Ferulic acid improves glucose homeostasis by modulation of key diabetogenic activities and restoration of pancreatic architecture in diabetic rats.

There are increasing concerns on the rising cases of diabetes mellitus with type 2 diabetes (T2D) being of major interest as well as the cost of its treatment. Plant phenolic compounds are natural and potent antioxidants that have been widely reported for their antidiabetic activities properties, one of which is ferulic acid. The effect of ferulic acid (FA) on major diabetogenic activities and pancreatic architecture linked to T2D was investigated in T2D rats. T2D was induced in male Sprague-Dawley rats using the fructose-streptozotocin model. Diabetic rats were treated with FA at 150 or 300 mg/kg bodyweight (bw). Normal control consisted of rats administered with food and water, while diabetic control consisted of untreated diabetic rats. Metformin was used as the standard drug. The rats were humanely sacrificed after 5 weeks of treatment. Their blood, liver, and pancreas were collected for analysis. Total glycogen content and carbohydrate metabolic enzymes activities were analyzed in the liver, while the pancreas and serum from blood were analyzed for oxidative stress biomarkers, purinergic and cholinergic enzyme activities, and amylase and lipase activities. The pancreatic tissue was further subjected to microscopic and histological examinations. FA caused a significant (p < 0.05) decrease in blood glucose level, with concomitant increase in serum insulin level. Treatment with FA also led to elevated levels of GSH, HDL-c, SOD, and catalase activities, while concomitantly suppressing malondialdehyde, cholesterol, triglyceride, LDL-c, NO, ALT, AST, creatinine, urea, and uric acid levels, acetylcholinesterase, ATPase, ENTPDase, 5'-nucleotidase, lipase, glycogen phosphorylase, glucose-6-phosphatase, and fructose-1,6-biphosphatase activities. Histology analysis revealed an intact pancreatic morphology in FA-treated diabetic rats. While transmission electron microscopy (TEM) analysis revealed an intact pancreatic ultrastructure and increased number of insulin granules in ß-cells. Taken together, these results portray that the antidiabetic potentials of ferulic acid involves modulation of major diabetogenic activities and maintenance of the pancreatic ultrastructure architecture.

Cardiomyocyte p38 MAPKα suppresses a heart-adipose tissue-neutrophil crosstalk in heart failure development.

Although p38 MAP Kinase α (p38 MAPKα) is generally accepted to play a central role in the cardiac stress response, to date its function in maladaptive cardiac hypertrophy is still not unambiguously defined. To induce a pathological type of cardiac hypertrophy we infused angiotensin II (AngII) for 2 days via osmotic mini pumps in control and tamoxifen-inducible, cardiomyocyte (CM)-specific p38 MAPKα KO mice (iCMp38αKO) and assessed cardiac function by echocardiography, complemented by transcriptomic, histological, and immune cell analysis. AngII treatment after inactivation of p38 MAPKα in CM results in left ventricular (LV) dilatation within 48 h (EDV: BL: 83.8 ± 22.5 µl, 48 h AngII: 109.7 ± 14.6 µl) and an ectopic lipid deposition in cardiomyocytes, reflecting a metabolic dysfunction in pressure overload (PO). This was accompanied by a concerted downregulation of transcripts for oxidative phosphorylation, TCA cycle, and fatty acid metabolism. Cardiac inflammation involving neutrophils, macrophages, B- and T-cells was significantly enhanced. Inhibition of adipose tissue lipolysis by the small molecule inhibitor of adipocytetriglyceride lipase (ATGL) Atglistatin reduced cardiac lipid accumulation by 70% and neutrophil infiltration by 30% and went along with an improved cardiac function. Direct targeting of neutrophils by means of anti Ly6G-antibody administration in vivo led to a reduced LV dilation in iCMp38αKO mice and an improved systolic function (EF: 39.27 ± 14%). Thus, adipose tissue lipolysis and CM lipid accumulation augmented cardiac inflammation in iCMp38αKO mice. Neutrophils, in particular, triggered the rapid left ventricular dilatation. We provide the first evidence that p38 MAPKα acts as an essential switch in cardiac adaptation to PO by mitigating metabolic dysfunction and inflammation. Moreover, we identified a heart-adipose tissue-immune cell crosstalk, which might serve as new therapeutic target in cardiac pathologies.

