RESUMEN
PURPOSE: To evaluate the inflammatory reaction and measure the content of mucins, in the colonic mucosa without fecal stream submit to intervention with mesalazine. METHODS: Twenty-four rats were submitted to a left colostomy and a distal mucous fistula and divided into two groups according to euthanasia to be performed two or four weeks. Each group was divided into two subgroups according daily application of enemas containing saline or mesalazine at 1.0 g/kg/day. Colitis was diagnosed by histological analysis and the inflammatory reaction by validated score. Acidic mucins and neutral mucins were determined with the alcian-blue and periodic acid of Schiff techniques, respectively. Sulfomucin and sialomucin were identified by high iron diamine-alcian blue technique. The tissue contents of mucins were quantified by computer-assisted image analysis. Mann-Whitney test was used to analyze the results establishing the level of significance of 5%. RESULTS: Enemas with mesalazine in colonic segments without fecal stream decreased the inflammation score and increased the tissue content of all subtypes of mucins. The increase of tissue content of neutral, acid and sulfomucin was related to the time of intervention. CONCLUSION: Mesalazine enemas reduce the inflammatory process and preserve the content of mucins in colonic mucosa devoid of fecal stream.
Asunto(s)
Antiinflamatorios no Esteroideos/farmacología , Colon/efectos de los fármacos , Enema/métodos , Mucosa Intestinal/efectos de los fármacos , Mesalamina/farmacología , Mucinas/análisis , Animales , Antiinflamatorios no Esteroideos/uso terapéutico , Colitis/patología , Colitis/prevención & control , Colon/metabolismo , Colon/patología , Colostomía , Heces , Tránsito Gastrointestinal , Histocitoquímica , Procesamiento de Imagen Asistido por Computador , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patología , Masculino , Mesalamina/uso terapéutico , Mucinas/efectos de los fármacos , Estrés Oxidativo , Ratas Wistar , Reproducibilidad de los Resultados , Factores de Tiempo , Resultado del TratamientoRESUMEN
Abstract Purpose: To evaluate the inflammatory reaction and measure the content of mucins, in the colonic mucosa without fecal stream submit to intervention with mesalazine. Methods: Twenty-four rats were submitted to a left colostomy and a distal mucous fistula and divided into two groups according to euthanasia to be performed two or four weeks. Each group was divided into two subgroups according daily application of enemas containing saline or mesalazine at 1.0 g/kg/day. Colitis was diagnosed by histological analysis and the inflammatory reaction by validated score. Acidic mucins and neutral mucins were determined with the alcian-blue and periodic acid of Schiff techniques, respectively. Sulfomucin and sialomucin were identified by high iron diamine-alcian blue technique. The tissue contents of mucins were quantified by computer-assisted image analysis. Mann-Whitney test was used to analyze the results establishing the level of significance of 5%. Results: Enemas with mesalazine in colonic segments without fecal stream decreased the inflammation score and increased the tissue content of all subtypes of mucins. The increase of tissue content of neutral, acid and sulfomucin was related to the time of intervention. Conclusion: Mesalazine enemas reduce the inflammatory process and preserve the content of mucins in colonic mucosa devoid of fecal stream.
Asunto(s)
Animales , Masculino , Antiinflamatorios no Esteroideos/farmacología , Colon/efectos de los fármacos , Mesalamina/farmacología , Enema/métodos , Mucinas/análisis , Factores de Tiempo , Procesamiento de Imagen Asistido por Computador , Tránsito Gastrointestinal , Colostomía , Antiinflamatorios no Esteroideos/uso terapéutico , Reproducibilidad de los Resultados , Resultado del Tratamiento , Ratas Wistar , Colitis/patología , Colitis/prevención & control , Colon/metabolismo , Colon/patología , Estrés Oxidativo , Mesalamina/uso terapéutico , Heces , Histocitoquímica , Mucosa Intestinal/efectos de los fármacos , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patología , Mucinas/efectos de los fármacosRESUMEN
This study aimed to investigate the potential effect of plumieride, an iridoid glycoside isolated from Alamanda cathartica L. flowers, against dextran sulfate sodium (DSS)-induced colitis in mice. Colitis was induced in female swiss mice by adding DSS 3% to the drinking water. The animals were treated with vehicle (water), 5-aminosalicylic acid (100?mg/kg) or plumieride (10, 30 and 100?mg/kg) once a day, during 7 days. The body weight progression and the disease activity index was evaluated daily. On the eighth day, colons were collected for the measurement of the size, histological, histochemical, biochemical and inflammatory analysis. The cytotoxicity of plumieride on intestinal epithelial cell (IEC-6 cell line) was also evaluated. Plumieride, at dose of 100?mg/kg, significantly attenuated the mice weight loss, showed lower score in the disease activity index, diminished the colon shortening, improved the histological damage and avoided mucosa intestinal mucus depletion when compared with vehicle-treated only group. Moreover, plumieride was able to reduce the amount of colonic lipid hydroperoxides, while augmented reduced glutathione levels and superoxide dismutase activity. Although DSS intake stimulated an increase in myeloperoxidase activity and in tumor necrosis factor content on the colon tissue of the vehicle-treated group, the colons obtained from mice treated with plumieride did not present any of these changes. Taking together, the results of the present study disclose that plumieride exhibited a significant efficacy in attenuating the parameters of experimental ulcerative colitis, which may be mediated by an antioxidant and anti-inflammatory effect.
