Esomeprazole induces upper gastrointestinal tract transmucosal permeability increase.

BACKGROUND: Proton pump inhibitors (PPIs) are one of the most widely used drug classes in the US and are now frontline medications for gastro-oesophageal reflux disease (GERD) and dyspepsia. In a previous work, we observed that a transmucosal, upper gastrointestinal (GI) leak exists in Barrett's oesophagus (BO) patients. PPI medications are commonly used by Barrett's patients. AIM: To examine if the PPI, esomeprazole, affects the barrier function of the upper GI tract. METHODS: The sucrose permeability test (SPT) was used to assess the possible effect of the PPI, esomeprazole, on upper GI leak in 37 first-time-presenting GERD patients and 25 healthy controls. RESULTS: Esomeprazole induced a significant transmucosal leak in the upper GI tract of patients taking the drug for the first time. The leak occurred quickly, within days of first taking the drug. The leak was also reversed within days of stopping the medication. CONCLUSIONS: This is the first patient-based study showing that a PPI compromises upper GI barrier function. There are potential implications for transmucosal leak of other medications that a patient on a PPI may be taking, as well as possible leak of endogenous peptides/proteins. The clinical consequences of this phenomenon are currently unknown, but are potentially important.

Transepithelial leak in Barrett's esophagus.

Using orally administered sucrose as a probe of gastrointestinal permeability, this study focused on determining whether Barrett's metaplasia exhibits a paracellular transepithelial leak to small nonelectrolytes. Subjects in five separate classes (nonendoscoped, asymptomatic controls; endoscoped, asymptomatic controls; gastroesophageal reflux disease without mucosal complications; grossly visible esophagitis; and Barrett's esophagus) consumed a sucrose solution at bedtime and collected all overnight urine. Urine volume was measured and sucrose concentration was determined by high-performance liquid chromatography. Patients with Barrett's were observed to exhibit a transepithelial leak to sucrose whose mean value was threefold greater than that seen in healthy control subjects or patients with reflux but without any mucosal defect. A parallel study of claudin tight junction proteins in endoscopy biopsy samples showed that whereas Barrett's metaplasia contains dramatically more claudin-2 and claudin-3 than is found in normal esophageal mucosa, it is markedly lower in claudins 1 and 5, indicating very different tight junction barriers.

Alternate-day prednisone treatment and treatment maintenance in Crohn's disease.

We have reviewed our data from 55 patients with Crohn's disease (CD) treated with alternate-day prednisone (average dose: 25 mg every other morning) between 1966 and 1989 for a mean duration of 6.6 yr. Daily divided corticosteroid doses were given to all patients with active disease that had not been responsive to supportive measures and, in almost all cases, not responsive to sulfasalazine alone. After initial remission was achieved, patients were switched to alternate-day doses. Treatment evaluations utilized global assessment and the CD activity index of Harvey and Bradshaw (CDAI-HB) shown to correlate closely with the National Cooperative Crohn's Disease Study (NCCDS) activity index (CDAI). CDAI-HB scores of 0-1 indicated no or minimal activity, whereas scores of 2-15 indicated progressive activity. With the CDAI-HB and global assessments, in agreement in all cases, 33 patients (60%) showed favorable responses with 95% confidence intervals (CI) of 46.8 to 73.2. Comparing the results with a literature-based 20% spontaneous long-term remission rate, the data are significant at p less than 0.01. Serious complications were gratifyingly low, with no observed instances of osteonecrosis. It is concluded that alternate-day prednisone treatment and treatment maintenance, with or without concomitant sulfasalazine, after conventional induction of remission with daily steroid doses, is a reasonable treatment option for patients with CD not responsive to sulfasalazine alone.

Favorable effects of sulfasalazine on small bowel Crohn's disease: a long-term study.

Due to conflicting reports in the literature regarding the efficacy of sulfasalazine for Crohn's disease (CD) involving small bowel alone, we reviewed the treatment results of our systematic sulfasalazine treatment in CD over a 23-yr period. We identified 28 patients with CD of small bowel alone treated between 1 and 23 yr by means of sulfasalazine alone and who went into complete clinical remission. Of these, 12 also showed total regression of radiographic abnormalities, 12 showed partial regression, while four patients still await radiographic reexamination. While our data do not permit a precise estimate, it seems that about 25% of patients with small bowel CD respond to sulfasalazine alone. Reasons are discussed why our data are at variance with some and in accord with other reports. While our study of necessity could not be carried out in double-blind fashion, patients served as their own controls, having previously failed to respond to other treatment modalities or no treatment. We conclude that sulfasalazine should be tried in the treatment of CD of small bowel because of its relatively low toxicity and reasonably high efficacy.

