Lipase Units Research Articles

Dose optimization of pancreatic enzyme replacement therapy is essential to mitigate muscle loss in patients with advanced pancreatic cancer and exocrine pancreatic insufficiency

Background & AimsExocrine pancreatic insufficiency (EPI) contributes to malnutrition, marked by muscle loss during chemotherapy for advanced pancreatic cancer (aPC). Pancreatic enzyme replacement therapy (PERT) is recommended for patients with EPI; however, it’s efficacy for attenuating muscle loss has not been demonstrated. We aimed to delineate the impact of PERT dose on muscle loss using a 7-year population-based cohort with aPC who were provided PERT at the discretion of their oncologist or dietitian according to clinical indications of EPI. MethodsAll patients treated with chemotherapy for aPC from 2013-2019 in Alberta, Canada (population ∼4.3 million) were included if they had computed tomography (CT) scans both prior to and 12 ± 4 weeks after chemotherapy initiation. Change in muscle area (cm2) was measured at 3rd lumbar level on repeated CT scans. Muscle loss was defined by measurement error (loss >2.3 cm2). Clinical and pharmaceutical data were retrieved from provincial registries. For patients who were dispensed PERT -8 to +6 weeks from chemo start (PERT users), estimated dose consumed per day was calculated as: (total dose dispensed)/(days, first to last dispensation). PERT users were categorized as high dose or low dose users according to the median estimated dose consumed. Non-users were classified as No PERT. Association between PERT use and muscle loss was analyzed with multivariable logistic regression. ResultsAmong 210 patients, 81 (39%) were PERT users. Median estimated dose consumed per day of 75 000 USP lipase units defined the cutoff between low dose and high dose uses. There were no significant differences in baseline characteristics between high dose and low dose groups. Muscle loss was more prevalent among low dose compared to both high dose and No PERT groups (88% vs. 58% and 67%, p < .05). In the multivariable model predicting muscle loss, low dose PERT was independently associated with greater odds of muscle loss (OR 5.4, p=.004) vs. high dose, independent of tumour response, disease stage, and chemotherapy regimen. ConclusionIn patients with clinical indications of EPI during chemotherapy for aPC, low doses of PERT were insufficient to prevent muscle loss. Patients with EPI consuming higher doses of PERT had similar odds of muscle maintenance to patients without clinical indications of EPI. Provider education for optimal PERT dosing in patients with EPI should be prioritized, and resources must be allocated to support dose titration.

Optimization of Classical Lipase Activity Assays for Fish Digestive Tract Samples

Fish possess lipases from embryonic development to adulthood. Lipase activity methods vary and significantly differ in terms of the concentration of the substrate used, bile salt, Ca2+, temperature, pH, and type of lipase units, which limits comparative studies. The three most-used substrates are p-nitrophenyl (p-NP), β-naphthyl (β-N) derivates, and emulsified natural oils. These were selected to be redesigned in this study to measure lipase activity under temperature, pH, ion, and bile salt conditions closer to fish physiology, using the appropriate molar absorption coefficient to calculate the lipase units. Cynoscion parvipinnis (CP), Seriola rivoliana (SR), Centropomus viridis (CV), Elop affinis (EA), and Canthidermis maculate (CM) pyloric caeca-intestine extracts were studied. Sodium taurocholate showed the highest activity for intestinal lipases, and the fatty acid length in the substrates changed the lipase hydrolysis rate. The highest lipase activity was obtained with p-NP butyrate and p-NP caprylate in four fish species. Lipase activity was highly activated with Ca2+ (4–7 mM). The β-N absorption spectrum indicates a plateau between 534 and 554 nm for fish lipases. Salmon oil was identified as the most digestible lipid in the four fish species using the in vitro digestibility assay. The lipase zymogram showed an apparent size of 46.3 kDa for CP, 40.2 kDa for SR, 46.2 kDa for CM, 106.6 kDa for EA, and 58.3, 84.6, and 162.1 kDa for CV.

