Validation of an omega-3 substrate challenge absorption test as an indicator of global fat lipolysis.

INTRODUCTION: The coefficient of fat absorption (CFA) quantifies fat that remains in stool after digestion and is not a direct measure of lipolysis. CFA has been used to assess treatment of pancreatic insufficiency but does not correlate with pancreatic enzyme replacement therapy dose. We explored use of an omega-3 substrate absorption challenge test as a sensitive test of lipolysis and absorption. METHODS: We studied a novel microbially-derived lipase (SNSP003) employing an established surgical model commonly used to study the uptake of macronutrients, the exocrine pancreatic insufficient pig. Pigs were fed a high-fat diet and given a standardized omega-3 substrate challenge to test the effect of lipolysis on its absorption. Blood was drawn at 0, 1, 2, 4, 6, 8, 12, and 24 hours following the substrate challenge and was analyzed for omega-3 and total fat levels (c14:c24). SNSP003 was also compard to porcine pancrelipase. RESULTS: The absorption of omega-3 fats was significantly increased following administration of 40, 80 and 120 mg SNSP003 lipase by 51% (p = 0.02), 89%, (p = 0.001) and 64% (p = 0.01), respectively, compared to that observed when no lipase was administered to the pigs, with Tmax at 4 hours. The two highest SNSP003 doses were compared to porcine pancrelipase and no significant differences were observed. Both doses increased plasma total fatty acids (141% for the 80 mg dose (p = 0.001) and 133% for the 120 mg dose (p = 0.006), compared to no lipase) and no significant differences were observed between the SNSP003 lipase doses and porcine pancrelipase. CONCLUSION: The omega-3 substrate absorption challenge test differentiates among different doses of a novel microbially-derived lipase and correlates with global fat lipolysis and absorption in exocrine pancreatic insufficient pigs. No significant differences were observed between the two highest novel lipase doses and porcine pancrelipase. Studies in humans should be designed to support the evidence presented here that suggests the omega-3 substrate absorption challenge test has advantages over the coefficient of fat absorption test to study lipase activity.

The effect of HTLV1 infection on inflammatory and oxidative parameters in the liver, kidney, and pancreases of BALB/c mice.

Viral infections are linked to the progression of inflammatory reactions and oxidative stress that play pivotal roles in systemic diseases. To confirm this phenomenon, in the present study, TNF-α level and oxidative stress markers were examined in the liver, kidney, and pancreas of HTLV1-infected male BALB/c mice. To this end, twenty BALB/c mice were divided into HTLV1-infected mice that were inoculated with 1-million HTLV1-infected cells (MT-2), and the control groups. Two months after inoculation, the peripheral blood, mesenteric lymph nodes, liver, kidney, and pancreas were collected after deep anesthetization of mice (ketamine, 30 mg/kg). The extracted DNA of mesenteric lymph nodes was obtained to quantify proviral load (PVL) using quantitative real-time polymerase chain reaction (qRT-PCR). The levels of lipid peroxidation, total thiol (SH), nitric oxide (NO), TNF-α, catalase (CAT), and superoxide dismutase (SOD) activities were examined in the liver, kidney, and pancreases. Furthermore, histopathological changes in the liver and kidney were evaluated. In liver tissue, the levels of MDA, TNF-α, and blood cell infiltration were significantly increased, and the levels of CAT and SOD were significantly decreased. In the kidney, a reduction in SOD, CAT, and total SH and an increase in MDA and NO were observed. In the pancreas, CAT activity, total SH, and SOD were decreased, and the levels of MDA and NO were enhanced. In terms of TNF-α production, it has been shown that the level of this inflammatory cytokine was increased in the liver, kidney, and pancreas. The HTLV1 may have a role in inducing inflammatory reactions and oxidative stress pathways in the tissues.

Digestive Enzyme Replacement Therapy: Pancreatic Enzymes and Lactase.

Maldigestion occurs when digestive enzymes are lacking to help break complex food components into absorbable nutrients within the gastrointestinal tract. Education is needed to help patients manage the intricacies of digestive enzyme replacement therapies and ensure their effectiveness in reducing symptoms of maldigestion.