Intralesional steroid therapy of pyoderma gangrenosum.

Treatment of pyoderma gangrenosum complicating ulcerative colitis has in the past been frustrating and usually unsuccessful, frequently resulting in colectomy. Intralesional steroid therapy has been used off and on in a few patients, but the treatment is not widely known to gastroenterologists. We report two patients successfully treated for early pyoderma gangrenosum by intralesional injection of triamcinolone acetonide (Kenalog, 40 mg injection) together with conventional doses of systemic steroids. A single series of injections was sufficient to bring about healing of the lesions in both patients. The treatment permitted early discharge of patients from the hospital, and the skin lesions were completely healed within 2 months. The lesions have not recurred in follow-up examinations of 11/2 and 21/2 years, respectively. We hope that other physicians will find this approach equally effective.

Early gastric cancer in a United States hospital.

Early gastric cancer (EGC) confined to mucosa and submucosa, described by Japanese physicians over 20 years ago, yields about 90% 5-year postoperative survival. EGC has been increasingly reported from centers outside Japan, but rarely from the United States. Between 1976-1981, EGC was found in six patients or about 8.5% of all gastric carcinomas diagnosed in our hospital. Diagnoses were established by following suspicious upper gastrointestinal series or negative x-rays in patients with dyspepsia by means of gastroscopy and gastroscopically obtained biopsies, brush, and/or wash cytology. All six patients underwent subtotal gastrectomy with histological findings of EGC not invading the muscularis and with no metastases. So far no tumor recurrences have been found in these six patients. The results suggest that EGC as defined by Japanese investigators occurs in our hospital and presumably across the United States more often than heretofore appreciated. Previous fatalistic attitudes toward diagnosing gastric cancer should be replaced by efforts at early diagnosis. Patients with symptoms suggestive of gastric carcinoma, including unexplained dyspepsia, should undergo early upper gastrointestinal x-ray and endoscopic examinations with biopsies and cytological tests of any suspicious raised, flat, or depressed area.

Bile reflux gastritis and esophagitis in patients without prior gastric surgery, with pilot study of the therapeutic effects of metoclopramide.

We reviewed our upper endoscopic records over a 27-month period, retrospectively for 23 months and prospectively for four months and identified patients with substantial bile reflux. Patients with prior gastrectomies were excluded. Of the remaining 36 patients, 23 had prior cholecystectomies. Bile reflux gastritis and esophagitis were found in the majority of patients with bile reflux and occurred more often than is generally appreciated. Patients were seen with a fairly consistent and protracted clinical pattern, usually with severe early postprandial epigastric pain, tenderness and frequent heartburn. Cholecystectomy appeared to be a most important predisposing factor. The correct diagnosis can only be made by upper gastrointestinal endoscopic inspection and biopsies. A pilot therapeutic trial of metoclopramide suggests beneficial effects of this drug in the majority of afflicted patients. A randomized controlled trial of metoclopramide is being prepared to define more clearly the role of this drug in bile reflux gastritis and esophagitis.

Acute and relapsing pancreatitis caused by bile pigment aggregates and diagnosed by biliary drainage.

Over a three-year period 10 patients were observed with acute and relapsing pancreatitis for which no conventional cause could be identified. In all 10 patients the gallbladders visualized on oral cholecystography and no stones were identified by cholecystography or ultrasonography but biliary drainage revealed aggregates of bile pigment granules. In eight of the 10 patients, cholecystectomy was eventually performed, recommended on the basis of the abnormal findings on biliary drainage. None of the eight patients who underwent cholecystectomy and followed for up to two years have had further bouts of pancreatitis. It is proposed that: 1. aggregates of bile pigment granules in the passage from gallbladder to duodenum can cause acute and relapsing pancreatitis; 2. preoperative identification of such aggregates can only be made by biliary drainage; 3. aggregates of pigment granules and cholesterol crystals should be looked for in the bile of all patients with pancreatitis without a clearcut etiology and 4. in the absence of other overt causes, the presence of crystals and pigment granules in bile of patients with pancreatitis justifies therapeutic cholecystectomy with a realistic expectation that pancreatitis will not recur after this operation.

Anti-inflammatory drug treatment of Crohn's disease: a prospective evaluation of 100 consecutively treated patients.