Pancreatic-enzyme replacement therapy with pancrelipase plus chemotherapy for patients with pancreatic adenocarcinoma with cachexia and exocrine pancreatic insufficiency (PANCAX-3).

e24059 Background: 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). The utility of this therapy for patients with EPI in the setting of pancreatic ductal adenocarcinoma (PDAC) is unclear. We report results of a single site phase 2 trial for PERT with Pancreaze® plus standard of care (SOC) chemotherapy in PDAC patients with cachexia and EPI. The primary outcome measure was to assess feasibility of completing PERT during the first 8 weeks of treatment. Secondary outcome measures included weight stability, mean change in stool frequency, stool consistency from Cycle 1 (C1) to Cycle 3 (C3) (after 8 weeks of PERT), mean change in serum levels of fat soluble vitamins (A, D, E, K) from baseline to end of study, functional activity, and safety. Methods: Feasibility was defined as adherence to therapy of ≥50% of the needed total lipase units in the first 8 weeks of treatment (84,000 IU lipase units per meal, 42,000 IU lipase units per snack). Data are presented as frequencies (%) for categorical variables and means ± standard deviation for continuous variables. Weight stability, stool frequency, fat soluble vitamin levels, walk speed, and hand grip strength compared using two-sample paired t-tests. Stool consistency (Bristol stool type) compared using Fisher’s exact test. Results: Of 36 patients enrolled, 30 were evaluable for primary endpoint. Median age was 70. 73.3% (22/30) were female. 33.3% (10/30) were borderline resectable, 33.3% (10/30) locally advanced, and 33.3% (10/30) advanced/metastatic. 30 patients completed 8 weeks of PERT and 96.7% (29/30) were compliant. Efficacy results include PR (6.7%, 2/30), SD (66.7%, 20/30) and PD (23.3%, 7/30). Imaging not available for 1 patient. 6 patients experienced grade 1/2 GI toxicities (nausea, bloating, diarrhea, abdominal pain) deemed possibly/probably related to PERT. Grade 3/4 AEs included fatigue, infection, and hematologic toxicities deemed unrelated to PERT. Among evaluable patients, weight remained stable (-0.01±0.07 kg/BMI, p = 0.511) and there was a trend toward reduced stool frequency (p = 0.052) from C1 to C3. Stool consistency from C1 to C3 showed significant association (p = 0.035). Serum fat soluble vitamins, functional activity by walk speed and hand grip strength were also explored and no statistically significant differences were observed from C1 to C3 among the evaluable patients. Conclusions: PERT plus SOC chemotherapy for PDAC patients with cachexia and EPI is feasible and well-tolerated. Patients taking PERT experienced weight stability. PERT may aid in reducing stool frequency and further analysis is warranted into how PERT affects stool consistency. Clinical trial information: NCT04098237 .

Investigation of lipid digestion by fungal and porcine lipase supplements for severe pancreatic insufficiency using the in vitro dynamic TIM model

Exocrine pancreaticinsufficiency (EPI) is caused by insufficient secretion or limited activity ofpancreatic enzymes, especially lipase. Chronic pancreatitis (CP) is the mostcommon EPI disease. CP patients suffer from gastrointestinal symptoms such asdiarrhea, abdominal pain, and decreased uptake of nutrients as a consequence ofinadequate food digestion. To improve their nutritional status, pancreaticenzyme supplements can be orally administered, known as pancreatic enzymereplacement therapy (PERT). PERT is commonly based on oral porcinepreparations, despite their pH sensitivity which results in a limited timeframefor optimal activity. Instead, fungal enzymes could be used to prolong enzymeactivity duration, since they are active over a wide pH range. The performanceof fungal enzymes was compared to porcine enzymes by measuring total fattyacids under severe pancreatic insufficiency conditions in the tiny-TIMsgdynamic in vitro gastrointestinal model. Administration of 14.000 fungallipase units (Nortase) led to similar lipid digestion compared to 20.000porcine lipase units (Kreon and Pangrol). Additionally, opening the Nortasecapsules had no negative effect on fungal lipase activity. This workdemonstrates that fungal lipases, administered as capsules or powder, can beused as an alternative treatment for EPI patients.

