/prevenção & controle , Etodolac/farmacologia , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Caderinas/metabolismo , Carcinoma/genética , Carcinoma/patologia , Colite/induzido quimicamente , Colite/genética , Neoplasias do Colo/genética , Neoplasias do Colo/patologia , Ciclo-Oxigenase 2/genética , Ciclo-Oxigenase 2/metabolismo , Progressão da Doença , Avaliação Pré-Clínica de Medicamentos , Etodolac/uso terapêutico , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos BALB C , Índice de Gravidade de Doença , Carga Tumoral , Regulação para Cima/efeitos dos fármacos
14.
J Pharmacol Exp Ther ; 332(2): 684-9, 2010 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-19996300

RESUMO

The side effects of nonsteroidal anti-inflammatory drugs (NSAIDs) include gastrointestinal damage not only in the stomach but also in the small intestine. Chymase converts promatrix metalloproteinase-9 to matrix metalloproteinase (MMP)-9, which plays an important role in NSAID-induced gastric damage, but it has been unclear whether chymase-dependent MMP-9 activation is involved in the NSAID-induced small intestinal damage. To clarify the involvement of chymase-dependent MMP-9 activation on NSAID-induced small intestinal damage, the effect of a chymase inhibitor, 2-[4-(5-fluoro-3-methylbenzo[b]thiophen-2-yl)sulfonamido-3-methanesulfonylphenyl] thiazole-4-carboxylic acid (TY-51469), on indomethacin-induced small intestinal damage in rats was evaluated. Until 6 h after oral administration of indomethacin in rats, intestinal MMP-9 activity was unchanged compared with normal rats, but significant increases in MMP-9 activity were observed 12 and 24 h after indomethacin administration. Significant increases in the small intestinal damage score were also observed 12 and 24 h after indomethacin administration. In the extract from the small intestine 24 h after indomethacin administration, the MMP-9 activation was significantly attenuated by TY-51469. Intraperitoneal injection of TY-51469 (10 mg/kg) 3 h before indomethacin administration significantly attenuated the MMP-9 activity in the small intestine compared with placebo treatment. Myeloperoxidase activity, which indicates accumulation of neutrophils, was significantly increased in the small intestine in the placebo-treated rats, but its activity was significantly attenuated by TY-51469 treatment. The area of small intestinal damage was also significantly ameliorated by TY-51469 treatment. These findings suggest that chymase-dependent MMP-9 activation has a significant role in indomethacin-induced small intestinal damage in rats.


Assuntos
Enterite/metabolismo , Indometacina/efeitos adversos , Intestino Delgado/efeitos dos fármacos , Metaloproteinase 9 da Matriz/biossíntese , Animais , Anti-Inflamatórios não Esteroides/efeitos adversos , Quimases/antagonistas & inibidores , Quimases/metabolismo , Enterite/induzido quimicamente , Enterite/tratamento farmacológico , Enterite/patologia , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/uso terapêutico , Intestino Delgado/metabolismo , Intestino Delgado/patologia , Masculino , Inibidores de Metaloproteinases de Matriz , Peroxidase/antagonistas & inibidores , Peroxidase/metabolismo , Éteres Fenílicos/farmacologia , Éteres Fenílicos/uso terapêutico , Ratos , Ratos Sprague-Dawley , Sulfonamidas/farmacologia , Sulfonamidas/uso terapêutico , Tiofenos/farmacologia , Tiofenos/uso terapêutico , Fatores de Tempo
15.
Neurosci Lett ; 448(1): 125-9, 2008 Dec 19.
Artigo em Inglês | MEDLINE | ID: mdl-18938210

RESUMO

The present study was aimed at determining whether human recombinant hepatocyte growth factor (HGF) ameliorates cerebral edema induced by microsphere embolism (ME). Rats were injected with 700 microspheres (48 microm in diameter). Continuous administration of HGF at 13 microg/3 days/animal into the right ventricle was started from 10 min after embolism to the end of the experiment by using an osmotic pump. On day 3 after the ME, the rats were anesthetized, and their brains were perfused with an isotonic mannitol solution to eliminate constituents in the vascular and extracellular spaces. Thereafter, tissue water and cation contents were determined. A significant increase in tissue water content of the right hemisphere by ME was seen. This ME-induced increase in water content was associated with increases in tissue sodium and calcium ion contents and decreases in tissue potassium and magnesium ion contents of the right hemisphere. The treatment of the animal with HGF suppressed the increases in water and sodium and calcium ion contents, but not the decreases in potassium and magnesium ion contents. These results suggest that HGF suppresses the formation of ischemic cerebral edema provoked intracellularly in rats with ME.