Asunto(s)
Antiinflamatorios/farmacología , Antioxidantes/farmacología , Colitis/tratamiento farmacológico , Furanos/farmacología , Compuestos de Espiro/farmacología , Animales , Antiinflamatorios/administración & dosificación , Antiinflamatorios/aislamiento & purificación , Antioxidantes/administración & dosificación , Antioxidantes/aislamiento & purificación , Apocynaceae/química , Línea Celular , Colitis/patología , Colitis Ulcerosa/tratamiento farmacológico , Colitis Ulcerosa/patología , Sulfato de Dextran/toxicidad , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Femenino , Furanos/administración & dosificación , Furanos/aislamiento & purificación , Mucosa Intestinal/efectos de los fármacos , Mucosa Intestinal/patología , Mesalamina/farmacología , Ratones , Ratas , Compuestos de Espiro/administración & dosificación , Compuestos de Espiro/aislamiento & purificación , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
Mesalamine (5-ASA) consists of the first-line therapy for the treatment of ulcerative colitis; however, it has low bioavailability, can cause several systemic adverse events, and has low treatment adherence due to the inconvenient dosing scheme. In this work, a new drug delivery system consisting of chondroitin sulfate linked to 5-ASA was synthesized using a carbodiimide as conjugating agent. The system was characterized by spectroscopic techniques (UV, ATR-FTIR, XRD, and NMR 1H) and thermal analysis (TG/DTG and DSC), suggesting the conjugation between the drug and the polymer. The in vitro release and the corresponding kinetics were also evaluated, revealing that approximately 40% of the drug linked was released at pH9 for up to 50h, following Higuchi's model. The conjugate did not show cytotoxicity for the human monocytic cell line at the doses tested, and an in vivo biodistribution study showed that the conjugate remained in the lower GIT for up to 8h with no uptake in the upper GIT. These data corroborate with the radiation found per segment of GIT and in blood. For this last test the conjugate was radiolabeled with Technetium-99m to allow the scintigraphy evaluation and radiation quantification. In conclusion, the polymeric conjugate was successfully synthesized and demonstrated a mucoadhesiveness on the colon as desired, thus supporting its potential use in the treatment of ulcerative colitis.
Asunto(s)
Sulfatos de Condroitina/química , Portadores de Fármacos/química , Mucosa Intestinal/metabolismo , Mesalamina/administración & dosificación , Profármacos/administración & dosificación , Disponibilidad Biológica , Línea Celular , Colitis Ulcerosa/tratamiento farmacológico , Preparaciones de Acción Retardada , Composición de Medicamentos , Humanos , Mesalamina/farmacocinética , Mesalamina/farmacología , Monocitos/efectos de los fármacos , Monocitos/inmunología , Profármacos/farmacocinética , Profármacos/farmacología , Distribución Tisular , Factor de Necrosis Tumoral alfa/antagonistas & inhibidoresRESUMEN
BACKGROUND: PPARs play an important role in the regulation of intestinal inflammation. METHODS: We included a total of 46 UC patients and 31 controls. The gene expression of PPARs was measured by RT-PCR and protein expression by immunohistochemistry. RESULTS: PPARα gene expression was significantly decreased in patients with active UC compared with remission UC group (P = 0.001) and controls (P = 0.001). We found that low gene expression of PPARα in mucosa confers a higher risk of UC activity (P ≤ 0.0001, OR = 22.6). We observed an increase of PPARα expression in patients with UC who were treated with 5-aminosalicylates compared with those who received any other combined therapy (P = 0.03, OR = 0.08). PPARγ gene expression was decreased in the active UC group compared with UC in remission (P = 0.001) and control group (P = 0.001). An increased expression of PPARγ gene was associated with mild clinical course of the disease (P ≤ 0.001, OR = 0.05). No gene expression of PPARß/δ was found in the colonic mucosa from UC patients and controls. CONCLUSION: Our results suggest that patients with high gene expression of PPARs have a better response to medical treatment and a mild clinical course of the disease.
