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BACKGROUND AND AIM: Comprehensive reports on the risk factors for bleeding and early death after percutaneous endoscopic gastrostomy (PEG) are limited. In this multicenter study, we retrospectively investigated the risk factors for bleeding and early death after PEG. METHODS: Patients (n = 1234) who underwent PEG between 2015 and 2020 at Osaka Medical and Pharmaceutical University and its affiliated hospitals (11 institutions in total) were evaluated for postoperative bleeding and early death (within 60 days) after PEG according to patient characteristics, construction method, medical history, medications, preoperative hematological findings, and perioperative adverse events. Multivariate logistic regression was performed to identify independent predictors of bleeding and early death after PEG. RESULTS: The risk factors for bleeding after PEG were PEG tube insertion using the modified introducer method (odds ratio [OR], 4.37; P = 0.0003), low platelet count (OR, 0.99; P = 0.014), antiplatelet therapy (OR, 2.11; P = 0.036), and heparinization (OR, 4.50; P = 0.007). Risk factors for early death were low body mass index (BMI) (OR, 0.89; P = 0.015), low serum albumin levels (OR, 0.50; P = 0.035), and comorbidity of active cancer (OR, 4.03; P < 0.0001). There was no significant association between bleeding and early death after PEG. CONCLUSIONS: We identified several risk factors for bleeding and early death after PEG. Risk factors for bleeding were PEG tube insertion using the modified introducer method, low platelet count, antiplatelet therapy, and heparinization. Risk factors for early death were low BMI, low serum albumin levels, and comorbidity of active cancer.
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Gastrostomia , Mortalidade Prematura , Hemorragia Pós-Operatória , Gastrostomia/efeitos adversos , Humanos , Neoplasias/epidemiologia , Inibidores da Agregação Plaquetária/efeitos adversos , Hemorragia Pós-Operatória/epidemiologia , Estudos Retrospectivos , Fatores de Risco , Albumina SéricaRESUMO
AIMS: While bowel preparation for colonoscopy is the key to successful examination, taking laxatives and showing stools to others causes both physical and mental distress to the patient. Thus, an alternative method to evaluation bowel preparation is necessary. In the current study, we studied the colonic fecal retention by ultrasonography (US) and examined the US finding which reflected completion of BP. MATERIAL AND METHODS: The subjects were outpatients who underwent colonoscopy. This report summarizes the ultrasonographic images of patients who underwent multiple US examinations for all five sites of the colon just before, during, and immediately after bowel preparation. According to the standard protocol, the patients took 2 L of polyethylene glycol-ascorbic acid as a laxative, which was discontinued when the nurse visually judged the stool to be clear. RESULTS: Seven patients in their 50s-80s, none of whom were unable to complete a colonoscopy due to residual feces were included in study. Following bowel preparation, the US images showed anechoic areas with haustration in four or all five areas of the colon. Three of the seven patients received low-dose laxatives (1.1-1.2 L); all three had watery stools in three or more colon areas and none of them were constipated at the time of taking 1 L of laxatives. CONCLUSIONS: Completion of bowel preparation can be assessed by the observation of anechoic areas with haustration in multiple colonic sites by ultrasonography.
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Colonoscopia , Fezes , Colo , Humanos , Laxantes , PolietilenoglicóisRESUMO
Reversible post-translational modification of serine and threonine residues by O-linked N-acetylglucosamine (O-GlcNAc), termed O-GlcNAcylation has been indicated to regulate the activities of a number of different proteins. Augmented O-GlcNAcylation contributes to the etiologies of type 2 diabetes mellitus (T2DM) and cancer. Moreover, diabetic conditions increase the risk of colorectal cancer. However, the effect of O-GlcNAcylation in patients with colorectal cancer and concurrent T2DM has not been elucidated. The current study evaluated the level of O-GlcNAcylation in patients with colorectal cancer with or without T2DM. Notably, O-GlcNAcylation levels were significantly higher in tissues from patients with T2DM compared with those in patients without T2DM, and higher in cancer tissues compared with corresponding adjacent tissues. O-GlcNAcylation and cancer stage were more strongly correlated in cancer tissues from patients with T2DM compared with those from patients without T2DM. Additionally, distant metastasis was significantly correlated with O-GlcNAcylation in cancer tissues from patients with T2DM. ß-catenin levels in colorectal cancer tissues were the highest in patients with advanced-stage cancer and concurrent T2DM. In SW480 human colon cancer cells, thiamet G (TMG) treatment and OGA silencing, which increased O-GlcNAcylation, significantly increased ß-catenin and SNAIL in high-glucose, but not during normal-glucose conditions. These data suggest that O-GlcNAcylation is closely associated with distant metastasis, most likely through upregulation of the ß-catenin/SNAIL signaling pathway in colorectal cancer patients with T2DM.
