Development of an Animal Model for Inducing Various Degrees of Severity of Incontinence-Associated Dermatitis.

PURPOSE: The purpose of this study was to describe the biological changes after incontinence-associated dermatitis (IAD) induction by pancreatin in the guinea pigs and to explore the potentially appropriate timing and pancreatin concentration for IAD induction with different severity. DESIGN: In vivo, experimental study. SUBJECTS AND SETTING: An experimental animal model (guinea pig) in a controlled laboratory setting was used for investigation. METHODS: We developed an IAD model in guinea pigs by occluded application of 1%, 5%, and 10% pancreatin solutions for 1, 3, and 5 days, respectively. The irritant was applied to the posterior aspect of shaved guinea pigs. We used an adapted visual scoring system to evaluate IAD and its severity. We also measured differences of the fluid absorption rate as a proxy for transepidermal water loss and enzyme-linked immunosorbent assays of interleukin 2 and interferon-γ expression as indicators of IAD-related inflammation. Analysis of variance (ANOVA) was used to examine group differences. RESULTS: Higher pancreatin concentrations led to more severe skin responses and higher mean visual scale scores, yet the statistically score differences were only observed in the 1% and 5% pancreatin groups after 3 and 5 days of exposure compared with 1 day of exposure (P < .05). The average absorbed fluid rate increased from 1 to 3 days of exposure and reached a plateau at 3 days; significant differences were observed in 3 and 5 days of exposure (P < .05) when compared with 1 day of exposure but not between 3 and 5 days of exposure. CONCLUSIONS: Exposure of a guinea pig animal model to 1%, 5%, and 10% pancreatin solutions over a 3-day period induced IAD with different levels of severity. Additional studies using this model are warranted.

Efficacy of pancreatic exocrine replacement therapy for patients with unresectable pancreatic cancer in a randomized trial.

BACKGROUND: Weight loss in pancreatic cancer is associated with maldigestion due to pancreatic duct obstruction. Pancreatic exocrine replacement therapy (PERT) may significantly improve fat and protein absorption. OBJECTIVES: This prospective, double-blind, randomized, placebo-controlled phase II trial assessed whether PERT could reduce or prevent weight loss in patients with unresectable pancreatic cancer. METHODS: Sixty seven patients with unresectable pancreatic cancer were randomized to receive enteric coated PERT, consisting of 6-9 capsules of pancreatin (457.7 mg/capsule), or placebo. Patients took two capsules each three times daily during main meals and one capsule each up to three times daily when having between-meal snacks. The primary endpoint was the percentage change in body weight at eight weeks. RESULTS: The mean percentage change in body weight (1.49% [1.12 kg] vs. 2.99% [1.63 kg], P = 0.381) and the mean percent change in Patient-Generated Subjective Global Assessment (PG-SGA) score (8.85% vs. 15.69%, p = 0.18) did not differ significantly between the PERT and placebo groups. There was no improvement in quality of life and overall survival did not differ significantly between the PERT and placebo groups (5.84 months vs 8.13 months, p = 0.744). CONCLUSIONS: PERT did not reduce weight loss in patients with unresectable pancreatic cancer. Larger randomized trials are needed to identify those patients who may benefit from PERT. TRIAL REGISTRATION: ClinicalTrials.gov Number NCT01587534.

Chronic pancreatitis.

PURPOSE OF REVIEW: We review selected important clinical observations reported in 2012. RECENT FINDINGS: Celiac disease is a risk factor for pancreatitis. Patients with recurrent acute pancreatitis likely have chronic pancreatitis, do not benefit from pancreatic sphincterotomy, and may not benefit from biliary sphincterotomy. Analysis of endoscopic ultrasonography (EUS) images with an artificial neural network (ANN) program may improve chronic pancreatitis diagnosis compared with clinical interpretation of images. In a multicenter, randomized controlled trial of chronic pancreatitis patients, 90 000 USP U of pancreatin with meals decreased fat malabsorption compared with placebo. Detection of visceral pain in chronic pancreatitis predicts pain relief from various treatments, but nonvisceral pain due to altered central pain processing may respond to agents such as pregabalin. Predictors of surgical pain relief include onset of symptoms less than 3 years and preoperatively no opioid use and less than five endoscopic procedures. Total pancreatectomy for presumed painful chronic pancreatitis remains controversial. SUMMARY: Celiacs are at risk for pancreatitis. The diagnosis of chronic pancreatitis may be enhanced by ANN analysis of EUS imaging. Treatment of fat malabsorption requires 90,000 USP U of lipase with meals. Relief of pain from organ directed treatment of chronic pancreatitis may depend upon timing of interventions and whether pain is visceral or nonvisceral.