Selenium and vitamin B6 cosupplementation improves dyslipidemia and fatty liver syndrome by SIRT1/SREBP-1c pathway in hyperlipidemic Sprague-Dawley rats induced by high-fat diet.

Previously, our group found that the dietary trace mineral element selenium and vitamin B6 (VitB6) alone was involved in lipid metabolism. However, the effects of selenium combined with VitB6 on hyperlipidemia and lipid metabolism have not been reported until now. We hypothesized that selenium and VitB6 cosupplementation would alleviate the hyperlipidemic and hepatic dysfunction and with minimum side effects in a Sprague-Dawley rat model of hyperlipidemia induced by a high-fat diet. Our results showed that selenium combined with VitB6 could improve dyslipidemia and displayed better in vivo hypocholesterolemic abilities at early intervention. Moreover, cosupplementation reduced atherogenic indexes (atherogenic index and atherogenic index of plasm) and the ratio of ApoB/ApoA1. The liver function index aspartate aminotransferase in serum was reduced, as was and total cholesterol, triacylglycerol, and low-density lipoprotein cholesterol in liver. The intervention also increased the levels of ApoA1 in serum and high-density lipoprotein cholesterol of liver. In addition, the combination of selenium and VitB6 decreased liver lipid deposition and alleviated steatosis, reduced adipocyte size of white adipose tissue, increased the activities of hepatic lipase and total lipase and the hepatic 3-hydroxy-3-methyl glutaryl coenzyme A reductase (HMGR) level, decreased the hepatic mRNA transcription of lipogenic and regulatory genes including Srebf1 and downstream fat synthesis-related enzymes (Acc and Fasn) and cholesterol synthesis speed limiting enzyme Hmgr, increased the mRNA abundance of Lcat and Cyp7a1, increased the protein expression of SIRT1 and PPARα, and up-regulated the protein expression of sterol regulatory element-binding protein 1c in the livers of hyperlipidemia rats. We first demonstrated that oral selenium and VitB6 cosupplementation exerted synergism in lowering blood and liver lipid profiles and antiatherosclerotic effects in hyperlipidemic rats by reducing endogenous cholesterol and lipid synthesis, enhancing the transport of cholesterol to hepatocytes and promoting fatty acid beta oxidation.

Pancreatic enzyme treatment in chronic pancreatitis: Quality of management and adherence to guidelines-A cross-sectional observational study.

OBJECTIVES: Pancreatic exocrine insufficiency (PEI) is a common complication in patients with chronic pancreatitis (CP), leading to increased morbidity and mortality if not treated adequately. Pancreatic enzyme replacement therapy|pancreas enzyme replacement therapy (PERT) is the cornerstone in treatment of patients with PEI. In the present study, we use data from the Scandinavian Baltic Pancreatic Club database to examine adherence of PERT according to United European Gastroenterology evidence-based guidelines treatment of CP. PATIENTS AND METHODS: Patients with definitive or probable CP according to M-ANNHEIM diagnostic criteria were included. We collected information on exposures, exocrine function, intake of pancreatic enzymes, and markers of nutrition. Fecal elastase <200 µg/g was defined as a marker for PEI. Enzyme replacement therapy of 100,000 lipase units or more was defined as adequate treatment. RESULTS: We included 1006 patients from 8 centers in five countries. Sixty-four percent of the patients were correctly treated. Twenty-five per cent of PEI patients were not taking enzymes at all, and 20% of PEI patients were undertreated with insufficient PERT doses according to the guidelines. Fourteen percent of patients with sufficient pancreatic function were receiving enzymes despite normal exocrine pancreatic function. There were center differences. Current smoking was associated with lack of treatment and alcohol abuse was associated with under-treatment. There were no associations between "no treatment" or "under-treatment" for underweight or vitamin D deficiency. CONCLUSION: In our CP expert centers, the adherence to guidelines for enzyme treatment is insufficient. Both patient factors and center differences have influence on treatment adherence.

