RESUMO
BACKGROUND: Ulcerative colitis (UC) pathophysiology is characterized by an imbalance between pro- and anti-inflammatory cytokines. Interferon (IFN)-beta-1a has potent immunoregulatory properties, including stimulation of host defence mechanisms and thus represents a potential treatment. AIM: To extend pilot data and identify a suitable dose of IFN-beta-1a to achieve endoscopically confirmed remission (ECR) in patients with moderately active UC and to evaluate safety. METHODS: In this multicentre, double-blind, placebo-controlled trial, adults with moderately active UC were randomized to IFN-beta-1a 44 or 66 microg, or placebo, subcutaneously three times weekly for 8 weeks, with a 4-week follow-up. RESULTS: Endoscopically-confirmed remission was observed in 23.4% [95% confidence interval (CI): 13.8-35.7] of placebo patients, 29.2% (95% CI: 18.6-41.8) of the IFN-beta-la 44 microg group and 20.0% (950% CI: 11.1-31.8) of the 66 microg group (P = 0.45). Improvements with IFN-beta-1a 44 microg were greater than with placebo for most secondary efficacy outcomes, although significance was not achieved. Placebo response rates were higher than expected from previous trials. Adverse events were similar to the known safety profile of IFN treatment. CONCLUSIONS: Interferon-beta-1a was generally well tolerated at the doses tested, but a significant therapeutic benefit in patients with UC was not observed.
Assuntos
Colite Ulcerativa/tratamento farmacológico , Fatores Imunológicos/uso terapêutico , Interferon beta/uso terapêutico , Adulto , Colite Ulcerativa/patologia , Relação Dose-Resposta a Droga , Método Duplo-Cego , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , Endoscopia Gastrointestinal , Europa (Continente)/epidemiologia , Feminino , Humanos , Injeções Subcutâneas , Masculino , Placebos , Qualidade de Vida , Indução de Remissão , Índice de Gravidade de Doença , Resultado do TratamentoRESUMO
It has been suggested that the arteriolar vasodilatation and hyperdynamic circulation observed in rats with partial portal vein ligation (PPVL) is caused by increased splanchnic and systemic delivery of vasodilator substances. The aims of our study were to determine organ-specific generation of prostaglandin E(2) (PGE(2)) in rats with PPVL during the evolution of portal hypertension. Rats with PPVL and sham-operated (S) rats were studied in the first, third, fourth and 14th postoperative days. They were anesthetized and splenic pulp pressure and blood pressure were measured. Spleen, colon and lungs were removed and the splenic, pulmonary and mucosal colonic PGE(2) were determined. All PPVL rats developed sequential hemodynamic changes compatible with evolving portal hypertension. Splenic pulp pressure was higher in PPVL rats compared with S rats during all days of the study. Within the group of PPVL the splenic pulp pressure was higher in the first postoperative day and decreased in the ensuing days. No changes in splenic and colonic PGE(2) generation were noted during the study period. Pulmonary PGE(2) generation increased significantly in the first postoperative day in PPVL rats compared with S rats. However, similar increase was observed on the third postoperative day in S rats. PGE(2) probably has no role in splanchnic hemodynamic changes during evolution of portal hypertension. Pulmonary PGE(2) generation may increase as a response to increased portal pressure, or to abdominal surgery.
Assuntos
Dinoprostona/biossíntese , Hipertensão Portal/metabolismo , Animais , Peso Corporal , Dinoprostona/metabolismo , Progressão da Doença , Hemodinâmica , Hipertensão Portal/patologia , Fígado/metabolismo , Fígado/patologia , Pulmão/metabolismo , Pulmão/patologia , Masculino , Especificidade de Órgãos , Ratos , Ratos Sprague-Dawley , Baço/metabolismo , Baço/patologia , Baço/fisiopatologia , Fatores de TempoRESUMO
Ozone is one of the most powerful oxidants available, with many applications in industry and medicine. Medically relevant features of ozone include bacterial and virucidal properties, disinfection, sterilization, circulatory stimulation, and disruption of malignant cells. Ozone therapy is administered in various ways, including intravenously, intramuscularly, and intrarectally. The latter modality is used for the treatment of colitis and hepatitis. Our aim was to examine the effect of ozone water enema on normal and inflamed rat colonic mucosa. Ozone water (20 microg/ml) was prepared via ozone generator and administered intrarectally (0.5 ml) daily. Rats were killed one, three, and seven days after rectal ozone water administration, and their colons resected, rinsed, and weighed (grams per 10 cm). Damage was assessed macro- and microscopically and tissue processed for myeloperoxidase and nitric oxide synthase activity. Rats receiving saline served as controls. In an additional experiment colitis was induced by intrarectal iodoacetamide. Ozone therapy caused no macroscopic damage. Ozone therapy induced microscopic colitis, which lasted for at least a week and was accompanied by increase in segmental weight, myeloperoxidase and nitric oxide activity, and prostaglandin E2 generation. Ozone therapy had no protective effect on inflamed mucosa. In conclusion, ozone water therapy had a deleterious effect on normal colonic mucosa, suggesting intrarectal administration be reevaluated. Ozone water enema may serve as a model of microscopic colitis.
