Mesalamine in pediatric inflammatory bowel disease: a 10-year experience.

: Mesalamine is an enteric-coated 5-aminosalicylic acid formulation effective in the treatment of ulcerative colitis, and in decreasing the relapse rate in Crohn's disease. However, little data are available regarding its use in children and adolescents. To determine the modalities of use, safety, and the optimal dose in this age group, charts of 153 pediatric patients with inflammatory bowel disease treated with mesalamine were reviewed, representing >150 patient years of use. Among these, more than half of the children diagnosed with Crohn's disease (120 patients) had ileocolonic involvement, and pancolitis predominated in those with ulcerative colitis (33 patients). Patients with ulcerative colitis were diagnosed at a younger age than those with Crohn's disease, and thus mesalamine therapy was initiated earlier. When used as monotherapy, no difference was noted in the average dose used for the treatment of active disease versus maintenance therapy (36 mg/kg/day). However, the average dose used did increase since 1992, for both the treatment of active disease and relapse prevention (43 mg/kg/ day). Overall, 18 patients (11.8%) were withdrawn from mesalamine therapy; however only 8 (5.2%) had objective side effects. Exacerbation of diarrhea was the most common reason for withdrawal. Although reported rarely, no serious adverse reactions such as pancreatitis or hepatic or renal dysfunction were observed. This study suggests that mesalamine is a safe and well-tolerated medication in the long-term treatment of pediatric patients with ulcerative colitis and Crohn's disease.

On the metabolic detoxication of thymol in rabbit and man.

The metabolic detoxication of thymol was investigated in rabbit and man. Thymol glucuronide which the aglycone is intact, was isolated from thymol medicated rabbit urine and identified as a acetyl derivative of methyl glucuronate. The hydroxylated product of thymol, thymohydroquinone, was recognized in a small amount in thymol medicated human urine. It was presumed that thymohydroquinone is excreted as ethereal sulfuric acid conjugate in man.

Metabolic detoxication of bis-(2-hydroxy-3, 5-dichlorophenyl)-sulfoxide in man.

The metabolic detoxication of bis(2-hydroxy-3, 5-dichlorophenyl)sulfoxide (BTS) in man was investigated. Bis(2-hydroxy-3, 5-dichlorophenyl)sulfide (BT) was identified in beta-glucuronidase treated urine following the administration of BTS by thin-layer chromatography, gas chromatography, ultraviolet spectrum and quantitative analysis. No other metabolites were detectable. BT-glucuronide was also identified in urine. It was assumed that BTS was reduced to BT and successively conjugated with glucuronide in man, and excreted as BT-glucuronide in the urine.

[Studies on caffeic acid derivatives in medicinal plants].

The components of Artemisia and Labiatae species were isolated and their chemical structures were determined. These compounds were found to have tannic activity for the first time. The activity of the compounds comes from the caffeic acid moiety in their molecules, not from structural features of usual tannins (hydrolyzable and condensed tannins). These also showed several other biological activities. Furthermore, the research on dimerization of caffeic acid derivatives was performed.

Phase II Trial of Cetuximab and Conformal Radiotherapy Only in Locally Advanced Pancreatic Cancer with Concurrent Tissue Sampling Feasibility Study.

BACKGROUND: Preclinical data have indicated the anti-epidermal growth factor receptor (EGFR) agent cetuximab (Erbitux) as a radiosensitizer in pancreatic cancer, but this has not been specifically addressed in a clinical study. We report the results of an original study initiated in 2007, where cetuximab was tested with radiotherapy (RT) alone in locally advanced pancreatic cancer in a phase II trial (PACER). METHODS: Patients (n = 21) received cetuximab loading dose (400 mg/m(2)) and weekly dose (250 mg/m(2)) during RT (50.4 Gy in 28 fractions). Toxicity and disease response end point data were prospectively assessed. A feasibility study of on-trial patient blood and skin sampling was incorporated. RESULTS: Treatment was well tolerated, and toxicity was low; most patients (71%) experienced acute toxicities of grade 2 or less. Six months posttreatment, stable local disease was achieved in 90% of evaluable patients, but only 33% were free from metastatic progression. Median overall survival was 7.5 months, and actuarial survival was 33% at 1 year and 11% at 3 years, reflecting swift metastatic progression in some patients but good long-term control of localized disease in others. High-grade acneiform rash (P = .0027), posttreatment stable disease (P = .0059), and pretreatment cancer antigen 19.9 (CA19.9) level (P = .0042) associated with extended survival. Patient skin and blood samples yielded sufficient RNA and good quality protein, respectively. CONCLUSIONS: The results indicate that cetuximab inhibits EGFR-mediated radioresistance to achieve excellent local control with minimal toxicity but does not sufficiently control metastatic progression in all patients. Translational studies of patient tissue samples may yield molecular information that may enable individual treatment response prediction.

