Comparative Trial of Pancrex V Forte and Nutrizym in Treatment of Malabsorption in Cystic Fibrosis

A cross-over trial of pancreatic enzyme replacement therapy has been conducted on 12 children with cystic fibrosis using Pancrex V forte and Nutrizym tablets in equivalent dosage. No differences were found in the effectiveness of these products as measured by stool volume, number of bowel actions, faecal fat excretion, and urine urea excretion. Neither product eliminated the steatorrhoea. Though there was no laboratory evidence to support their choice nine patients expressed a preference for Nutrizym at the conclusion of the trial. This preference was based partly on the smaller number of tablets which are required.     

Fat absorption in cystic fibrosis mice is impeded by defective lipolysis and post-lipolytic events

Cystic fibrosis (CF) is frequently associated with progressive loss of exocrine pancreas function, leading to incomplete digestion and absorption of dietary fat. Supplementing patients with pancreatic lipase reduces fat excretion, but it does not completely correct fat malabsorption, indicating that additional pathological processes affect lipolysis and/or uptake of lipolytic products. To delineate the role of such (post) lipolytic processes in CF-related fat malabsorption, we assessed fat absorption, lipolysis, and fatty acid uptake in two murine CF models by measuring fecal fat excretion and uptake of oleate- and triolein-derived lipid. Pancreatic and biliary function was investigated by determining lipase secretion and biliary bile salt (BS) secretion, respectively. A marked increase in fecal fat excretion was observed in cftr null mice but not in homozygous DeltaF508 mice. Fecal BS loss was enhanced in both CF models, but biliary BS secretion rates were similar. Uptake of free fatty acid was delayed in both CF models, but only in null mice was a specific reduction in lipolytic activity apparent, characterized by strongly reduced triglyceride absorption. Impaired lipolysis was not due to reduced pancreatic lipase secretion. Suppression of gastric acid secretion partially restored lipolytic activity and lipid uptake, indicating that incomplete neutralization of gastric acid impedes fat absorption. We conclude that fat malabsorption in cftr null mice is caused by impairment of lipolysis, which may result from aberrant duodenal pH regulation.     

Pancreatic triglyceride lipase deficiency minimally affects dietary fat absorption but dramatically decreases dietary cholesterol absorption in mice

This study generated pancreatic triglyceride lipase (PTL)-null mice to test the hypothesis that PTL-mediated hydrolysis of dietary triglyceride is necessary for efficient dietary cholesterol absorption. The PTL-/- mice grew normally and displayed similar body weight as their PTL+/+ littermates. Plasma lipid levels between animals of various PTL genotypes were similar when they were maintained on either a basal low fat diet or a western-type high fat/high cholesterol diet. Although the lack of a functional PTL delayed fat absorption during the initial hour of feeding a bolus load of olive oil containing [3H]triolein and [14C]cholesterol, the rate of [3H]triolein absorption was similar between PTL+/+ and PTL-/- mice after the initial 1-h period. Importantly, comparison of fecal fat content revealed similar overall fat absorption efficiency between PTL+/+ and PTL-/- mice. In contrast, the PTL-/- mice displayed significant decrease in both the rate and the amount of cholesterol absorbed after a single meal. The plasma appearance of [14C]cholesterol was found to be 75% lower (p < 0.0005) in PTL-/- mice compared with PTL+/+ mice after 4 h. The total amount of [14C]cholesterol excreted in the feces was 45% higher (p < 0.0004) in PTL-/- mice compared with PTL+/+ mice over a 24-h period. These results indicate that the delayed fat digestion due to PTL deficiency results in a significant reduction in cholesterol absorption, although other enzymes in the digestive tract may compensate for the lack of PTL in PTL-/- mice in fat digestion and absorption.     

Decreasing Effect of Chitosan on the Apparent Fat Digestibility by Rats Fed on a High-fat Diet

We investigated the effects of various dietary fibers or their likenesses on the apparent fat digestibility by rats fed on a high-fat diet. Each of 23 different fibers was added at 5% (w/w) to a purified diet containing 20% (w/w) corn oil. The rats were fed these diets for 2 weeks, and the feces were collected from each animal during the last 3 days. When compared with cellulose (control), 10 of the tested fibers significantly increased the fecal lipid excretion. Among these fibers, chitosan markedly increased the fecal lipid excretion and reduced the apparent fat digestibility to about a half relative to the control. The apparent protein digestibility was not greatly affected by chitosan. The fatty acid composition of the fecal lipids closely reflected that of the dietary fat. These results suggest that chitosan has potency for interfering with fat digestion and absorption in the intestinal tract, and for facilitating the excretion of dietary fat into the feces.     