Assuntos
Edema Encefálico/tratamento farmacológico , Edema Encefálico/etiologia , Embolia/complicações , Fator de Crescimento de Hepatócito/uso terapêutico , Animais , Cálcio/metabolismo , Cobalto/administração & dosagem , Modelos Animais de Doenças , Lateralidade Funcional , Masculino , Microesferas , Potássio/metabolismo , Ratos , Ratos Wistar , Sódio/metabolismo , Fatores de Tempo
16.
J Gastroenterol ; 43(7): 576-80, 2008.
Artigo em Inglês | MEDLINE | ID: mdl-18648746

RESUMO

A case of primary NK/T-cell lymphoma of the rectum accompanied with ulcerative colitis (UC) in a 73-year-old man is reported. He had a 6-year history of repeated admission to our hospital for UC. Total colonoscopy performed 4 months after resolution of refractory UC complicated by cytomegalovirus colitis showed a markedly submucosal tumor in the rectum, which was histologically diagnosed as malignant lymphoma. The findings of computed tomography of the chest and abdomen, gallium scintigraphy, abdominal ultrasonography, and upper gastrointestinal endoscopy showed no abnormal lesions. Therefore, based on a diagnosis of localized rectal lymphoma with UC, proctocolectomy was performed. The resected specimen showed three submucosal tumors in the rectum with local nodal involvement. Histologically, the tumors were characterized by diffusely infiltrating sheets of large atypical lymphoid cells, which were negative for CD4, CD8, and CD20 but were positive for CD56, CD3, and granzyme B. The presence of Epstein-Barr virus (EBV) infection in neoplastic cells was shown by in situ hybridization for EBV-encoded early small RNA1 (EBER-1). Based on these findings, the patient was diagnosed with primary CD56+ NK/T-cell lymphoma of the rectum (stage IIE). This is the first case report of primary rectal NK/T-cell lymphoma accompanied with UC.


Assuntos
Antígeno CD56/análise , Colite Ulcerativa/complicações , Linfoma Extranodal de Células T-NK/complicações , Neoplasias Retais/complicações , Idoso , Humanos , Imuno-Histoquímica , Linfoma Extranodal de Células T-NK/imunologia , Linfoma Extranodal de Células T-NK/patologia , Masculino , Neoplasias Retais/imunologia , Neoplasias Retais/patologia
17.
J Pharmacol Exp Ther ; 324(2): 422-6, 2008 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-18024785

RESUMO

Matrix metalloproteinase (MMP)-9 plays an important role in the pathogenesis of colitis. Recent studies have demonstrated that chymase is involved in the conversion of promatrix metalloproteinase (proMMP)-9 to MMP-9. However, whether chymase contributes to the activation of proMMP-9 in colitis has remained unclear. In this study, we administered 5% dextran sodium sulfate (DSS) solution to mice for 7 days. At 7 days after starting administration, both chymase activity and MMP-9 activity were significantly increased. In extract from colitis in DSS-treated mice, MMP-9 activity was significantly increased after 8 h of incubation, but increased activity was almost completely suppressed in the presence of a chymase inhibitor, 2-(5-formylamino-6-oxo-2-phenyl-1,6-dihydropyrimidine-1-yl)-N-[{3,4-dioxo-1-phenyl-7-(2-pyridyloxy)}-2-heptyl] acetamide (NK3201). At 7 days after starting administration, intestinal length was significantly shorter in DSS-treated mice than in normal mice, but these changes were significantly prevented by NK3201 (10 mg/kg per day i.p.). Disease activity index and histological damage score were also significantly reduced by NK3201. The filtrated neutrophil number was significantly decreased by NK3201. Furthermore, NK3201 significantly attenuated not only chymase activity but also MMP-9 activity in DSS-treated mice. These findings suggest that chymase plays an important role in the development of colitis via MMP-9 activation.