Impact of the PNPLA3 genotype on the risk of hepatocellular carcinoma after hepatitis C virus eradication.

Almost all chronic hepatitis C (CHC) patients can achieve sustained virological response (SVR) with direct-acting antivirals. However, the development of hepatocellular carcinoma (HCC), even after the achievement of SVR, continues to be a serious problem. The aim of this study was to assess the association between host genetic factors and de novo HCC after SVR. This single-center, retrospective study consisted of 442 consecutive CHC patients without a history of HCC who achieved SVR through interferon (IFN)-based and IFN-free therapy. Predictive factors associated with the development of HCC were determined by the Cox proportional hazards model. The single-nucleotide polymorphism (SNP) genotyping data of 223 patients were available for analysis. Of the seven SNPs analyzed in this study, only the patatin-like phospholipase domain containing 3 (PNPLA3) rs738409 GG genotype was significantly, positively associated with the development of de novo HCC after adjusting for age, sex, and fibrosis status (adjusted hazard ratio [aHR] 5.66, p = 0.003). In multivariable analysis, age (aHR 1.05, p = 0.007), advanced fibrosis (aHR 2.69, p = 0.019), α-fetoprotein at post-12 weeks of treatment ≥7.0 ng/ml (aHR 3.85, p = 0.001), and PNPLA3 GG genotype (aHR 3.02, p = 0.004) were extracted as independent predictors of the development of de novo HCC. In conclusion, the PNPLA3 genotype was independently associated with the de novo HCC of CHC patients who achieved SVR. Such detailed knowledge of host genetic factors will be useful for HCC surveillance after HCV elimination.

Improvement of liver fibrosis, but not steatosis, after HCV eradication as assessment by MR-based imaging: Role of metabolic derangement and host genetic variants.

Significant liver fibrosis regression occurs after hepatitis C virus (HCV) therapy. However, the impact of direct-acting antivirals (DAAs) on steatosis is less clear. This study was aimed at evaluating serial fibrosis and steatosis alterations in patients with HCV genotype 1, who achieved sustained virological response (SVR). We enrolled 55 HCV mono-infected and 28 HCV/HIV co-infected patients receiving elbasvir/grazoprevir from a clinical trial. Fibrosis and steatosis were assessed at baseline, follow-up week-24 (FUw24) and week-72 (FUw72) by magnetic resonance elastography (MRE) and proton density fat fraction (PDFF), respectively. Patatin-like phospholipase domain-containing protein 3 (PNPLA3) rs738409, transmembrane six superfamily member 2 (TM6SF2) rs58542926 and membrane bound O-acyltransferase domain-containing 7 (MBOAT7) rs641738 polymorphisms were determined by allelic discrimination. Overall, mean MRE decreased significantly from baseline to FUw24 and FUw72. At FUw72, patients with baseline F2-F4 had higher rate of ≥30% MRE decline compared with individuals with baseline F0-F1 (30.2%vs.3.3%, P = 0.004). In multivariate analysis, significant fibrosis was associated with MRE reduction. The prevalence of steatosis (PDFF≥5.2%) at baseline was 21.7%. Compared to baseline, there were 17 (20.5%) patients with decreased PDFF values at FUw72 (<30%), while 23 (27.7%) patients had increased PDFF values (≥30%). Regarding the overall cohort, mean PDFF significantly increased from baseline to FUw72, and displayed positive correlation with body mass index (BMI) alteration. In multivariate analysis, the presence of diabetes, PNPLA3 CG+GG genotypes and increased BMI at FUw72 were significantly associated with progressive steatosis after SVR. Other genetic variants were not related to fibrosis and steatosis alteration. This study concluded that HCV eradication was associated with fibrosis improvement. However, progressive steatosis was observed in a proportion of patients, particularly among individuals with metabolic derangement and PNPLA3 variants. The combined clinical parameters and host genetic factors might allow a better individualized strategy in this sub-group of patients to alleviate progressive steatosis after HCV cure.

