Early treatment efficacy of S-adenosylmethionine in patients with intrahepatic cholestasis: A systematic review.

BACKGROUND: S-adenosylmethionine (AdoMet) is a metabolically pleiotropic molecule used to treat intrahepatic cholestasis (IHC) and chronic liver diseases. While the efficacy of AdoMet has been demonstrated previously, it has not been systematically investigated within the early weeks of treatment. AIM: To systematically review the early treatment efficacy of AdoMet in adult patients with IHC. METHODS: Studies reporting the efficacy of intravenous, intramuscular, or oral forms of AdoMet within 8 wk of treatment initiation were considered; three randomized and six non-randomized studies were eligible for inclusion (PROSPERO registration number CRD42018090936). Of the three randomized studies, two were double-blind and placebo-controlled, and one was comparator-controlled with unclear blinding and a relatively high risk of bias. Mean serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), and gamma-glutamyl transferase (γGT) following AdoMet treatment vs placebo, comparator, or baseline were summarized to determine differences in liver enzymes. Changes in patient-reported clinical symptoms of cholestasis were also summarized. RESULTS: Both placebo-controlled randomized studies reported significant reductions in serum ALT levels with AdoMet vs placebo within 2 wk. One of these also reported significant ALP reductions, and the other reported significant AST and γGT reductions within 2 wk. The comparator-controlled randomized study, which had a number of notable limitations, reported significant reductions in serum ALT and AST levels with AdoMet vs potassium magnesium aspartate within 4 wk, but not within2 wk. All of the non-randomized studies (4/4) that investigated ALT, AST, ALP and/or γGT reported significant reductions in at least two of these parameters within 2 wk. Of the five studies that evaluated fatigue, reductions were observed within 2 wk in one randomized and two non-randomized studies. The remaining two non-randomized studies reported improvements in fatigue within 6 and 8 wk. Of the four studies reporting symptoms of depression, two non-randomized studies observed improvements within 2 wk and the other two observed improvements within 17 d and 8 wk. CONCLUSION: Data from both randomized and non-randomized studies suggest that AdoMet improves some biochemical liver parameters and symptoms of cholestasis within 2 wk, with further improvements observed in some studies after 4 and 8 wk of treatment.

Open-label study of ademetionine for the treatment of intrahepatic cholestasis associated with alcoholic liver disease.

BACKGROUND: The effect of oral and/or parenteral ademetionine (500 mg intravenous [IV] and tablet formulation) on clinical symptoms and biochemical markers of intrahepatic cholestasis (IHC) was investigated in subjects with alcoholic liver disease (ALD) and compensated liver function. METHODS: Prospective, multicenter, open-label study consisting of a screening period and an 8-week treatment period and performed in subjects (18-75 years) with compensated ALD and confirmed IHC. Subjects with a baseline serum conjugated bilirubin value above normal range were initially treated with IV ademetionine for two weeks (500-800 mg daily) and continued with oral ademetionine 1500 mg daily for a further six weeks. Subjects with a baseline serum conjugated bilirubin value within normal range were treated with oral ademetionine for eight weeks. RESULTS: A total of 72 subjects were treated; 41 initially with IV ademetionine and 31 with oral ademetionine. Clinical symptoms status improved from baseline to end of treatment with an increase in the proportion of subjects with no symptoms. Ademetionine showed significant improvements in primary efficacy parameters alkaline phosphatase (ALP) and γ-glutamyltransferase (γGT) (P<0.0001). Although decreases of ALP were higher for subjects initially treated with IV ademetionine, these subjects also had higher baseline values. No safety concerns with ademetionine arose with respect to the severity or frequency of adverse events (AEs) during the treatment period, laboratory parameters, and vital signs. CONCLUSIONS: Administration of oral or IV/oral ademetionine step-therapy for 8 weeks to subjects with IHC due to ALD was safe and provided a significant improvement of disease burden.