A 51-week, open-label clinical trial in India to assess the efficacy and safety of pancreatin 40000 enteric-coated minimicrospheres in patients with pancreatic exocrine insufficiency due to chronic pancreatitis.

BACKGROUND/OBJECTIVES: To assess the efficacy and safety of pancreatin (pancrelipase) enteric-coated minimicrospheres (MMS) over a one-year period in patients with pancreatic exocrine insufficiency (PEI) due to chronic pancreatitis (CP). METHODS: This was a 51-week, open-label extension (OLE) of a one-week, multicenter, double-blind, randomized, placebo-controlled trial in India that enrolled patients ≥18 years of age with confirmed PEI due to CP. Patients received pancreatin (Creon(®) 40000 MMS™) at a dose of 80,000 Ph. Eur. lipase units with each of three main meals/day and 40,000 with each of up to three snacks/day. RESULTS: Of 61 patients entering the OLE, 48 completed treatment (nine were lost to follow up, two withdrew consent, one discontinued due to adverse event [acute exacerbation of CP], one protocol violation). There were significant improvements from baseline to end of OLE in mean ± SD coefficient of fat absorption (CFA: 22.7 ± 12.2%), coefficient of nitrogen absorption (CNA: 6.5 ± 7.9%), body weight (4.9 ± 4.9 kg), BMI (1.9 ± 1.9 kg/m(2)), and most nutritional laboratory parameters tested (p ≤ 0.001). Mean daily stool frequency was reduced from 2.8 to 1.6 (p < 0.001). Improvements in clinical symptoms, clinical global impression of disease symptoms, and quality of life were also observed. Treatment-emergent adverse events (TEAEs) were observed in 64% of patients overall. Only 13% of patients experienced TEAEs judged treatment related. CONCLUSIONS: In patients with PEI due to CP, treatment with pancreatin for one year was associated with significant improvements in fat absorption, nitrogen absorption, and nutritional parameters, improvements in clinical symptoms, and a favorable safety and tolerability profile.

A blinded randomised controlled trial to determine the effect of enteric coating on enzyme treatment for canine exocrine pancreatic efficiency.

BACKGROUND: Enzyme treatment is the mainstay for management of exocrine pancreatic insufficiency (EPI) in dogs. 'Enteric-coated' preparations have been developed to protect the enzyme from degradation in the stomach, but their efficacy has not been critically evaluated. The hypothesis of the current study was that enteric coating would have no effect on the efficacy of pancreatic enzyme treatment for dogs with EPI.Thirty-eight client-owned dogs with naturally occurring EPI were included in this multicentre, blinded, randomised controlled trial. Dogs received either an enteric-coated enzyme preparation (test treatment) or an identical preparation without the enteric coating (control treatment) over a period of 56 days. RESULTS: There were no significant differences in either signalment or cobalamin status (where cobalamin deficient or not) between the dogs on the test and control treatments. Body weight and body condition score increased in both groups during the trial (P<0.001) but the magnitude of increase was greater for the test treatment compared with the control treatment (P<0.001). By day 56, mean body weight increase was 17% (95% confidence interval 11-23%) in the test treatment group and 9% (95% confidence interval 4-15%) in the control treatment group. The dose of enzyme required increased over time (P<0.001) but there was no significant difference between treatments at any time point (P=0.225). Clinical disease severity score decreased over time for both groups (P=0.011) and no difference was noted between groups (P=0.869). No significant adverse effects were reported, for either treatment, for the duration of the trial. CONCLUSIONS: Enteric coating a pancreatic enzyme treatment improves response in canine EPI.

