Effect of pancreatin on acute pancreatitis resulting from L-arginine administration in mice, a morpho-histopathological and biochemical study

Abstract Acute pancreatitis (AP) is a life-unpleasant situation with contradictory and inadequate treatments. In this regard, the present study evaluated the effect of the possible pretreatment of lipase-pancreatin on L-arginine-induced AP. Forty adult mice were selected and divided into five groups: I) control group, II and III) AP groups (i.p.) receiving L-arginine of 2×300 and 2×400 mg/100 g body weight (b.w.), IV) AP (2×300 L-arginine) group + pancreatin (mice were i.p. injected by 350 U-lipase), and V) AP (2×400 L-arginine) group + pancreatin (mice were i.p. injected by 350 U-lipase). All AP groups displayed a significant increase in serum levels of ALT, AST, TBARS, and TNF-alpha compared to the control group. Moreover, pancreatic tissue edema, inflammation, and vacuolization of acinar cells were significantly higher in the untreated L-arginine group compared to the control and pancreatin groups. Conversely, the diameter of pancreatic islets significantly declined after induction of pancreatitis compared with control and pancreatin groups. Pancreatin treatment can be used in pancreatic dysfunction, however, this medicine showed no protective effect against L-arginine-induced AP in the mouse model.

[Treatment of postprandial discomfort syndrome in the elderly: a multi-centered prospective randomized controlled clinical study].

Objective: To evaluate the efficacy and safety of Oryz-Aspergillus enzyme and pancreatin tablets (Combizym(®)) in the treatment of postprandial distress syndrome (PDS) in the elderly, compared with gastrointestinal motility drugs. Methods: A prospective randomized controlled trial was designed and registered in the China Clinical Trials Registry (ChiCTR-IPR-16008185). The elderly patients with PDS were randomly divided into three groups, including Mosapride group with Mosapride citrate tablets 5 mg 3 times per day for 2 weeks; Combizym(®) group with Combizym tablets 244 mg 3 times per day for 2 weeks; combined treatment group with both drugs and same doses for 2 weeks. The modified Nepean dyspepsia index (NDSI) score, discomfort intensity score and PDS score were calculated on patients before treatment, at the end of first and second week of treatment, as well as 4 weeks after treatment finished, respectively. Adverse effects were evaluated. Results: A total of 323 patients from 16 tertiary hospitals in China were enrolled in this study. Among them, 105 patients were in Mosapride group, 109 in Combizym(®) group and 109 in combined treatment group. There were 148 males (45.8%) and 175 females (54.2%) with median age 71.4±9.0 years (60-100 years). Baseline characteristics of three groups were comparable. After treatment, the NDSI scores in three groups all decreased significantly (P<0.001), while they were similar between groups (P>0.05). The discomfort intensity score and PDS score in three groups showed a significant reduction after treatment (P<0.001), especially in the combined treatment group. Compared with Mosapride group, the scores in Combizym(®) group decreased significantly after one or two weeks [discomfort intensity score: after one week, 4.0(2.5, 8.0) vs. 6.0(3.0, 10.0); after two weeks, 3.0(0.0, 5.0) vs. 4.0(2.0, 6.0); all P<0.05. PDS score: after one week, 6.0(3.0, 9.0) vs. 7.0(3.5, 10.5); after two weeks, 3.0(0.0, 5.0) vs. 4.0(2.0, 7.0); all P<0.05]. The efficacy rate in all patients after first week of treatment was over 15.0%. The efficacy rates after two weeks were 55.2%, 68.8% and 73.4% in Mosapride group, Combizym(®) group and combined treatment group, respectively. After two week treatment, the efficacy rates in Combizym(®) group (P=0.041) and combined group (P=0.006) were higher than that of Mosapride group. The recurrence rate of Mosapride group was 9.5%, which was significantly higher than that of Combizym(®) group (1.8%, P<0.05) and combined treatment group (1.8%, P<0.05). There were no serious adverse effects in the three groups. Conclusions: The efficacy of Oryz-Aspergillus enzyme and pancreatin tablets is comparable with that of Mosapride in elderly PDS patients, with fewer adverse effects and low recurrence rate. Combination regimen indicates better efficacy than that of Oryz-Aspergillus enzyme and pancreatin tablets or Mosapride alone.

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

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

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

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

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.

Randomised clinical trial: a 1-week, double-blind, placebo-controlled study of pancreatin 25 000 Ph. Eur. minimicrospheres (Creon 25000 MMS) for pancreatic exocrine insufficiency after pancreatic surgery, with a 1-year open-label extension.