Kombucha drink enriched with sea grapes (Caulerpa racemosa) as potential functional beverage to contrast obesity: An in vivo and in vitro approach.

BACKGROUND AND AIMS: Obesity is currently a global issue and is a major cause of the metabolic disorder, including dyslipidemia. However, currently approved treatments have various limitations including serious side effects, numerous contraindications, and lack of acceptance. Caulerpa racemosa, also referred as Sea grapes, is a seaweed known for its various benefits. C. racemosa extract has the potential to improve lipid profile and role as an anti-obese agent. In order to maximize its health benefits, C. racemosa was made using kombucha drink as a carrier medium. This study aims to assess the effect of Sea grapes kombucha drink on lipase activity in vitro and lipid profile in vivo. METHODS: A lipase inhibition test was carried out by incubating Sea grapes kombucha drink compared with orlistat as the control in porcine pancreatic lipase and p-nitrophenyl butyrate in reaction buffer. A total of four groups were made, each containing 10 male swiss webster albino mice; group A received standard dry pellet diet as control, group B received cholesterol and fat-enriched diets (CFED), group C and D received CFED and 150 and 300 mg/kgBW of kombucha drink from Sea grapes respectively for 4 weeks. RESULTS: Sea grapes kombucha drink improved lipid profiles in the way of reducing total cholesterol, triglyceride, LDL, and increasing HDL levels compared to CFED and normal groups. The effect was more robust following the incrementing dose of the Sea grapes excluding total cholesterol. The lipase inhibitory activity of Sea grapes kombucha drink was similar to orlistat at a dose of 250 µg/mL, otherwise, orlistat was superior in the lower doses. CONCLUSIONS: Sea grapes kombucha drink treatment also induced weight loss and increased level of liver SOD. Kombucha drink from C. racemosa has good potential as a functional beverage with anti-obese and lipid improving activity.

Paeoniflorin Can Improve Acute Lung Injury Caused by Severe Acute Pancreatitis through Nrf2/ARE Pathway.

Objective: To evaluate the potential therapeutic effect of paeoniflorin on acute lung injury induced by severe acute pancreatitis (SAP) and to initially explore the possible protective mechanisms of paeoniflorin. Method: The SAP lung injury rat model was established by retrograde injection of 5% sodium taurocholate to the cholangiopancreatic duct. H&E staining was used to detect pathological changes in rat lung tissue. W/D ratio method, serum amylase (AMY), and lipase activity were used to assess the degree of lung injury in rats. Oxidation indicators such as LDH, MDA, and SOD in lung tissue were measured. Levels of inflammatory factors TNF-α, IL-6, and IL-10 were measured in bronchoalveolar lavage fluid (BALF). At the same time, Western blot was used to detect the expression of related proteins in the Nrf2/ARE signaling pathway. Results: In SAP rats, paeoniflorin treatment could significantly alleviate lung injury conditions such as pulmonary edema and inflammatory cell infiltration in lung tissue and reduce serum amylase and lipase activities. Paeoniflorin can reduce the content of LDH and MDA in lung tissue and increase the content of SOD. In addition, ELISA results showed that paeoniflorin could inhibit the levels of TNF-α and IL-6 in BALF and upregulate the levels of IL-10. Paeoniflorin could upregulate the expression of Nrf2/ARE signaling pathway proteins Cyt-Nrf2, HO-1, and NQO1 in lung tissue of SAP rats. Conclusion: Paeoniflorin may improve acute lung injury in rats with severe pancreatitis by inhibiting inflammation and oxidative stress response. These effects may be related to activating the Nrf2/ARE signaling pathway.

The Effect of Orlistat on Sterol Metabolism in Obese Patients.

