Pancreatin

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.

Abbott Laboratories de México S.A. de C.V. developed a new fixed-dose combination of mosapride 5 mg, pancreatin 170 mg, and simethicone 125 mg as an alternative to the mosapride monotherapy to improve overall satisfaction and adequate relief of gastrointestinal disorders symptoms and to reduce multiple pill burden. As a part of the fixed-dose combination registration process in Mexico, a pharmacokinetic and relative bioavailability study was carried out to demonstrate nonexistence of pharmacokinetic interaction when mosapride is administered alone or in combination with pancreatin and simethicone using DOSIER® (mosapride) 5-mg tablets as a reference product. Tolerability of the fixed-dose combination tablet was assessed. In this open-label, randomized, oral single-dose, two-way crossover study, 65 healthy male and female subjects received either the fixed-dose combination tablet or the reference product during each study period. The two study periods were separated by a 7-day washout period. Mosapride concentrations in plasma samples were determined using a validated ultra-performance liquid chromatography coupled with tandem mass spectrometry (UPLC-MS/MS) method. Blood samples were collected for up to 16 h post dose. The primary evaluation criteria were Cmax and AUC0-t for mosapride. The 90% confidence intervals for the ratio of geometric means for Cmax (96.12% to 110.90%) and AUC0-t (99.07% to 108.06%) were within the defined acceptance limits of 75% to 133% and 80% to 125% for Cmax and AUC0-t , respectively, indicating bioequivalence between the two products. Both products were safe and well tolerated. Therefore, mosapride in combination with pancreatin and simethicone tablet is bioequivalent to mosapride alone, and no new safety signals emerged. © 2021 Société Française de Pharmacologie et de Thérapeutique.

Zoonotic avian influenza viruses have continued to infect people on occasion. During treatment, antiviral resistant viruses have occasionally emerged, highlighting the need for a novel strategy for treating human illness. After pancreatin treatment, edible bird's nest (EBN), swiftlet saliva consumed for health purposes, possesses anti-avian viral activity by inhibiting receptor-binding hemagglutinin (HA) activity. Glycan analysis revealed an abundance of α2,3Neu5Ac decoy receptors in pancreatin-treated EBN. Fucosylated tri-α2,3Neu5Ac tri-antennary N-glycans (N-35) and di-α2,3Neu5Ac core 2 O-glycans (O-15) are predominant, accounting for 53.46% and 44.66% of total N- and O-glycan amounts, respectively. Isobologram analysis revealed that the treated EBN had a strong synergistic effect with either oseltamivir carboxylate or zanamivir, a competitive inhibitor of receptor-destroying neuraminidases (NAs), against the avian H5N1 virus. Taken together, EBN has the potential to be developed as a food-derived avian viral trap to prevent and decrease avian virus infection as well as in combination with a viral releasing-NA inhibitor to increase therapeutic potency, reduce toxicity, delay resistance development, and potentially prevent pandemic onset.

In order to develop bacteriocins, like the lantibiotic nisin A, into effective alternatives to existing antibiotics, their biophysical and physicochemical properties must first be assessed, from solubility, to susceptibility and absorption. It has been well established that formulation strategies at early drug development stages can be crucial for successful outcomes during preclinical and clinical phases of development, particularly for molecules with challenging physicochemical properties. This work elucidates the physicochemical challenges of nisin A in terms of its susceptibility to digestive enzymes like pepsin, pancreatin and proteinase K and its poor solubility at physiological pHs. Low solution concentrations, below the minimum inhibitory concentration against Staphylococcus aureus, were obtained in phosphate buffered saline (PBS, pH 7.4) and in fasted state simulated intestinal fluid (FaSSIF, pH 6.5), while higher solubilities at more acidic pH's such as in a KCl/HCl buffer (pH 2) and in fasted state simulated gastric fluid (FaSSGF, pH 1.6) are observed. Tween® 80 (0.01% v/v) significantly increased the solution concentration of nisin A in PBS (pH 7.4, 24 hr). Pancreatin doubled nisin A's solution concentration at pH 7.4 (PBS) but reduced its' inhibitory activity to ∼ 20%, and pepsin almost completely degraded nisin (after 24 hr), but retained activity at biologically relevant exposure times (∼15 min). Harnessing synergism between nisin A and either glycol chitosan or ε-poly lysine, combined with the solubilizing effect of Tween®, increased the antimicrobial activity of nisin A six fold in an in vitro oral administration model.