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Linked color imaging (LCI) is a novel endoscopic system used to increase color contrast. As LCI does not decrease luminal brightness, it may improve the detection of colonic neoplasms. However, the extent to which LCI improves the visibility of colonic polyps has not yet been determined. Between December 2016 and May 2017, patients who received total colonoscopy were consecutively recruited into this retrospective, single-center study. For each polyp identified, images obtained from white light (WL) imaging, blue laser imaging (BLI), and LCI of the same lesion and its surrounding mucosa were evaluated. The color differences (ΔE) between each lesion and its surrounding mucosa in non-magnified images were computed quantitatively using the CIELAB color space, which defines color perception according to colorimetric values, and compared among WL, BLI, LCI, and chromoendoscopy. The ΔE between the vessel and non-vessel areas in magnified images was also assessed. Of the 64 patients who were incorporated into this study, non-magnified and magnified (×80) images from 113 and 95 polyps, respectively, were assessed. The ΔE was intensified by LCI and chromoendoscopy compared with WL and BLI. The ΔE of neoplastic lesions was also intensified by LCI. In magnified images, BLI and LCI significantly increased the ΔE between the vessel and non-vessel areas compared with WL. Luminal brightness, indicated by L*, was not impaired by LCI; however, was reduced by BLI compared with WL and LCI. These results suggest that LCI enhanced the detection of colonic neoplasms without impairing luminal brightness. We propose the routine use of LCI for colonic polyp detection and BLI for magnifying observations of colonic polyps detected by LCI.
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We investigated the risk factors of and appropriate treatment for cytomegalovirus colitis in patients with ulcerative colitis, using quantitative polymerase chain reaction analysis to detect cytomegalovirus in the colonic mucosa. Between February 2013 and January 2017, patients with exacerbated ulcerative colitis who were admitted to our hospital were consecutively enrolled in this retrospective, single-center study. Patients were evaluated for cytomegalovirus using serology (antigenemia) and quantitative polymerase chain reaction analyses of the colonic mucosa, which were sampled during colonoscopy. Of 86 patients, 26 (30.2%) had positive quantitative polymerase chain reaction results for cytomegalovirus; only 4 were also positive for antigenemia. The ages of the cytomegalovirus DNA-positive patients were significantly higher than those of negative patients (p = 0.002). The mean endoscopic score of cytomegalovirus DNA-positive patients was significantly higher than that of cytomegalovirus DNA-negative patients. Treatment with combined immunosuppressants was associated with an increased risk of cytomegalovirus. Fourteen of 15 (93.3%) cytomegalovirus DNA-positive patients who were negative for antigenemia showed a clinical response to treatment with additional oral tacrolimus, without ganciclovir. cytomegalovirus reactivation in active ulcerative colitis is associated with age and combined immunosuppressant therapy. Because additional treatment with tacrolimus was effective, patients who are negative for antigenemia and cytomegalovirus DNA-positive colonic mucosa may recover without antiviral therapy.