Effects of phytate reduction,fat extraction,and level of Ca on Ca and Zn bioavailability

The effect of phytate reduction, fat extraction, and addition of Ca in the form of skim or whole milk on Ca and Zn bioavailability from a breakfast containing bran muffins was studied in vitro and in vivo. Ca and Zn solubility were measured after in vitro simulated peptic and pancreatic digestion under pH conditions resembling those in the human GI tract. Absorption of Ca and Zn was measured in rats fed test meals tagged with 45Ca and 65Zn. Radioactivity in the femur and liver relative to levels found in rats injected with the isotopes served as criteria for 45Ca and 65Zn absorption, respectively. In vitro solubility was significantly depressed by the presence of phytate and inversely correlated with the phytate:Zn and the (phytate)(Ca):(Zn) ratios. Ca solubility was enhanced by extraction of fat and markedly increased by reduction in both fat and phytate. None of these effects was seen in vivo. However, 65Zn absorption was significantly decreased by fat extraction and phytate reduction although this treatment increased in vitro Zn solubility. Possible reasons for these discrepancies are discussed.     

Use of 3H-labeled triether, a nonabsorbable oil-phase marker, to estimate fat absorption in rats with cholestyramine-induced steatorrhea

A tritium-labeled glycerol triether was tested as a nonabsorbable oil-phase marker in studies of fat absorption in normal rats and in rats with steatorrhea induced by various doses of cholestyramine. Animals were fed a test meal containing (3)H-labeled triether and (14)C-labeled trilinolein. Fat absorption was estimated in the following three ways: (a) by isotope ratios (the change in (3)H/(14)C in the test meal and in feces); (b) by isotope recovery (the total fecal excretion of (14)C radioactivity); and (c) by chemical recovery (the total fecal fat excretion). Absorption calculated from isotope ratios agreed well with that calculated from isotope recovery over a range of fat absorption of 50-100%, thus validating the use of this lipid marker under these conditions of fat malabsorption. Absorption calculated from chemical recovery was consistently poorer than that calculated from isotope ratios or isotope recovery, thus suggesting that cholestyramine increased the excretion of nondietary (endogenous) fat. Triether may be of value for studying the absorption of compounds present predominantly in the oil phase during digestion and may have significant advantages over other proposed lipid markers.     

The metabolism of structured triacylglycerols

The triacylglycerol (TAG) structure in addition to the overall fatty acid profile is of importance when considering the nutritional effect of a dietary fat. This review aims at summarizing our current knowledge of the digestion, absorption, uptake, and transport of structured TAGs, with particular emphasis on the following aspects: gastric emptying, specificity of pancreatic lipase, lymphatic transport and clearance of chylomicrons, effects of lipid structure on tissue lipid compositions and the fecal loss of fats. So an overview will be provided for how the structure and fatty acid composition of TAGs affect their absorption and the distribution of the fatty acids in the body following digestion and absorption.     

Hydrochlorothiazide lowers urinary hydroxyproline in parathyroidectomized rats

This study was undertaken to examine the effects of hydrochlorothiazide treatment on urinary hydroxyproline excretion in parathyroidectomized rats. Urinary hydroxyproline (mumol/24 hr) fell significantly in thiazide-treated rats compared with control animals (5.66 +/- 0.37 versus 7.30 +/- 0.6, P less than 0.05, means +/- SEM). This fall in hydroxyproline excretion occurred without a decrease in glomerular filtration rate. It is concluded that the ability of thiazide diuretics to reduce urinary hydroxyproline excretion is not dependent upon suppression of parathyroid hormone-mediated bone turnover.     

Antroduodenal motility in chronic pancreatitis: are abnormalities related to exocrine insufficiency?

In patients with chronic pancreatitis (CP) the relation among exocrine pancreatic secretion, gastrointestinal hormone release, and motility is disturbed. We studied digestive and interdigestive antroduodenal motility and postprandial gut hormone release in 26 patients with CP. Fifteen of these patients had pancreatic insufficiency (PI) established by urinary para-aminobenzoic acid test and fecal fat excretion. Antroduodenal motility was recorded after ingestion of a mixed liquid meal. The effect of pancreatic enzyme supplementation was studied in 8 of the 15 CP patients with PI. The duration of the postprandial antroduodenal motor pattern was significantly (P < 0.01) prolonged in CP patients (324 +/- 20 min) compared with controls (215 +/- 19 min). Antral motility indexes in the first hour after meal ingestion were significantly reduced in CP patients. The interdigestive migrating motor complex cycle length was significantly (P < 0.01) shorter in CP patients (90 +/- 8 min) compared with controls (129 +/- 8 min). These abnormalities were more pronounced in CP patients with exocrine PI. After supplementation of pancreatic enzymes, these alterations in motility reverted toward normal. Digestive and interdigestive antroduodenal motility are abnormal in patients with CP but significantly different from controls only in those with exocrine PI. These abnormalities in antroduodenal motility in CP are related to maldigestion.     