Fish digestive lipase quantification methods used in aquaculture studies

The proportion of fats or oils in natural or artificial feed is generally 6%–30%, since this is essential to cover fish’s energetic and structural requirements. Therefore, studies of the ontogeny or response of lipase activity to food treatments are widespread. A systematic review of articles published over 5 years (2016–2020) on lipase activity in fish in aquaculture was carried out; however, this was taken only as a representative example. Any 5-year period between 201-2022 would have shown similar results in terms of the actual lipase method used. As a result of this review, it was found that the methods used by the authors are very varied and have significant differences in terms of the type of substrate, substrate concentration, bile salt type and concentration, pH, temperature, incubation time, measurement of hydrolysis products, and definition of lipase units. The above does not mean that comparison of these studies is of no value, but that it is significantly limited. The most used methods (with p-nitrophenyl derivates, β-naphthyl derivates, and emulsified natural oils as substrate) can be reviewed to determine the most appropriate standard curves or the corresponding molar extinction coefficient for defining the lipase units. Standardizing current lipase analytical procedures should improve the reliability of comparative studies of aquaculture fish species.

How macronutrients and pancreatic enzyme supplements dose variability affect fat, protein and starch absorption in children with cystic fibrosis.

low evidence on the dose of enzymatic supplements used in pancreatic enzyme replacement therapy (PERT) is available. assessing if fat, protein and starch absorption could be related to the dose of the enzymatic supplement, the intra-patient variability in the dose and macronutrient intake. Four-day food records and 3-day faecal samples were prospectively collected in 69 children with cystic fibrosis. Pearson correlations between enzyme dose and macronutrient absorption, and beta regression models were applied to explain the results. the supply of protease units per protein intake (PU/g protein) in relation to lipase units per fat intake (LU/g fat) was low and the intra-patient variability in the dose of enzymes was ±1331 LU/g fat. Fat and starch absorption was >90% while for protein it was 81.5%. The coefficient of fat absorption was associated with an interaction between the dose of LU/g fat and its variability among different days. Lipid and protein intake were also determinants of the coefficient of fat absorption. the dose of PERT should be re-adjusted to the amount of dietary fat of every meal (constant LU/g fat) to minimize variability and increase fat absorption. Also, the supply of protease should be increased to prevent from protein malabsorption.

PREVALENCE AND CURRENT TREATMENT STANDARDS IN THE MANAGEMENT OF DISTURBED FUNCTION OF THE PANCREAS - A PHYSICIAN-BASED CROSS-SECTIONAL

Acute pancreatitis (AP), chronic pancreatitis (CP) and cystic fibrosis are frequent causes of disturbed function of thepancreas. Currently, there is insufficient data on the prevalence of disturbed function of the pancreas and its managementwith pancreatic enzyme replacement therapy in Indian clinical practice. A questionnaire-based survey was conductedacross 8 Indian cities involving 63 gastroenterologists who provided their opinions by completing 30-question surveyforms based on their experience with treating 15 patients each with disturbed function of the pancreas. Data werecollected, compiled, analyzed, and presented as frequency and percentage of physicians. According to 50% of thegastroenterologists, 5%-15% of patients presented with symptoms of disturbed pancreatic function every month in theirclinical practice, with common symptoms being abdominal pain (61.9%) and indigestion (38.1%). Pancreatic enzymereplacement therapy (PERT) was the most preferred treatment with 87.3% of specialists recommending it. Acombination of amylase, protease, and lipase was prescribed for patients with symptoms like steatorrhea, indigestion, andabdominal pain by 30.2%, 27.0%, and 25.4% of gastroenterologists, respectively, with 46.0% of the specialistsprescribing them for an average duration of 4-12 weeks. Most gastroenterologists (65.1%) opined that 15,000 units oflipase dosing were very beneficial as compared to 10,000 units. In conclusion, findings from this survey indicate that acombination of amylase, protease, and lipase may be beneficial in patients with disturbed function of the pancreas,especially in those with symptoms of steatorrhea or indigestion; nevertheless, counseling, diet, economic assistance,lifestyle modification, and regular follow-up of patients are warranted.

Eye repaceet fwig tta pacreatecty ppuati aaysis.

