Omeprazole, a proton pump inhibitor, improves residual steatorrhoea in cystic fibrosis patients treated with high dose pancreatic enzymes. Omeprazole enhances the efficacy of pancreatin (pancrease) in cystic fibrosis. Placebo-controlled trial of misoprostol in cystic fibrosis. Effect of misoprostol on fat malabsorption in cystic fibrosis. Use of famotidine in severe exocrine pancreatic insufficiency with persistent maldigestion on enzymatic replacement therapy. A long-term study in cystic fibrosis. Effect of cimetidine and pancreatic enzymes on serum and fecal bile acids and fat absorption in cystic fibrosis. Ranitidine and omeprazole as adjuvant therapy to pancrelipase to improve fat absorption in patients with cystic fibrosis. Effect of cimetidine and sodium bicarbonate on pancreatic replacement therapy in cystic fibrosis. Long-term cimetidine in children with cystic fibrosis: a randomized double-blind study. The influence of long-term cimetidine as an adjuvant to pancreatic enzyme therapy in cystic fibrosis.
Despite treatment with supra-physiological doses of pancreatic enzyme supplements, residual steatorrhoea is a common problem in patients with cystic fibrosis (CF) and pancreatic insufficiency. Strategies to enhance the activity of pancreatic enzymes include decreasing duodenal acidity. The aim of this study was to evaluate the effect of omeprazole (Losec), a proton-pump inhibitor, on fat absorption in CF patients with residual steatorrhoea despite high dose pancreatic enzyme supplements (> or =10,000 U lipase/kg per day). A random cross-over design was chosen. Fat digestion was evaluated with and without omeprazole by means of chemical fat measurements in 3-day stool collections together with 3-day weighed food records for calculation of fat absorption. The results of 15 patients (3 girls and 12 boys) with confirmed steatorrhoea during the control evaluation were analysed. Median age was 8.7 years (range 3.5-15.9 years). Median daily lipase intake was 13,500 U/kg per day (range 10,000-22,000 U/kg per day). During treatment with omeprazole, median faecal fat loss (g fat/day) decreased from 13 g (quartiles 11.5-16.5 g/day) to 5.5 g (quartiles 4.9-8.1 g/day) (P<0.01). The same improvement was noted when fat absorption was calculated: 87% (quartiles 81-89%) without versus 94% (quartiles 90-96%) with omeprazole (P<0.001).
                Omeprazole improves fat digestion and absorption in cystic fibrosis patients with residual faecal fat loss despite maximal pancreatic enzyme substitution. We studied the effect of the addition of omeprazole (20 mg once a day) to treatment with pancreatin (Pancrease, Cilag, Herentals, Belgium), two or four capsules three times a day, on fecal fat excretion in a double-blind, crossover fashion in nine patients with cystic fibrosis having persistent steatorrhea while taking Pancrease, two capsules three times a day (mean fecal fat excretion, 22.3%; range, 12% to 44%). Neither doubling of the dose of Pancrease nor addition of omeprazole to the lower dose of Pancrease significantly reduced fecal fat excretion (mean, 19.6% [range, 10% to 34%]; mean, 16.4% [range, 6% to 32%], respectively). However, addition of omeprazole to the higher dose of Pancrease (four capsules three times a day) significantly reduced fecal fat excretion when compared with the two doses of Pancrease alone (mean, 10.7%; range, 4% to 25%; P less than 0.01). We conclude that adjunct therapy with omeprazole reduces fecal fat excretion in cystic fibrosis provided that a high dose of Pancrease is supplied. Seventeen children with cystic fibrosis were studied in a 6-week double-blind, placebo-controlled, crossover trial to determine the efficacy of misoprostol, 100 micrograms, four times a day, in improving fat absorption in patients already on pancreatic enzyme therapy. In those patients who had greater than 90% absorption on enzyme therapy alone, no further significant increase in absorption was achieved with misoprostol administration. Those patients who had absorption of less than 90% on standard enzyme therapy showed a significant improvement with misoprostol administration (p less than 0.01). One patient had a significant elevation in the eosinophil count during the period of misoprostol administration, but there were no significant changes in any other hematological or biochemical parameter. Misoprostol appears to be of benefit to those children with cystic fibrosis who have residual malabsorption on standard enzyme therapy. Misoprostol, a synthetic prostaglandin that is known to reduce gastric acid production and stimulate duodenal bicarbonate production, was evaluated in 22 