Comparative Evaluation of Fecal Fat Excretion Induced by Orlistat and Chitosan

Objective: To compare the effects of chitosan and orlistat on fecal fat excretion. Research Methods and Procedure: A randomized, open‐label, two‐period sequential design study was used. A total of 12 healthy adult volunteers within 20% of their ideal body weight entered a 7‐day run‐in diet period before being randomized to orlistat (120 mg) or chitosan (890 mg) three times daily for 7 days. Subjects then crossed over treatment regimens for an additional 7‐day period. Subjects followed a standardized diet (2500 kcal/d, 30% as fat) for the entire 21‐day study. Feces were collected on days 4 to 7 of the run‐in period (baseline) and during the two treatment periods. Mean daily fecal fat excretion was measured at baseline and during each treatment regimen. Results: Mean baseline fecal fat excretion for all subjects was 1.36 ± 0.45 g/d. During orlistat treatment, mean fecal fat excretion significantly increased from baseline (+16.13 ± 7.27 g/d; p < 0.001). No significant effect was observed with chitosan (+0.27 ± 1.02 g/d; p = 0.379). Fecal fat excretion was significantly greater with orlistat than with chitosan (p < 0.001; 95% confidence intervals: 11.73; 20.00 g/d). Discussion: This study provides additional evidence of the inhibitory effect of orlistat on dietary fat absorption. Chitosan, however, has no effect on fecal fat excretion.     

Defective dietary fat processing in transgenic mice lacking aquaporin-1 water channels

Immunocytochemistry showed expression of aquaporin-1 (AQP1) water channels at sites involved in dietary fat processing, including intrahepatic cholangiocytes, gallbladder, pancreatic microvascular endothelium, and intestinal lacteals. To determine whether AQP1 has a role in dietary fat digestion and/or absorption, mice were placed on a diet that contained 50% fat. Whereas wild-type mice (3-3.5 wk of age, 10-12 g) gained 49 +/- 5% (SE, n = 50) body weight in 8 days, and heterozygous mice gained 46 +/- 4%, AQP1 null mice gained only 4 +/- 3%; weights became similar after return to a 6% fat diet after 6 days. The null mice on a high-fat diet acquired an oily appearance, developed steatorrhea with increased stool triglyceride content, and manifested serum hypotriglyceridemia. Supplementation of the high-fat diet with pancreatic enzymes partially corrected the decreased weight gain in null mice. Absorption of [(14)C]oleic acid from small intestine was not affected by AQP1 deletion, as determined by blood radioactivity after duodenal infusion. Lipase activity in feces and small intestine was remarkably greater in AQP1 null than wild-type mice on low- and high-fat diets. Fluid collections done in older mice (that are less sensitive to a high-fat diet) by ductal cannulation showed threefold increased pancreatic fluid flow in response to secretin/cholecystokinin, but volumes, pH, and amylase activities were affected little by AQP1 deletion, nor were bile flow rates and bile salt concentrations. Together, these results establish a dietary fat misprocessing defect in AQP1 null mice.     

Antibiotic therapy and fat digestion and absorption in cystic fibrosis

Antibiotic therapy in the cystic fibrosis (CF) mouse model has been shown to result in reduced bacterial load of the intestine and significant body mass gain. The effect was suggested to be linked to the improvement of intestinal digestion and absorption. Therefore, we aimed to assess the influence of routinely applied antibiotic therapy in CF patients on fat assimilation. Twenty-four CF patients aged 6 to 30 years entered the study. Inclusion criteria comprised confirmed exocrine pancreatic insufficiency and bronchopulmonary exacerbation demanding antibiotic therapy. Exclusion criteria comprised: antibiotic therapy six weeks prior to the test, liver cirrhosis, diabetes mellitus, oxygen dependency, the use of systemic corticosteroids. In all enrolled CF subjects, (13)C-labelled mixed triglyceride breath test ((13)C MTG-BT) was performed to assess lipid digestion and absorption, before and after antibiotic therapy. Sixteen subjects were treated intravenously with ceftazidime and amikacin, eight patients orally with ciprofloxacin. Cumulative percentage dose recovery (CPDR) was considered to reflect digestion and absorption of lipids. The values are expressed as means (medians). The values of CPDR before and after antibiotic therapy did not differ in the whole studied group [4.6(3.3) % vs. 5.7(5.3) %, p = 0.100] as well as in the subgroup receiving them intravenously [4.6(3.2) % vs. 5.7(5.3) %, p = 0.327] or in that with oral drug administration [4.6(3.4) % vs. 5.7(5.4) %, p = 0.167]. In conclusion, antibiotic therapy applied routinely in the course of pulmonary exacerbation in CF patients does not seem to result in an improvement of fat digestion and absorption.     