Long-term experience with ZENPEP in infants with exocrine pancreatic insufficiency associated with cystic fibrosis.

The objective of our study was to determine whether infants with cystic fibrosis who developed exocrine pancreatic insufficiency in early infancy would tolerate long-term treatment with ZENPEP (pancrelipase) delayed-release capsules, containing 3000 US Pharmacopeia units of lipase/capsule, and demonstrate consistent long-term growth. The most common treatment-emergent adverse events were diarrhea, vomiting, and constipation (mild or moderate). At study completion, median weight-for-age percentiles increased from 22nd to 49th, median length-for-age percentiles increased from 36.5th to 42nd, and median weight-for-length percentiles increased from 41.5th to 55.5th. Long-term treatment (up to 12 months) of infants with exocrine pancreatic insufficiency owing to cystic fibrosis with ZENPEP was well tolerated and associated with improved growth parameters. This is the first long-term study of pancreatic enzyme replacement therapy conducted in this patient population.

Stimulating effect of pancreatic-like enzymes on the development of the gastrointestinal tract in piglets.

Use of nutritional components from the milk and eventually from the solid feed relates to the growth and development of gastrointestinal tract (GIT). We studied the effect of pancreatic-like enzymes [porcine pancreatic enzymes (Creon) or microbial-derived amylase, protease, and lipase] on GIT morphology and lipid absorption in suckling piglets. Both enzyme preparations, in low or high dose, were fed via a stomach tube twice a day for 7 d starting at 8 d of age and controls received vehicle, n = 6. The day after treatments ended, lipid absorption was tested after which pigs were euthanized and GIT was examined. Enzyme cocktails, irrespective of their origin, increased (P < 0.001) triglyceride level in blood. Enzyme preparation affected (P < 0.001) small intestinal mucosal thickness, villi length, and crypt depth and (P < 0.01) mitotic division of enterocytes. In addition, the external administration of pancreatic enzymes stimulated pancreatic growth as observed by increased (P < 0.05) mitotic division of pancreatic cells. The study revealed that pancreatic or pancreatic-like enzymes of microbial origin administrated in the early postperinatal period enhance GIT development and may be used to better prepare the GIT of piglets for milk use and weaning.

Administration of CREON® pancrelipase pellets via gastrostomy tube is feasible with no loss of gastric resistance or lipase activity: an in vitro study.

BACKGROUND AND OBJECTIVES: In clinical practice, the need sometimes arises to administer pancreatic enzyme replacement therapy via gastrostomy tube (G-tube) by mixing the pellets contained in the capsules with soft food. The objective of this study was to identify G-tubes that allow administration of pancrelipase gastro-resistant pellets without clogging, sticking, pellet damage or loss of enteric coating integrity. METHODS: In this in vitro study, CREON® (pancrelipase) Delayed-Release Capsules were opened and the pellets sprinkled onto a small amount of baby food of pH <4.5 (applesauce and bananas manufactured by both Gerber and Beech-Nut). The mixture was stirred gently and after 15 minutes poured into a 35 mL syringe and pushed slowly (~15 mL in 10-15 seconds) through a G-tube. Pellets were collected and the tube flushed with water. G-tubes were inspected visually for clogging/sticking and damage to pellets was assessed. If there was none with all four foods, pellet integrity (gastric resistance and lipase activity) was assessed by an in vitro dissolution method with a 2-hour gastric simulation step. The activity required to confirm integrity was ≥80% of actual US Pharmacopeia lipase activity per capsule. G-tubes initially tested were Kimberly-Clark MIC Bolus® size 14 French (Fr) and upwards and Kimberly-Clark MIC-KEY® 14 Fr and upwards. Following successful testing, assessment of Bard® Tri-Funnel 18 Fr and Bard® Button 18 Fr G-tubes was carried out. RESULTS: Based on the absence of clogging, sticking and visible damage to pellets, and the maintenance of pellet integrity, administration of CREON® pancrelipase pellets was feasible through the following G-tubes: Kimberly-Clark MIC Bolus® size 18 Fr, Kimberly-Clark MIC-KEY® 16 Fr, Bard® Tri-Funnel 18 Fr and Bard® Button 18 Fr. Lipase activity met the predetermined specification and was ≥90% for all four tubes and all four foods, with no differences versus untreated pellets (i.e. pellets not mixed with baby food or pushed through a G-tube). These data apply to all CREON® pancrelipase capsule formulations, regardless of their strength in lipase units, as pellet composition, size and quality are identical. CONCLUSION: CREON® pancrelipase pellets can be mixed with baby food of pH <4.5 and administered via the following G-tubes without clogging, sticking or visible pellet damage, and with no loss of gastric resistance or lipase activity: Kimberly-Clark MIC Bolus® size 18 Fr and larger, Kimberly-Clark MIC-KEY® 16 Fr and larger, Bard® Tri-Funnel 18 Fr and larger and Bard® Button 18 Fr and larger.