patients with cystic fibrosis. In those patients who had greater than 10% fat malabsorption while taking pancrease the addition of misoprostol significantly reduced the degree of fat malabsorption. In patients with pancreatic exocrine insufficiency, the use of pancreatic enzyme does not abolish steatorrhea in some cases. We carried out a long-term prospective study in an attempt to clarify the effectiveness of the associated use of famotidine to enzymatic supplementation on fat absorption and nutritional parameters of patients with pancreatic insufficiency due to cystic fibrosis. We studied 10 patients, mean age 12.5 years, with persistent steatorrhea on enzymatic supplementation. A double-blind crossover design was used and famotidine (1 mg/kg/day) or placebo was given as adjuvant to enzymatic preparations for either of two six-month periods. A statistically significative reduction in fecal wet weight (P less than 0.0001), an improvement in the coefficient of fat absorption (P less than 0.01) and in the steatocrit values (P less than 0.028) were found on famotidine. Moreover, the weight and the height increases were greater after famotidine than after placebo period (respectively, P less than 0.012 and P less than 0.01); also the serum calcium and triglycerides levels were higher after the period on famotidine (respectively, P less than 0.0025 and P less than 0.025). No adverse effects of famotidine were noted. These data suggest that famotidine is a useful adjuvant to pancreatic enzyme therapy in patients with severe pancreatic insufficiency and persistent maldigestion on large doses of pancreatic supplements; in fact, famotidine improves not only fat absorption but the nutritional status of the patients. Steatorrhea persists in most cystic fibrosis patients with exocrine pancreatic insufficiency despite enzyme replacement, perhaps because gastric acid inactivates oral enzymes. Bile acid malabsorption may parallel steatorrhea. We studied the effect of adding cimetidine (300 mg a.c.) to pancreatic enzyme therapy in 8 patients with cystic fibrosis and steatorrhea. Fecal bile acid, weight and fat, and postprandial serum bile acids were measured with and without cimetidine. D-Xylose absorption was normal in all patients. On constant diets, 72-hr stools were collected during enzyme therapy and during a 5-day course of enzymes plus cimetidine. Addition of cimetidine to enzyme decreased fecal weight (257 +/- 32.6 to 198.6 +/- 32.5 g/day), increased the percent of dietary fat absorbed (75.0 +/- 4.9 to 80.1 +/- 4.1%, P less than 0.05), but had no effect on fecal bile acids (4.7 +/- 0.9 to 4.2 +/- 1.0 mmol/m2/day). Compared with no therapy, enzymes increased postprandial serum bile acid at 60 min (9.56 +/- 1.0 to 14.0 +/- 1.3 muM/liter, P less than 0.05) and at 120 min (9.4 +/- 1.2 to 12.4 +/- 1.6 muM/liter, P less than 0.02). The addition of cimetidine to enzymes abolished this postpranidial bile acid rise. In conclusion, addition of cimetidine to oral pancreatic enzyme therapy decreases stool weight and fat but perhaps not stool bile acids in cystic fibrosis. However, correction of fat absorption is incomplete. Enzyme therapy increases postprandial serum bile acids, and this increase is abolished with oral cimetidine. In view of the incomplete correction of steatorrhea and the alterations in serum bile acids induced by cimetidine, further research with this new medication is needed before it can be recommended for routine clinical use in patients with cystic fibrosis. Inadequate treatment of pancreatic insufficiency in patients with cystic fibrosis (CF) causes malabsorption of nutrients with significant sequelae. The objective of this study was to measure the effect of acid suppressant therapy on fat absorption in patients with CF who received a pH-sensitive, enteric-coated microtablet enzyme product.
                A double-blind, placebo-controlled crossover study of 12 children and 10 adults with pancreatic insufficient CF was performed. All subjects were receiving pancrelipase therapy (Pancrease MT10 and MT16; Ortho-McNeil, Springhouse, PA, U.S.A.) and for the study also received either placebo or ranitidine (Zantac; Glaxo-Wellcome, Research Triangle Park, NC U.S.A.) 5 mg/kg or 10 mg/kg daily. The adult subjects also received omeprazole therapy (Prilosec; AstraZeneca/Merck, Wilmington, DE, U.S.A.), 20 mg daily, as adjuvant therapy to pancreatic enzymes. Serial 3-day fat-balance studies were performed in the Clinical Research Center. The data were analyzed using individual paired t tests that compared each treatment with placebo and two repeated-measures, general linear model F tests.