Effects of interaction of tannins with co-existing substances. VII. Inhibitory effects of tannins and related polyphenols on xanthine oxidase.

The inhibitory effects of hydrolyzable tannins, condensed tannins and related polyphenols on the activity of xanthine oxidase (XOD), catalyzing uric acid formation from xanthine, were investigated. Marked differences in the strength of the inhibition were observed. Some of the differences among the monomeric hydrolyzable tannins were due to their molecular weights, reflecting the number of phenolic hydroxyl groups in the molecule. However, the inhibitory activity of several oligomeric hydrolyzable tannins seemed particularly low in spite of their large molecular size. It was also observed that differences in location of acyl groups on the carbohydrate cores caused differences in the inhibitory activity among monomeric and oligomeric hydrolyzable tannins. A caffeic acid derivative (caffeetannin), 3,5-di-O-caffeoylquinic acid (24), also inhibited this enzyme. Galloylation and the degree of polymerization in proanthocyanidins were also shown to affect remarkably the strength of the inhibition. Among the compounds tested in the present study, valoneic acid dilactone (29), isolated from Mallotus japonicus, inhibited the enzyme most effectively. A kinetic study showed that this dilactone inhibited XOD non-competitively. Comparison of the inhibitory effect on XOD, with the binding activity to hemoglobin, for each tannin, suggests that their inhibition of XOD is not based on non-specific binding to the protein. Similar comparison of the inhibitory effect on XOD with the inhibitory effect on the generation of superoxide anion radical (O2-.) from the hypoxanthine-XOD system revealed that the inhibition of O2-. generation by tannins is due to their radical-scavenging activity, and not due to their inhibitory activity upon the enzyme.

Inhibitory effects of various flavonoids isolated from leaves of persimmon on angiotensin-converting enzyme activity.

The leaves of the persimmon Diospyros kaki, have been traditionally used for treatment of hypertensive diseases in Japan. We have studied the inhibitory effects of four flavonoids isolated from the leaves of the persimmon on angiotensin-converting enzyme activity. The four flavonoids astragalin [1], kaempferol-3-O-(2"-O-galloyl)-glucoside [2], isoquercitrin [3], and quercetin-3-O-(2"-O-galloyl)-glucoside [4] inhibited the angiotensin-converting enzyme activity in a dose-dependent fashion. Compounds 1-4 produced 67%, 53%, 33%, and 48% inhibition at a concentration of 300 micrograms/ml, respectively. The 50% inhibitory concentrations (IC50) of 1 and 2 for the angiotensin-converting enzyme were 180 micrograms/ml and 280 micrograms/ml, respectively. On the other hand, 2 and 4 were shown to have tannin activities, but 1 and 3 had no tannin activities. These results suggest that there is no relationship between the inhibition for angiotensin converting enzyme activity and the tannin activity for the four flavonoids.

Quantitative PCR analysis of TNF-alpha and IL-1 beta mRNA levels in pediatric IBD mucosal biopsies.

Inflammatory bowel disease (IBD) is associated with increased activation of intestinal immune cells, whose overproduction of proinflammatory cytokines such as tumor necrosis factor-alpha (TNF-alpha) and interleukin-1 beta (IL-1 beta) is implicated in mediating the sustained inflammatory response. Studies to date have largely reported qualitative differences in cytokine gene expression between IBD and controls. Our aim was to perform quantitative analysis of intestinal mucosal mRNA expression in colonic biopsies from pediatric IBD patients using a competitive polymerase chain reaction. IL-1 beta and TNF-alpha were expressed in all IBD and control biopsies. Compared to controls, IL-1 beta mRNA levels were increased in involved tissue from Crohn's disease (CD) patients, but not in histologically uninvolved CD or in ulcerative colitis (UC) mucosa. IL-1 beta expression in the latter groups were equivalent to those found in tissue from patients with eosinophilic colitis (EOC). Significantly higher levels of IL-1 beta mRNA were found in uninvolved mucosa from CD patients who presented with a relapse of disease activity, as compared to newly diagnosed cases with histological features of CD at an early stage. TNF-alpha mRNA transcripts were also significantly elevated in involved CD mucosa, but not in the other groups. TNF-alpha gene expression in CD-involved tissue decreased with disease duration. Follow-up of the patients revealed that high cytokine expression in uninvolved CD tissue correlated with an early clinical relapse. In conclusion, quantitative determination of proinflammatory cytokine gene expression reveals differences between the type, severity, and clinical course in patients with IBD.

