[Two cases of successful sorafenib retreatment with the addition of steroid therapy following sorafenib-induced erythema multiforme in two patients with hepatocellular carcinoma].

Erythema multiforme (EM) is a known side effect of sorafenib therapy in cancer patients; at onset, the causative medication should be permanently discontinued. Here we report two cases of hepatocellular carcinoma (HCC) that developed sorafenib-induced EM. In both cases, retreatment with sorafenib combined with steroid therapy achieved effective tumor control without EM recurrence. The first patient was a 72-year-old woman who showed a dramatic response to sorafenib retreatment, with complete remission after 8 months of therapy. There was no rash recurrence after the steroid dose was gradually tapered and stopped. The second patient was a 69-year-old man who responded to sorafenib and exhibited stable disease, with no recurrence of the rash after the steroid dose was tapered. However, mild hand-foot syndrome persisted throughout sorafenib therapy. Although sorafenib should be discontinued if EM occurs, if there is no suitable alternative treatment, retreatment may be considered with steroid cover in patients with unresectable HCC.

Changes of energy metabolism, nutritional status and serum cytokine levels in patients with Crohn's disease after anti-tumor necrosis factor-α therapy.

We investigated the effects of treatment with antibodies against tumor necrosis factor (TNF)-α on energy metabolism, nutritional status, serum cytokine levels in patients with Crohn's disease (CD). Twelve patients were enrolled. Resting energy expenditure (REE) levels were measured by indirect calorimetry. Crohn's disease activity index (CDAI) significantly decreased after treatment with anti-TNF-α therapy. Anti-TNF-α therapy did not affect REE, but respiratory quotient (RQ) significantly increased after treatment. Serum interleukin-6 levels were significantly decreased and RQ were significantly increased in high REE (≥25 kcal/kg/day) group as compared to low REE (<25 kcal/kg/day) group. In conclusion, high REE value on admission is a predictive factor for good response to treatment with anti-TNF-α antibodies in active CD patients.

The herbal medicine rikkunshito exhibits strong and differential adsorption properties for bile salts.

Anti-secretory drugs, particularly proton pump inhibitors (PPIs), are the preferred treatment agents for patients with gastroesophageal reflux disease (GERD). However, refractory GERD, which may manifest as an incomplete or lack of response to PPI therapy, is common. Despite the administration of PPIs for symptomatic control, duodenogastroesophageal reflux (DGER) containing bile is successfully controlled in only one-third of patients. It has previously been reported that the traditional Japanese herbal medicine rikkunshito, which has a prokinetic action on gastric emptying, exhibits clinically therapeutic effects against GERD and DGER that does not respond to PPIs. However, the precise mechanisms responsible for the effects of rikkunshito are still unknown. It has been suggested that the cytotoxicity of the bile salts in the gut lumen is important in GERD and DGER. The aim of the present study was to investigate whether rikkunshito is able to adsorb bile salts through the mechanism by which it ameliorates the symptoms of GERD and DGER. The binding capacities of rikkunshito for bile salts were measured using Langmuir's method. The morphology of rikkunshito was also observed by light microscopy. Rikkunshito strongly adsorbed bile salts. The binding capabilities of rikkunshito were far beyond those of a typical dietary fiber, α-cellulose, or an oral adsorbent. In addition, rikkunshito had higher binding capacities for hydrophobic bile salts as compared with hydrophilic bile salts. In conclusion, rikkunshito has a great capacity to adsorb bile salts. This may be part of the mechanism(s) responsible for the therapeutic effects of rikkunshito in patients with GERD and DGER.

Curcumin prevents the development of dextran sulfate Sodium (DSS)-induced experimental colitis.