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

ObjectivesPancreatic 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 methodsPatients 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.ResultsWe 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.ConclusionIn our CP expert centers, the adherence to guidelines for enzyme treatment is insufficient. Both patient factors and center differences have influence on treatment adherence.

Projected 30-day out-of-pocket and total spending on pancreatic enzyme replacement therapy under Medicare Part D.

401 Background: Pancreatic enzyme replacement therapy (PERT) can reduce symptoms of indigestion and improve nutrition in patients with exocrine pancreatic insufficiency. PERT is under-prescribed, and this may be related to actual costs and prescriber sensitivity to these costs. Thus, we aimed to assess PERT costs. Methods: We used Medicare Part D formulary and pricing files for the first quarter of 2020 to conduct a patient-level modeling study to describe point-of-sale and out-of-pocket costs for each PERT formulation among Part D stand-alone and Medicare Advantage prescription drug plans. We calculated costs across nationwide plans under three scenarios: (1) standard benefit design ($435 deductible and 25% coinsurance after the deductible is met); (2) 25% coinsurance (for fills after the deductible and in the coverage gap until the patient spends $6,350 out-of-pocket); and (3) 5% coinsurance (once catastrophic coverage is reached). PERT doses are identified by the lipase content per capsule (in United States Pharmacopeia, USP, units). We calculated the number of units for each PERT formulation/ dose form that would provide optimally dosed PERT for the average US adult (250,000 USP units of lipase per day), based on guidelines and consensus. We first calculated costs for a single unit of PERT. Next, we calculated the number of units needed daily for each formulation/ dose form to provide optimally dosed PERT, and multiplied it by 30 to generate 30-day requirements and costs. Results: Across 3,974 plans nationwide, five PERT formulations in seventeen different doses were covered by Medicare plans in 2020. The range of lipase content in a single unit ranged from 3,000 to 40,000 USP units, and the per-unit list price ranged from $1.44 to $13.89. The point-of-sale price for a 30-day supply of optimally dosed PERT ranged from $2,109 to $4,840. For patients, the expected out-of-pocket costs for a 30-day supply of optimally dosed PERT averaged $999 across formulations (range, $853 to $1536) for those paying a deductible and coinsurance, $673 (range, $527 to $1210) for fills made after meeting the deductible until reaching catastrophic coverage, and $135 (range, $105 to $242) after reaching catastrophic coverage. Conclusions: In this analysis of 2020 Medicare Part D plans, the estimated out-of-pocket cost for just a 30-day supply of optimally dosed PERT was high— at least $100 in the catastrophic phase and approximately $1,000 in the initial phase. In the setting of pancreas cancer, already associated with heavy symptom burden and distress, the financial burden from a supportive care intervention (such as PERT) has been underappreciated. These costs may serve as a barrier to Medicare beneficiary drug access and contribute to financial toxicity.

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

IntroductionThe Food and Drug Administration in 2006 required that all pancreatic enzyme products demonstrate bioavailability of lipase, amylase, and protease in the proximal small intestine. MethodsIn 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. ResultsZenpep 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. ConclusionsIn 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.

The use of pancreatic enzyme replacement therapy in patients with a diagnosis of chronic pancreatitis and pancreatic cancer in the US is infrequent and inconsistent.

Patients with chronic pancreatitis or pancreatic cancer commonly develop exocrine pancreatic insufficiency, and may not be adequately treated with pancreatic enzyme replacement therapy (PERT). To estimate the frequency of diagnostic testing for exocrine insufficiency, and appropriate use of PERT, in a commercially insured population in the US. We utilised a nationally representative administrative database representing 48.67 million individuals in over 80 US healthcare plans to assess testing for and treatment of exocrine insufficiency in patients who received a diagnosis of chronic pancreatitis (n=37061) or pancreatic cancer (n=32461) from 2001to 2013. We identified the details of any testing for exocrine insufficiency and PERT use. We defined appropriate PERT use as a dosage of ≥120000 USP units of lipase daily. Multiple logistic regression was used to identify predictors of appropriate use of PERT. In patients with chronic pancreatitis, 6.5% had any testing for exocrine insufficiency, 30.4% filled a prescription for PERT, and 8.5% were prescribed an adequate dose. In those with pancreatic cancer, 1.9% had testing for exocrine insufficiency, 21.9% filled a prescription for PERT, and 5.5% were prescribed an adequate dose. Number of comorbidities, testing for exocrine insufficiency, pancreatic surgery and duration of enrolment were independent predictors for use and appropriate dosing. Testing for exocrine insufficiency, and appropriate dosing of PERT in patients with chronic pancreatitis or pancreatic cancer, is infrequent and inconsistent in an insured US population. Efforts are needed to educate medical providers on the best practices for managing exocrine pancreatic insufficiency in these patients.