Assuntos
Colite/induzido quimicamente , Colite/terapia , Ozônio/efeitos adversos , Ozônio/uso terapêutico , Administração Retal , Animais , Colo/efeitos dos fármacos , Colo/patologia , Dinoprostona/metabolismo , Enema , Iodoacetamida , Masculino , Óxido Nítrico Sintase/metabolismo , Ozônio/administração & dosagem , Peroxidase/metabolismo , Ratos , Ratos Sprague-DawleyRESUMO
BACKGROUND AND AIMS: The anticoagulants, unfractionated heparin and low-molecular-weight heparin, demonstrated anti-inflammatory effects in animal models and in humans. Because of its dual effects, high-dose heparin was proposed as a therapeutic modality for ulcerative colitis. We investigated whether a low dose of low-molecular-weight heparin-enoxaparin (Clexane, Rhône-Poulenc Rorer, France)-ameliorates the inflammatory response in two models of experimental colitis. METHODS: Colitis was induced in rats by intrarectal administration of dinitrobenzene sulphonic acid. Enoxaparin (40, 80 and 200 microg/kg) or unfractionated heparin (100, 200 and 400 U/kg) were administered subcutaneously immediately after the induction of damage. Enoxaparin, 80 microg/kg, was also administered after induction of colitis by intrarectal administration of iodoacetamide. Rats were sacrificed 1, 3 or 7 days after induction of injury. Colonic damage was assessed macroscopically and histologically. Mucosal prostaglandin E2 generation, myeloperoxidase and nitric oxide synthase activities and tumour necrosis factor-alpha levels in blood were determined. RESULTS: Enoxaparin and heparin significantly ameliorated the severity of dinitrobenzene sulphonic acid- and iodoacetamide-induced colitis as demonstrated by a decrease in mucosal lesion area, colonic weight and mucosal myeloperoxidase and nitric oxide synthase activities. The dose-response curve had a bell-shaped configuration: enoxaparin, 80 microg/kg, and unfractionated heparin, 200 U/kg, were the optimal doses. CONCLUSIONS: Low-dose enoxaparin and unfractionated heparin ameliorate the severity of experimental colitis. This effect is related to their anti-inflammatory rather than anticoagulant properties.
Assuntos
Anticoagulantes/uso terapêutico , Colite/tratamento farmacológico , Enoxaparina/uso terapêutico , Heparina/uso terapêutico , Animais , Anti-Inflamatórios/farmacologia , Benzenossulfonatos/farmacologia , Colite/induzido quimicamente , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Iodoacetamida/farmacologia , Masculino , Óxido Nítrico Sintase/metabolismo , Peroxidase/metabolismo , Ratos , Ratos Wistar , Fator de Necrose Tumoral alfaRESUMO
BACKGROUND: High doses of mesalazine usually result in an inconvenient dosage schedule and reduced compliance. The goal of this trial was to compare the effects of mesalazine 4 g daily given as prolonged-release granules in packets of 1 g with that of prolonged-release tablets of 0.5 g. METHODS: Two hundred twenty-seven patients with mild-to-moderate ulcerative colitis were randomized to treatment with two packets twice daily (Gr-b.i.d.), 1 packet four times daily (Gr-q.i.d.) or 2 tablets four times daily (Ta-q.i.d.) for 8 weeks. A disease activity index (ulcerative colitis disease activity index: UC-DAI) was calculated, and the granules were defined as noninferior to the tablets if the lower limit of the 95% CI for the differences was more than -1 UC-DAI score unit. RESULTS: Noninferiority of the granules compared with the tablets was demonstrated. The mean improvement in the UC-DAI in the treatment groups Gr-b.i.d., Gr-q.i.d., and Ta-q.i.d. were 3.2, 2.9, and 2.4, respectively; the proportion of complete responders in the three groups 39%, 37%, and 31%, respectively. There were no differences in side effects. CONCLUSION: Mesalazine 4 g daily given as prolonged-release granules twice and four times daily is at least as effective as prolonged-release tablets four times daily in patients with mild to moderate ulcerative colitis. The patients preferred the twice daily dosing.