Background: Orlistat, a reversible inhibitor of pancreatic and gastric lipase, is known to have anti-obesity and antioxidant properties. Cholesterol intermediates and metabolites have diverse and important functions in cardiovascular disease. Therefore, we aimed to evaluate the effect of orlistat on sterol metabolism in overweight and obese adults after weight loss during the intervention or weight loss at 12 weeks. Methods: A total of 51 (27 in the control group and 24 in the experimental group), patients with a BMI of 27 or greater were randomly assigned in a 1:1 ratio to receive either orlistat (120 mg) three times a day plus phentermine hydrochloride (37.5 mg) once daily or a placebo three times a day plus phentermine hydrochloride (37.5 mg) once daily. The primary study outcome was sterol metabolism. Results: The experimental group exhibited significantly decreased metabolic signatures of serum sterols, free cholesterol, sitosterol, 7α-hydroxycholesterol (7α-OHC), and 7ß-OHC at 12 weeks. The experimental group also exhibited significantly decreased metabolic ratios of sitosterol and 7α-OHC to cholesterol at 12 weeks. Regarding changes in sterol signatures from baseline to 6-month follow-up, free cholesterol, plant sterols, and cholesterol precursors tended to decrease with weight loss during the intervention and increase again as the weight was regained in both groups. Conclusion: Orlistat treatment improves oxysterol metabolism in overweight and obese adults. Our findings support that orlistat plays a crucial role in the process of endothelial dysfunction and atherosclerosis via oxysterol modulation.

Difference in Performance of EPI Pigs Fed Either Lipase-Predigested or Creon®-Supplemented Semielemental Diet.

Pancreatic enzyme replacement therapy (PERT) and fat predigestion are key in ensuring the optimal growth of patients with cystic fibrosis. Our study attempted to highlight differences between fat predigestion and conventional PERT on body composition of young pigs with exocrine pancreatic insufficiency (EPI). EPI and healthy pigs were fed with high-fat diet for six weeks. During the last two weeks of the study, all pigs received additional nocturnal alimentation with Peptamen AF (PAF) and were divided into three groups: H-healthy pigs receiving PAF; P-EPI pigs receiving PAF+PERT; and L-EPI pigs receiving PAF predigested with an immobilized microbial lipase. Additional nocturnal alimentation increased the body weight gain of EPI pigs with better efficacy in P pigs. Humerus length and area in pigs in groups L and P were lower than that observed in pigs in group H (p value 0.005-0.088). However, bone mineral density and strength were significantly higher in P and L as compared to that of H pigs (p value 0.0026-0.0739). The gut structure was improved in P pigs. The levels of neurospecific proteins measured in the brain were mainly affected in P and less in L pigs as compared to H pigs. The beneficial effects of the nocturnal feeding with the semielemental diet in the prevention of EPI pigs' growth/development retardation are differently modified by PERT or fat predigestion in terms of growth, bone properties, neurospecific protein distribution, and gut structure.

Malnutrition after pancreatic enzyme replacement therapy in chronic pancreatitis: Risk factors in real world practice.

BACKGROUND: RCTs that have shown improvement in coefficient of fat absorption with pancreatic enzyme replacement therapy (PERT) have seldom evaluated the impact on overall nutritional status. OBJECTIVE: In this study we evaluated factors responsible for persistence of malnutrition after PERT. METHODS: In this cross-sectional observational study, patients were enrolled based on predefined enrolment criteria. Patients were divided into those taking PERT regularly (Group A), irregularly (Group B) and not taking (Group C) for at least 3 months. Comprehensive evaluation of anthropometric measurements, nutritional assessment and dietary intake was performed. Malnutrition was measured using the Subjective Global Assessment (SGA) tool. Relationship between PERT status, dietary intake and nutritional status were evaluated using standard statistical methods. Logistic regression was performed to identify factors associated with persistence of malnutrition after PERT. RESULTS: 377 patients with CP and 50 controls were included. 95 (25.2%) patients with CP were in Group A, 106 (28.1%) in Group B and 176 (46.7%) in Group C. 130 (34.5%) patients were malnourished, of which 76 (58.5%) were continuing PERT. There were no differences in clinical and biochemical nutritional markers between Groups A, B, and C. Calorie deficit and daily intake of calorie, protein, carbohydrates and fats were not different between those with and without PERT, but was significantly less in those with malnutrition. Logistic regression demonstrated inadequate dietary intake as independent risk factor for persistence of malnutrition. CONCLUSION: Even though PERT is effective in PEI, comprehensive nutritional assessment, personalized nutritional counselling and therapy along with PERT is mandatory.