Pancreatic enzyme products: digesting the changes.

OBJECTIVE: To review the pharmacology, dosage regimens, efficacy, and safety of currently marketed pancreatic enzyme products (PEPs). DATA SOURCES: Studies were identified by PubMed (1966-January 2011), clinicaltrials.gov, fda.gov, and International Pharmaceutical Abstracts. Search terms included pancreatic enzyme, lipase, Creon, Zenpep, Pancreaze, and exocrine pancreatic insufficiency (EPI). STUDY SELECTION AND DATA EXTRACTION: All human studies evaluating the efficacy of currently approved or potential PEPs were reviewed. DATA SYNTHESIS: PEPs are composed of porcine lipase, amylase, and protease and are used in patients with EPI secondary to cystic fibrosis, chronic pancreatitis, and pancreatectomy. In 1938, PEPs were exempted from the Food, Drug, and Cosmetic Act of 1938 and never underwent a formal Food and Drug Administration (FDA) review process. In response to reports of treatment failures during product interchange, the FDA conducted a review of available PEP products. This review found a large variability of response between the unapproved PEP products, which resulted in the FDA requiring approval of all PEP products by April 2010. The 3 delayed-release, enteric-coated PEPs currently approved by the FDA (Creon, Zenpep, and Pancreaze) have demonstrated efficacy and safety in EPI secondary to cystic fibrosis. Creon has also demonstrated safety and efficacy in EPI secondary to chronic pancreatitis and pancreatectomy. Cost difference between the 3 products is minimal. Treatment-related adverse events in clinical studies for all PEPs were less than or similar to those with placebo. CONCLUSIONS: At this time, Creon is an appropriate first-line agent, as it has been approved for chronic pancreatitis, pancreatectomy, and cystic fibrosis.

Efficacy and tolerability of a new formulation of pancrelipase delayed-release capsules in children aged 7 to 11 years with exocrine pancreatic insufficiency and cystic fibrosis: a multicenter, randomized, double-blind, placebo-controlled, two-period crossover, superiority study.