Assuntos
Quimases/metabolismo , Colite/enzimologia , Sulfato de Dextrana/toxicidade , Metaloproteinase 9 da Matriz/metabolismo , Acetamidas/farmacologia , Acetamidas/uso terapêutico , Animais , Quimases/antagonistas & inibidores , Colite/induzido quimicamente , Colite/tratamento farmacológico , Ativação Enzimática/efeitos dos fármacos , Ativação Enzimática/fisiologia , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/uso terapêutico , Masculino , Inibidores de Metaloproteinases de Matriz , Camundongos , Camundongos Endogâmicos BALB C , Pirimidinas/farmacologia , Pirimidinas/uso terapêutico
18.
Oncol Rep ; 18(6): 1457-62, 2007 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-17982630

RESUMO

Patients with ulcerative colitis (UC) exhibit an increased risk for the development of cancer of the colon and rectum. This association is widely attributed to colonic inflammation. However, the severity of colonic inflammation necessary for the development of dysplasia and/or cancer remains unknown. In this study, we investigated the pattern of cell proliferation in colorectal carcinogenesis in an experimental murine model of UC. Chronic colitis was induced by administration of four cycles of dextran sulfate sodium (DSS) (each cycle: 5% or 2% DSS for 7 days and then distilled water for 14 days). Mice were sacrificed after every cycle and at 120 days following the completion of the fourth cycle. Colonic cell proliferation was immunohistochemically evaluated using the thymidine analogue bromodeoxyuridine and the labeling index (LI) was determined. The incidence of dysplasia and/or cancer was 28%, 6.7%, and 0% in the 5% DSS, 2% DSS, and normal control groups respectively. All gross lesions were present in the middle to distal colon. Disease activity index and total LI after four cycles of DSS were significantly higher in the 5% DSS group compared to the 2% DSS group. In the 5% DSS group, the LI was significantly higher in the middle colon than in the proximal colon. Simple repeated administration of the non-genotoxic colon carcinogen DSS induced dysplasia and/or cancer. In addition, we have demonstrated the presence of regional differences in proliferation pattern between the middle and the proximal colon during carcinogenesis in experimental murine UC. These findings may provide insight into the development of colorectal cancer in humans with long-standing UC.


Assuntos
Colite Ulcerativa/complicações , Colo/patologia , Neoplasias Colorretais/patologia , Animais , Carcinógenos , Neoplasias Colorretais/etiologia , Sulfato de Dextrana , Modelos Animais de Doenças , Feminino , Camundongos , Camundongos Endogâmicos BALB C
19.
World J Gastroenterol ; 11(33): 5241-4, 2005 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-16127763

RESUMO

Various hepato-biliary complications are an increased incidence in patients with inflammatory bowel disease, and portal bacteremia is well documented in patients with ulcerative colitis (UC). However, few reports mention UC in association with liver abscesses. Recently, there are several reports describing cytomegalovirus (CMV) infection in association with disease exacerbation and steroid refractoriness in patients with UC. Here we present a case of refractory UC accompanied with multiple liver abscesses and CMV colitis. The patient, a 72-year-old male, with a five-year history of repeated admissions to our hospital for UC, presented with an exacerbation of his UC. Sigmoidoscopy performed on admission suggested that his UC was exacerbated, then he was given prednisolone and mesalazine orally, and betamethasone enemas. However, he had exacerbated symptoms. Repeat sigmoidoscopy revealed multiple longitudinal ulcers and pseudopolyps in the rectosigmoid colon. Although immunohistochemical staining of biopsy specimens and the serum testing for antigenemia were negative on admission and after the repeat sigmoidoscopy, they became histologically positive for CMV. Nonetheless, the patient developed spiking fevers, soon after ganciclovir was administered. Laboratory studies revealed an increased white cell count with left shift, and Enterococcus fecalis grew in blood cultures. An abdominal computed tomography (CT) scan was obtained and the diagnosis of liver abscesses associated with UC was made, based on CT results. The hepatic abscesses were successfully treated with intravenous meropenem for 6 wk, without further percutaneous drainage. To our knowledge, this is the first reported case of multiple liver abscesses that develop during UC exacerbation complicated by CMV colitis.


Assuntos
Colite Ulcerativa/complicações , Colite/complicações , Colite/virologia , Infecções por Citomegalovirus , Abscesso Hepático/complicações , Idoso , Colite Ulcerativa/fisiopatologia , Humanos , Masculino
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