Assuntos
Anti-Inflamatórios não Esteroides/administração & dosagem , Colite Ulcerativa/tratamento farmacológico , Mesalamina/administração & dosagem , Adolescente , Adulto , Idoso , Anti-Inflamatórios não Esteroides/uso terapêutico , Preparações de Ação Retardada/administração & dosagem , Esquema de Medicação , Feminino , Humanos , Masculino , Mesalamina/uso terapêutico , Pessoa de Meia-Idade , Índice de Gravidade de Doença , Resultado do TratamentoRESUMO
Smoking has a dichotomous effect on inflammatory bowel disease, ameliorating disease activity in ulcerative colitis but having a deleterious effect on Crohn's disease. This effect is thought to be due to nicotine. We investigated the effect of chronic nicotine administration on the small and large bowel in iodoacetamide-induced jejunitis and colitis. Jejunitis was induced in Sprague-Dawley rats by intrajejunal administration of 0.1 ml 2% iodoacetamide and colitis by intrarectal administration of 0.1 ml 3% iodoacetamide. Nicotine was dissolved in drinking water (12.5 or 250 micrograms/ml), rats drinking ad libitum. Nicotine administration started 10 days prior to damage induction and throughout the experiment and had no effect on weight gain or daily food intake of rats. Rats were killed 5 days after iodoacetamide-induced colitis and 7 days after induction of jejunitis. The jejunum and colon were resected, rinsed, weighed, damage assessed macroscopically and microscopically and tissue processed for myeloperoxidase and nitric oxide synthase (NOS) activities and prostaglandin E2 (PGE2) generation. Effects of nicotine on gut microcirculation were also assessed. Nicotine by itself caused no damage to the colon. Nicotine had a dichotomous effect on jejunitis and colitis. At a dose of 12.5 micrograms/ml nicotine improved the macroscopic damage of colitis from 252 +/- 66 to 70 +/- 31 mm2, and segmental weight also declined significantly in the colon (from 1.7 +/- 0.2 to 1.2 +/- 0.1 g/10 cm). In contrast, the same dose of nicotine had a deleterious effect on iodoacetamide-induced jejunitis, increasing the macroscopic damage from 368 +/- 38 to 460 +/- 97 mm2 in rats treated with injury escalating to 970 +/- 147 in rats treated with 250 micrograms/ml nicotine. Nicotine treatment also significantly increased jejunal segmental weight. By itself nicotine did not change NOS activity or PGE2 generation compared to control rats, but it enhanced microcirculation in the colon, whereas in the jejunum nicotine decreased PGE2 generation and increased NOS activity but not jejunal microcirculation. Nicotine has opposite effects on iodoacetamide-induced colitis and jejunitis, which may be partly explained by decreased PGE2 generation and increased NOS activity in the jejunum and an increase in the colonic microcirculation.
Assuntos
Colite/tratamento farmacológico , Mucosa Intestinal/efeitos dos fármacos , Doenças do Jejuno/patologia , Nicotina/administração & dosagem , Animais , Colite/induzido quimicamente , Colite/patologia , Dinoprostona/análise , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Esquema de Medicação , Enterite/induzido quimicamente , Enterite/tratamento farmacológico , Enterite/patologia , Mucosa Intestinal/patologia , Iodoacetamida , Doenças do Jejuno/induzido quimicamente , Masculino , Nicotina/efeitos adversos , Óxido Nítrico Sintase/análise , Óxido Nítrico Sintase/metabolismo , Peroxidase/análise , Peroxidase/metabolismo , Probabilidade , Ratos , Ratos Sprague-Dawley , Valores de Referência , Sensibilidade e Especificidade , Estatísticas não ParamétricasRESUMO
TNF alpha is a pro-inflammatory cytokine in Crohn's disease and it's neutralization is beneficial in patients with active disease. Remicade is a chimeric monoclonal anti-TNF antibody. Remicade is used in our center since December 1998 in 13 patients who were treated for active disease or fistula. We followed the patients and treatment results in order to estimate the efficacy and safety of this preparation. Response to treatment was measured by the Crohn's Disease Activity Index (CDAI) in patients treated due to active disease, or by the presence of discharge from external fistulae. Five out of seven patients with fistulae had less or no discharge after completing a course of 3 infusions. Four out of 6 patients treated due to active disease improved significantly after a single infusion. Five out of the six needed additional injections due to symptom recurrence. Intervals between infusions were 2 weeks--for fistulae patients to 32 weeks for patients with active disease. Adverse events for the 13 patients were usually mild except for 4 patients that suffered from anaphylactic shock, disseminated eruption (2) and eosinophilic pneumonitis. In summary, treatment of patients with active Crohn's disease or fistulae with monoclonal anti-TNF antibodies is an effective and relatively safe option after established treatment has failed. Analyzing the results of on going clinical trials and of the patients treated off-protocol will enable to establish new treatment strategies for patients with active Crohn's disease and fistulae.