Efficacy and Safety of Pancrelipase/Pancreatin in Patients With Exocrine Pancreatic Insufficiency and a Medical History of Diabetes Mellitus.

OBJECTIVES: The aim of this study was to perform exploratory analyses of the efficacy and safety of pancrelipase delayed-release capsules (Creon) in patients with exocrine pancreatic insufficiency (EPI) with (n = 36) and without (n = 18) concurrent diabetes mellitus (DM). METHODS: This was a retrospective, post hoc, subgroup (±DM) analysis of a double-blind, randomized, placebo-controlled trial of pancrelipase in patients with EPI due to chronic pancreatitis or pancreatectomy (total or partial). After a 5-day placebo run-in period (baseline), patients were randomized to pancrelipase (72,000 lipase units/meal, 36,000/snack) or placebo for 7 days. Outcomes included changes in coefficients of fat absorption (CFA) and nitrogen absorption (CNA) from baseline to the end of the double-blind period. RESULTS: Mean changes in nutrient absorption were greater with pancrelipase versus placebo in patients with DM (CFA, 36.0% vs 7.5%, P < 0.0001; CNA, 33.4% vs 3.7%, P = 0.0002) and without DM (CFA, 25.2% vs 12.3%, P = 0.0326; CNA, 39.1% vs 17.6%, P = 0.1187). Diabetes mellitus was not significantly associated with outcomes for CFA (P = 0.0802) and CNA (P = 0.2934). Incidences of adverse events, including hypoglycemia and hyperglycemia, were similar in the pancrelipase and placebo arms. CONCLUSIONS: Pancrelipase improved fat and protein absorption in patients with EPI due to chronic pancreatitis or pancreatectomy, with or without DM, and matched the safety profile previously reported.

Safety and efficacy of Creon® micro in children with exocrine pancreatic insufficiency due to cystic fibrosis.

BACKGROUND: Pancreatic enzyme replacement therapy is the foundation of nutritional management for exocrine pancreatic insufficiency (EPI). METHODS: A 3-month, open-label, multicentre study in Russia assessing safety, efficacy, and ease-of-use of Creon(®) Micro (5000 lipase units/spoon) in children aged 1 month to <4 years with EPI due to cystic fibrosis. Efficacy assessments included growth parameters. RESULTS: All 40 subjects (mean age 26.5 months) completed treatment. Adverse events occurred in 40% of the subjects (most commonly respiratory tract infection [15%], frequent bowel movements [8%], rhinitis, stomatitis, nasopharyngitis, and diarrhoea [all 5%]), none were serious or led to discontinuation. After 3 months, mean±SD increases from baseline z-scores were height/length-for-age 0.13±0.48, weight-for-age 0.20±0.39, and BMI-for-age 0.29±0.65. Treatment was rated 'easy' to administer by 95% caregivers and acceptance 'good'/'very good' by 90%. CONCLUSIONS: Creon Micro was well tolerated. Growth development parameters increased over the 3-month treatment period. Treatment was considered easy to use and acceptance was good.

The effect of oral pancreatic enzyme supplementation on the course and outcome of acute pancreatitis: a randomized, double-blind parallel-group study.