Curcumin is a phenolic natural product isolated from the rhizome of Curcuma longa (turmeric). We evaluated the effects of curcumin on the development of dextran sulfate sodium (DSS)-induced experimental colitis. BALB/c mice were fed a chow containing either 3.5% (wt/wt) DSS or 3.5% DSS + 2.0% (wt/wt) curcumin. The body weight loss was more apparent in DSS-treated mice than in DSS + curcumin-treated mice. The disease activity index, histological colitis score, and MPO activity were all significantly higher in DSS-treated mice than in DSS plus curcumin-treated mice. Microscopically, mucosal edema, cellular infiltration, and epithelial disruption were much more severe in DSS-treated mice than in DSS + curcumin-treated mice. In DSS + curcumin-treated mice, NF-kappaB activation was blocked in the mucosa. In conclusion, the development of DSS-induced colitis was significantly attenuated by curcumin. Being a nontoxic natural dietary product, curcumin could be useful in treatment of IBD patients.

Serum concentrations of trace elements in patients with Crohn's disease receiving enteral nutrition.

We investigated the trace element status in Crohn's disease (CD) patients receiving enteral nutrition, and evaluated the effects of trace element-rich supplementation. Thirty-one patients with CD were enrolled in this study. All patients were placed on an enteral nutrition regimen with Elental(R) (Ajinomoto pharmaceutical. Ltd., Tokyo, Japan). Serum selenium, zinc and copper concentrations were determined by atomic absorption spectroscopy. Serum selenoprotein P levels were determined by an ELISA system. Average serum levels of albumin, selenium, zinc and copper were 4.1 +/- 0.4 g/dl, 11.2 +/- 2.8 microg/dl, 71.0 +/- 14.8 microg/dl, and 112.0 +/- 25.6 microg/dl, respectively. In 9 patients of 31 CD patients, serum albumin levels were lower than the lower limit of the normal range. Serum selenium, zinc and copper levels were lower than lower limits in 12 patients, 9 patients and 1 patient, respectively. Serum selenium levels significantly correlated with both serum selenoprotein P levels and glutathione peroxidase activity. Supplementation of selenium (100 microg/day) and zinc (10 mg/day) for 2 months significantly improved the trace element status in CD patients. In conclusion, serum selenium and zinc levels are lower in many CD patients on long-term enteral nutrition. In these patients, supplementation of selenium and zinc was effective in improving the trace element status.

Therapeutic efficacy of infliximab on active Crohn's disease under nutritional therapy.

OBJECTIVE: The aim of this investigation was to elucidate retrospectively the therapeutic effect of infliximab in patients with active Crohn's disease (CD) under nutritional therapy. MATERIAL AND METHODS: Using a review of the clinical records in 24 nationwide institutions specializing in inflammatory bowel disease, the short-term effect of infliximab in 97 patients with active CD was retrospectively investigated. The Crohn's disease activity index (CDAI) at baseline and after 2 weeks of a single infliximab administration (5 mg/kg) was compared among patients under total parenteral nutrition (TPN group, n=36), those following an elemental or polymeric diet (EN group, n=49) and those without TPN and EN (NN group, n=12). A decrease in CDAI >or= 70 or a CDAI value <150 at 2 weeks was regarded as effective. RESULTS: There was no difference in CDAI at baseline among the three groups. In each group, CDAI decreased significantly (from 250 (195-290) [median (interquartiles)] to 152 (123-233) in the TPN group, p<0.0001; from 259 (200-325) to 180 (130-238) in the EN group, p<0.0001; from 278 (222-291) to 164 (132-196) in the NN group, p=0.003). Infliximab was effective in 63.9% of patients in the TPN group, in 55.1% of those in the EN group and in 75% of the NN group. There was no statistical difference in efficacy among the three groups (p=0.4). Multivariate logistic regression analysis revealed younger age to be a significant factor related to the efficacy of infliximab. CONCLUSIONS: Infliximab is effective in patients with CD under TPN or EN. Age at infliximab administration may be predictive of response to infliximab.

Serum selenoprotein-P levels in patients with inflammatory bowel disease.

