Norton J. Greenberger

Double blind, placebo controlled trial of metronidazole in Crohn's disease.

A double blind study compared the efficacy of metronidazole in two doses (20 mg/kg, 10 mg/kg) with placebo in patients with Crohns disease. One hundred and five patients participated but only 56 completed the 16 week study -21 were withdrawn for deterioration of symptoms, 17 for adverse experiences, and 11 for protocol violation. Significant improvement in disease activity as measured by the Crohns disease activity index (metronidazole 20 mg/kg, 97 units; metronidazole 10 mg/kg, 67 units; placebo -1 unit, p = 0.002) and serum orosomucoid (metronidazole 20 mg/kg/day, 49; 10 mg/kg/day, 38; placebo, -9, p = 0.001)) were detected. Changes in C reactive protein concentrations did not achieve significance when all three groups were considered but were significant when all metronidazole treated patients were grouped and compared with the placebo treated patients (0.8 v -0.9, p less than 0.05). Although patients receiving metronidazole 20 mg/kg/day had a greater improvement in disease activity than those receiving 10 mg/kg/day (difference 30 units (95% confidence intervals -27-87), the small sample size may have precluded the detection of statistical significance. Preliminary analysis suggests that metronidazole was more effective in patients with disease confined to the large intestine or affecting both small and large bowel than in those with small bowel disease only. There were no differences in remission rates between metronidazole and placebo treated patients. We conclude that metronidazole warrants further assessment in the treatment of patients with active Crohns disease.

5-Aminosalicylic acid enemas: Effective agent in maintaining remission in left-sided ulcerative colitis

The efficacy of 5-aminosalicylic acid enemas in maintaining remission in left-sided ulcerative colitis was studied. Twenty-five patients in remission for at least 2 mo were randomized to receive either 1-g 5-aminosalicylic acid or placebo enemas daily and were followed up for 1 yr. Eleven of 13 patients randomized to placebo relapsed after a mean of 16 wk. Nine of 12 patients randomized to 5-aminosalicylic acid remained in remission for 1 yr, 2 others in remission withdrew by request, and 1 relapsed at 10 wk. The difference between relapse rate on 1-g 5-aminosalicylic acid versus placebo was significant (p less than 0.005). Seven patients entered the blinded trial a second time. Three of 4 patients randomized to 5-aminosalicylic acid remained in remission and 1 relapsed. Three randomized to placebo relapsed at a mean of 14 wk. One-gram 5-aminosalicylic acid enemas are safe and effective in maintaining remission in patients with left-sided ulcerative colitis.

Interruption of the enterohepatic circulation of digitoxin by cholestyramine: I. Protection against lethal digitoxin intoxication

Previous studies have demonstrated that considerable amounts of parenterally administered cardiac glycosides are excreted in the bile and reabsorbed across the intestinal mucosa in several species. It is currently believed that the more prolonged action of nonpolar digitalis glycosides is due to their retention and recycling in the enterohepatic circulation. This report describes studies carried out to evaluate the effects of pharmacologic interruption of this enterohepatic cycle with the intraluminal sequestering agent cholestyramine. Cholestyramine was found to bind substantial quantities of digitoxin-(3)H and digoxin-(3)H in vitro and this binding was only modestly inhibited by the presence of bile. Administration of cholestyramine to rats by intragastric catheter before the subcutaneous injection of the LD(100) dose of digitoxin (10 mg/kg) resulted in a 70% survival rate. Further, oral administration of cholestyramine to rats before the subcutaneous injection of digitoxin-(3)H resulted in accelerated fecal excretion of radioactivity and lower levels of digitoxin-(3)H and metabolites in brain tissue compared to controls. Similarly, pretreatment of guinea pigs with cholestyramine orally before the injection of digitoxin in dosages of 10.0 and 4.0 mg/kg resulted in a 25 and 70% survival rate respectively as compared to survival rates of 0 and 30% in control animals. Cholestyramine pretreatment of guinea pigs was also accompanied by lower levels of digitoxin-(3)H and metabolites in heart and liver 90 min after injection of digitoxin-(3)H. Cholestyramine therapy did not result in significant changes in serum potassium levels excluding the possibility that drug-induced hyperkalemia might have affected the cardiac uptake of digitoxin. The data obtained in this study indicate that cholestyramine treatment affords a significant degree of protection against lethal digitoxin intoxication in rats and guinea pigs. It is suggested that cholestyramine binds appreciable amounts of digitoxin in the intestinal lumen resulting in reduced reabsorption, increased fecal excretion, and lower tissue levels of glycoside in critical organs. The protective effects of cholestyramine appear to be mediated by interruption of the enterohepatic circulation of digitoxin.

Effect of vegetable and animal protein diets in chronic hepatic encephalopathy

In the present investigation, studies were carried out to examine the effect of a vegetable-protein diet as compared to an animal-protein diet on standard clinical and laboratory parameters in 3 patients with chronic hepatic encephalopathy. To evaluate more objectively the effects of vegetable or animal protein diets, an hepatic encephalopathy index was developed, and this included the following parameters: fetor hepaticus, asterixis, stage of hepatic coma (Parson-Smith), arterial ammonia levels, EEG, Reitan trail test, and any reduction or improvement in dietary protein tolerance. In controlled, randomized, single-blind trials, it was found that a vegetable-protein diet resulted in overall clinical improvement, decreased hepatic encephalopathy index scores, decreased arterial ammonia levels, improved performance on intellectual tasks, and in one case, markedly improved protein tolerance. Further, the beneficial effects of a vegetable-protein diet were enhanced by the use of the synthetic disaccharide, lactulose. These studies do not provide a clear-cut definition of the mechanism for the observed beneficial effects of vegetable protein in chronic hepatic encephalopathy. However, the most plausible explanation is that vegetable-protein diets contain lower amounts of certain amino acids and other putative materials which may be important in the pathogenesis of hepatic encephalopathy.