SUCCESSFUL USE OF IMMOBILIZED LIPASE CARTRIDGE FOR REINTRODUCTION OF ENTERAL FEEDS IN INFANT WITH CYSTIC FIBROSIS AND NECROTIZING ENTEROCOLITIS

SESSION TITLE: Tuesday Medical Student/Resident Case Report Posters SESSION TYPE: Med Student/Res Case Rep Postr PRESENTED ON: 10/22/2019 01:00 PM - 02:00 PM INTRODUCTION: Pancreatic enzyme replacement therapy (PERT) improves nutrition and growth in patients with cystic fibrosis and pancreatic insufficiency. CASE PRESENTATION: A 2-month old term female presented with bloody stools and poor weight gain. Her medical history was significant for cystic fibrosis (ΔF508 and 1210-2_1210-1delAG splice site mutation), complicated by pancreatic insufficiency, meconium ileus, and in-utero bowel perforation requiring postnatal bowel resection. Patient was discharged from the NICU on PERT and 22 kcal per oz of Pregestimil formula. She was followed by a nutritionist who recently increased her formula to 26 kcal per oz. Her PERT was increased from 3000 to 6000 lipase units per feed. Abdominal radiographs revealed peripheral, bubble lucencies around the bowel concerning for extensive pneumatosis. Patient was admitted for management of necrotizing enterocolitis (NEC). She was kept NPO and started on 7 days of IV piperacillin-tazobactam and parenteral nutrition. Repeat studies showed resolution of pneumatosis. Contrast enema was reassuring with no sign of stricture. Patient was restarted on oral feeds on Day 8. Within 72 hours, patient developed abdominal distension. Repeat imaging revealed new evidence of pneumatosis, requiring another course of antibiotics and bowel rest prior to slow re-initiation of feeds. 1 month after second occurrence of NEC, patient was discharged on full feeds of 22 kcal per oz formula with PERT at 6000 lipase units per feed. Due to continued difficulty gaining weight, patient was later readmitted for gastrostomy tube placement. To facilitate more uniform administration of PERT, an immobilized lipase cartridge (Relizorb) was used in-line with her continuous tube feeds. Though this route of PERT administration was not approved for use in infants, good outcomes were reported in children as young as 5 years old. Patient's weight increased over the next month from 4.08 to 4.46 kg. She was discharged home with no complications. DISCUSSION: It was concluded that the inciting event for this patient’s necrotizing enterocolitis was likely the increased caloric density of formula. Little data exists to describe the incidence of NEC in infants with cystic fibrosis, but it is assumed to be rare. Careful reintroduction of enteral feedings is paramount in NEC and may be problematic in cystic fibrosis patients who receive tube feeds, as they often require pancreatic enzyme replacement to prevent bowel obstruction. Traditionally this requires interruption of tube feeds with periodic administration via enteral tube. In this case, an in-line immobilized lipase cartridge was utilized successfully to provide consistent enzyme administration during tube feeds. CONCLUSIONS: Our case suggests there may be a benefit for additional study of immobilized lipase within the pediatric population in order to address and improve malabsorption challenges in cystic fibrosis patients. Reference #1: Borowitz DS, Grant RJ. PR, the Consensus Committee. Pancreatic Enzymes Clinical Care Guidelines. J Pediatrics. 1995; 127:681-84. Reference #2: Paranjape S, MD and Mogayzel PJ, MD, PhD. Cystic Fibrosis. Pediatrics in Review. May 2014, 35 (5) 194-205; https://doi.org/10.1542/pir.35-5-194 Reference #3: Abbo O, Harper L, Michel JL, Ramful D, Breden A, Sauvat F. Necrotizing enterocolitis in full term neonates: is there always an underlying cause?. J Neonatal Surg. 2013;2(3):29. Published 2013 Jul 1. DISCLOSURES: No relevant relationships by Manuel Izquierdo, source=Web Response No relevant relationships by Nicole Stephenson, source=Web Response No relevant relationships by William Wooten, source=Web Response