Assuntos
Anticorpos Monoclonais/uso terapêutico , Doença de Crohn/tratamento farmacológico , Fármacos Gastrointestinais/uso terapêutico , Fator de Necrose Tumoral alfa/imunologia , Adolescente , Adulto , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/efeitos adversos , Feminino , Fármacos Gastrointestinais/administração & dosagem , Fármacos Gastrointestinais/efeitos adversos , Humanos , Infliximab , Infusões Intravenosas , Masculino , Pessoa de Meia-Idade , SegurançaRESUMO
Crohn's disease is a heterogeneous entity. Previous attempts of classification have been based primarily on anatomic location and behavior of disease. However, no uniform definition of patient subgroups has yet achieved broad acceptance. The aim of this international Working Party was to develop a simple classification of Crohn's disease based on objective variables. Eight outcome-related variables relevant to Crohn's disease were identified and stepwise evaluated in 413 consecutive cases, a database survey, and by clinical considerations. Allocation of variables was conducted with well-defined Crohn's disease populations from Europe and North America. Cross-table analyses were performed by chi-square testing. Three variables were finally elected: Age at Diagnosis [below 40 years (A1), equal to or above 40 years (A2)], Location [terminal ileum (L1), colon (L2), ileocolon (L3), upper gastrointestinal (L4)], and Behavior [nonstricturing nonpenetrating (B1), stricturing (B2), penetrating (B3)]. The allocation of patients to these 24 subgroups proved feasible and resulted in specific disease clusters. Cross-table analyses revealed associations between Age at Diagnosis and Location, and between Behavior and Location (all p < 0.001). The Vienna classification of Crohn's disease provides distinct definitions to categorize Crohn's patients into 24 subgroups. Operational guidelines should be used for the characterization of patients in clinical trials as well as for correlation of particular phenotypes with putative biologic markers or environmental factors.
Assuntos
Doença de Crohn/classificação , Adulto , Idade de Início , Doença de Crohn/epidemiologia , Saúde Global , Humanos , Cooperação Internacional , Reprodutibilidade dos Testes , Projetos de Pesquisa , Estudos RetrospectivosRESUMO
BACKGROUND: Both in experimental colitis and in inflammatory bowel disease, colonic eicosanoid generation is enhanced and may contribute to the pathogenesis of the inflammatory response. AIMS: To evaluate the effect of selective cyclo-oxygenase-2 (COX-2) inhibitors on the extent and severity of two models of experimental colitis. METHODS: Colitis was induced by intra-caecal administration of 2 ml 5% acetic acid or intra-colonic administration of 0.1 ml 3% iodoacetamide. Rats were treated intra-gastrically with nimesulide 2 x 10 mg/kg/day, or once with SC-236 6 mg/kg, and killed 1 or 3 days after damage induction. The colon was isolated, weighed, macroscopic damage was measured, and mucosal samples were obtained for histology and for determination of myeloperoxidase (MPO) and nitric oxide synthase (NOS) activities and eicosanoid generation. The serum levels of thromboxane B2 (TXB2), tumour necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta) were determined. RESULTS: Nimesulide significantly decreased the extent of colitis induced by acetic acid. Both nimesulide and SC-236 significantly decreased the extent of iodoacetamide-induced colonic damage. The decrease in the extent of colitis induced by nimesulide was accompanied by a significant decrease in mucosal MPO and NOS activities. Nimesulide and SC-236 decreased the enhanced colonic eicosanoid generation in acetic acid and iodoacetamide-induced colitis, and, in iodoacetamide-treated rats, nimesulide also decreased the elevated serum TNF-alpha and IL-1beta levels. CONCLUSIONS: The effective nimesulide and SC-236-induced amelioration of the severity of the colitis in acetic acid and iodoacetamide-treated rats confirms the role of eicosanoids in their pathogenesis and suggests that COX-2 inhibitors may be of value in the treatment of inflammatory bowel disease.