Effects of porcine pancreatic enzymes on the pancreas of hamsters. Part 1: basic studies.

CONTEXT: Porcine pancreatic enzymes (PPE) extracted from glandular stomach has been used for the treatment of pancreatic cancer patients. Unfortunately, no information is available on the in vitro and in vivo effect on the pancreas and other tissues. OBJECTIVE: We used Syrian Golden hamsters, a unique pancreatic cancer model, to obtain basic information on PPE for its eventual use for the treatment of pancreatic cancer. DESIGN: PPE was used in different concentrations in vitro and in vivo. The stability of the enzyme in the water solution was investigated. It was given to the hamsters by gavage in concentrations of 1g/kg and 400 mg/kg for short periods and in aqueous solution for 65 days. Plasma enzyme and insulin, the size of islets and the number of the insulin cells per islet were examined. RESULTS: The enzyme activity of PPE was maintained in water solution for at least 24 hours. Due to its content of calcium chloride it showed a high toxicity to normal and malignant hamster pancreatic cancer cells and human pancreatic cancer cell lines in vitro. PPE did not alter the plasma pancreatic enzyme levels regardless of the dose, duration and application route. On the contrary, PPE reduced their levels significantly. Remarkably, it also reduced the level of insulin, the size of the islets and the number of insulin cells in the islets significantly. CONCLUSION: The results imply that PPE does not enter the blood circulation but it appears to slow down the function of both the exocrine and endocrine pancreas.

[Peculiarities of diabetes mellitus course in chronic pancreatitis].

In order to identify features of the course pancreatic diabetes and discussion of the principles of conservative therapy were examined 66 patients with CP in age of 30 to 65 years (55 men, 11 women). Among them in 22 cases disease was followed with formation of calcification of pancreas, 13 - pancreatic cysts, and 5 revealed pseudo tumor form of CP, 10 patients had clinical and laboratory evidence of diabetes. Concerning CP complicated course were performed 14 resection and 11 draining operations on the pancreas. Based on clinical, instrumental and laboratory data was made the diagnosis of CP. Exocrine pancreatic function was assessed on the results of the breath test, using 13C-trioktanaine, which is applied for exocrine pancreatic function in vivo test. The content of C-peptide was investigated by enzyme-linked immunosorbent assay (ELISA). The data indicate pancreatic exocrine function decrease in patients with CP with complications and without complications in compare with the norm of 44% (24,3 +/- 1,7, 26,6 +/- 1,3%, respectively) according to the breath test. Significant decrease of the cumulative output tags based on the test data of patients with CP and pancreatic calcification, diabetes mellitus, after resection surgery with CP complications, and there were significant differences in compare with a group of patients with CP without complications (p = 0.5). The level of C-peptide in these groups of patients decreased significantly in compare with a group of patients with CP without complications, and patients with CP and Diabetes was reduced to 0,11 +/- 0,02 ng/ml, at a rate range of 0.7-1.9 ng/ml, ie below the minimum values of norm. Obtained a direct correlation between the level of C-peptide and indicators breath test in patients after resection HP (r = 0,84, p = 0,03). Antibodies to insulin in the whole group of studied patients CPs were negative, which proves the specific type of Diabetes at HP. Antibodies to insulin can be detected only at diabetes type 1. In 7 patients with CP and CD detected calcification, 5 patients performed resection surgery, 3 patients had calcification and conducted the pancreas resection. Thus, we can conclude that in patients with CP and formation of pancreas calcification, pancreas resections may predict the development of diabetes.

[Chronic pancreatitis: microbe-intestinal tissue complex and systemic inflammatory response].

Today in Russian Federation, we observe significant growth of the chronic pancreatitis incidence with the depression of its therapy efficiency (more than 20% of the patients) and complications rate growth. In many respects given tendency is associated with the inefficiency of traditional medications combination in the context of inflammation process reduction, gut dysbiosis correction and chronic inflammation reaction depression. Present-day studies indicates, that the grade and character of inflammation in the pancreas depends on the pro- and anti-inflammatory cytokines balance, which is associated with the elevation of the pathogenic microbiota concentration and permeability of the gut. We estimate clinical efficacy of complex treatment regimen (PPI, spasmolytic, multienzyme and prebiotic therapy) in the patients with chronic pancreatitis and its effect on chronic system inflammation. We established that efficacy of modern complex treatment regimen depends on its influence on chronic system inflammation and that prebiotics addition potentiates correction of dysbiotic changes in the gut microbial-tissular complex and reduces grade of system inflammation.