Asunto(s)
Colitis Ulcerosa/metabolismo , PPAR alfa/metabolismo , PPAR gamma/metabolismo , PPAR-beta/metabolismo , Adulto , Antiinflamatorios no Esteroideos/farmacología , Antiinflamatorios no Esteroideos/uso terapéutico , Estudios de Casos y Controles , Colitis Ulcerosa/tratamiento farmacológico , Colon/metabolismo , Femenino , Humanos , Mucosa Intestinal/metabolismo , Masculino , Mesalamina/farmacología , Mesalamina/uso terapéutico , Resultado del TratamientoRESUMEN
BACKGROUND: Although the cost of Crohn's disease (CD) treatment differs considerably, hospitalization and surgery costs account for most of the total treatment cost. Decreasing hospitalization and surgery rates are pivotal issues in reducing health-care costs. MATERIAL/METHODS We evaluated the effect of azathioprine (AZA) compared with mesalazine on incidence of re-hospitalizations due to all causes and for CD-related surgeries. In this controlled, randomized study, 72 subjects with sub-occlusive ileocecal CD were randomized for AZA (2-3 mg/kg per day) or mesalazine (3.2 g per day) therapy during a 3-year period. The primary end point was the re-hospitalization proportion due to all causes, as well as for surgical procedures during this period evaluated between the groups. RESULTS: On an intention-to-treat basis, the proportion of patients re-hospitalized within 36 months due to all causes was lower in patients treated with AZA compared to those on mesalazine (0.39 vs. 0.83, respectively; p=0.035). The AZA group had also significantly lower proportions of re-hospitalization for surgical intervention (0.25 vs. 0.56, respectively; p=0.011). The number of admissions (0.70 vs. 1.41, p=0.001) and the length of re-hospitalization (3.8 vs. 7.7 days; p=0.002) were both lower in AZA patients. CONCLUSIONS: Patients with sub-occlusive ileocecal CD treated with AZA had lower re-hospitalization rates due to all causes and for surgical management of CD compared to those treated with mesalazine during a 3-year period. The long-term use of AZA in ileocecal CD patients recovering from a sub-occlusion episode can save healthcare costs.
Asunto(s)
Azatioprina/farmacología , Enfermedad de Crohn/tratamiento farmacológico , Enfermedad de Crohn/economía , Enfermedad de Crohn/epidemiología , Mesalamina/farmacología , Readmisión del Paciente/estadística & datos numéricos , Adulto , Azatioprina/uso terapéutico , Enfermedad de Crohn/cirugía , Humanos , Incidencia , Estimación de Kaplan-Meier , Mesalamina/uso terapéutico , Persona de Mediana EdadRESUMEN
Mesalazine (5-ASA) is the standard drug for the treatment of inflammatory bowel disease (IBD) due to its local effect on intestinal and colonic mucosa. The effective and safe treatment of this disease requires more efficient delivery of the active substance to its site of action. The focus of this study was the use of multiparticulate systems, a modified release form in which the drug is divided into several functional subunits of release in the form of granules or pellets. When these forms are administered, they are rapidly disintegrated, distributing their content throughout the gastrointestinal tract. The aim of this study was to develop and evaluate a multiparticulate system consisting of pellets coated with polymer for pH-dependent release, derived from methacrylic acid and incorporated into the tablet dosage form of mesalazine as a model drug. The extrusion-spheronisation technique was used, resulting in smooth and spherical pellets with uniform size distribution, which were coated in fluidized bed using Opadry® Enteric 94K28327 containing Eudragit® S100 as the agent regulating drug release. The dissolution profile of coated pellets showed good control of drug release from the polymer at the two levels of coating evaluated (8 percent and 10 percent), but only the 10 percent coated pellets were statistically similar to Asalit® 400 mg.