A Comparison of Laboratory Tests in the Malabsorption Syndrome

Absorption of radioiodinated triolein was tested in 93 individuals (15 controls, 28 cases of functional diarrhea, and 50 patients with suspected or manifest malabsorption syndrome).The results so obtained were compared in 59 cases with estimations of fecal radioactivity and chemically determined fecalfat excretion. A highly significant correlation was found.The urinary xylose excretion test was performed in 96 individuals. The diagnostic value of the radioactive fat absorption test was compared with that of the xylose excretion test in 78 cases. Both tests were diagnostic in cases of non-tropical sprue, but the xylose excretion test reflected the clinical improvement more accurately in treated cases. The radioactive fat absorption test was more reliable in the diagnosis of malabsorption secondary to bowel resection than was the xylose excretion test, but the converse was true in the diagnosis of malabsorption secondary to gastrectomy. The simultaneous use of these two tests was found to be a simple and reliable screening procedure.     

Kinetic properties of mouse pancreatic lipase-related protein-2 suggest the mouse may not model human fat digestion

Genetically engineered mice have been employed to understand the role of lipases in dietary fat digestion with the expectation that the results can be extrapolated to humans. However, little is known about the properties of mouse pancreatic triglyceride lipase (mPTL) and pancreatic lipase-related protein-2 (mPLRP2). In this study, both lipases were expressed in Pichia Pastoris GS115, purified to near homogeneity, and their properties were characterized. Mouse PTL displayed the kinetics typical of PTL from other species. Like mPTL, mPLRP2 exhibited strong activity against various triglycerides. In contrast to mPTL, mPLRP2 was not inhibited by increasing bile salt concentration. Colipase stimulated mPLRP2 activity 2- to 4-fold. Additionally, mPTL absolutely required colipase for absorption to a lipid interface, whereas mPLRP2 absorbed fully without colipase. mPLRP2 had full activity in the presence of BSA, whereas BSA completely inhibited mPTL unless colipase was present. All of these properties of mPLRP2 differ from the properties of human PLRP2 (hPLRP2). Furthermore, mPLRP2 appears capable of compensating for mPTL deficiency. These findings suggest that the molecular mechanisms of dietary fat digestion may be different in humans and mice. Thus, extrapolation of dietary fat digestion in mice to humans should be done with care.     

Role of Intraduodenally Administered Enterostatin in Rats: Inhibition of Food

Central and peripheral administration of enterostatin have been reported to reduce fat or high-fat food intake in rats. Enterostatin is formed in the intestinal lumen by tryptic cleavage of pancreatic procolipase during intraluminal fat digestion. The present experiments were designed to test if enterostatin following intraintestinal infusion would affect food intake in a similar way as intracerebraventricularly or intravenously administered enterostatin. Female Sprague-Dawley rats were fitted with a duodenal catheter and adapted to a feeding schedule for 6 hours each day. After 10 days enterostatin (5.65 and 11.3 nmol/kg/min) or saline were infused into the duodenum and food intake measured. Enterostatin significantly reduced high-fat food intake during the 6 hours of feeding, but had no inhibitory effect on low-fat food intake. Addition of tetracaine to the enterostatin infusates blocked the satiating potency of intestinal enterostatin. These results support the hypothesis of a preabsorptive site of action for enterostatin.     

Day-care surgery in British Columbia: a 7-year experience (1968-74).