The effect of binding of flavonoids, (-)-epigallocatechin-3-gallate (EGCG) and green tea extract (GTE), to beta-lactoglobulin (β-Lg) and micellar casein (micellar casein isolate, MCI) on protein digestibility was investigated. β-Lg resisted digestion by pepsin, but in the presence of EGCG the digestion of β-Lg was enhanced. Binding of EGCG to β-Lg was identified by nitro blue tetrazolium (NBT) staining and found, by isothermal titration calorimetry, to be an enthalpy-driven exothermic process, with a binding constant of 19 950 L mol-1. Binding promoted a more rapid digestion of β-Lg during simulated upper duodenal digestion. NBT staining indicated a loss of binding of EGCG to β-Lg during combined gastric and distal small intestinal digestion and correlated with the cleavage of β-Lg. However, increased β-Lg heteromer formation and reduced β-Lg monomer digestibility were observed for the β-Lg-GTE complex. MCI was more digestible than β-Lg during pepsin digestion, but reduced digestibility was observed for both MCI-EGCG and MCI-GTE complexes, with loss of binding during intestinal digestion. The free radical scavenging capacity (FRSC) of EGCG remained stable for the β-Lg-EGCG complex throughout the gastric and intestinal phases of digestion, but this was significantly lowered for the MCI-EGCG complex. These results indicated that polyphenols bind to milk proteins modulating the in vitro digestibility and FRSC of β-Lg and MCI as a result of the formation of complexes.

Staphylococcal enterotoxin A (SEA) functions both as superantigens that stimulate non-specific T cell proliferation as well as potent gastrointestinal toxins. We previously reported that (-)-epigallocatechin gallate (EGCG) binds to SEA. Therefore, the ability of EGCG to inhibit SEA toxin activity was examined. As a result, EGCG significantly decreased SEA-induced expression and production of interferon gamma (IFN-γ). In addition, EGCG inhibited SEA-induced spleen cell proliferation. To investigate the role of the galloyl group in EGCG on SEA cytotoxicity in more detail, the effect of the binding of a hydroxyl group at position 3 of the galloyl group in EGCG to SEA on SEA cytotoxicity was examined using two methylated EGCG. SEA cytotoxicity was significantly controlled in both (-)-3''-Me-EGCG and (-)-4''-Me-EGCG. These results suggest that EGCG inhibits toxic activity via direct interaction with SEA or without any interaction with SEA. The binding affinity between SEA and EGCG under in vivo conditions was examined using a model solution. Although after treatment under acidic and alkaline conditions, the presence of protein and the digestive tract model solution, EGCG still interacted with SEA. Our studies are the first to demonstrate the effect of the binding of EGCG to SEA on toxin activity.

PURPOSE: Abiraterone acetate (AbA) is a poorly water-soluble drug with an oral bioavailability of <10% and a significant pharmaceutical food effect. We aimed to develop a more efficient oral solid-state lipid-based formulation for AbA using a supersaturated silica-lipid hybrid (super-SLH) approach to achieve high drug loading, improve in vitro solubilization and mitigate the food effect, while gaining a mechanistic insight into how super-SLH are digested and release drug. METHODS: The influence of super-SLH saturation level and lipid type on the physicochemical properties and in vitro solubilization during lipolysis of the formulations was investigated and compared to the commercial product, Zytiga. RESULTS: Super-SLH achieved significantly greater levels of AbA solubilization compared to Zytiga. Solubilization was influenced by the AbA saturation level, which determined the solid state of AbA and the relative amount of lipid, and the lipid utilized, which determined its degree of digestion and the affinity of the lipid and digestion products to the silica. A fine balance existed between achieving high drug loads using supersaturation and improving performance using the lipid-based formulation approach. The non-supersaturated SLH prepared with Capmul PG8 mitigated the 3-fold in vitro food effect. CONCLUSION: SLH and super-SLH improve in vitro solubilization of AbA, remove the food effect and demonstrate potential to improve oral bioavailability in vivo. Graphical Abstract Abiraterone acetate was formulated as silica-lipid hybrids and demonstrated enhanced in vitro solubilization in comparison to pure abiraterone acetate and commercial product, Zytiga.