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The relationship between type 2 diabetes mellitus and intestinal neoplasia has been shown epidemiologically. A high-fat diet (HFD) is also known to promote insulin resistance, which is a risk factor for intestinal neoplasia. Dipeptidyl peptidase-4 (DPP-4) inhibitors are used in the clinic for the treatment of type 2 diabetes and also to prolong the effects of glucagon-like peptide-1 (GLP-1). However, since the intestinotrophic hormone GLP-2 and chemokines, such as CXCL5 and stromal cell-derived factor-1 (SDF-1), are also substrates of DPP-4, DPP-4 inhibitors may increase the risk of intestinal carcinogenesis. In this study, we evaluated the impact of a DPP-4 inhibitor on intestinal tumorigenesis in ApcMin/+ mice fed a HFD. Six-week-old male ApcMin/+ mice were randomized to either a normal diet (10 kcal% fat) group, a HFD (60 kcal% fat) group, or a HFD group treated with sitagliptin (STG). The mice were euthanized nine weeks after the start of treatment. Daily treatment with STG did not increase number of intestinal tumors in the HFD group; however, this increase was not statistically significant. The mucosal concentration of total GLP-2 was significantly increased in the HFD group. The chemokine protein array showed elevated plasma concentrations of CXCL5 and SDF-1 in the HFD group. The administration of STG significantly suppressed the levels of plasma CXCL5 and SDF-1 in mice fed a HFD. Since CXCL5 expression is increased in patients with type 2 diabetes, and GLP-2, CXCL5 and SDF-1 are associated with tumor progression, DPP-4 inhibition may have potential as an agent for decreasing the risk of cancer in obese or diabetic patients.
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Mesenteric panniculitis (MP) is a benign fibroinflammatory process characterized by the presence of fat necrosis, chronic inflammation and fibrosis in the mesentery. Although various causal factors, such as malignancy, chronic inflammatory conditions and autoimmune processes, have been identified, the precise etiology remains unknown. We herein report a rare case of MP accompanying Sjögren's syndrome in which a mass lesion and intestinal stenosis were observed simultaneously. This condition led to ileus, which was effectively treated using prednisolone.
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Íleus/etiologia , Enteropatias/etiologia , Paniculite Peritoneal/complicações , Paniculite Peritoneal/epidemiologia , Síndrome de Sjogren/complicações , Síndrome de Sjogren/epidemiologia , Idoso , Feminino , Humanos , Íleus/tratamento farmacológico , Mesentério/patologia , Prednisolona/uso terapêuticoAssuntos
Neoplasias da Medula Óssea/secundário , Neoplasias Gástricas/patologia , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Medula Óssea/diagnóstico por imagem , Quimioterapia Adjuvante , Coagulação Intravascular Disseminada/etiologia , Evolução Fatal , Humanos , Masculino , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/cirurgiaRESUMO
Patients with type 2 diabetes mellitus are known to have an increased risk of colorectal neoplasia. Dipeptidyl peptidase-4 (DPP-4) inhibitors have been used as a new therapeutic tool for type 2 diabetes. Since the substrates for DPP-4 include intestinotrophic hormones and chemokines such as GLP-2 and stromal cell-derived factor-1 (SDF-1), which are associated with tumor progression, DPP-4 inhibitors may increase the risk of colorectal tumors. However, the influence of DPP-4 inhibitors on colorectal neoplasia in patients with type 2 diabetes remains unknown. In the present study, we show that long-term administration of a DPP-4 inhibitor, sitagliptin (STG), suppressed colon carcinogenesis in leptin-deficient (ob/ob) C57BL/6J mice. Colonic mucosal concentrations of glucagonlike peptide-1 (GLP-1) and GLP-2 were significantly elevated in the ob/ob mice. However, mucosal GLP concentrations and the plasma level of SDF-1 were not affected by the administration of STG. Realtime PCR analysis revealed that colonic mucosal IL-6 mRNA expression, which was significantly upregulated in the ob/ob mice, was significantly suppressed by the long-term administration of STG. These results suggest that a DPP-4 inhibitor may suppress colon carcinogenesis in mice with type 2 diabetes in a GLP-independent manner. Since DPP-4 has multiple biological functions, further studies analyzing other factors related to colon carcinogenesis are needed.
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Carcinogênese/efeitos dos fármacos , Neoplasias Colorretais/etiologia , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Tipo 2/complicações , Inibidores da Dipeptidil Peptidase IV/farmacologia , Fosfato de Sitagliptina/farmacologia , Animais , Neoplasias Colorretais/prevenção & controle , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Obesos , Reação em Cadeia da Polimerase em Tempo RealRESUMO
Crohn's disease (CD) is characterized by transmural inflammation of the gastrointestinal tract, which predisposes patients to the formation of a fistula. The efficacy of adalimumab (ADA) for an enterocutaneous fistula remains unclear. In this report, we present a case series of 3 patients with enterocutaneous fistulizing CD treated with ADA. ADA treatment achieved sustained complete fistula closure in one patient. The other two cases, which failed to achieve fistula closure, had intestinal stenosis and were not receiving concomitant azathioprine. Combination therapy with ADA and azathioprine may be a useful option and an alternative to surgery for enterocutaneous fistulizing CD.