A mesalazina (5-ASA) tem se apresentado como fármaco padrão para o tratamento da doença inflamatória intestinal (DII) devido ao seu efeito local na mucosa intestinal e colônica. A terapia efetiva e segura desta doença requer a chegada da substância ativa ao seu local de ação com maior eficiência. Nessa busca, tem se destacado o uso de Sistemas Multiparticulados, forma farmacêutica de liberação modificada, em que o fármaco está dividido em várias subunidades funcionais de liberação, sob a forma de grânulos ou péletes, que quando administrados, são rapidamente desintegrados distribuindo seu conteúdo por todo trato gastrintestinal. Este trabalho teve como objetivo desenvolver e avaliar péletes revestidos com polímero de liberação pH-dependente, derivado do ácido metacrílico, tendo como fármaco modelo a mesalazina. A técnica de extrusão-esferonização foi utilizada obtendo-se péletes lisos e esféricos com distribuição granulométrica uniforme, que foram revestidos em leito fluidizado utilizando Opadry® Enteric 94K28327 contendo Eudragit® S100 como agente regulador da liberação do fármaco. O perfil de dissolução dos péletes revestidos demonstrou bom controle na liberação do fármaco por parte do polímero nos dois níveis de revestimento avaliados (8 e 10 por cento), porém, apenas os péletes revestidos a 10 por cento demonstraram semelhança estatística com o medicamento de referência Asalit® 400 mg.
Asunto(s)
Ácidos Polimetacrílicos/farmacología , Ácidos Polimetacrílicos/uso terapéutico , Mesalamina/agonistas , Mesalamina/farmacología , Composición de Medicamentos , Estabilidad de Medicamentos , Sinergismo FarmacológicoRESUMEN
BACKGROUND: No studies have evaluated the effectiveness of 5-ASA against oxidative DNA damage in experimental models of diversion colitis. AIM: To evaluate the effects of 5-ASA against oxidative DNA damage in an experimental model of diversion colitis. METHODS: Twenty-six Wistar rats were divided into two groups corresponding to sacrifice at 2 or 4 weeks after fecal diversion of the left colon by means of proximal colostomy and distal mucosa fistula. Each group was divided into two subgroups according to intervention in excluded colon performed with 0.9% saline solution or 5-ASA. Level of oxidative DNA damage was determined by comet assay in cells obtained from segments with and without fecal stream before and after H2O2 challenge. For statistical analysis, was used one-way analysis of variance (ANOVA), adopting a 5% significance level (P<0.05). RESULTS: Levels of DNA damage were always higher in colon segments without fecal stream, regardless of the intervention solution employed. DNA damage in colon segments with and without fecal stream in animals irrigated with 5-ASA was lower when compared with those treated with saline solution, regardless of time of irrigation. These levels remained lower after intervention with 5-ASA, even after H2O2 challenge. CONCLUSIONS: Enema with 5-ASA reduces oxidative DNA damage in epithelial cells of colon segments without fecal stream, even after H2O2 challenge, confirming the effects of 5-ASA against DNA damage by oxygen free radicals.
Asunto(s)
Antiinflamatorios no Esteroideos/farmacología , Colon/efectos de los fármacos , Daño del ADN/efectos de los fármacos , Mucosa Intestinal/efectos de los fármacos , Mesalamina/farmacología , Animales , Colitis/tratamiento farmacológico , Colitis/patología , Colon/patología , Heces , Peróxido de Hidrógeno/efectos adversos , Mucosa Intestinal/patología , Masculino , Estrés Oxidativo/efectos de los fármacos , Ratas , Ratas WistarRESUMEN
This article reviews the literature concerning rheumatic manifestations of inflammatory bowel disease (IBD), including common immune-mediated pathways, frequency, clinical course and therapy. Musculoskeletal complications are frequent and well-recognized manifestations in IBD, and affect up to 33% of patients with IBD. The strong link between the bowel and the osteo-articular system is suggested by many clinical and experimental observations, notably in HLA-B27 transgenic rats. The autoimmune pathogenic mechanisms shared by IBD and spondyloarthropathies include genetic susceptibility to abnormal antigen presentation, aberrant recognition of self, the presence of autoantibodies against specific antigens shared by the colon and other extra-colonic tissues, and increased intestinal permeability. The response against microorganisms may have an important role through molecular mimicry and other mechanisms. Rheumatic manifestations of IBD have been divided into peripheral arthritis, and axial involvement, including sacroiliitis, with or without spondylitis, similar to idiopathic ankylosing spondylitis. Other periarticular features can occur, including enthesopathy, tendonitis, clubbing, periostitis, and granulomatous lesions of joints and bones. Osteoporosis and osteomalacia secondary to IBD and iatrogenic complications can also occur. The management of the rheumatic manifestations of IBD consists of physical therapy in combination with local injection of corticosteroids and nonsteroidal anti-inflammatory drugs; caution is in order however, because of their possible harmful effects on intestinal integrity, permeability, and even on gut inflammation. Sulfasalazine, methotrexate, azathioprine, cyclosporine and leflunomide should be used for selected indications. In some cases, tumor necrosis factor-alpha blocking agents should be considered as first-line therapy.