Assuntos
Anti-Inflamatórios não Esteroides/uso terapêutico , Colite/tratamento farmacológico , Inibidores de Ciclo-Oxigenase/uso terapêutico , Pirazóis/uso terapêutico , Sulfonamidas/uso terapêutico , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Inibidores de Ciclo-Oxigenase/farmacologia , Modelos Animais de Doenças , Eicosanoides/metabolismo , Indometacina/farmacologia , Indometacina/uso terapêutico , Inflamação , Interleucina-1/sangue , Masculino , Óxido Nítrico Sintase/efeitos dos fármacos , Peroxidase/efeitos dos fármacos , Pirazóis/farmacologia , Ratos , Ratos Sprague-Dawley , Índice de Gravidade de Doença , Sulfonamidas/farmacologia , Fator de Necrose Tumoral alfa/análiseRESUMO
OBJECTIVE: Reduced bone mineral density (BMD) is common in patients with inflammatory bowel disease (IBD), but the factors associated with its longitudinal rate of change have not been established. We prospectively assessed the rate of change in BMD, and its association with biochemical markers of bone turnover. METHODS: Twenty-two patients with Crohn's disease and 14 ulcerative colitis patients age 37.1 +/- 11.6 yr were followed for 2 yr. Lumbar spine (L2-L4) and femoral neck BMD were measured by dual x-ray absorptiometry at baseline and 24 months. Bone-specific alkaline phosphatase, osteocalcin, urinary N-telopeptide crosslinked type 1 collagen (NTx), parathyroid hormone, and 25-hydroxyvitamin-D were determined at baseline. RESULTS: At baseline, 59% of Crohn's patients and 43% of ulcerative colitis patients were osteoporotic, with spine or femoral neck BMD T-score < -2.5. Spine BMD, and spine and femoral neck T-scores were lower and disease duration was longer in nine patients with ileal resection compared with nonoperated patients (0.84 +/- 0.15 g/cm2 vs 0.96 +/- 0.11 g/cm2, -3.0 +/- 1.5 vs -1.7 +/- 1.3, -3.2 +/- 1.5 vs -2.2 +/- 1.0, respectively; all p < 0.05). At 24 months, 13/36 (36%) and 14/36 (39%) patients experienced spinal and femoral neck bone loss, respectively, with mean annual percent BMD changes of -2.0% and -1.5%, respectively. NTx, a bone resorption marker, inversely correlated with spinal BMD rate of change (r = -0.4, p < 0.05). Using quartiles analysis, patients with the highest NTx (Q4) experienced the greatest decrease in spine BMD compared with patients with the lowest NTx (Q1). CONCLUSIONS: Spine and femoral neck bone loss continues over time in more than one-third of IBD patients. Increased NTx level predicts spinal bone loss in IBD patients.
Assuntos
Densidade Óssea/fisiologia , Colite Ulcerativa/diagnóstico , Colágeno/urina , Doença de Crohn/diagnóstico , Osteoporose/diagnóstico , Peptídeos/urina , Absorciometria de Fóton , Adulto , Reabsorção Óssea/diagnóstico , Reabsorção Óssea/urina , Colite Ulcerativa/urina , Colágeno Tipo I , Doença de Crohn/urina , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Osteoporose/urinaRESUMO
OBJECTIVE: To obtain information on the clinical experience with azathioprine (AZA), 6-mercaptopurine (6-MP), cyclosporin A (CyA) and methotrexate (MTX) in the treatment of patients with inflammatory bowel disease (IBD) by gastroenterologists and internists in different countries. DESIGN: A questionnaire designed by the International Organization for the Study of Inflammatory Bowel Disease (IOIBD) was mailed to 300 gastroenterologists, living in North America (n = 76) and Europe (n = 224) (12 countries), to obtain information on clinical experience. PARTICIPANTS: More than half of the respondents (168/298; 56.4%) worked in university hospitals and 58/298 (19.5%) in general (non-university) hospitals. Two-thirds (65%) had more than 10 years' experience in gastroenterology. RESULTS: The respondents had personal experience with AZA (88.4%), 6-MP (33.3%), CyA (48.7%) and MTX (36.3%). AZA was prescribed more frequently in Europe (92.6%) than in North America (74.2%) (P = 0.0002), 6-MP less frequently by the European than the North American respondents (23.8 and 53.3% respectively, P = 0.0001). Two-thirds (69.7%) usually prescribed AZA together with steroids to Crohn's disease patients; 62.4% of the respondents prescribed AZA for periods longer than 24 months. For ulcerative colitis, 77.9% had experience with AZA (Europe > North America, P = 0.0001). AZA had been prescribed by 69 respondents to pregnant patients, without apparent toxicity. Acute pancreatitis had been observed after AZA by 56.7% respondents; 25 malignancies were mentioned (six lymphoma, three leukaemia, three colon cancer, four renal carcinoma, nine others). CyA had been prescribed in acute ulcerative colitis by 140/291 respondents (North America 45.1%, Europe 49.1 %); of all respondents 63.9% treated < 5 patients with CyA, 36.1% 6-20 cases. CyA results were considered good in 29.5%, acceptable but with recurrences in 58.6%, and poor in 14.3%. MTX was prescribed in North America by 47.8% of the respondents, and by 33.9% in Europe (not significant). Several significant differences were observed between the prescription behaviour of respondents working at university hospitals and non-university hospitals, in particular in relation to participation in clinical trials. CONCLUSIONS: Considerable experience exists in the use of immunosuppressive therapy in IBD; however, differential prescription behaviour exists in the choice of immunosuppressives between North America and Europe. These IOIBD study results may contribute to a better insight in the daily use of immunosuppressive agents in IBD by gastroenterologists and other specialists.