Leucocyte adhesion deficiency presenting as a chronic ileocolitis.

CD11/CD18 leucocyte glycoprotein deficiency is a rare, congenital adhesion molecule disorder which, in its severe form, is usually fatal. Leucocytes in affected subjects have abnormal migration and adherence, rendering patients susceptible to life threatening infections. The CD11/CD18 integrins, and other adhesion molecules, are considered essential to the normal inflammatory response. It has been postulated that adhesion molecules may be responsible for mediating in part, the inflammatory changes observed in inflammatory bowel diseases and related disorders. This report describes the first case of CD11/CD18 deficiency characterised by a chronic ileocolitis. Bone marrow transplantation completely resolved the gastrointestinal symptoms, supporting a role for neutrophil dysfunction in the pathogenesis of the gut lesions. This case suggests that specific blockade of CD11/CD18 integrins alone may not halt the chronic inflammatory response observed in immune mediated bowel disorders, and that abnormalities of leucocyte function must be included in the differential diagnosis of paediatric Crohn's disease.

Colonic explant production of IL-1and its receptor antagonist is imbalanced in inflammatory bowel disease (IBD).

IBD is associated with an increased activation of intestinal immune cells, which causes overproduction of proinflammatory cytokines such as IL-1beta. IL-1beta is implicated in mediating the sustained inflammatory response. IL-1 receptor antagonist (IL-1Ra), the naturally occurring inhibitor of IL-1, has been shown to have beneficial effects in experimental models of colitis. In this study we investigated the hypothesis that an imbalance between IL-1 and IL-1Ra exists in IBD by measuring their secretion by explant cultures of colonic biopsies. Freshly homogenized biopsies from involved tissue in IBD patients exhibited significantly lower IL-1Ra/IL-1beta ratios than control and uninvolved IBD mucosal tissue. Using explant cultures, in vitro production of IL-1beta and IL-1Ra increased progressively during the 4-18-h culture periods. IL-1beta secretion was higher in supernatants from involved Crohn's disease (CD) and ulcerative colitis tissue compared with control tissue, and IL-1beta levels increased with severity of inflammation. IL-1Ra secretion was not elevated in involved IBD samples, but significantly higher levels were released when moderate to severely involved tissue samples were compared with noninflammatory controls. Similar to freshly homogenized tissue, explant studies showed that the IL-1Ra/IL-1beta ratios were significantly decreased in involved IBD tissue, but not in uninvolved CD or inflammatory control specimens. These data support the hypothesis of an imbalance between IL-1beta and IL-1Ra in IBD.

Tyrosine kinase and MAPK inhibition of TNF-alpha- and EGF-stimulated IEC-6 cell growth.

The role of TNF-alpha in modulating intestinal crypt cell growth was examined, in comparison with EGF. Both significantly increased IEC-6 cell proliferation. Neither EGF nor TNF-alpha overcame the inhibitory effect on growth exerted by the tyrosine kinase inhibitor genistein. Immunoblots with phosphotyrosine antibodies showed increased tyrosine phosphorylation of IEC-6 cell proteins in response to EGF and TNF-alpha stimulation. TNF-alpha increased ERK1 and ERK2 MAPK phosphorylation. A MAPK assay confirmed the increased activity upon TNF-alpha stimulation. Selective inhibition of MAPK activation by PD98059 resulted in a dose dependent inhibition of TNF-alpha or EGF-induced IEC-6 cell growth. These findings suggest a role for TNF-alpha in the regulation of intestinal epithelial cell growth and that the mitogenic effect of TNF-alpha requires protein tyrosine phosphorylation and MAPK activation.