Functionalization of Enzymatically Synthesized Rigid Poly(itaconate)s via Post‐Polymerization Aza‐Michael Addition of Primary Amines

AbstractThe bulky 1,4‐cyclohexanedimethanol was used as co‐monomer for introducing rigidity in lipase synthetized poly(itaconate)s. Poly(1,4‐cyclohexanedimethanol itaconate) was synthetized on a 14 g scale at 50 °C, under solvent‐free conditions and 70 mbar using only 135 Units of lipase B from Candida antarctica per gram of monomer. The mild conditions preserved the labile vinyl group of itaconic acid and avoided the decomposition of 1,4‐cyclohexanedimethanol, both observed in chemical polycondensations. Experimental and computational data show that the enzymatic polycondensation proceeds despite the low reactivity of C1 of itaconic acid. The rigid poly(1,4‐cyclohexanedimethanol itaconate) was investigated in the context of aza‐Michael addition of hexamethylenediamine and 2‐phenylethylamine to the vinyl moiety. The enzymatically synthesized linear poly(1,4‐butylene itaconate) was studied as a comparison. The two oligoesters (Molecular Weights ranging from 720 to 2859 g mol−1) reacted on a gram scale, at 40–50 °C, at atmospheric pressure and in solvent‐free conditions. The addition of primary amines led to amine‐functionalized oligoesters but also to chain degradation, and the reactivity of the poly(itaconate)s was influenced by the rigidity of the polymer chain. Upon the formation of the secondary amine adduct, the linear poly(1,4‐butylene itaconate) undergoes fast intramolecular cyclization and subsequent degradation via pyrrolidone formation, especially in the presence of hexamethylenediamine. On the contrary, the bulky 1,4‐cyclohexanedimethanol confers rigidity to poly(1,4‐cyclohexanedimethanol itaconate), which hampers the intramolecular cyclization. Also, the bulkiness of the amine and the use of solvent emerged as factors that affect the reactivity of poly(itaconate)s. Therefore, the possibility to insert discrete units of itaconic acid in oligoesters using biocatalysts under solvent‐free mild conditions opens new routes for the generation of bio‐based functional polymers or amine‐triggered degradable materials, as a function of the rigidity of the polyester chain.magnified image

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

BackgroundPatients 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.ObjectiveIn 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.MethodsA 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.ResultsThe 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.ConclusionsDepending 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.

A Multicenter Open-Label Randomized Controlled Trial of Pancreatic Enzyme Replacement Therapy in Unresectable Pancreatic Cancer.

Exocrine pancreatic insufficiency may impair the nutritional status in pancreatic cancer (PC), but the role of pancreatic enzyme replacement therapy (PERT) is not fully evaluated. Therefore, we conducted this multicenter open-label randomized controlled trial to evaluate the role of PERT in PC patients. Patients with unresectable PC receiving chemotherapy were randomly assigned to pancrelipase and nonpancrelipase groups. Patients in the pancrelipase group took oral pancrelipase of 48,000 lipase units per meal. N-benzoyl-tryrosyl para-aminobenzoic acid (NBT-PABA) test was performed at baseline. Our primary endpoint was change in body mass index (BMI) at 8 weeks. Secondary endpoints were change in other nutritional status at 8 weeks and overall survival. A total of 88 patients were enrolled between May 2014 and May 2016. The NBT-PABA test was lower than the normal range in 90%. There were no significant differences in change in BMI at 8 weeks: 0.975 and 0.980 in the pancrelipase and the nonpancrelipase groups, respectively (P = 0.780). The other nutritional markers were also comparable. The median overall survival was 19.0 and 12.0 months (P = 0.070). In this randomized controlled trial, pancrelipase failed to improve the change in BMI at 8 weeks in PC patients receiving chemotherapy.