Assuntos
Imunossupressores/uso terapêutico , Doenças Inflamatórias Intestinais/tratamento farmacológico , Padrões de Prática Médica/estatística & dados numéricos , Azatioprina/uso terapêutico , Ciclosporina/uso terapêutico , Europa (Continente)/epidemiologia , Feminino , Gastroenterologia , Humanos , Medicina Interna , Masculino , Mercaptopurina/uso terapêutico , Metotrexato/uso terapêutico , América do Norte/epidemiologia , Gravidez , Complicações na Gravidez/tratamento farmacológico , Inquéritos e QuestionáriosRESUMO
Iron is pivotal is producing tissue-damaging reactive oxygen metabolites. Our aim is to determine the antiinflammatory activity of deferiprone, an oral iron chelator, in experimental colitis and gastritis. Colitis was induced by intraceccal administration of 2 ml 5% acetic acid or by intracolonic administration of 0.1 ml 3% iodoacetamide, with or without cotreatment with deferiprone. Gastritis was induced by intragastric administration of ethanol or hydrochloric acid (HCl) and by subcutaneous injection of indomethacin, with and without deferiprone. Rats were killed 24 hours after acetic acid and iodoacetamide, 30 minutes after ethanol, one hour after HCl, and three hours after indomethacin administration. The colon or stomach was isolated, macroscopic damage was measured, and mucosal samples were obtained for determination of eicosanoid generation, myeloperoxidase (MPO), and nitric oxide synthase (NOS) activities. Deferiprone decreased iodoacetamide and acetic acid-induced macroscopic colonic damage by 67% and 69%, respectively, and macroscopic gastric damage by 91%, 68%, and 46% induced by ethanol, HCl, and indomethacin, respectively. The effect of deferiprone was accompanied by significant decrease in colonic and gastric, MPO and NOS activities, and colonic prostaglandin E2 (PGE2) generation, in acetic acid, ethanol, and indomethacin models, whereas in the iodoacetamide and HCl models attenuation of the decrease in PGE2 generation was seen. Deferiprone is protective in experimental colitis and gastritis, probably due to decreased production of iron-dependent oxygen-free radicals. Oral iron chelators may constitute a novel approach to ameliorate gastrointestinal inflammatory disorders.
Assuntos
Colite/complicações , Gastrite/complicações , Quelantes de Ferro/administração & dosagem , Piridonas/administração & dosagem , Úlcera Gástrica/tratamento farmacológico , Acetatos , Administração Oral , Animais , Colite/induzido quimicamente , Deferiprona , Modelos Animais de Doenças , Mucosa Gástrica/efeitos dos fármacos , Mucosa Gástrica/patologia , Gastrite/induzido quimicamente , Indometacina , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/patologia , Iodoacetamida , Masculino , Ratos , Ratos Sprague-Dawley , Estatísticas não Paramétricas , Úlcera Gástrica/etiologia , Úlcera Gástrica/patologia , Resultado do TratamentoRESUMO
Reactive oxygen-derived species and redox-active metals are implicated in mediation of the pathogenesis of gastric mucosal damage and ulceration. Therefore, common strategies of intervention employ metal chelators, antioxidative enzymes, and low-molecular-weight antioxidants (LMWA). The aim of the present study was to elaborate the mechanism(s) responsible for the protection provided by nitroxide radicals in the experimental model of gastric ulceration. Fasted male rats were treated ig with 1 ml 96% ethanol, with or without ig pretreatment with nitroxide or hydroxylamine. In several experiments, rats were injected ip or iv with iron(III) or iron(II) prior to ethanol administration. Rats were sacrificed 10 min after ethanol administration, the stomach was removed, washed and lesion area measured. Pretreatment with iron(III) complexed to nitrilotriacetate or citrate, aggravated the extent of the gastric injury. Conversely, iron(II) inhibited the formation of lesions. The nitroxides were rapidly reduced to their respective hydroxylamines and demonstrated antiulcerative activity for rats treated with iron. However, injecting the hydroxylamine resulted in a similar tissue distribution of nitroxide/hydroxylamnine but did not provide protection. The results show that: (a) the nitroxide radicals, rather than their respective non-radical reduced form, are the active species responsible for protection; (b) nitroxides protect by dismutating O2*- and possibly indirectly increasing the NO level; (c) unlike classical LMWA which are reducing agents, nitroxides inhibit gastric damage by acting as mild oxidants, oxidizing reduced metals and pre-empting the Fenton reaction; and (d) the nitroxides act catalytically as recycling antioxidants.