OBJECTIVE: Selenoprotein-P is a selenium-rich serum protein that carries more than 50% of serum selenium. We evaluated changes in serum selenoprotein-P levels in patients with inflammatory bowel disease. METHODS: Serum selenoprotein-P levels were measured by enzyme-linked immunosorbent assay. Twenty healthy individuals (controls), 34 patients with ulcerative colitis, and 37 patients with Crohn's disease (CD) were studied. RESULTS: A highly significant correlation was found between the serum selenium and selenoprotein-P levels. There was no significant difference in serum selenoprotein-P levels between healthy controls (average 3.4+/-0.8 microg/mL, n=20) and patients with ulcerative colitis (3.0+/-1.0 microg/mL, n=34). Serum selenoprotein-P levels were significantly lower in patients with CD (average 1.8+/-0.5 microg/mL, n=37). Serum selenoprotein-P levels were significantly lower in the elemental diet group of patients who had CD (average 1.4+/-0.4 microg/mL, n=17) than in the non-elemental diet group of patients who had CD (average 2.1+/-0.3 microg/mL, n=20). CONCLUSION: We found that the serum selenoprotein-P level is decreased in patients with CD. It may be a useful marker to monitor the systemic selenium status in various disorders.

Germinated barley foodstuff prolongs remission in patients with ulcerative colitis.

Germinated barley foodstuff (GBF) is a prebiotic which increases luminal butyrate production by modulating the microfloral distribution. GBF has been shown to reduce both clinical activity and mucosal damage in active ulcerative colitis (UC) with mild to moderate activity. However, the efficacy of GBF in patients with UC during the remission stage is unknown. The aim of this study was to investigate the efficacy of GBF as a maintenance therapy in patients with UC while in remission. Fifty-nine patients with UC in remission according to Rachmilewitz's clinical activity index (CAI) score of

Treatment of ulcerative colitis patients by long-term administration of germinated barley foodstuff: multi-center open trial.

Germinated barley foodstuff (GBF), which mainly consists of dietary fiber and glutamine-rich protein, is a prebiotic for ulcerative colitis (UC). In our previous study, we carried out a clinical trial of GBF with mildly to moderately active UC patients and showed that GBF treatment was able to attenuate the symptoms of UC in a relatively short-term. The aim of this study was to investigate the efficacy of long-term administration of GBF in the treatment of UC in a multi-center open trial. Twenty-one patients with mildly to moderately active UC received 20-30 g of GBF for 24 weeks in an open-label protocol while baseline treatments (5-amino-salicyrate compounds and/or steroids) were continued. The response to the GBF treatment was evaluated using a clinical scoring and after 24 weeks of observation, the GBF group showed a significant decrease in clinical activity index (especially, the degree of visible blood in stools and the presence of nocturnal diarrhea) compared with the control group (p<0.05). No side effects related to GBF were observed. In conclusion, GBF can reduce the clinical activity of UC over long-term as well as short-term administration. Nutraceutical GBF therapy may have a place in long-term management of UC, but controlled studies are needed to demonstrate its efficacy in the treatment of this disorder.

The long-term oral administration of a product derived from a probiotic, Clostridium butyricum induced no pathological effects in rats.

Recent studies have suggested that short chain fatty acids (SCFAs) exert a therapeutic effect on some human and experimental animal diseases. In our previous study, we showed that Clostridium butyricum produces high levels of SCFAs in the culture system used. In addition, an additive based on yogurt was effective in eliminating and masking the odor derived from these SCFAs in the product. Recently, we reported that the oral administration of a high concentration (50% w/w) of this product derived from Clostridium butyricum for 17 days caused no pathological abnormalities in rats. The aim of the present study was to investigate the effects of the prolonged oral administration of this product in rats. Male and female Wistar Hannover GALAS rats, 5 weeks old, were given a mixture of a standard diet plus the product derived from Clostridium butyricum (5% w/w) with 0.1% additive for 16 months (n=6). The control rats were allowed the same standard diet plus tap water (5% w/w) with 0.1% additive (n=6). After 16 months, a laparotomy was performed. A hemocyte count, and biochemical and electrolyte analyses were subsequently carried out. The esophagus, stomach, small intestine, large intestine and pancreas were investigated macroscopically and microscopically. The results showed that the rats grew normally for the duration of the experimental period. The body weights of the product-fed rats were comparable with those of the control-fed rats. There were no significant differences in the organ weight between the product- and control-fed rats, except for a significantly increased weight of the large intestine in the product-fed male rats. No pathological abnormalities were found in the hemocyte count, the biochemical and electrolyte analyses, or the macroscopic and microscopic findings.