BACKGROUND: Pancreatic exocrine insufficiency (PEI) often occurs following pancreatic surgery. AIM: To demonstrate the superior efficacy of pancreatin 25 000 minimicrospheres (Creon 25000 MMS; 9-15 capsules/day) over placebo in treating PEI after pancreatic resection. METHODS: A 1-week, double-blind, randomised, placebo-controlled, parallel-group, multicentre study with a 1-year, open-label extension (OLE). Subjects ≥18 years old with PEI after pancreatic resection, defined as baseline coefficient of fat absorption (CFA) <80%, were randomised to oral pancreatin or placebo (9-15 capsules/day: 3 with main meals, 2 with snacks). In the OLE, all subjects received pancreatin. The primary efficacy measure was least squares mean CFA change from baseline to end of double-blind treatment (ancova). RESULTS: All 58 subjects randomised (32 pancreatin, 26 placebo) completed double-blind treatment and entered the OLE; 51 completed the OLE. The least squares mean CFA change in the double-blind phase was significantly greater with pancreatin vs. placebo: 21.4% (95% CI: 13.7, 29.2) vs. -4.2% (-12.8, 4.5); difference 25.6% (13.9, 37.3), P < 0.001. The mean ± s.d. CFA increased from 53.6 ± 20.6% at baseline to 78.4 ± 20.7% at OLE end (P < 0.001). Treatment-emergent adverse events occurred in 37.5% subjects on pancreatin and 26.9% on placebo during double-blind treatment, with flatulence being the most common (pancreatin 12.5%, placebo 7.7%). Only two subjects discontinued due to treatment-emergent adverse events, both during the OLE. CONCLUSIONS: This study demonstrates superior efficacy of pancreatin 25 000 over placebo in patients with PEI after pancreatic surgery, measured by change in CFA. Pancreatin was generally well tolerated at the high dose administered (EudraCT registration number: 2005-004854-29).

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

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

[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.

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.

[Use of Panzytrat in the replacement therapy of exocrine pancreatic insufficiency (an analytical review)]. / Ispol'zovanie pantsitrata v zamestitel'noi terapii ékzokrinnoi nedostatochnosti podzheludochnoi zhelezy (analiticheskii obzor).

The development of new drug formulations of pancreatine based on the principle of microdosage with a pH-sensitive coating produced the most demonstrative clinical result--a considerable increase in duration and quality of life of patients with chronic pancreatitis and cystofibrosis, most of which are children. Clinical studies confirmed high efficiency and safety of Panzytrat in open and double blind comparative clinical studies with the participation of 4,557 patients with chronic pancreatitis, mucoviscidosis, and pancreathogenous digestion disorders. In addition to the above-mentioned symptoms, indications for application of Panzytrat also include any clinical symptoms of the pancreas relative excretory insufficiency, in particular, states after oncological diseases and surgical operations (obstruction of ducts, resection, cholecystectomy, etc.) up to a failure to adhere to a diet and overeating.

Proper usage of pancreatic enzymes.

With the recognition of the close link between nutritional status and pulmonary function in cystic fibrosis (CF), treatment and prevention of malnutrition have become a major focus in the modern therapeutic approach for patients with CF. Thereby, pancreatic enzyme replacement therapy plays a central role. This article reviews key publications on important aspects of pancreatic enzyme replacement therapy contained in the literature over the last 12 months. New insights into the pathogenesis of exocrine pancreatic disease, efficacy and dosing of pancreatic enzyme preparations, occurrence of fibrosing colonopathy, enzyme replacement in the context of enteral nutrition, and assessment of pancreatic function are addressed.

Fibrosing colonopathy revealing cystic fibrosis in a neonate before any pancreatic enzyme supplementation.

Although its pathogenesis remains still unknown, fibrosing colonopathy (FCP) is considered to be the result of prolonged treatment by high doses of pancreatic enzyme preparations, in a small proportion of patients who present with cystic fibrosis (CF). We present the case of a newborn with meconium ileus (treated by conservative measures), in which, at the age of 3 weeks, the features of intestinal obstruction made necessary the removal of 15 cm of the proximal large intestine. Macroscopical and especially microscopical appearances typical for FCP were found, despite the absence of any enzymatic treatment. These findings raised the suspicion of CF, which was confirmed 4 weeks later at necropsy by the presence of characteristic pancreatic lesions. This case and another similar report in the literature suggest that the mechanism of FCP must be linked with the disease itself, at least in some patients. Thus, for us, FCP is not a "closed subject" and we sustain the importance of continuing studies, which will shed light on its etiopathogenesis.