Клинические рекомендации Российской гастроэнтерологической ассоциации по диагностике и лечению экзокринной недостаточности поджелудочной железы

The aim of publication. To present the modern concept of etiology and pathogenesis of exocrine pancreatic insufficiency to general practitioners as well as with the established approach to diagnostics and treatment of this syndrome. Summary. Exocrine pancreatic insufficiency (EPI) develops if activity of the enzymes in duodenal lumen in response to meal stimulation is insufficient to maintain normal nutrient digestion. This state can develop primarily, due to various pancreatic diseases (chronic pancreatitis, pancreatic cancer, cystic fibrosis), and secondarily, due to impaired stimulation of pancreatic secretion or non-physiological conditions for activity of digestive enzymes. Basic manifestations of EPN the syndromes of maldigestion and malabsorption leading to development of nutritional failure. At the present time there is no standardized diagnostic method for estimation of pancreatic exocrine function, therefore there are no standard diagnostic criteria for EPN. In clinical practice EPN is diagnosed according to decreased fecal elastase activity in patients with verified pancreatic disease, which can cause decrease of pancreatic exocrine function. The basic EPN treatment method is pancreatic enzyme replacement therapy (PERT). For last 50 years there was an significant progress in development of PERT, numerous pancreatin-containing preparations were developed. Treatment of PERT require prescription of capsules, containing pancreatin microparticles protected by enteric coating. The highest evidential base at EPN is accumulated for pancreatin mini-microspheres. The starting dose of pancreatic enzymes for adults is 25 000 units of lipase per meal, which should be subsequently increased up to achievement of complete response confirmed by both clinical and laboratory scores. Digestive enzymes should be taken at the beginning of food intake, to increase treatment efficacy PERT should be accompanied by prescription of proton pump inhibitors. Patient’s diet quantity and content should be adjusted with participation of nutritionist. Patient should intake at least normal daily amount of fat and divide daily ration to at least six meals. Patients should be motivated to restrain from alcohol consumption and smoking as they can lead to further progression of pancreatic exocrine insufficiency and symptoms of pancreatitis.

Pancreatic exocrine insufficiency (PI) secondary to chronic use of long-acting (LA) somatostatin analogues (SA) in patients (pts) with gastroenteropancreatic neuroendocrine tumors (GEP-NETs).

454 Background: SA are used in GEP-NETs and acromegaly. Side effects of SAs include biliary disorders, gastrointestinal disorders, injection-site pain and hyperglycemia. PI is often misdiagnosed as disease progression or failure to SA or diagnosed after a delay in pts receiving SA. We present our experience with PI developing in pts following chronic use of SA. Methods: Retrospective chart and pharmacy review of GEP-NETs pts (6/2009 - 6/2017) was completed. Data including demographics, dose/duration of long and short-acting SA, antidiarrheal, pancreatic enzyme replacement (PER), proton pump inhibitors (PPI), chromogranin A (CgA), urine 5-HIAA and quantitative fecal fat test (QFFT) was collected. Results: 110 GEP-NETs pts (Med. age: 56 yr) were identified. 104 pts received LA Octreotide acetate and 6 Somatuline Depot Injection. Of these, 23 received SA octreotide for worsening diarrhea, 96 had intensification of antidiarrheal and 1 got telotristat ethyl. 79 pts were evaluated by nutritionist and/or gastroenterology. QFFT was performed in 47 pts with worsening diarrhea despite stable or improved CgA/urine 5-HIAA. 19 had evidence of steattorrhea and received PER at a dose of 72,000 lipase units per meal. 13 received PPI concomitantly while 6 started when symptoms did not improve with PER. In addition, low fat diet was recommended. 14 of 19 had improvement in diarrhea within 4-8 weeks. 2 pts were non-compliant and 3 were found to have motility disorders. Deficiency of vitamins and trace elements was found in 11 of 19 pts, who received supplementation. Conclusions: Our experience constitutes first study addressing PI as a rare but serious complication of chronic use of SA. Although SA are used to treat diarrhea, paradoxically they can worsen diarrhea secondary to PI. It is believed that SA may inhibit secretion and release of hormones (amylase, trypsin, lipase, secretin, CCK, motilin, bile acid) leading to PI. Early recognition and diagnosis of this under-diagnosed and under-reported side effect of SA can improve not only diarrhea and weight in these pts but also can reduce cost of using short-acting SA and antidiarrheal.