CONTEXT: Pancreatic exocrine insufficiency is a significant problem after acute pancreatitis. OBJECTIVE: To evaluate whether oral pancreatic enzyme supplementation improves the recovery of pancreatic exocrine function and to explore the efficacy, safety and tolerability of pancreatic enzyme supplementation in patients during the refeeding period after acute pancreatitis. DESIGN: Prospective double-blind, placebo controlled, randomized study. PATIENTS: The sudy included 56 patients with acute pancreatitis. MAIN OUTCOME MEASURES: Primary efficacy variable was recovery from pancreatic exocrine insufficiency. Secondary objectives were body weight, abdominal pain, course of APACHE II score, patient's symptoms and quality of life. RESULTS: Twenty of the 56 patients showed low fecal elastase values indicating pancreatic exocrine insufficiency after acute pancreatitis. Median time to recovery from exocrine pancreatic insufficiency was 14 days in the enzyme supplementation group and 23 days in the placebo group but overall differences for primary and all but one secondary endpoint did not reach statistical significance. However, a positive tendency in favour of enzyme supplementation was found for quality of life parameters (FACT-Pa) in all subscores. There were no relevant differences between placebo and oral pancreatic enzyme supplementation detected with respect to safety and tolerability. CONCLUSION: Enzyme supplementation positively effects the course of acute pancreatitis if administered during the early refeeding phase after acute pancreatitis. There is evidence that oral pancreatic enzyme supplementation has a positive impact on the course of the disease and the global health status (less weight loss, less flatulence, improved quality of life). Oral pancreatic enzyme supplementation was safely administered and can be added to the treatment regimen of patients in a refeeding status after severe acute pancreatitis.

Retrospective analysis to investigate the effect of concomitant use of gastric acid-suppressing drugs on the efficacy and safety of pancrelipase/pancreatin (CREON®) in patients with pancreatic exocrine insufficiency.

OBJECTIVES: This study aimed to determine whether the efficacy of pancrelipase/pancreatin (CREON®) may be affected by the concomitant use of proton pump inhibitors (PPIs)/histamine-2 receptor antagonists (H2RAs). METHODS: An analysis of integrated data from all clinical trials of pancrelipase/pancreatin supported by Abbott (34 trials, 1142 unique subjects) was conducted. All trials included patients with pancreatic exocrine insufficiency, and most cases were associated with cystic fibrosis, chronic pancreatitis, or pancreatic surgery. Study designs included single and double blind, open label, parallel group, and crossover, and most were randomized. The primary end point for this analysis was on-treatment coefficient of fat absorption (CFA) according to concomitant PPI/H2RA use (yes/no). RESULTS: There were no meaningful differences in mean CFA values at the end of pancrelipase/pancreatin treatment by concomitant PPI/H2RA use: yes (n = 254), 82.7% versus no (n = 449), 84.2%. No meaningful differences were observed when the same analysis was carried out by disease type (cystic fibrosis, chronic pancreatitis, and pancreatic surgery). CONCLUSIONS: This analysis of data from clinical trials enrolling patients with pancreatic exocrine insufficiency suggests that the efficacy of pancrelipase/pancreatin is not affected by concomitant PPI/H2RA use, as determined by end-of-treatment CFA values, and supports the treatment guidelines' recommendation that acid suppression is not routinely required with pancreatic enzyme replacement therapy.

Evaluation of stool collections to measure efficacy of PERT in subjects with exocrine pancreatic insufficiency.

OBJECTIVE: The standard measure of pancreatic enzyme replacement therapy (PERT) efficacy in treating exocrine pancreatic insufficiency (EPI) is the coefficient of fat absorption (CFA). CFA measurement involves 72-hour stool collection, which presents a logistical challenge because, although the test may be performed on an outpatient basis in clinical practice, hospitalization is needed if assurance of complete collection and 100% compliance is required, for example, in controlled situations such as clinical trials. Our aim was to investigate sparse stool sample collection as an alternative to complete 72-hour collection for measurement of stool fat in subjects with EPI. SUBJECTS AND METHODS: Prospective data analysis from a previously published, double-blind, randomized, placebo-controlled, 2-period crossover trial in subjects ages 7 to 11 years with EPI caused by cystic fibrosis. Percentage fat (PF) data from sparse stool samples were compared with 72-hour CFA values as a dichotomous variable (<80%, ≥80%), with evaluation of sensitivity, specificity, and positive predictive value. Area under the curve values were obtained from receiver operating characteristic plots of sensitivity versus 1-specificity. RESULTS: Twelve subjects provided samples for this analysis. Multiple-sample PF values ≤30% were greatly predictive for CFA values ≥80%, as shown by positive predictive value, sensitivity, and specificity values ≥0.89, with high accuracy (AUCs ≥0.93). CONCLUSIONS: Sparse stool sampling for PF analysis appears to be a valid, practical alternative to 72-hour CFA determination and has potential as a screening tool in clinical practice to identify both suboptimal dosing in subjects with EPI receiving PERT and substantial fat malabsorption in subjects not receiving PERT.