                The linear model for all subjects showed no overall adjuvant drug effect on fat absorption, P = 0.32. A second linear model F test analysis of adult subjects, comparing all four drug treatments (placebo, ranitidine 5 and 10 mg/kg daily and omeprazole), also showed no difference in fat absorption, P = 0.15. Paired t test subgroup analysis of the adults showed an improvement of 4.97% (P = 0.003) in mean fat absorption comparing low-dose ranitidine to placebo. All other t test analyses showed no significant change in fat absorption between placebo and acid suppressant treatment. There was marked intersubject and intrasubject variability in fat absorption.
                No overall significant improvement in fat absorption could be demonstrated with adjuvant therapy. Fat absorption measured by 3-day fat-balance studies varied greatly even when comparing the same subject for placebo and baseline treatments, despite identical dietary fat and enzyme intakes. The large variability limited our ability to test for a difference in fat absorption and has significant implication for the use of this test, considered the gold standard, for determining enzyme dosage adequacy. Fifteen patients with cystic fibrosis and pancreatic insufficiency were studied during four randomised seven day treatment periods in which they received only pancreatic supplement (Pancrelipase, 27 capsules per day) or supplement plus cimetidine (20 mg/kg body weight/24 h) or sodium bicarbonate (15 g/m2/24 h) alone or in combination. Dietary intake was not fixed but was restricted to foods of known fat and nitrogen content from which daily intakes could be computed. Faecal fat and nitrogen were calculated as g/24 h and percentage of intake. Addition of either cimetidine or bicarbonate resulted in significant improvement in fat and nitrogen excretion, which was not greater with the combination of both drugs. Cimetidine and sodium bicarbonate in these doses are therefore sufficient to produce maximal improvement in digestive activity of pancreatic supplements. Fat excretion per gram of intake fell with cimetidine and bicarbonate from 12 times the normal level, to normal, in patients consuming less than 120 g fat daily. Above this intake the dose of pancreatic supplement appeared to be inadequate. Faecal nitrogen excretion increased with nitrogen intake in all four periods, but, in contrast with fat excretion, the response to cimetidine and bicarbonate was not affected by the level of intake. Dietary intake appears to be a significant factor in determining the faecal output of fat and nitrogen in patients with pancreatic insufficiency and should be considered when determining the optimum amount of pancreatic supplementation. A prospective, randomized double-blind study of 38 children with cystic fibrosis (CF) was designed to evaluate the effectiveness of cimetidine in improving fat absorption and clinical condition. The treatment consisted of cimetidine or placebo, 600 mg/m2 body surface/day, over a 4-mo period. Clinical state, weight, height, skinfold thickness, lung function tests, para-aminobenzoic acid (PABA) peptide test, and plasma lipid and lipoprotein determinations were performed before and after the treatment period. Compared with age-matched healthy children, patients showed decreased cholesterol (150.2 +/- 31.2 mg/dl, mean +/- SD), decreased high density lipoprotein cholesterol (44.1 +/- 11.8 mg/dl), and decreased low density lipoprotein cholesterol (84.1 +/- 25.5 mg/dl) whereas the triglycerides and the very low density lipoprotein triglycerides were slightly elevated (118.2 +/- 33.0 mg/dl and 60.5 +/- 17.5 mg/dl, respectively). Apoprotein B and AI were slightly reduced and Apoprotein AII was in the normal range. After the 4-mo treatment no significant change in clinical condition, weight, or lipoprotein patterns could be detected between the two groups. The total PABA recovery in urine also did not change significantly (36.6 +/- 19.4% of the dosage given before versus 28.7 +/- 12.9% after 4 mo in the cimetidine group). Cimetidine gave rise to bronchoconstriction as shown by an increase in airway resistance (mean increase 14.8%) whereas the placebo group had a decreased Raw with a mean of 8.3%. Patients with CF have a dyslipoproteinemia that was not influenced by cimetidine. We conclude that cimetidine does not improve fat absorption and has, therefore, no place and no benefit in the treatment of children with CF. Seventeen patients on constant doses of pancreatic enzymes were randomised to receive either cimetidine or placebo for either of two successive six month periods. Nutritional state and maldigestion were assessed at the beginning and end of each period. Reductions in mean values of faecal fat, nitrogen, wet weight, and bile salts of approximately 30% were found on cimetidine therapy. Results showed considerable variation and only the fall in faecal fat was statistically significant. No benefit was demonstrated for height, weight, skinfold thickness, albumin, vitamin A, bone age or Crispin-Norman score.
Trials have shown limited evidence that agents that reduce gastric acidity are associated with improvement in gastro-intestinal symptoms and fat absorption. Currently, there is insufficient evidence to indicate whether there is an improvement in nutritional status, lung function, quality of life, or survival. We therefore recommend that large, multicentre, randomised controlled clinical trials are undertaken to evaluate these interventions.