BACKGROUND: Pancreatic enzyme replacement therapy (PERT) is essential for maintaining adequate nutrition in children with exocrine pancreatic insufficiency (EPI) due to cystic fibrosis (CF). The US Food and Drug Administration regulations now require all PERT products to undergo clinical efficacy and safety studies before they can be considered for marketing approval. OBJECTIVE: This study was conducted to compare the efficacy of a new formulation of pancrelipase (pancreatin) delayed-release 12,000-lipase unit capsules with placebo in children with EPI due to CF. METHODS: This was a multicenter, randomized, double-blind, placebo-controlled, 2-period crossover, superiority study of the new formulation of pancrelipase delayed-release 12,000-lipase unit capsules in children aged 7 to 11 years with CF and EPI. In each period, pancrelipase or identical placebo capsules were taken for 5 days. The primary outcome measure was the coefficient of fat absorption (CFA); secondary outcome measures were the coefficient of nitrogen absorption (CNA) and clinical symptoms. The latter were assessed based on patient-reported daily stool frequency, stool consistency (hard, formed/normal, soft, or watery), flatulence (none, mild, moderate, or severe), and abdominal pain (none, mild, moderate, or severe). Safety measures included vital signs, physical examinations, standard laboratory safety tests (hematology and biochemistry), and adverse events. RESULTS: Seventeen patients were randomized to treatment and 16 completed the study; 1 patient withdrew consent during the first treatment period and was not included in the efficacy analysis. Patients' median age was 8.0 years (range, 7-11 years); 12 patients (70.6%) were male. CFA values were significantly greater for pancrelipase compared with placebo, with least squares mean (SE) values of 82.8% (2.7%) and 47.4% (2.7%), respectively (P < 0.001). The results were similar for CNA, with mean values of 80.3% (3.2%) and 45.0% (3.2%) (P < 0.001). Pancrelipase treatment had significantly greater effects on CFA and CNA in patients with a placebo CFA <50% than in those with a placebo CFA >50% (both parameters, P < 0.001 and P = 0.008, respectively). Significant improvements in stool fat, weight, and nitrogen and a significant reduction in daily stool frequency were observed with pancrelipase compared with placebo (all, P < 0.001). Symptoms of EPI were less severe and remained relatively stable during pancrelipase treatment, but worsened slightly during receipt of placebo. Treatment-emergent adverse events were reported in 5 patients (29.4%) during receipt of pancrelipase and in 9 patients (56.3%) during receipt of placebo; these were predominantly gastrointestinal events. There were no discontinuations due to treatment-emergent adverse events and no serious adverse events. CONCLUSIONS: In this study in children with EPI due to CF, the new formulation of pancrelipase delayedrelease capsules was associated with improvements in CFA, CNA, stool properties, and EPI symptoms compared with placebo. Pancrelipase delayed-release capsules appeared to be well tolerated. ClinicalTrials.gov identifier: NCT00690820. (Clin Ther.

Pharmacokinetics of erlotinib for the treatment of high-grade glioma in a pediatric patient with cystic fibrosis: case report and review of the literature.

A 12-year-old girl with cystic fibrosis was diagnosed with a high-grade glioma after radiographic and biopsy results confirmed the primary intracranial lesion. She was treated with single-agent erlotinib during and after daily localized radiation therapy. Pharmacokinetic studies were conducted to assess the effect of pancreatic enzyme deficiency and intestinal malabsorption secondary to cystic fibrosis on the bioavailability of orally administered erlotinib, a lipophilic drug. Pharmacokinetic analysis of plasma samples from days 1 and 8 demonstrated that absorption of oral erlotinib was not affected by the patient's cystic fibrosis when the drug was given concomitantly with pancreatic enzyme replacement. When pediatric patients with cystic fibrosis are receiving erlotinib or other lipophilic oral drugs, continued supplementation of pancreatic enzymes is recommended, with therapeutic drug monitoring of plasma drug concentrations when feasible, and close observation for therapeutic responses and adverse effects.

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.

Assessment of the effectiveness of drug therapies on nutritional status in the elderly: "concerning a randomised, double-blind clinical study of the activity of pancreatic extracts and a placebo during the renutrition of elderly subjects suffering from protein caloric undernutrition".

AIMS: to study, versus placebo, the value of administering pancreatic extracts in elderly subjects suffering from denutrition. METHODS: 52 subjects over 70 years of age, living in the Toulouse region of France, were included in this study. Each subject was required to present with an impaired nutritional status of their food intake, anthropometric and laboratory markers. RESULTS: among the 52 patients included in the study, 26 received the placebo and 26 received a pancreatic extract (Créon 12,000). 88% of these patients were women and 12% were men, the mean age of patients was 87+/-6 years. The groups were comparable at entry into the study. Nutritional intake increased in the two groups. There was a non-significant increase in body weight in the treated group when compared with the placebo group. DISCUSSION: we think that in the future, it would be preferable to conduct studies in convalescent subjects, reducing the frequency of nutritional assessments (food intake on D0 and D90, to reduce interference with the patient's habits.