Effect of lubricant on spreading of coating liquid on surface of tablets containing pancreatin.

The objective of this study was to evaluate the spreading of the coating liquid on different tablets containing pancreatin and microcrystalline cellulose. The effects of the ratio of the components, the presence of magnesium stearate and the blending circumstances were investigated. The contact angle of the liquids on the different tablets did not change linearly. For the mixture containing 50% pancreatin, the deviation of the measured value from the predicted one was more than 25%. This deterioration was also detected for mixtures containing 1% lubricant, but the extent was lower and was not modified by change of the mixing circumstances. This phenomenon was explained by the special microstructure of the surface of the tablet. This was predicted from the spreading coefficient, calculated from the surface free energy. The enrichment of pancreatin on the surface was preferred in binary mixtures. The spreading of magnesium stearate was most preferred for the powder mixture, and thus prediction of the properties of the tablet was easier for these mixtures. The extent of the effect of this excipient on the surface properties was very wide-ranging. The change in the spreading of the coating liquid was significant; however, the change in the work of friction was negligible.

[Eurand Minitabs--the innovative application formula of a pancreatic enzyme complex (Pangrol 10,000, 25,000)]. / Eurand Minitabs--innowacyjna formula aplikacji kompleksu enzymatycznego pankreatyny (Pangrol 10,000, 25,000).

Modern technology of solid oral drug forms, through the application of macromolecular polymers, generates a number of new formulation solutions. New technologies provide optimal parameters for the release of biologically active substances, increasing by these means pharmacotherapeutic effectiveness of a medicinal product. Basic properties of the innovative Eurand Minitabs technology, making possible the tableting of technologically and applicatively labile substances such as a pancreatic enzyme complex were dicussed. The application of encapsulated minitablets coated with a methacrylic acid copolymer guarantees an optimal range of lipase pharmacological activity.

[Effect of enzyme supportive therapy of the Ermital' on a quality of life of patients with chronic pancreatitis].

The purpose of the study was to evaluate the quality of life in patients with chronic pancreatitis with the presence of complications treated conservatively and surgical treatment. With the help of a questionnaire MOS SF-36 were asked 80 patients with CP, of whom 15 patients were after the operation, the PDR, 10 patients underwent draining operations, 15 patients had a history of pancreatic necrosis, in 20 patients with CP were characterized by complications (cyst calcification, kalkulez, pseudotumoral form of HP, diabetes) and surgical interventions were not performed in 20 CPs proceeded without complications. Were obtained significant differences on all scales of the questionnaire with the control group all CP patients. Assessment of coping with pain in long-terms after various operations was revealed significantly better results and got rid of persistent pain in patients with a complicated course, who underwent surgery. 23 CP patients with a complicated course, as enzyme replacement therapy received in ermital dose of 20,000 IU lipase 3-4 times a day for 3 weeks. The assessment of quality of life before and after therapy with ermital. The intensity of pain significant changes in the groups received. On the other hand the improvement in general health, physical and social functioning.

Preventive Effect of High-Dose Digestive Enzyme Management on Development of Nonalcoholic Fatty Liver Disease after Pancreaticoduodenectomy: A Randomized Controlled Clinical Trial.