Diagnosis of pancreatic disease by a synthetic peptide. A new test of exocrine pancreatic function.

Abstract N-benzoyl-L-tyrosyl- p -aminobenzoic acid, a synthetic peptide, is specifically cleaved by the pancreatic endopeptidase chymotrypsin; the released p -aminobenzoic acid (P.A.B.A.) is absorbed and excreted in the urine. To evaluate its diagnostic value, the urinary excretion of P.A.B.A. after oral administration of this peptide was examined in patients with pancreatic disease (chronic pancreatitis with pancreatic insufficiency and pancreatic carcinoma). Recovery of P.A.B.A. in the urine was significantly lower in patients with pancreatitis (40%) and pancreatic carcinoma (56%) than in the control group (75%) (P

The effect of chronic alcohol administration on the immune responsiveness of rats

Abstract A series of studies were carried out to determine the effect of chronic alcohol administration on cellular and humoral immunity in the rat. Alcohol-treated rats received an alcohol liquid formula diet for 3 months, and this uniformly resulted in the development of a fatty liver. In alcohol-treated rats there was a delay in antibody production to both typhoid H and B. abortus antigens following a primary immunization. The peak titers obtained, however, were not significantly different from those of the control animals. The secondary response to typhoid H antigen was not affected. The expression of cutaneous delayed hypersensitivity to a potent skin sensitizing chemical, 2, 4-dinitrofluorobenzene, was also depressed in alcohol-treated rats. Animals receiving alcohol also had markedly atrophic thymuses and small spleens. The normal thymuses and adrenal glands found in control animals treated with ACTH injections indicate that the changes were not due to hyperactivity of the adrenal cortex in a stressful situation. It is postulated that the deleterious effects of alcohol on the immune system of rats may be due to alteration in either reticuloendothelial or thymic function.

Interruption of the enterohepatic circulation of digitoxin by cholestyramine: II. Effect on metabolic disposition of tritium-labeled digitoxin and cardiac systolic intervals in man

Previous studies of digitalis glycoside metabolism and excretion have indicated that these compounds undergo a significant enterohepatic cycle in some species. It has been suggested that the existence of such a cycle in man contributes to the prolonged action of certain cardiac glycosides. Previous studies have demonstrated that cholestyramine binds digitoxin and digoxin in vitro and accelerates the metabolic disposition of digitoxin in rats and guinea pigs, presumably by interrupting the enterohepatic circulation. In order to assess the role of the enterohepatic circulation in the metabolism of digitalis glycosides in humans, maintenance doses of cholestyramine were administered to 7 of 15 normal human subjects beginning 8 hr after digitalization with 1.2 mg of digitoxin-(3)H. All subjects had frequent measurements of serum radioactivity, left ventricular ejection time (LVET), and electromechanical systole (QS(2)), the latter recorded as the interval from onset of Q wave to first major component of second heart sound. Measurement of the LVET and QS(2) intervals affords a sensitive index of the cardiac response to digitalis. In addition, chloroform extraction of serum was performed to separate unchanged digitoxin and active metabolites from cardioinactive metabolites of digitoxin. Cholestyramine treatment resulted in reduction in half-life to total serum radioactivity from 11.5 to 6.6 days, and in chloroform-extractable radioactivity from 6.0 to 4.5 days, as compared to controls. In addition, cholestyramine treatment was accompanied by more rapid return to base line values of digitoxin-induced changes in the LVET and QS(2) intervals. A significant positive correlation was found between QS(2) values and chloroform-extractable radioactivity, the latter reflecting unchanged digitoxin-H(3) (r=0.64; P=<0.01). The results indicate that administration of cholestyramine to digitalized human subjects accelerates the metabolic disposition of digitoxin and abbreviates the physiologic response to the glycoside. This effect is presumably mediated by interruption of the enterohepatic circulation of digitoxin by cholestyramine.

Criteria for diagnosis

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Intestinal atony in progressive systemic sclerosis (scleroderma)

Abstract Small bowel involvement in systemic sclerosis is common, but grossly impaired peristalsis resulting in intestinal atony develops in only a small number of patients. This report describes such a patient who experienced repeated episodes of nausea, emesis and abdominal distention and in whom refractory stasis of intestinal contents with severe malabsorption ultimately developed. Excessive enteric protein loss was demonstrated by a Cr 51 -albumin test. Electron microscopic studies of the jejunum revealed atrophy of smooth muscle associated with striking collagen deposition and a marked paucity of smooth muscle nexuses (cell junctions). It is suggested that the extensive fibrosis and loss of muscle cell to muscle cell contact resulted in nonsynchronized muscular contractions and the development of intestinal dilatation and atony.

Pancreatitis and hyperlipemia.

It has long been recognized that hyperlipemia* may occur in association with pancreatitis. In earlier reports of cases of acute and recurrent pancreatitis, the rate of hyperlipemia varied between 3...