Pancreatic-like enzymes of microbial origin restore growth and normalize lipid absorption in a pig model with exocrine pancreatic insufficiency.

IntroductionThe standard therapy for exocrine pancreatic insufficiency (EPI) is porcine-derived pancreatic enzyme replacement therapy (PERT). In the present study we tested a new approach with a mixture of pancreatic-like enzymes of microbial origin (PLEM) in a 1-week efficacy study in EPI pigs. In addition to the conventionally used coefficient of fat and nitrogen absorption (CFA and CNA), parameters that more accurately reflect the nutritional and health status, such as changes in the lipemic index (LI), plasma triglyceride (TG) and non-esterified fatty acid (NEFA) levels, and somatic growth, were determined.Material and methodsA PLEM dose containing 120 000 active lipase units, 80 000 active protease units and 12 000 active amylase units (all from Sigma, St. Louis, MO) was given as a powder, twice daily with a meal (40 g fat/meal) to 8 EPI pigs for 7 days. Ten healthy pigs were used as a comparator.ResultsThe PLEM enhanced fat and protein digestion, and reversed growth impairment in EPI pigs. With treatment, CFA and CNA increased by 59% and 43% (p < 0.05), respectively. Although fat and protein absorption were lower than in the comparator, the postprandial blood lipid profile was normal as in healthy pigs. The mucosal thickness significantly increased by 27%, 50% and 26%, in the proximal, middle, and distal jejunum (p < 0.05) with treatment and resembled that of healthy animals.ConclusionsPancreatic-like enzymes of microbial origin supported somatic growth and normalized the postprandial lipid profile. As a measure of efficacy, postprandial LI, TG and NEFA are viable endpoints to be explored in human trials.

Diagnosis and management of pancreatic exocrine insufficiency.

In 2015, the Australasian Pancreatic Club (APC) published the Australasian guidelines for the management of pancreatic exocrine insufficiency (http://pancreas.org.au/2016/01/pancreatic-exocrine-insufficiency-guidelines). Pancreatic exocrine insufficiency (PEI) occurs when normal digestion cannot be sustained due to insufficient pancreatic digestive enzyme activity. This may be related to a breakdown, at any point, in the pancreatic digestive chain: pancreatic stimulation; synthesis, release or transportation of pancreatic enzymes; or synchronisation of secretions to mix with ingested food. Main recommendations: The guidelines provide advice on diagnosis and management of PEI, noting the following: A high prevalence of PEI is seen in certain diseases and conditions, such as cystic fibrosis, acute and chronic pancreatitis, pancreatic cancer and pancreatic surgery. The main symptoms of PEI are steatorrhoea or diarrhoea, abdominal pain, bloating and weight loss. These symptoms are non-specific and often go undetected and untreated. PEI diagnosis is predominantly based on clinical findings and the presence of underlying disease. The likelihood of PEI in suspected patients has been categorised into three groups: definite, possible and unlikely. If left untreated, PEI may lead to complications related to fat malabsorption and malnutrition, and have an impact on quality of life. Pancreatic enzyme replacement therapy (PERT) remains the mainstay of PEI treatment with the recommended adult initial enzyme dose being 25 000-40 000 units of lipase per meal, titrating up to a maximum of 75 000-80 000 units of lipase per meal. Adjunct acid-suppressing therapy may be useful when patients still experience symptoms of PEI on high dose PERT. Nutritional management by an experienced dietitian is essential. Changes in management as a result of these guidelines: These are the first guidelines to classify PEI as being definite, possible or unlikely, and provide a diagnostic algorithm to facilitate the early diagnosis of PEI and appropriate use of PERT.