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is a complication of pancreaticoduodenectomy (PD). We conducted a randomized clinical trial to determine if high-dose digestive enzymes prevented the development of NAFLD after PD. STUDY DESIGN: This parallel-group, nonblinded, multicenter study enrolled patients undergoing elective PD at Shinshu University School of Medicine, from June 2011 to April 2017. Patients were randomly assigned to receive normal-dose (Excelase: 3.0 g/day [Meiji Seika Pharma Holdings Co, Ltd]) or high-dose digestive enzyme treatment (Excelase: 3.0 g/day; Pancreatin [Tokyo Chemical Industry Co Ltd]: 3.0 g/day; Berizym [Kyowa Pharmaceutical Industry Co Ltd]: 3.0 g/day; and Toughmac-E [Ono Pharmaceutical Co, Ltd]: 3.0 g/day) within 1 week after surgery. Because patients in the control group switched interventions upon receiving a diagnosis of NAFLD, intention-to-treat analysis was used. The primary endpoint was incidence of NAFLD within 1 year, and the secondary endpoints were the incidences of NAFLD at 1, 3, 6, and 12 months and the rate of improvement in NAFLD with high-dose transfer in the control group. The secondary analysis comprised assessment of risk factors for the development of NAFLD. RESULTS: Eighty-four patients were randomly assigned (42 per group), 80 of whom were finally analyzed (39 normal-dose, 41 high-dose). The incidence of NAFLD was significantly lower in the high-dose (8 of 41) compared with the normal-dose (25 of 39) patients (p < 0.001). Multivariate analysis identified normal-dose (odds ratio [OR] 14.65, p < 0.001), total protein ≤ 6.5g/dL (OR 9.01, p = 0.018), pre-albumin ≤ 22.0 mg/dL (OR 7.71, p = 0.018), and pancreatic function diagnostic test ≤ 70% (OR 6.66, p = 0.009) as independent risk factors. There were no adverse effects. The model was accurate (c-index = 0.92) and reliable (Hosmer-Lemeshow test p = 0.32). CONCLUSIONS: High-dose administration of digestive enzymes significantly reduced the onset of NAFLD after PD compared with normal-dose administration. Registration number: UMIN000005595 (http://www.umin.ac.jp/ctr/).

Preparation and in vivo efficacy study of pancreatin microparticles as an enzyme replacement therapy for pancreatitis.

Deficiency manifestations because of pancreatic insufficiency are treated by oral administration of pancreatic enzymes. As pancreatic enzymes get denatured in hostile acidic conditions of stomach, this investigation was aimed at formulating multiparticulates of pancreatic enzymes coated with enteric polymers such as eudragit L100, cellulose acetate phthalate, and hydroxyl propyl methyl cellulose phthalate, which will circumvent gastric inactivation in addition to providing optimal mixing with chyme. Pancreatin microspheres were prepared by emulsification phase separation by nonsolvent addition and solvent evaporation techniques. This process was optimized for core : coat ratio (1:0.5), stirrer speed (350-400 rpm), dispersant concentration, and amount of nonsolvent added to precipitate microspheres. Optimized formulations were assessed for % enzyme content, acid resistance, flow properties, particle size, particle morphology (by standard electron microscopy), compatibility of drug and polymer in formulation (by differential scanning calorimetry), in vitro release kinetics, and in vivo efficacy study in pancreatitis-induced animal model. Capsules containing enteric-coated pancreatin microspheres offered adequate protection to enzymes and prevented their denaturation in acidic environment. Developed multiparticulate dosage forms promoted effective mixing, instant and complete in vitro release compared with marketed tablets.

[Effectiveness of panzytrat--modern physiological enzyme preparation in complex therapy of pancreatic exocrine secretory insufficiency in cholelithiasis].

In the article the analysis of the survey with 102 patients with gallstone disease involved, 68 of whom underwent cholecystectomy and 34 were treated conservatively, is made. The content of fecal elastase 1 in stool was estimated for diagnostics of exocrine enzyme insufficiency of pancreas by immune-enzyme analysis. It was stated that 90% of patients possess secondary exocrine insufficiency of pancreas in case of gallstone disease. It is the result of complex metabolic liver abnormalities, portal and mesenterial haemodynamics, dysbiosis of large intestine which are the components of a syndrom of maldigestion and appear during gallstone disease progressing long time before hospitalization. Cholecystectomy doesn't eliminate enzyme insufficiency of pancreas. The effectiveness of using new physiological enzymatic drug Panzytrat in a complex therapy of a syndrom of maldigestion in case of gallstone disease is shown.

Effect of liquid pancreatic enzymes on the assimilation of fat in different liquid formula diets.