Study of the gastrointestinal bioavailability of a pancreatic extract product (Zenpep) in chronic pancreatitis patients with exocrine pancreatic insufficiency.

INTRODUCTION: The Food and Drug Administration in 2006 required that all pancreatic enzyme products demonstrate bioavailability of lipase, amylase, and protease in the proximal small intestine. METHODS: In this phase I open-label, randomized, crossover trial, 17 adult chronic pancreatitis (CP) patients with severe exocrine pancreatic insufficiency (EPI) underwent two separate gastroduodenal perfusion procedures (Dreiling tube suctioning and [14C]-PEG instillation by an attached Dobhoff tube in the duodenal bulb). Patients received Ensure Plus® alone and Ensure Plus with Zenpep (75,000 USP lipase units) in random order. The bioavailability of Zenpep was estimated by comparing the recovery of lipase, amylase, chymotrypsin activity in two treatment conditions. 14C-PEG was used to correct duodenal aspirates volume. The primary efficacy endpoint was lipase delivery in the duodenum after Zenpep administration under fed conditions. Secondary efficacy endpoints included chymotrypsin and amylase delivery, serum CCK levels, and measuring duodenal and gastric pH. RESULTS: Zenpep administration with a test meal was associated with significant increase in duodenal aspiration of lipase (p = 0.046), chymotrypsin (p = 0.008), and amylase (p = 0.001), compared to the test meal alone, indicating release of enzymes to the duodenum. Lipase delivery was higher in the pH subpopulation (the efficacy population with acid hypersecretors excluded) (p = 0.01). Recovery of [14C]-PEG was 61%. Zenpep was generally well tolerated. All adverse events were mild and transient. CONCLUSIONS: In CP patients with severe EPI, lipase, chymotrypsin and amylase were released rapidly into the duodenum after ingestion of Zenpep plus meal compared to meals alone. Results also reflected the known pH threshold for enzyme release from enteric coated products.

Clinical validation of an evidence-based method to adjust Pancreatic Enzyme Replacement Therapy through a prospective interventional study in paediatric patients with Cystic Fibrosis.

BACKGROUND: A method to adjust Pancreatic Enzyme Replacement Therapy in Cystic Fibrosis is not currently available. OBJECTIVES: To assess the in vivo efficacy of a method to adjust the dose of enzymatic supplement in CF extrapolated from previous in vitro digestion studies (theoretical optimal dose, TOD). Secondly, to assess how individual patient characteristics influence the expected coefficient of fat absorption (CFA) and thus to identify an individual correction factor to improve TOD. METHODS: A prospective interventional study in 43 paediatric patients with CF from 5 European centres. They followed a 24h fixed diet with the theoretical optimal dose for each meal. Faecal collection was carried out between colorimetric markers in order to include all the faeces corresponding to the fixed diet. Beta regression models were applied to assess the associations of individual patient characteristics with the CFA. RESULTS: Median CFA was 90% (84, 94% 1st, 3rd Q.) with no significant differences among centres. Intestinal transit time was positively associated with CFA (p = 0.007), but no statistical associations were found with and age, gender, phenotype or BMI. Regression model showed no improvement of the in vitro predicted theoretical optimal dose when taking individual patient characteristics into account. CONCLUSION: Strict adherence to the theoretical optimal dose of enzymatic supplement for a prescribed meal, led to median CFA levels at the clinical target of 90% with a low variability between patients. The proposed method can be considered as a first approach for an evidence-based method in PERT dosing based on food characteristics. Results have to be confirmed in free dietary settings.

A first approach for an evidence-based in vitro digestion method to adjust pancreatic enzyme replacement therapy in cystic fibrosis.