A 2-year post-authorization safety study of high-strength pancreatic enzyme replacement therapy (pancreatin 40,000) in cystic fibrosis.

OBJECTIVE: At the request of the Medicines and Healthcare Regulatory Agency and in agreement with the appropriate authorities, an observational, multi-center, non-interventional, post-authorization safety study of high-strength pancreatic enzymes was conducted. RESEARCH DESIGN AND METHODS: Patients with exocrine pancreatic insufficiency due to cystic fibrosis (CF) who had previously taken high doses of pancreatic enzymes received pancreatin 40,000 capsules (Creon 40,000 Minimicrospheres, Abbott GmbH, Hanover, Germany) as part of their normal treatment for up to 2 years. Initial doses were calculated to match previous established doses in lipase units, with adjustment if required. MAIN OUTCOME MEASURES: Safety focused on serious suspected adverse drug reactions. Maldigestion symptoms and body weight were also monitored. Patients were managed according to general guidelines common to all major CF units in the UK, although minor variations were expected. The coefficient of fat absorption was not assessed as this was a safety rather than an efficacy study. RESULTS: Sixty-four patients were enrolled at nine UK centers. Two deaths occurred during the study, which were considered unrelated to therapy by investigators. There were no further serious suspected adverse drug reactions related to pancreatin 40,000 and no cases of fibrosing colonopathy. Daily lipase doses were reduced by 11% after switching to pancreatin 40,000. Maldigestion symptoms improved and mean body weight increased from baseline to last observation (mean + 6.1 kg in patients < 18 years old). CONCLUSIONS: No safety concerns were identified with pancreatin 40,000 therapy for up to 2 years. Daily lipase doses were not increased when switching to pancreatin 40,000.

Pancrelipase delayed-release capsules (CREON) for exocrine pancreatic insufficiency due to chronic pancreatitis or pancreatic surgery: A double-blind randomized trial.

OBJECTIVES: Pancreatic-enzyme replacement therapy (PERT) is the standard of care to prevent maldigestion, malnutrition, and excessive weight loss in patients with exocrine pancreatic insufficiency (EPI) due to chronic pancreatitis (CP) or pancreatic surgery (PS). Our objective was to assess the efficacy and safety of a new formulation of pancrelipase (pancreatin) delayed-release 12,000-lipase unit capsules (CREON) in patients with EPI due to CP or PS. METHODS: This was a double-blind, randomized, multicountry, placebo-controlled, parallel-group trial enrolling patients ≥18 years old with confirmed EPI due to CP or PS conducted in clinical research centers or hospitals. After a 5-day placebo run-in period (baseline), patients were randomized to pancrelipase (72,000 lipase units per meal; 36,000 per snack) or placebo for 7 days. All patients received an individually designed diet to provide at least 100 g of fat per day. The primary efficacy measure was the change in coefficient of fat absorption (CFA) from baseline to end of the double-blind period, analyzed using non-parametric analysis of covariance. Secondary outcomes included the coefficient of nitrogen absorption (CNA), clinical symptoms, and safety parameters. RESULTS: In total, 25 patients (median age of 54 years, 76% male) received pancrelipase and 29 patients (median age of 50 years, 69% male) received placebo. Th e mean ± s.d. change from baseline in CFA was significantly greater with pancrelipase vs. placebo: 31.9 ± 18.6 vs. 8.7 ± 12.4 % ( P < 0.0001) [corrected]. Similarly, the mean ± s.d. change from baseline in CNA was greater for pancrelipase vs. placebo: 35.2 ± 29.1 vs. 8.9 ± 28.0 % ( P = 0.0005) [corrected].Greater improvements from baseline in stool frequency, stool consistency, abdominal pain, and flatulence were observed with pancrelipase vs. placebo. Treatment-emergent adverse events (TEAEs) were reported in five patients (20.0%) in the pancrelipase group and in six (20.7%) in the placebo group; the most common were gastrointestinal (GI) events and metabolism/nutrition disorders. There were no treatment discontinuations due to TEAEs. CONCLUSIONS: Pancrelipase delayed-release 12,000-lipase unit capsules were effective in treating fat and nitrogen maldigestion with a TEAE rate similar to that of placebo in patients with EPI due to CP or PS.