In this study, we investigated the interaction between apple polyphenols (AP; mainly consisting of procyanidin (PC) from an apple) and staphylococcal enterotoxin A (SEA), and the inhibitory effects of AP on SEA activity. According to the degree of polymerization, in particularly highly polymerized PC (more than pentamer) strongly interacted with SEA. The binding affinity of AP with SEA molecules was determined using Biacore analysis. AP reacted with SEA immobilized on a Biacore sensor chip. After treatment with pepsin and pancreatin, to examine the changes of binding affinity of AP in intragastric conditions, AP maintained interaction with SEA. We examined whether AP inhibits the proliferation and interferon-γ (IFN-γ) production induced by SEA in mouse spleen cells. AP strongly inactivated the proliferation and IFN-γ production induced by SEA. These results suggest that AP, which has a higher degree of polymerization, inactivates stronger biological activity of SEA through interaction with SEA. Our studies are the first to demonstrate the relationship between the degree of polymerization of AP and the inhibitory effects on SEA activities.

: Orlistat, a lipase inhibitor taken with meals at doses of 60 mg (available over-the-counter) or 120 mg (prescription only) for treatment of obesity, is known to impair the absorption of fat-soluble molecules. Dalcetrapib, a modulator of cholesteryl ester transfer protein activity, is a lipophilic thioester prodrug. Lipase-induced and pancreatin-induced hydrolysis of dalcetrapib in biorelevant media in vitro was very efficiently inhibited by orlistat. Thus, the potential for orlistat to affect the bioavailability of concomitantly administered dalcetrapib was studied in an open-label 2-cohort study in 24 healthy volunteers as follows: single 600-mg doses of dalcetrapib were administered with increasing doses of orlistat (cohort A: 10, 40, 120 mg; cohort B: 20, 60, 120 mg). Exposure to the active form of dalcetrapib was more than 50% lower when taken with orlistat 60 mg or 120 mg than when taken alone. Similar trends were observed with lower orlistat doses (20 mg and 40 mg). Concomitant administration of orlistat also reduced the pharmacodynamic effects of dalcetrapib treatment on cholesteryl ester transfer protein activity. The interaction exceeds that predicted on the basis of dalcetrapib lipophilicity. These findings demonstrate the potential for large interactions between orlistat and esters that undergo de-esterification in the gastrointestinal tract, independent of lipophilicity.

BACKGROUND: The mineral status in hypertensive patients may be affected by hypotensive drugs. The aim of this study was to estimate the influence of hypotensive drugs (angiotensine converting enzyme inhibitors (ACE-I), β-blockers, Ca-antagonists, diuretics) on the potential bioavailability of magnesium, iron, zinc and copper from buckwheat groats in vitro enzymatic digestion. MATERIAL AND METHODS: The degree of release of magnesium, iron, zinc and copper from buckwheat groats was determined with and without (the control sample) an addition of hypotensive drugs. Four antihypertensive drugs in one dose (one tablet per sample) were analysed: metocard (a β-blocker), cardilopin (a Ca-antagonist), apo-perindox (ACE-I) and indapen (a diuretic). The samples were subjected to enzymatic digestion under in vitro conditions. The content of minerals in buckwheat groats before and after enzymatic digestion was determined by flame atomic absorption spectrometry (AAS). RESULTS: It was found that cardilopin (amlodipine) and indapen (indapamide) significantly increased the release of zinc from groats. The degree of release of magnesium was higher and the release of iron was lower in samples with apo-perindox (perindopril) than in the control group. The release of copper was significantly decreased by indapen (indapamid). CONCLUSIONS: Amlodipine, perindopril and indapamide affected the release of magnesium, iron, zinc and copper from buckwheat groats in vitro enzymatic digestion.