BACKGROUND: Patients with cystic fibrosis have to take enzymatic supplements to allow for food digestion. However, an evidence-based method to adjust Pancreatic Enzyme Replacement Therapy (PERT) is inexistent, and lipid content of meals is used as a rough criterion. OBJECTIVE: In this study, an in vitro digestion model was set up to determine the theoretical optimal dose (TOD) of enzymatic supplement for a selection of foods, which is the dose that allows for maximum lipolysis extent. METHODS: A static in vitro digestion model was applied to simulate digestion of eight foods covering a wide range of lipid contents. First, the dose of the enzymatic supplement was fixed at 2000 lipase units per gram of fat (LU/g fat) using intestinal pH and bile salt concentration as variables. Second, intestinal pH and bile salt concentrations were fixed and the variable was the dose of the enzymatic supplement. Lipolysis extent was determined by measuring the free fatty acids released from initial triglycerides content of foods after digestion. Results in terms of percentage of lipolysis extent were fitted into a linear-mixed segmented model and the deducted equations were used to predict the TOD to reach 90% of lipolysis in every food. In addition, the effect of intestinal pH and bile salt concentration were investigated. RESULTS: The predictive equations obtained for the assessed foods showed that lipolysis was not only dependent on the dose of the enzyme supplement or the lipid content. Moreover, intestinal pH and bile salt concentration had significant effects on lipolysis. Therefore an evidence-based model can be developed taking into account these variables. CONCLUSIONS: Depending on food characteristics, a specific TOD should be assigned to achieve an optimal digestion extent. This work represents a first step towards an evidence-based method for PERT dosing, which will be applied in an in vivo setting to validate its efficacy.

Pancreatic enzyme replacement therapy (PERT) in children with persistent diarrhea: avoidance of elemental diet need, accessibility and costs.

BACKGROUND AND OBJECTIVES: Persistent diarrhea has been proven to cause pancreatic exocrine insufficiency, due to decreased stimulation to the pancreas caused by prolonged mucosal injury. Pancreatic enzyme replacement therapy (PERT) given in conjunction to regular treatment is thought to be beneficial in replacing this pancreatic enzyme deficiency, avoiding the need of elemental diet. This study aims to evaluate the benefit of PERT in chil-dren with persistent diarrhea. METHODS AND STUDY DESIGN: This is a randomized, two double-blind parallel group, placebo-controlled clinical trial to evaluate the effects of pancreatic enzyme supplementation in persistent diar-rhea. Children age 6-60 months were recruited from pediatric inpatient and outpatient units of five hospitals in Jakarta. Subjects was randomly assigned to either pancreatic enzyme 8371 USP unit of lipase or placebo, 3 times daily for 1 month, as an adjunctive therapy to standard treatment. Subjects were then reevaluated at 2 weeks and 4 weeks interval after administration of enzyme or placebo. Variables observed were length of diarrhea after the start of intervention, change in serum prealbumin, and change in FE-1 between week 0 and week 4. RESULTS: Pan-creatic enzyme supplementation shortens the length of diarrhea by 7 days in the intervention group compared to placebo (p=0.019). Serum prealbumin and FE-1 shows trend that favors the intervention group, although not sta-tistically significant (p>0.05). CONCLUSION: PERT is clinically effective in reducing the length of diarrhea, thus minimizing the need, accessibility and costs of an elemental diet.

Russian consensus on exo- and endocrine pancreatic insufficiency after surgical treatment.

The Russian consensus on exo- and endocrine pancreatic insufficiency after surgical treatment was prepared on the initiative of the Russian "Pancreatic Club" on the Delphi method. His goal was to clarify and consolidate the opinions of specialists on the most relevant issues of diagnosis and treatment of exo- and endocrine insufficiency after surgical interventions on the pancreas. An interdisciplinary approach is provided by the participation of leading gastroenterologists and surgeons.

Exocrine pancreatic insufficiency is common in people living with HIV on effective antiretroviral therapy.