Enteral alanyl-glutamine supplement promotes intestinal adaptation in rats.

Although parental administration of glutamine promotes intestinal adaptation, it is controversial whether enteral glutamine is effective after small bowel resection. To further evaluate the benefits of enteral supplementation, peptide and amino acid peptide transporter function must be considered. We evaluated the effect of enteral alanyl-glutamine based on the alteration of peptide and amino acid transporter expressions after massive small intestinal resection. Rats underwent 80% proximal intestinal resection. Expression of the glutaminase (GA), amino acid transporter B0 and peptide transporter PepT1 mRNA in the residual intestinal cells was initially examined by Northern blot analysis. Rats with a small bowel received a bolus supplement of glutamine (2.0 g/kg/day) + alanine (1.22 g/kg/day) mixture, alanyl-glutamine (2.972/kg/day) or saline for 3 days from one day before operation. On the 3rd postoperative day (POD) and the 7th POD, residual intestinal tissue was removed, and mucosal parameters were measured. The GA activity and GA mRNA significantly increased on the 1st POD. Although the levels of B0 mRNA gradually decreased, the PepT1 mRNA increased after surgery, and reached 150% of the initial level on the 5th POD. In the rats administered alanyl-glutamine, mucosal wet weight and protein content similarly increased with increasing villus height on the 7th POD. Enteral supplementation with alanyl-glutamine but not glutamine + alanine mixture promotes intestinal adaptation as evidenced by increased peptide transport after intestinal resection.

The use of short-course zidovudine to prevent perinatal transmission of human immunodeficiency virus in rural Kenya.

To determine the feasibility of using short-course zidovudine (ZDV) to prevent mother-to-child transmission of human immunodeficiency virus (HIV) in a breastfeeding population in a rural area in Kenya, pregnant mothers attending clinics in seven health centers in western Kenya between 1996 and 1998 were requested to volunteer for participation in this study. The HIV-infected mothers were given a daily dose of 400 mg of ZDV starting at 36 weeks of gestation and another 300 mg every three hours intrapartum. After delivery, mothers and their children were followed-up and clinically monitored every 3-4 months for two years, and child and mother mortality rates were analyzed. Of the 825 mothers who consented, 216 (26.2%) were infected with HIV. Of those infected, 51 (23.6%) took the full prescribed dose, 69 (31.9%) took only the prenatal dose, and the remaining 96 (44.4%) did not take any dose. Failure to take ZDV was attributed mainly to delivery occurring earlier than expected, while non-compliance to the intrapartum dose was due to mothers giving birth at home and fear of traditional birth attendants. By the end of the second year, 75 HIV-exposed children (34.7%) and 33 HIV-infected mothers (15.3%) had died. The HIV-free survival of children at 24 months was significantly associated with mother survival (P < 0.001) and prenatal ZDV compliance (P < 0.003). Our findings suggest that implementation of programs for prevention of mother-to-child transmission of HIV in rural areas of Africa need to consider the various socioeconomic and cultural barriers that may prevent successful uptake of antiretroviral prophylaxes. Similarly, the rapid disease progression in mothers may eliminate the increase in child survival due to ZDV prophylaxis.

Nutritional benefits of enteral alanyl-glutamine supplementation on rat small intestinal damage induced by cyclophosphamide.