Assuntos
Antiulcerosos/farmacologia , Mucosa Gástrica/efeitos dos fármacos , Óxidos de Nitrogênio/farmacologia , Úlcera Gástrica/tratamento farmacológico , Animais , Antiulcerosos/metabolismo , Antiulcerosos/uso terapêutico , Antioxidantes/metabolismo , Antioxidantes/farmacologia , Antioxidantes/uso terapêutico , Cobre/farmacologia , Óxidos N-Cíclicos/farmacologia , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Etanol/antagonistas & inibidores , Etanol/farmacologia , Mucosa Gástrica/metabolismo , Hidroxilaminas/metabolismo , Hidroxilaminas/farmacologia , Compostos de Ferro/farmacologia , Masculino , Óxidos de Nitrogênio/metabolismo , Óxidos de Nitrogênio/uso terapêutico , Oxidantes/metabolismo , Oxidantes/farmacologia , Oxidantes/uso terapêutico , Piperidinas/farmacologia , Ratos , Ratos Sprague-Dawley , Marcadores de Spin , Úlcera Gástrica/induzido quimicamenteRESUMO
A rat model of experimental colitis and jejunitis induced by iodoacetamide (IA), a sulphydryl blocker is accompanied by increased leukotriene, prostaglandin E2 (PGE2) generation, and nitric oxide synthase (NOS) activity. Rat small intestinal and colonic surfactant-like particles (SLP) that accumulate on the apical surface of mucosal cells have been identified and specific antibodies to them have been produced. The aim of this study was to evaluate a possible role of SLP in IA-induced colitis and jejunitis. Inflammation was induced in Sprague-Dawley rats either by intracolonic administration of 3% IA (0.1 ml) or by intrajejunal administration of 2% IA (0.1 ml). Antisera raised against either colonic SLP, pulmonary SP-A (a major protein associated with colonic SLP), or small intestinal SLP were injected into the tail vein of rats 48 h before, simultaneous with, or 24 h after IA administration. Rats were killed 2 or 10 days after IA was given, their colon or small intestine was isolated and rinsed, and a segment of colon (10 cm) or small bowel (30 cm) was weighed and processed for microscopy, NOS and myeloperoxidase (MPO) activities, and PGE2 generation. Intracolonic or jejunal IA resulted after 48 h in extensive macroscopic and microscopic damage, accompanied by increased segmental weight, MPO and NOS activity, and PGE2 generation. Colonic SLP antibody administration, either 48 h before or at the time of damage induction, significantly decreased macroscopic as well as microscopic damage, segmental weight, MPO activity, and PGE2 generation, but had no effect on NOS activity. Neither control sera nor antisera against SP-A had any protective effect, nor did injection of anti-colonic SLP antisera given 24 h after IA. Small bowel SLP antibody offered no protection against IA jejunitis. IA-induced colitis but not jejunitis is ameliorated by intravenous injection of SLP antibody by a mechanism yet to be determined. These data provide further evidence of a physiologic role for gastrointestinal SLP.
Assuntos
Anticorpos/farmacologia , Colite/tratamento farmacológico , Colite/patologia , Mucosa Intestinal/patologia , Doenças do Jejuno/patologia , Tensoativos/farmacologia , Animais , Colite/induzido quimicamente , Modelos Animais de Doenças , Enterite/tratamento farmacológico , Enterite/patologia , Injeções Intravenosas , Mucosa Intestinal/efeitos dos fármacos , Iodoacetamida , Doenças do Jejuno/induzido quimicamente , Doenças do Jejuno/tratamento farmacológico , Masculino , Óxido Nítrico/análise , Óxido Nítrico/metabolismo , Tamanho da Partícula , Ratos , Ratos Sprague-Dawley , Valores de Referência , Reagentes de SulfidrilaRESUMO
BACKGROUND: Hyperbaric oxygen (HBO) has been suggested to be beneficial in inflammatory bowel disease but the mechanisms responsible for its therapeutic effects have not been elucidated. AIM: To assess the effect of HBO treatment on colonic damage in two models of experimental colitis, and to examine whether this effect is mediated by modulation of NO synthesis. METHODS: Colitis was induced by either flushing the colon with 2 ml 5% acetic acid or intracolonic administration of 30 mg trinitrobenzenesulphonic acid (TNB) dissolved in 0.25 ml 50% ethanol. Rats were exposed to HBO (100% oxygen at 2.4 atmosphere absolute) for one hour twice on the day of colitis induction and once daily thereafter. Control rats were treated only with acetic acid or TNB. Rats were killed 24 hours after acetic acid administration or one and seven days after TNB treatment. The colon was isolated, washed, and weighed, the lesion area was measured, and mucosal scrapings were processed for determination of myeloperoxidase (MPO) and NO synthase (NOS) activities, prostaglandin E2 (PGE2) and leukotriene B4 (LTB4) generation. RESULTS: In control rats exposed for seven days to HBO, colonic NOS activity was significantly decreased by 61%, compared with its activity in untreated rats (2.93 (0.17) nmol/g/min). HBO significantly reduced by 51 and 62% the extent of injury induced by acetic acid and TNB respectively. The protection provided by HBO was accompanied by a significant decrease in colonic weight, PGE2 generation, MPO, and NOS activities. In acetic acid colitis, LTB4 generation was also significantly decreased. CONCLUSIONS: (1) HBO effectively decreases colitis induced by acetic acid and TNB. (2) The decreased NOS activity induced by HBO suggests that reduction in NO generation may be among the mechanisms responsible for the anti-inflammatory effect of HBO. (3) HBO may be considered in the treatment of patients with refractory inflammatory bowel disease.