We have analyzed the results of anti-inflammatory drug treatment of 100 consecutively treated patients with Crohn's disease. The disease affected the colon in 12 patients, small bowel in 36, and both colon and small intestine in 52. Thirty-two patients had had a prior resection of Crohn's disease. According to an adaptive design, patients were treated with sulfasalazine if able to take oral drugs; with steroids if unable to take, or unresponsive to, sulfasalazine; and with added azathioprine if unresponsive to sulfasalazine and steroids and unsuitable for surgery. Drug regimens included sulfasalazine alone in 39 patients, steroids alone in seven patients, both sulfasalazine and steroids in 43 patients, and added azathioprine in 11 patients. All patients completed at least 1 year, or were regarded as treatment failures after 3 months of drug treatment. We analyzed clinical and radiographic responses. Significant improvement occurred in all categories of patients: complete or partial clinical remission was observed in 79%, and complete or partial radiographic regression was observed in 55%; 30% of patients were not reexamined radiographically and the remainder showed no improvement. Our study suggests that properly selected anti-inflammatory drug therapy has definite benefits and is indicated for patients with Crohn's disease.

Diagnosis and treatment of diffuse ileojejunitis.

Thirteen patients with diffuse ileojejunitis have been diagnosed and treated by us over the past ten years. The disease bears close resemblance to Crohn's disease and may represent a variant of it. No clearcut relationship to celiac sprue was observed in this group of patients. Therapeutic success was obtained in the majority of patients treated with the anti-inflammatory drugs, sulfasalazine and steroids, with four patients requiring resectional surgery, all others manageable by nonsurgical means. There was no mortality in this series of patients.

Ileojejunitis in a pair of identical twins.

A pair of identical twin brothers with identical white and red blood cell antigens and diffuse ileojejunitis is reported. One brother initially presented with granulomatous gastritis, presumably Crohn's disease of the stomach. The relationship of diffuse ileojejunitis to Crohn's disease and the suspected genetic predisposition to develop Crohn's disease are briefly discussed.

Anti-inflammatory drug treatment in Crohn's disease.

In a prospective evaluation of all patients with Crohn's disease treated by us since 1970, 62 have completed at least one year, or required bowel resection after at least three months, of anti-inflammatory drug treatment. Sulfasalazine alone was used in 24 patients, steroids alone were used in four patients, both drugs were used together in 29 patients and azathioprine was added to the drug regimen of five patients. The initial choice of drug followed a set design but the regimens ultimately arrived at depended upon patient responses. Favorable complete or partial clinical responses were obtained in 54 patients, while 37 patients showed objective radiographic improvement or regression. No radiographic improvement was found in the eight patients with clinical treatment failure as well as in 11 patients with clinical improvement. Six clinically improved patients had not yet been re-examined radiographically. The study provides objective evidence that the majority of patients with Crohn's disease can be successfully treated by means of anti-inflammatory drugs.

Treatment of chronic radiation enteritis and colitis with salicylazosulfapyridine and systemic corticosteroids. A pilot study.

Four patients with severe chronic radiation enteritis and/or colitis were treated with anti-inflammatory drugs that are used conventionally in the treatment of idiopathic inflammatory bowel disease. Salicylazosulfapyridine (SASP) was used in the treatment of all four patients, while one patient received oral prednisone together with SASP. All four patients were treated and observed for over one year, with follow-up observations now extending to over three years. The four patients showed striking clinical improvement, accompanied by improvement in the radiographic appearance of affected bowel, complete or almost complete in three and incomplete in the fourth patient. The results of this pilot investigation are encouraging and call for wider clinical trials of the same and related drugs in larger groups of patients with chronic radiation enterocolitis, a serious condition that has until now not been successfully treated with drugs.

Laboratory studies with wild rodents and viruses native to Trinidad. Studies on the behavior of cocal virus

The response of the laboratory-reared Oryzomys laticeps velutinus and Zygodontomys b. brevicauda to inoculation with cocal virus was studied. Zygodontomys appears to be the more susceptible. Low-level viremia of short duration was detected in some animals of this species. Regular virus isolations were made from the crust of superficial skin wounds in Zygodontomys inoculated subcutaneously. Of 22 Zygodontomys inoculated subcutaneously or intradermally with 8th and 1st mouse brain passage virus, respectively, eight became paralyzed in the hind limbs. Death followed in 1 or 2 days in the four paralyzed animals that were not killed. In all eight animals, the virus content of the spinal cord exceeded that of the brain. No illness was observed in Oryzomys. Virus could be isolated with some regularity from the crusts of superficial skin wounds in this species only when the virus had been inoculated in the edge of the wound. Both rodent species appeared to become infected after intradermal inoculation by the multiple pressure method. Nasal instillation of virus infected both species and produced high mortality in Zygodontomys. Virus was recovered from the lungs of two dead Zygodontomys. Both species were refractory to infection by the oral route. The implications of the results for a further understanding of the epozootiology of cocal virus infection are discussed. (SUMMARY)