Twenty-eight patients with symptomatic Paget''s disease of bone were treated with synthetic salmon calcitonin for periods of 9 to 42 months (average, 23 months). Serum alkaline phosphatase concentration and urinary hydroxyproline excretion, which had been elevated before treatment, were decreased by calcitonin treatment in all patients, and some decrease was sustained in 23 in association with variable decreases in pain, heat and stiffness of major joints. Improvement was sustained further in approximately half of these patients; the other half had partial return of symptoms. Calcium absorption was increased in 9 of 10 patients studied; the increase did not correlate with plasma concentrations of parathyroid hormone. The mean endogenous fecal calcium excretion was decreased significantly but there was no significant change in mean urinary calcium excretion. Mean accretion rate of calcium to bone, studied in 10 patients, was decreased by 35% after 6 months of treatment and by a further 23% 1 year later. There was no consistent effect of calcitonin treatment on bone mineral mass. No serious adverse effects of treatment such as allergic reactions were observed. Calcitonin appears to be effective initially in most patients with Paget''s disease of bone, but with long-term treatment resistance may be acquired.     

Toxicological effects of an organophosphorus pesticide (dimethoate) on urinary collagen metabolites in normal and high protein diets fed female albino rats

The effect of an organophosphorus pesticide (dimethoate) on the urinary excretion of hydroxyproline (total, nondialysable, dialysable and free fractions) and hydroxylysylglycosides, glucosylgalactosyl hydroxylysine and galactosehydroxylysine was investigated in two groups of female albino rats fed with normal and high protein diets. In comparison to controls, dimethoate treated animals were found to excrete significantly decreased amounts of urinary hydroxyproline fractions from 7th day onwards. The excretion of total hydroxylysylglycoside in urine parallels the excretion of hydroxyproline. The urinary output of both glu-gal-hyl and gal-hyl was also appreciably lower from dimethoate treated animals. The normal ratio of glu-gal-hyl and gal-hyl found in the urine of dimethoate treated animals was discussed in light of decreased turn over of collagen in both bone and skin. The effect of dimethoate in rats fed with high protein diet was comparatively less than those fed with normal diet.     

Peptide inhibitor of pancreatic lipase selected by phage display using different elution strategies

Interference with fat hydrolysis results in the reduced use of ingested lipids. Inhibition of pancreatic lipase reduces the efficiency of fat absorption in the small intestine and thereby initiates modest long-term reduction in body weight. In an attempt to select peptides with affinity for the surface of pancreatic lipase and potential inhibitory activity, a random, cyclic heptapeptide phage-displayed library was used. Five independent selections, differing in elution step, were performed. In three selection protocols, a sequential elution strategy was applied in anticipation of improving the selection of high-affinity clones. Four heptapeptides with the highest affinity, seemingly for pancreatic lipase, were selected, synthesized, and characterized for their capacity to inhibit enzyme function. Although no clear consensus among the sequenced peptides was found, one of the selected peptides inhibited pancreatic lipase with an apparent inhibition constant of 16 muM.     

Absence of effect of the incorporation of a milk phosphopeptide on the utilization of calcium and phosphorus in the young pig

Casein phosphopeptides are known to influence calcium absorption. A 50-day study was performed in 6-week old pigs fed either a control diet or a 5% casein phosphopeptide-containing diet (PP group). Both diets provided similar amounts of Ca (0.8%), P (0.5%), proteins, energy and vitamins. PP diet provided near 1/2 of total Ca, 1/3 of total P and 1/5 of proteins in the form of casein phosphopeptide. Ca and P excretion, absorption and retention were evaluated during a 10-day balance study. Bones were collected at slaughter to determine density, bending moment and bone mineral content. Calcium absorption and bone parameters (urinary hydroxyproline included) were not influenced by the type of diet. P absorption, but not retention, was slightly higher in the control group. Urinary Ca was higher and urinary P lower in PP pigs than in controls. These changes might result from the different kinds of dietary phosphorus, inorganic versus phosphopeptide, rather than from the difference between dietary proteins.     

Effects of aldosterone on the urinary excretion of total and non-dialyzable hydroxyproline

In order to explore the role of mineralocorticoids on collagen metabolism, the effects of aldosterone on the urinary excretion of total and non dialyzable hydroxyproline (HYPRO) was studied in rats. The administration of aldosterone in sesame oil, 75 microgram/100 g body weight to adrenalectomized rats maintained on 1% NaCl solution as drinking fluid and 1 mg of cortisone subcutaneously daily, provoked elevation of total and non dialyzable HYPRO in urine (P less than 0.001), when compared to similarly treated adrenalectomized rats receiving sesame oil but no aldosterone. Both groups showed a normal growth curve and had similar urinary excretion of creatinine. The effects of aldosterone are opposed to the known lowering effects of glucocorticoids on HYPRO excretion and may suggest an effect of aldosterone on collagen turnover. Alternatively, aldosterone may modify the metabolism or excretion of HYPRO in an opposite manner to that of glucocorticoids.