BACKGROUND: Glutamine is the principal fuel used by the small intestine. Although the parental administration of glutamine promotes intestinal mucosal growth, it is controversial whether enteral glutamine is effective against small intestinal damage caused by chemotherapy. To further evaluate the benefits of enteral supplementation, peptide and amino acid transporter functions must be considered. METHOD: Rats were given cyclophosphamide (CPM) intraperitoneally (300 mg/kg). Expression of the amino acid transporter, B0 and peptide transporter (PepT1) in the jejunal mucosa was initially examined by northern blot analysis. Rats received a bolus oral supplement of an alanine (1.22 g/kg/day) plus glutamine (2.0 g/kg/day) mixture, alanyl-glutamine (2.972 g/kg/day) or saline as a control, for 7 days after CPM administration. RESULTS: Levels of B0 mRNA remained unchanged at both 3 and 7 days after CPM administration. Conversely, PepT1 mRNA increased significantly after CPM administration, and reached 200% of the initial level 7 days later. In rats given alanyl-glutamine, the mucosal wet weight and protein content increased significantly with increasing villus height at 3 and 7 days, compared with the alanine plus glutamine mixture. The plasma glutamine concentration in the alanyl-glutamine group, but not the alanine plus glutamine mixture group, increased significantly compared with that in the saline group. CONCLUSION: Enteral supplementation with an alanyl-glutamine but not alanine plus glutamine mixture prevents intestinal damage, as demonstrated by increased peptide transport expression and an elevated plasma glutamine concentration after CPM administration.

Effects of the soluble fibre pectin on intestinal cell proliferation, fecal short chain fatty acid production and microbial population.

AIM: Although pectin, a dietary fibre, has been suggested to possess some trophic effects on the intestine, the mechanisms involved remain unclear. This study aimed to evaluate the effects of pectin on rat intestinal cell proliferation and the intraluminal environment. METHODS: Control and pectin-fed rats were given a fibre-free elemental diet (ED) and an ED containing 2.5% pectin, respectively. On the 15th day, the length, weight and number of Ki-67-positive cells from each intestinal segment, and the short chain fatty acids (SCFAs) and microbial population in the caecum were measured. Plasma glucagon-like peptide-2 (GLP-2) concentration and GLP-2 receptor (GLP-2R) mRNA levels in the epithelium were also determined. RESULTS: Pectin supplementation resulted in significant increases in the length, weight, and number of Ki-67-positive cells in the ileum, caecum and colon. Although pectin supplementation did not affect the caecal microbial flora that produced SCFAs, the caecal SCFA content was significantly increased. Pectin supplementation also induced an increase in the plasma GLP-2 concentration, but did not affect the GLP-2R mRNA levels in the small intestine. CONCLUSIONS: The increases in the caecal SCFAs and plasma GLP-2 levels induced by pectin supplementation may cause mucosal proliferation in the lower intestinal tract.

Germinated barley foodstuff, a prebiotic product, ameliorates inflammation of colitis through modulation of the enteric environment.

BACKGROUND: Germinated barley foodstuff (GBF), which contains glutamine-rich protein and hemicellulose-rich fiber, exhibits therapeutic effects in ulcerative colitis; however, its mechanism is still under investigation. The aim of this study was to evaluate the anti-inflammatory effects of GBF on colitis in terms of the epithelial inflammatory response. METHODS: Mice with dextran sulfate sodium-induced colitis were used. The effects of GBF on the colitis were evaluated by measuring the body weight; disease activity; mucosal damage (histology, mucosal inflammatory parameters, nuclear factor kappa B [NFkB] activation, and signal transducer and activator of transcription 3 [STAT3]); serum interleukin 6 (IL-6) level; cecal short-chain fatty acids (SCFAs); and bile acid contents. RESULTS: GBF significantly prevented disease activity and body weight loss after induction of colitis. Serum IL-6 level and mucosal STAT3 expression were also significantly attenuated, with a conspicuous reduction of mucosal damage; NFkB activity showed the same tendency. Cecal butyrate content was significantly higher and, interestingly, GBF mice had lower bile acid concentrations than the control group. CONCLUSIONS: GBF has the potential to reduce the epithelial inflammatory response by depressing STAT-3 expression and inhibiting NFkB binding activity. These effects may be brought about by an increase of butyrate production and adsorption of bile acids.