OBJECTIVES: The primary aim of this prospective study was to determine the prevalence of exocrine pancreatic insufficiency (EPI) in people living with HIV (PLHIV) on suppressive antiretroviral therapy (ART). METHODS: PLHIV ≥18 years of age and on ART for >6 months and with HIV RNA <50 copies/mL plasma were included. Faecal elastase-1 measurement was performed on a single stool sample, serum markers of malnutrition were collected, and participants answered a short questionnaire about gastrointestinal symptoms. Participants with EPI and symptoms were offered pancreatic enzyme replacement therapy (PERT), and the result of this therapy was also evaluated. RESULTS: Of 100 participants, 32% had EPI (faecal elastase-1 < 200 µg/g) and 20% severe EPI (faecal elastase-1 < 100 µg/g). We did not find any correlation between self-reported symptoms and degree of EPI. Twelve out of the 32 participants with EPI accepted to start PERT. Nine out of 12 (75%) reported improvement or became asymptomatic within 14 days. CONCLUSION: EPI is common in PLHIV on effective ART. We could, however, not find a correlation between gastrointestinal symptoms and the presence of EPI. Assessment of pancreatic exocrine function could be considered in PLHIV particularly in those with gastrointestinal discomfort, since there is a possible gain in treating them with relief of symptoms and improved quality of life. The effects of PERT in PLHIV on effective ART need further study.

Purification and characterization of recombinant human bile salt-stimulated lipase expressed in milk of transgenic cloned cows.

Bile salt-stimulated lipase (BSSL) is a lipolytic digestive enzyme with broad substrate specificity secreted from exocrine pancreas into the intestinal lumen in all species and from the lactating mammary gland into the milk of some species, notably humans but not cows. BSSL in breast milk facilitates digestion and absorption of milk fat and promotes growth of small for gestational age preterm infants. Thus, purified recombinant human BSSL (rhBSSL) can be used for treatment of patients with fat malabsorption and expressing rhBSSL in the milk of transgenic cloned cows would therefore be a mean to meet a medical need. In the present study, a vector pBAC-hLF-hBSSL was constructed, which efficiently expressed active rhBSSL in milk of transgenic cloned cows to a concentration of 9.8 mg/ml. The rhBSSL purified from cow milk had the same enzymatic activity, N-terminal amino acid sequence, amino acid composition and isoelectric point and similar physicochemical characteristics as human native BSSL. Our study supports the use of transgenic cattle for the cost-competitive, large-scale production of therapeutic rhBSSL.

Safety and Efficacy of a Novel Microbial Lipase in Patients with Exocrine Pancreatic Insufficiency due to Cystic Fibrosis: A Randomized Controlled Clinical Trial.

OBJECTIVE: To evaluate the safety and efficacy of a novel microbial lipase (NM-BL) in a liquid formulation for the treatment of exocrine pancreatic insufficiency (EPI) in patients with cystic fibrosis (CF) in a phase IIa proof-of-concept study. STUDY DESIGN: We conducted a double-blind, randomized, placebo controlled crossover study in patients with cystic fibrosis and exocrine pancreatic insufficiency. Adolescent and adult patients with CF were randomized to receive NM-BL or placebo for 1 week as replacement for their usual pancreatic enzyme formulation. They were subsequently crossed-over to the alternate study treatment. The coefficient of fat absorption was evaluated as the primary endpoint. Symptoms and adverse events were evaluated as secondary endpoints. RESULTS: A total of 35 patients were randomized into the study and 22 patients completed both treatment periods. During treatment with NM-BL, the coefficient of fat absorption was significantly greater (72.7%) compared with placebo (53.8%) with a difference between groups of 18.8% (P < .001). Subjective assessment of stool fat and stool consistency also improved under treatment with NM-BL. Adverse events were mostly gastrointestinal in nature and were more common in the group receiving NM-BL. CONCLUSIONS: Currently available pancreatic enzyme products are limited because of the lack of liquid formulations and being largely porcine based. The novel microbial lipase NM-BL was safe and effective in this short term trial. The trial provided clinical proof-of-concept for this novel microbial lipase as a treatment for EPI in CF. A larger phase 2 dose ranging trial is warranted. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01710644.