RESUMO
BACKGROUND: We recently reported the efficacy of indigo naturalis (IN) in patients with active ulcerative colitis (UC) in a randomized controlled trial (INDIGO study). However, few studies have been conducted to investigate whether IN is effective even in treatment-refractory cases, such as in those with steroid dependency and anti-TNF refractoriness. METHODS: In the INDIGO study, 86 patients with active UC were randomly assigned to an IN group (0.5-2.0 g daily) or placebo group. The rate of clinical response (CR), mucosal healing (MH), and change in fecal calprotectin (FCP) levels was compared between refractory [patients with steroid-dependent disease, previous use of anti-TNF-α, and concomitant use of immunomodulators (IM)] and non-refractory patients. We also analyzed factors predicting CR and MH at week 8. RESULTS: The rates of CR of IN group were significantly higher than placebo group, even in patients with steroid-dependent disease (p < 0.001), previous use of anti-TNF-α (p = 0.002), and concomitant use of IM (p = 0.013). The rates of MH in IN group were significantly higher than in placebo group in patients with steroid-dependent disease (p = 0.009). In the IN group, median FCP levels, at week 8, were significantly lower than baseline in patients with steroid-dependent disease and patients with the previous use of anti-TNF-α (p < 0.001, respectively). Multivariate analysis indicated that the previous use of anti-TNF-α was not a predictive factor for CR and MH at week 8. CONCLUSIONS: In a sub-analysis of data from a randomized placebo-controlled trial, we found that IN may be useful even in patients with steroid-dependent disease and patients with the previous use of anti-TNF-α.
Assuntos
Colite Ulcerativa/tratamento farmacológico , Medicamentos de Ervas Chinesas/uso terapêutico , Mucosa Intestinal/patologia , Cicatrização/efeitos dos fármacos , Adulto , Colite Ulcerativa/patologia , Fezes/química , Feminino , Humanos , Fatores Imunológicos/uso terapêutico , Complexo Antígeno L1 Leucocitário/análise , Masculino , Pessoa de Meia-Idade , Retratamento , Índice de Gravidade de Doença , Esteroides/uso terapêutico , Resultado do Tratamento , Inibidores do Fator de Necrose Tumoral/uso terapêutico , Adulto JovemRESUMO
BACKGROUND & AIMS: Indigo naturalis (IN) is a traditional Chinese medicine that contains ligands for the aryl hydrocarbon receptor and promotes regeneration of the mucosa by inducing production of interleukin 22. IN might induce mucosal healing in patients with ulcerative colitis (UC). We performed a randomized controlled trial to investigate the safety and efficacy of IN in patients with UC. METHODS: We performed a multicenter, double-blind trial evaluating the safety of 86 patients in Japan with active UC (Mayo scores of 6 or more), enrolled from March 30 through December 27, 2016. Patients were randomly assigned to groups and given a daily dose of 0.5, 1.0, or 2.0 g IN or placebo (1:1:1:1 ratio) for 8 weeks. The primary endpoint was the rate of clinical response at week 8, defined as a 3-point decrease in the Mayo score and a decrease of at least 30% from baseline, with a decrease of at least 1 point for the rectal bleeding subscore or absolute rectal bleeding score of 0-1. The main secondary endpoint was the rate of clinical remission at week 8, defined as a Mayo score or ≤2 and no subscores with a value >1. Mucosal healing was also assessed at week 8. RESULTS: The trial was terminated because of an external reason: a report of pulmonary arterial hypertension in a patient who used self-purchased IN for 6 months. In the intent-to-treat analysis, we observed a significant, dose-dependent linear trend in proportions of patients with clinical responses (13.6% with a clinical response to placebo; 69.6% to 0.5 g IN; 75.0% to 1.0 g IN; and 81.0% to 2.0 g IN) (Cochran-Armitage trend test P < .0001 compared with placebo). Proportions of patients in clinical remission at week 8 were significantly higher in the 1.0 g IN group (55.0%, P = .0004) and the 2.0 g IN group (38.1%, (P = .0093) than in the placebo group (4.5%). Proportions of patients with mucosal healing were 13.6% in the placebo group, 56.5% in the 0.5 g IN group, 60.0% in the 1.0 g IN group, and 47.6% in the 2.0 g IN group (P = .0278 compared with placebo). Although mild liver dysfunction was observed in 10 patients who received IN, no serious adverse events were observed. CONCLUSIONS: In a randomized, placebo-controlled trial, we found 8 weeks of IN (0.5-2.0 g per day) to be effective in inducing a clinical response in patients with UC. However, IN should not yet be used because of the potential for adverse effects, including pulmonary arterial hypertension. Clinical Trials Registry no: UMIN000021439 (http://www.umin.ac.jp/ctr/).