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Adalimumab/uso terapêutico , Doença de Crohn/complicações , Fístula Intestinal/tratamento farmacológico , Fístula Intestinal/etiologia , Adulto , Anticorpos Monoclonais/uso terapêutico , Terapia Combinada , Humanos , Masculino , Pessoa de Meia-Idade , Resultado do TratamentoRESUMO
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.
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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 BetulínicoRESUMO
Geranylgeranylacetone (GGA), an isoprenoid compound, is an anti-ulcer drug developed in Japan. GGA protects a variety of cells and tissues against numerous stresses via induction of heat shock protein (HSP) 70, and it has recently been reported to protect mice from experimental ulcerative colitis (UC). However, it is unknown whether GGA exhibits a preventive effect on UC-associated neoplasia. In the present study, we evaluated the preventive effects of GGA on colitis-related carcinogenesis in the mouse colon. Mice were administered 1,2-dimethylhydrazine (DMH) subcutaneously three times within a week, followed by 2 cycles of dextran sulfate sodium (DSS) (each cycle, 3% DSS for 7 days and then distilled water for 14 days) and they were sacrificed 28 days after the completion of the 2 cycles. The mice were divided into the following groups according to the diet received during the experiment: group A, which received a standard diet and served as a disease control; group B, which received a diet mixed with 0.25% GGA; group C, which received a diet mixed with 0.5% GGA; group D, which received a diet mixed with 1.0% GGA; group E, which received a diet mixed with 2.0% GGA; and group F, which received a diet containing no agents, including DSS and served as a normal control. The incidence of neoplasia was assessed. The expression of inducible nitric oxide synthase (iNOS) and 8-hydroxy-2'-deoxyguanosine (8-OHdG) was also determined. In addition, the expression of HSP70 in the colon tissues was determined by immunohistochemistry and western blot analysis. The mean number of tumors was 16.6, 11.0, 9.4, 5.8, 5.4 and 0 in groups A-F, respectively. GGA significantly suppressed the occurrence of neoplasia in a dose-dependent manner. GGA treatment enhanced the expression of HSP70 and suppressed the oxidative damage in the background mucosa (i.e. lesion-free colon). These results suggest that GGA could be useful in the prevention of UC-associated neoplasia.
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Antineoplásicos/uso terapêutico , Colite Ulcerativa/tratamento farmacológico , Neoplasias do Colo/prevenção & controle , Diterpenos/uso terapêutico , 8-Hidroxi-2'-Desoxiguanosina , Animais , Western Blotting , Colite Ulcerativa/complicações , Colite Ulcerativa/metabolismo , Neoplasias do Colo/etiologia , Neoplasias do Colo/metabolismo , Desoxiguanosina/análogos & derivados , Desoxiguanosina/metabolismo , Feminino , Proteínas de Choque Térmico HSP70/metabolismo , Imuno-Histoquímica , Camundongos , Camundongos Endogâmicos BALB C , Óxido Nítrico Sintase Tipo II/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
Chemokine (C-C motif) receptor 8 (CCR8), the chemokine receptor for chemokine (C-C motif) ligand 1 (CCL1), is expressed in T-helper type-2 lymphocytes and peritoneal macrophages (PMφ) and is involved in various pathological conditions, including peritoneal adhesions. However, the role of CCR8 in inflammatory responses is not fully elucidated. To investigate the function of CCR8 in macrophages, we compared cytokine secretion from mouse PMφ or bone marrow-derived macrophages (BMMφ) stimulated with various Toll-like receptor (TLR) ligands in CCR8 deficient (CCR8-/-) and wild-type (WT) mice. We found that CCR8-/- PMφ demonstrated attenuated secretion of tumor necrosis factor (TNF)-α, interleukin (IL)-6, and IL-10 when stimulated with lipopolysaccharide (LPS). In particular, LPS-induced IL-10 production absolutely required CCR8. CCR8-dependent cytokine secretion was characteristic of PMφ but not BMMφ. To further investigate this result, we selected the small molecule compound R243 from a library of compounds with CCR8-antagonistic effects on CCL1-induced Ca2+ flux and CCL1-driven PMφ aggregation. Similar to CCR8-/- PMφ, R243 attenuated secretion of TNF-α, IL-6, and most strikingly IL-10 from WT PMφ, but not BMMφ. CCR8-/- PMφ and R243-treated WT PMφ both showed suppressed c-jun N-terminal kinase activity and nuclear factor-κB signaling after LPS treatment when compared with WT PMφ. A c-Jun signaling pathway inhibitor also produced an inhibitory effect on LPS-induced cytokine secretion that was similar to that of CCR8 deficiency or R243 treatment. As seen in CCR8-/- mice, administration of R243 attenuated peritoneal adhesions in vivo. R243 also prevented hapten-induced colitis. These results are indicative of cross talk between signaling pathways downstream of CCR8 and TLR-4 that induces cytokine production by PMφ. Through use of CCR8-/- mice and the new CCR8 inhibitor, R243, we identified a novel macrophage innate immune response pathway that involves a chemokine receptor.