BACKGROUND: In some diseases, patients require high-calorie tube feeding with standard enteral formulas usually administered via temporal feeding tubes. One frequent pathophysiological condition in a relevant number of these patients is exocrine pancreatic insufficiency. Patients unable to swallow capsules might benefit from a liquid pancreatic enzyme (LPE) preparation. METHODS: LPEs were prepared and mixed with different commercially available formula diets produced for enteral feeding. Lipolysis was then measured by fatty acid titration. RESULTS: Complete lipolysis by liquid enzyme preparations was observed in diverse formula diets. Fat assimilation was even complete when LPE had been prepared 3.5 hours before the experiments, showing that the enzymes had been stable up to that time. CONCLUSIONS: The use of LPEs seems to be a good therapeutic option in patients with exocrine pancreatic insufficiency and the need for permanent high-calorie enteral feeding. Pharmaceutical companies should therefore be further encouraged to develop and distribute liquid enzyme preparations.

[Whether enzymatic and antisecretory drugs always correctly used in therapy of the chronic pancreatitis? An information for reflection].

Central scientific research institute of gastroenterology, Moscow It is presented debatable data of expediency of application of fermental medicines in therapies of chronic pancreatitis.

[Clinical and therapeutic aspects of combined course of the gastroesophageal reflux disease and the chronic pancreatitis].

Despite the meaningful achievements in modern diagnosis and farmacotherapy a problem of diseases which combine with each other still remains one of most complicated parts of therapy. In gastroenterology we could set for example combination GERD and pancreatitis. In this case pancreatitis is more severe and more often than not has a number of complications. This article includes the information about circumstances of pathogenesis and treatment such kind of patients. It has been regarded specialy the aspects of treatment of abdominal pain syndrome using secretolytic and enzymatic therapy.

Pancreatic enzyme pharmacotherapy.

Supplemental pancreatic enzyme preparations are provided to patients with conditions of pancreatic exocrine deficiency such as chronic pancreatitis and cystic fibrosis. These patients frequently experience steatorrhea, which occurs from inadequate fat absorption. The delivery of sufficient enzyme concentrations into the duodenal lumen simultaneously with meals can reduce nutrient malabsorption, improve the symptoms of steatorrhea, and in some cases alleviate the pain associated with chronic pancreatitis. Current clinical practices dictate administration of lipase 25,000-40,000 units/meal by using pH-sensitive pancrelipase microspheres, along with dosage increases, compliance checks, and differential diagnosis in cases of treatment failure. Despite the large number of specialty enzyme replacements available commercially, many patients remain dissatisfied with standard therapy, and future developments are needed to optimize treatment in these individuals.

Pancreatic Enzyme Supplements Are Not Effective for Relieving Abdominal Pain in Patients with Chronic Pancreatitis: Meta-Analysis and Systematic Review of Randomized Controlled Trials.

Background. Pancreatic enzyme supplementation is widely used to treat pain in patients with chronic pancreatitis, despite little evidence for efficacy. We performed a systematic review of the literature and a meta-analysis to investigate its effectiveness. Methods. All randomized controlled parallel or crossover trials in patients with chronic pancreatitis comparing pancreatic enzyme supplementation to placebo were included. The main outcome was improvement in pain score or reduced analgesic consumption. Two independent reviewers extracted data. Mantel-Haenszel random effect model meta-analysis was used whenever methodologically appropriate. Results. Five out of 434 retrieved studies were included in the systematic review. All studies used relatively similar methodology. Four studies using enteric-coated pancreatic enzyme supplementation failed to show any improvement in pain as compared to placebo. The only study using non-enteric-coated enzymes did show reduction in the pain score. There was significant heterogeneity among studies in both analyses. Random model meta-analysis of three studies showed no significant difference in the mean of daily pain score (mean difference: 0.09 (1.57-1.39), p = 0.91) or average weekly analgesic consumption (mean difference: -0.30 (-2.37-1.77), p = 0.77) between the periods of administering pancreatic enzyme supplementation versus placebo. Conclusion. Pancreatic enzyme supplements do not seem to relieve abdominal pain in patients with chronic pancreatitis and should not be prescribed solely for this purpose, given their significant cost and potential side effects.