Asunto(s)
Enfermedades Inflamatorias del Intestino/diagnóstico , Enfermedades Reumáticas/diagnóstico , Antiinflamatorios/farmacología , Antiinflamatorios no Esteroideos/farmacología , Cadherinas/metabolismo , Citocinas/metabolismo , Gastroenterología/métodos , Humanos , Inflamación , Enfermedades Inflamatorias del Intestino/complicaciones , Intestinos/patología , Mesalamina/farmacología , Permeabilidad , Enfermedades Reumáticas/complicaciones , Espondilitis/diagnóstico , Espondilitis/patología , Sulfasalazina/farmacología , Factor de Necrosis Tumoral alfa/antagonistas & inhibidoresRESUMEN
The ability of the widely employed therapeutic drugs 4-aminosalicylic acid and 5-aminosalicylic acid to act as singlet molecular oxygen (O(2)((1)delta(g))) scavengers was investigated at pH 7 and pH 12. The isomer 3-aminosalicylic acid was also included in the study for comparative purposes. All three compounds quench photochemically generated O(2)((1)delta(g)) with rate constants in the range of 10(7)-10(8) x M(-1)s(-1), depending on the experimental conditions. No chemical reaction (oxidation of the aminosalicylic acids) was detected at the neutral pH, whereas at pH 12 both chemical and physical interactions with O(2)((1)delta(g)) operated. The physical process implies the de-activation of the oxidant species without destruction of the aminosalicylic acid. The quotients between the overall and reactive rate constants for O(2)((1)delta(g)) quenching at pH 12 (k(r)/k(t) ratios), which account for the actual effectiveness of photodegradation, were relatively low (0.22, 0.04, and 0.06 for 3-, 4- and 5-aminosalicylic acids, respectively). This indicates that the drugs, particularly the 4- and 5-amino derivatives, de-activate the excited oxygen species, at both pH values studied, mainly in a physical fashion, preventing its photodegradation and providing an antioxidative protection for possible photo-oxidizable biological targets in the surroundings.
Asunto(s)
Ácido Aminosalicílico/farmacología , Antioxidantes/farmacología , Mesalamina/farmacología , Oxígeno/metabolismo , Concentración de Iones de Hidrógeno , FotólisisRESUMEN
The anti-inflammatory effect of c-phycocyanin extract was studied in acetic acid-induced colitis in rats. Phycocyanin (150, 200 and 300 mg kg(-1) p.o.) was administered 30 min gbefore induction of colitis with enema of 1 ml of 4% acetic acid per rat. Twenty-four hours later myeloperoxidase (MPO) activity was determined as well as histopathological and ultrastructural studies were carried out in colonic tissue. Phycocyanin substantially reduced MPO activity which was increase din the control colitis group. Also, histopathological and ultrastructural studies were carried out in colonic tissue. Phycocyanin substantially reduced MPO activity which was increased in the control colitis group. Also, histopathological and ultrastructural studies showed inhibition in inflammatory cell infiltration and reduction to some extent in colonic damage in rats treated with phycocyanin. The probable role of antioxidative and the scavenging properties of phycocyanin against reactive oxygen species in the anti-colitic effect is discussed in this paper. To our knowledge this is the first report on the anti-inflammatory effect of phycocyanin in an experimental model of colitis.