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Citocinas/biossíntese , Macrófagos Peritoneais/metabolismo , Receptores CCR8/metabolismo , Animais , Quimiocina CCL1/antagonistas & inibidores , Quimiotaxia/efeitos dos fármacos , Quimiotaxia/imunologia , Colite/genética , Colite/imunologia , Colite/metabolismo , Modelos Animais de Doenças , Inflamação/genética , Inflamação/imunologia , Inflamação/metabolismo , Espaço Intracelular/metabolismo , Lipopolissacarídeos/imunologia , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Macrófagos/metabolismo , Macrófagos Peritoneais/efeitos dos fármacos , Macrófagos Peritoneais/imunologia , Masculino , Camundongos , Camundongos Knockout , Transporte Proteico , Receptores CCR8/antagonistas & inibidores , Receptores CCR8/deficiência , Receptores CCR8/genética , Transdução de Sinais/efeitos dos fármacos , Receptores Toll-Like/metabolismoRESUMO
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.
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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 TratamentoRESUMO
Oral food intake influences the morphology and function of intestinal epithelial cells and maintains gastrointestinal cell turnover. However, how exactly these processes are regulated, particularly in the large intestine, remains unclear. Here we identify microbiota-derived lactate as a major factor inducing enterocyte hyperproliferation in starvation-refed mice. Using bromodeoxyuridine staining, we show that colonic epithelial cell turnover arrests during a 12- to 36-h period of starvation and increases 12-24 h after refeeding. Enhanced epithelial cell proliferation depends on the increase in live Lactobacillus murinus, lactate production and dietary fibre content. In the model of colon tumorigenesis, mice exposed to a carcinogen during refeeding develop more aberrant crypt foci than mice fed ad libitum. Furthermore, starvation after carcinogen exposure greatly reduced the incidence of aberrant crypt foci. Our results indicate that the content of food used for refeeding as well as the timing of carcinogen exposure influence the incidence of colon tumorigenesis in mice.
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Alimentos , Mucosa Intestinal/citologia , Lactatos/metabolismo , Lactobacillus/metabolismo , Inanição , Animais , Proliferação de Células , Mucosa Intestinal/microbiologia , CamundongosRESUMO
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.
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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 JovemRESUMO
BACKGROUND & AIMS: TWEAK, a member of the tumor necrosis factor (TNF) superfamily, promotes intestinal epithelial cell injury and signals through the receptor Fn14 following irradiation-induced tissue damage and during development of colitis in mice. Interleukin (IL)-13, an effector of tissue damage in similar models, has been associated with the pathogenesis of ulcerative colitis (UC). We investigated interactions between TWEAK and IL-13 following mucosal damage in mice. METHODS: We compared patterns of gene expression in intestinal tissues from wild-type and TWEAK knockout mice following γ-irradiation. Intestinal explants from these mice were used to detect cell damage induced by IL-13 and TNF-α. Levels of messenger RNA for IL-13, TWEAK, and Fn14 were measured in mucosal samples from patients with UC. RESULTS: Based on gene expression analysis, TWEAK mediates γ-irradiation-induced epithelial cell cycle arrest and apoptosis. However, TWEAK alone did not induce damage or apoptosis of primary intestinal epithelial cells. On the other hand, exogenous IL-13 activated caspase-3 in naïve intestinal explants; this process required TWEAK, Fn14, and secretion of endogenous TNF-α which was mediated by ADAM17. Conversely, activation of caspase by exogenous TNF-α required IL-13, TWEAK, and Fn14. In mucosa from patients with UC, messenger RNA levels of IL-13, TWEAK, and Fn14 increased with level of disease severity. CONCLUSIONS: IL-13-induced damage of intestinal epithelial cells requires TWEAK, its receptor (Fn14), and TNF-α. IL-13, TNF-α, TWEAK, and Fn14 could perpetuate and aggravate intestinal inflammation in patients with UC.