Assuntos
Colite Ulcerativa/tratamento farmacológico , Medicamentos de Ervas Chinesas/administração & dosagem , Fármacos Gastrointestinais/administração & dosagem , Índigo Carmim/administração & dosagem , Adolescente , Adulto , Idoso , Colite Ulcerativa/diagnóstico , Relação Dose-Resposta a Droga , Método Duplo-Cego , Medicamentos de Ervas Chinesas/efeitos adversos , Término Precoce de Ensaios Clínicos , Feminino , Fármacos Gastrointestinais/efeitos adversos , Humanos , Índigo Carmim/efeitos adversos , Análise de Intenção de Tratamento , Japão , Masculino , Pessoa de Meia-Idade , Indução de Remissão , Fatores de Tempo , Resultado do Tratamento , Adulto JovemRESUMO
BACKGROUND/AIMS: Chinese herbal medicine Qing-Dai (also known as indigo naturalis) has been used to treat various inflammatory conditions. However, not much has been studied about the use of oral Qing-Dai in the treatment for ulcerative colitis (UC) patients. Studies exploring alternative treatments for UC are of considerable interest. In this study, we aimed at prospectively evaluating the safety and efficacy of Qing-Dai for UC patients. METHODS: The open-label, prospective pilot study was conducted at Keio University Hospital. A total of 20 patients with moderate UC activity were enrolled. Oral Qing-Dai in capsule form was taken twice a day (daily dose, 2 g) for 8 weeks. RESULTS: At week 8, the rates of clinical response, clinical remission, and mucosal healing were 72, 33, and 61%, respectively. The clinical and endoscopic scores, CRP levels, and fecal occult blood results were also significantly improved. We observed 2 patients with mild liver dysfunction; 1 patient discontinued due to infectious colitis and 1 patient discontinued due to mild nausea. CONCLUSION: This is the first prospective study indicating that oral Qing-Dai is effective for inducing remission in patients with moderate UC activity and can be tolerated. Thus, Qing-Dai may be considered an alternative treatment for patients, although further investigation is warranted.
Assuntos
Colite Ulcerativa/tratamento farmacológico , Medicamentos de Ervas Chinesas/uso terapêutico , Mucosa Intestinal/efeitos dos fármacos , Medicina Tradicional Chinesa/métodos , Administração Oral , Adulto , Idoso , Idoso de 80 Anos ou mais , Cápsulas , Colite Ulcerativa/diagnóstico , Colonoscopia , Medicamentos de Ervas Chinesas/administração & dosagem , Medicamentos de Ervas Chinesas/efeitos adversos , Feminino , Humanos , Japão , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Estudos Prospectivos , Indução de Remissão/métodos , Resultado do Tratamento , Adulto JovemRESUMO
BACKGROUND AND AIM: We have reported that second-generation colon capsule endoscopy (CCE-2) might be feasible for assessing the severity of mucosal inflammation in ulcerative colitis (UC). However, because of the low rate (69%) of complete evaluation of the colon and owing to inadequate cleansing. We believe that the method of bowel preparation could be improved by reducing volume. In the present study, we attempted to improve the colon-cleansing regimen in order to optimize the usefulness of CCE-2 in the management of UC patients. METHODS: Twenty patients with histologically confirmed UC were enrolled. Patients took a maximum 2.2 L lavage solution (polyethylene glycol solution and magnesium citrate) in two or three divided doses. To assess the effectiveness of the modified bowel preparation regimen, we evaluated the rate of total colonobservation, the effectiveness of bowel cleansing, andinterobserver agreement in assessing UC disease activity. We used a four-point grading scale (poor, fair, good, and excellent) for evaluating the quality of bowel cleansing. Matts' endoscopic score was used to evaluate disease activity. RESULTS: The rate of total colon observation was 85%, and 15 patients (75%) excreted the CCE-2 within 8 h. The proportion of excellent plus good cleansing was approximately 60%. There was a substantial interobserver agreement (κ = 0.777) in assessment of overall cleansing, which was still substantial at the fair cleansing level (κ = 0.700). CONCLUSION: Using CCE-2, the modified bowel preparation regimen, with reduced volume has the potential to succeed in the evaluation of mucosal severity in UC.