Does the pancreas really produce much more lipase than required for fat digestion?

Thirty years ago, it was reported that a linear relationship does not exist between the amounts of human pancreatic lipase secreted in chronic pancreatitis and the degree of steatorrhea, which was considered to appear only after more than 90% of the pancreatic secretory capacity had been lost. From these observations, it was generally thought that the lipolytic potential of the pancreas is much higher than required. In recent years, however, it has been noted that: 1) the level of inhibition of digestive lipases and gastrointestinal lipolysis by the lipase inhibitor orlistat were almost linearly correlated with the amount of excreted fat; 2) in minipigs with experimentally-induced pancreatic exocrine insufficiency, the amounts of enteric-coated pancreatic extracts needed for restoring fat digestion to normal levels were estimated to be much higher than those usually administered; 3) human pancreatic lipase specific activity on meal triglycerides is 3 orders of magnitude lower than the very high specific activity usually measured under experimental in vitro conditions which are far from physiological conditions; 4) in patients with reduced human pancreatic lipase secretion, gastric lipase plays a significant role in fat digestion. This last observation might explain the absence of a linear relationship between human pancreatic lipase secretion in chronic pancreatitis and steatorrhea. From the low specific activity displayed by human pancreatic lipase on meal triglycerides, one can better understand why more lipase than expected is needed, why fat digestion lasts for more than a few minutes and, finally, why there is not such an excess secretory capacity for lipase as had been previously thought.

Quantitative study of digestive enzyme secretion and gastrointestinal lipolysis in chronic pancreatitis.

BACKGROUND & AIMS: The contribution of human gastric lipase (HGL) to the overall lipolysis process in chronic pancreatitis (CP), as well as the relative pancreatic enzyme levels, rarely are addressed. This study was designed to quantify pancreatic and extrapancreatic enzyme output, activity, and stability in CP patients vs. healthy volunteers. METHODS: Healthy volunteers (n = 6), mild CP patients (n = 5), and severe (n = 7) CP patients were intubated with gastric and duodenal tubes before the administration of a test meal. HGL, human pancreatic lipase (HPL), chymotrypsin, and amylase concentrations were assessed in gastric and duodenal samples by measuring the respective enzymatic activities. Intragastric and overall lipolysis levels at the angle of Treitz were estimated based on quantitative analysis of lipolysis products. Similar analyses were performed on duodenal contents incubated ex vivo for studying enzyme stability and evolution of lipolysis. RESULTS: Although HPL, chymotrypsin, and amylase outputs all were extremely low, HGL outputs in patients with severe CP (46.8 +/- 31.0 mg) were 3-4-fold higher than in healthy controls (13.3 +/- 13.8 mg). Intragastric lipolysis did not increase, however, in patients with severe CP, probably because of the rapid decrease in the pH level of the gastric contents caused by a higher gastric acid secretion. HGL remains active and highly stable in the acidic duodenal contents of CP patients, and, overall, can achieve a significant lipolysis of the dietary triglycerides (30% of the control values) in the absence of HPL. CONCLUSIONS: Although all pancreatic enzyme secretions are simultaneously reduced in severe CP, gastric lipase can compensate partly for the loss of pancreatic lipase but not normalize overall lipolytic activity.