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Colite Ulcerativa/patologia , Regulação da Expressão Gênica/fisiologia , Interleucina-13/metabolismo , Mucosa Intestinal/patologia , Receptores do Fator de Necrose Tumoral/genética , Fatores de Necrose Tumoral/genética , Animais , Morte Celular , Colite Ulcerativa/genética , Citocina TWEAK , Mucosa Intestinal/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , RNA Mensageiro/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transdução de Sinais/fisiologia , Receptor de TWEAK , Fator de Necrose Tumoral alfa/farmacologiaRESUMO
Novel prostaglandin D(2) (PGD(2)) receptor antagonists were synthesized as a potential new class of antiallergic agents having a bicyclo[2.2.1]heptane ring system with sulfonamide groups. Some of them exhibit extremely potent antagonism of the PGD(2) receptor in radioligand binding and cAMP formation assays with IC(50) values below 50 nM and much less antagonism of TXA(2) and PGI(2) receptors. These potent PGD(2) receptor antagonists, when given orally, dramatically suppress various allergic inflammatory responses such as increased vascular permeability in allergic rhinitis, conjunctivitis, and asthma models. The excellent pharmacological profiles of PGD(2) receptor antagonists, originally synthesized in our laboratories, are of potentially great clinical significance. This study also provides experimental evidence suggesting that PGD(2) plays an important role in the pathogenesis of allergic diseases.
Assuntos
Antialérgicos/síntese química , Compostos Bicíclicos com Pontes/síntese química , Hexanos/síntese química , Prostaglandina D2/metabolismo , Receptores Imunológicos , Receptores de Prostaglandina/antagonistas & inibidores , Sulfonamidas/síntese química , Administração Oral , Obstrução das Vias Respiratórias/tratamento farmacológico , Obstrução das Vias Respiratórias/imunologia , Animais , Antialérgicos/química , Antialérgicos/farmacologia , Plaquetas/efeitos dos fármacos , Plaquetas/metabolismo , Compostos Bicíclicos com Pontes/química , Compostos Bicíclicos com Pontes/farmacologia , Permeabilidade Capilar/efeitos dos fármacos , Túnica Conjuntiva/irrigação sanguínea , AMP Cíclico/biossíntese , Cobaias , Hexanos/química , Hexanos/farmacologia , Humanos , Técnicas In Vitro , Ensaio Radioligante , Receptores de Epoprostenol , Receptores de Tromboxanos/antagonistas & inibidores , Estereoisomerismo , Relação Estrutura-Atividade , Sulfonamidas/química , Sulfonamidas/farmacologiaRESUMO
In an earlier paper, we reported that novel prostaglandin D(2) (PGD(2)) receptor antagonists having the bicyclo[2.2.1]heptane ring system as a prostaglandin skeleton were a potent new class of antiallergic agents and suppressed various allergic inflammatory responses such as those observed in conjunctivitis and asthma models. In the present study, we synthesized PGD(2) receptor antagonists having the 6,6-dimethylbicyclo[3.1.1]heptane ring system. These derivatives have the amide moiety, in contrast to those with the bicyclo[2.2.1]heptane ring system, which have the sulfonamide group. The derivatives having the 6,6-dimethylbicyclo[3.1.1]heptane ring also exhibited strong activity in PGD(2) receptor binding and cAMP formation assays. In in vivo assays such as allergic rhinitis, conjunctivitis, and asthma models, these series of derivatives showed excellent pharmacological profiles. In particular, compound 45 also effectively suppressed eosinophil infiltration in allergic rhinitis and asthma models. This compound (45, S-5751) is now being developed as a promising alternative antiallergic drug candidate.