Assuntos
Colite/terapia , Oxigenoterapia Hiperbárica , Ácido Acético/efeitos adversos , Animais , Colite/induzido quimicamente , Colite/enzimologia , Mucosa Intestinal/enzimologia , Masculino , Óxido Nítrico Sintase/metabolismo , Peroxidase/metabolismo , Ratos , Ratos Sprague-DawleyRESUMO
OBJECTIVE: The mechanism of bone loss in patients with inflammatory bowel disease (IBD) is not completely understood. The aim of this study was to assess indices of bone turnover and bone mineral density (BMD) in the lumbar spine and femoral neck in IBD patients. METHODS: Sixty-three patients with Crohn's disease and 41 with ulcerative colitis were studied. Serum bone-specific alkaline phosphatase (B-ALP), osteocalcin, parathyroid hormone (PTH), 25 hydroxyvitamin D, interleukin-6 (IL-6), and urinary N-telopeptide cross linked type 1 collagen (NTX) were determined. BMD of the lumbar spine and femoral neck was determined by dual x-ray absorptiometry in 59 patients. RESULTS: In the femoral neck 42% of the patients had osteopenia (-2.5 SD < BMD T score < -1 SD) and another 41% had osteoporosis (BMD T score < -2.5). In the spine 34% of the patients had osteopenia and additional 42% had osteoporosis. BMD T scores were lower in the femoral neck compared to the spine. Reduced BMD was unrelated to gender, disease type, lifetime corticosteroid dose, but inversely correlated with disease duration (r = -0.36, p < 0.05). Serum IL-6 was higher in IBD patients compared to controls. A reduced level of osteocalcin, a marker of bone formation, was present in 7% of patients and an increase in NTX, a marker of bone resorption, in 25% of them. Osteoporotic IBD patients (spine or hip BMD T score < -2.5) had increased serum IL-6, osteocalcin and PTH level compared to nonosteoporotic patients. CONCLUSIONS: There is a high prevalence of reduced BMD at the spine and femoral neck in IBD patients, which is more severe in the hip. Bone turnover in osteoporotic IBD patients is associated with an increase in osteocalcin, PTH and IL-6. IL-6 may play a role in the pathogenesis of bone loss in IBD.
Assuntos
Densidade Óssea , Doenças Ósseas Metabólicas/fisiopatologia , Reabsorção Óssea/fisiopatologia , Colite Ulcerativa/fisiopatologia , Doença de Crohn/fisiopatologia , Colo do Fêmur/fisiopatologia , Adulto , Fosfatase Alcalina/sangue , Biomarcadores/sangue , Biomarcadores/urina , Doenças Ósseas Metabólicas/sangue , Doenças Ósseas Metabólicas/urina , Reabsorção Óssea/sangue , Colite Ulcerativa/sangue , Colágeno/urina , Doença de Crohn/sangue , Feminino , Humanos , Interleucina-6/sangue , Masculino , Osteocalcina/sangue , Hormônio Paratireóideo/sangue , Coluna Vertebral/fisiopatologia , Vitamina D/sangueRESUMO
OBJECTIVE: In active ulcerative colitis, colonic nitric oxide (NO) generation is enhanced and probably has an important role in its pathogenesis. We tested the reliability of an NO electrode in monitoring colonic NO levels in ulcerative colitis patients and control subjects and its possible usage as a marker of disease activity. METHODS: Colonic NO level was determined by the NO detection system model NO-501 (InterMedical, Nagoya, Japan). The working electrode was inserted into a 7-mm diameter polyvinyl tube and introduced at a distance 6 cm from the anus. In each subject sigmoidoscopy was performed and mucosal biopsies were obtained. NO synthase (NOS) activity was determined by monitoring the conversion of 3H-arginine to citrulline. RESULTS: Colonic NO level is significantly increased in patients with active ulcerative or Crohn's colitis--more than 2-fold higher than in control subjects. There was good correlation between colonic NO level and NOS activity and the clinical and endoscopic indices of disease activity. CONCLUSION: Direct determination of colonic NO level is convenient, and reliable, and may help to monitor disease activity in ulcerative colitis.