Assuntos
Endoscopia por Cápsula/métodos , Catárticos/administração & dosagem , Colite Ulcerativa/diagnóstico , Polietilenoglicóis/administração & dosagem , Adulto , Idoso , Enema/métodos , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Curva ROC , Reprodutibilidade dos Testes , Estudos Retrospectivos , Índice de Gravidade de Doença , Adulto JovemRESUMO
PURPOSE OF REVIEW: This review focuses on CD4+ T cells involved in the mediation of inflammatory tissue damage in murine models of inflammatory bowel diseases (IBDs). In particular, we describe the distinct roles of the homeostatic cytokine IL-7, which is essential to the maintenance of colitogenic memory CD4+ cells, and the newly discovered effector cytokine IL-17. We also discuss the close correlation between colitogenic Th17-type CD4+ T cells and inducible CD4+CD25+Foxp3+ regulatory T cells. RECENT FINDINGS: IBDs are characterized by wasting and chronic intestinal inflammation induced by many different cytokine-mediated pathways. It is clearly recognized that medical and surgical interventions do not cure Crohn's disease because relapse is the rule after remission. Until a few years ago, IBD was classified into Th1-dependent, that is, Crohn's disease, and Th2-dependent, that is, ulcerative colitis, phenotypes. However, in recent years, it has been shown that new T-cell subclasses, that is, Th17 and regulatory T cells (T(R)), exist independently of Th1 and Th2 and that they play a central role in modulating IBD. SUMMARY: The persistence of IL-7-dependent colitogenic memory CD4+ T cells is critical to the maintenance of experimental colitis. On the other hand, though Th1 and Th2 colitogenic memory CD4+ cells exist, in recent years the central role of IL-17-producing Th17-type cells in IBD has attracted renewed interest. The development of molecularly targeted therapies aimed at a variety of different Th-dependent pathogenic mechanisms may represent a novel approach to IBD therapy.
Assuntos
Imunossupressores/farmacologia , Doenças Inflamatórias Intestinais/tratamento farmacológico , Doenças Inflamatórias Intestinais/imunologia , Interleucina-17/metabolismo , Interleucina-7/metabolismo , Linfócitos T Auxiliares-Indutores/imunologia , Animais , Estudos de Coortes , Citocinas/efeitos dos fármacos , Citocinas/metabolismo , Modelos Animais de Doenças , Sistemas de Liberação de Medicamentos , Homeostase/imunologia , Memória Imunológica/imunologia , Interleucina-17/imunologia , Interleucina-7/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos SCID , Sensibilidade e Especificidade , Linfócitos T Auxiliares-Indutores/efeitos dos fármacos , Linfócitos T Reguladores/efeitos dos fármacos , Linfócitos T Reguladores/metabolismoRESUMO
BACKGROUND & AIMS: Elemental diet (ED) is effective for human Crohn's disease (CD). Although some of this effectiveness may be due to its low antigenic load and low fat content, the mechanisms remain unclear. We sought to assess the role of histidine, one of the constituent amino acids of ED, in controlling colitis. METHODS: The interleukin (IL)-10-deficient (IL-10(-/-)) cell transfer model of colitis was used. SCID mice with colitis induced by transfer of IL-10(-/-) cells were maintained on experimented diets containing either single amino acids or a mixture. The severity of colitis was assessed by wet colon weight. Colonic tumor necrosis factor (TNF)-alpha messenger RNA (mRNA) expression was detected by quantitative reverse-transcription polymerase chain reaction. Mouse peritoneal macrophages were stimulated by lipopolysaccharides (LPS), with or without amino acids. The concentration of cytokines in the supernatant was determined by enzyme-linked immunosorbent assay. Inhibitor of nuclear factor (NF)-kappaB-alpha and nuclear p65 were confirmed by immunoblotting. RESULTS: In the IL-10(-/-) transfer model, dietary histidine, but not alanine, reduced histologic damage and colon weight and TNF-alpha mRNA expression. Histidine inhibited LPS-induced TNF-alpha and IL-6 production by mouse macrophages in a concentration-dependent manner, whereas alanine or histidine-related metabolites had no such effect. Histidine inhibited LPS-induced NF-kappaB in macrophages. CONCLUSIONS: These results showed that histidine could be a novel therapeutic agent for CD by inhibition of NF-kappaB activation, following down-regulation of proinflammatory cytokine production by macrophages. Thus, our studies provided new insights into the roles of amino acid metabolism in the pathophysiology of CD and for therapeutic strategies.