Enteral and parenteral nutrition therapy for Crohn's disease.

Even with the development of new therapeutic agents, such as infliximab, enteral nutrition (EN) and parenteral nutrition (PN) therapies remain important for the treatment of Crohn's disease because Crohn's patients often require nutritional support. Furthermore, nutritional therapies can be used in the control of disease activity. Elemental diets, which are mainly used in EN therapy, consist of a refined amino acid mixture, glucose or maltodextrins and minimal essential fatty acids. EN therapy can reduce mucosal inflammation by the elimination of dietary antigens, which induce inflammation, and by reductions in fat, which activates inflammation. EN is applied not only as induction therapy, but also as maintenance therapy after remission (home EN). However, the unpalatability of elemental diets, difficulties related to self-intubation and the high cost of EN have limited its application as a primary therapy in western countries. PN is utilized as complete bowel rest supporting nutrition. However, since the therapeutic efficacies of EN and PN are similar, the indications for PN are limited and PN is mainly utilized in patients with bowel obstructions or severe fistulas. PN is also used as home therapy in the treatment of Crohn's patients with short bowel syndrome. However, long-term PN sometimes causes life-threatening complications including catheter-induced sepsis, liver failure and lethal mineral deficiencies. We suggest that gastroenterologists should recognize the advantages and limitations of all therapies and choose carefully or combine various therapies in order to maintain the quality of life in individual patients even if in cases where remission can not be achieved.

Supplement of a chitosan and ascorbic acid mixture for Crohn's disease: a pilot study.

OBJECTIVE: Although the pathogenesis of Crohn's disease remains unclear, dietary fat is thought to exacerbate intestinal inflammation. Chitosan is a water-insoluble dietary fiber, and a chitosan and ascorbic acid mixture has been shown in rats to increase fecal fat excretion without affecting protein digestibility. However, it remains unclear whether a chitosan and ascorbic acid mixture is safe and effective for patients with Crohn's disease. We designed a pilot trial to investigate the tolerability and amount of fat excretion after the oral administration of a chitosan and ascorbic mixture for inactive Crohn's disease. METHODS: Eleven outpatients were given seven tablets daily of a chitosan and ascorbic mixture (chitosan was given at 1.05 g/d) for 8 wk. Patients did not interrupt their respective therapies for Crohn's disease. RESULTS: The bowel movements of most patients increased slightly during the study. Nutritional and inflammatory markers in patients did not differ before and after treatment. The chitosan and ascorbic acid mixture significantly increased the fat concentration in the feces during treatment. CONCLUSIONS: These results indicated that oral administration of a chitosan and ascorbic acid mixture in patients with Crohn's disease is tolerable and increases fecal fat excretion without affecting disease activity.

A new prebiotic from germinated barley for nutraceutical treatment of ulcerative colitis.

A germinated barley foodstuff (GBF) containing glutamine-rich protein and hemicellulose-rich fiber was made from brewer's spent grain, by physical isolation. Our previous studies demonstrated that GBF supported maintenance of epithelial cell populations, facilitated epithelial repair, and suppressed epithelial nuclear factor kappaB-DNA-binding activity through generating increased short-chain fatty acid (especially butyrate) production by luminal microflora, which includes Bifidobacterium and Eubacterium, thereby preventing experimental colonic injury. The fiber fraction also modulates stool water content because of its high water-holding capacity. The patients with mild to moderate active ulcerative colitis who had been unresponsive to or intolerant of standard treatment received 20-30 g GBF, feeding daily in a non-randomized, open-label fashion. At 4 weeks, this treatment resulted in a significant clinical and endoscopic improvement. The improvement was associated with an increase in stool butyrate concentrations. These results indicate that GBF feeding is a potentially new, attractive prebiotic treatment in patients with ulcerative colitis. The potency of GBF on modulating microflora, as well as the high water-holding capacity, may play an important role in treatment and prolongation of remission in ulcerative colitis.