BACKGROUND: High-dose ibuprofen therapy limits the progression of lung disease in patients with cystic fibrosis. However, ibuprofen increases intestinal permeability, which potentiates intestinal damage caused by high-dose pancreatic enzyme treatment, as was shown in a previous study by this group. In the present study, the combined effects of ibuprofen and pancreatic enzyme treatment on the intestine and liver were examined. METHODS: Using a chronically catheterized rat model, high-dose ibuprofen (60 mg/kg x day in two doses), with or without pancreatic enzyme treatment was infused into gastric and duodenal catheters, respectively, for 20 days. Six groups were studied: control group; ibuprofen treatment alone; pancreatic enzyme treatment alone (two groups: normal dose, 10,000 U lipase/kg x day and high dose, 40,000 U lipase/kg x day); and ibuprofen combined with pancreatic enzyme (two groups: ibuprofen with high-dose pancreatic enzyme and ibuprofen and low-dose pancreatic enzyme). After treatment, rats were autopsied, and complete histologic analyses of the entire intestine and liver were performed. RESULTS: Ibuprofen caused mild ulceration of the small intestine in 50% of rats. Pancreatic enzyme treatment alone did not induce ulceration of the intestine. The combination of pancreatic enzyme and ibuprofen treatment increased the severity of the ulcers in the small intestine but not the number of ulcers or the percentage of rats affected. Ibuprofen treatment alone did not cause ulcers in the large intestine, but with the addition of pancreatic enzymes, ulceration and fibrosis were present. CONCLUSIONS: Ibuprofen at doses used to limit progression of cystic fibrosis lung disease caused enteropathy in 50% of rats. There was synergism between ibuprofen and pancreatic enzyme treatment in the production of severe ulcers. Ulcers in the cecum and colon were increased with combined ibuprofen and pancreatic enzyme treatment compared with incidence in control animals.

Cyclosporin (CsA) is currently the main immunosuppressive agent used in organ transplantation with considerable improvement in graft survival. Oral CsA solution is highly lipophilic, and its bioavailability may be reduced in cystic fibrosis (CF) heart-lung transplant recipients with pancreatic, gastrointestinal, and hepatic insufficiency. The bioavailability of oral CsA solution in 7 CF transplant recipients (5 male and 2 female with a mean age of 27 years and a mean weight of 49 kg) and 3 non-CF heart-lung recipients (1 male and 2 female with a mean age of 41 years and a mean weight of 60 kg) was studied. Following intravenous CsA administration, the kinetic curves were similar with no significant difference in the volume of distribution and clearance of CsA demonstrated between the CF and non-CF groups. The mean daily dose of oral CsA in 7 CF subjects (23.3 mg.kg-1) was significantly higher than the 3 non-CF heart-lung recipients (4.8 mg.kg-1). The mean maximum blood concentration of CsA for the oral dose was 776 ng.ml-1 for the 7 CF subjects, which was comparable with the mean peak values of 789 ng.ml-1 for the 3 non-CF control subjects. Poor enteral absorption of CsA probably accounts for the significantly lower mean bioavailability in the 7 CF subjects (14.9%) compared with the 3 non-CF control subjects (39.4%). The effects on the bioavailability of oral CsA solution by pancreatic enzymes (Creon) and histamine-2 antagonist (ranitidine) were also evaluated in the 7 CF subjects. No significant difference was demonstrated.

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 treatme

Bioactive peptides derived from native proteins modulate physiological processes in the metabolic pathways. Given that multiple protocols in the literature mimic the digestion of dietary components, gathering studies that use such models directed at protein digestion processes is critical. This systematic review aimed to gather evidence that adopted adequate experimental models to simulate human protein digestion. The databases searched were PubMed, Web of Science, ScienceDirect, Embase, Virtual Health Library, and Scopus. A total of 1985 articles were found, resulting in 20 eligible in vitro studies. The Office of Health Assessment and Translation was used to evaluate methodological quality. Seven studies used plant-based protein sources, twelve used animal protein sources, and one used both. The duration of the oral phase varied, although 60% of the studies employed a protein digestion period of 120 min. Amylase, pepsin, and pancreatin enzymes were utilized in 40% of the studies, with pH levels of 7, 3, and 7, respectively, during the oral, gastric, and intestinal phases. The INFOGEST harmonized static model was adopted by 65% of the studies; INFOGEST is the most effective model for simulating gastrointestinal protein processes in humans and can be used to answer several research questions because it describes experimental conditions close to the human physiological situation.

While lipase content and appropriate acid protection of pancreatin preparations (PP) are well defined determinants of an effective therapy of exocrine pancreatic insufficiency, the optimal sphere size of PP has remained a matter of discussion. We performed a systematic review to assess the optimal sphere size of enteric coated pancreatin products that may best guarantee coordinated delivery of PP and food to the duodenum. PubMed was searched for studies on gastric emptying of indigestible spheres in the digestive phase, using overlapping search algorithms; identified sources were searched for further leads, extending the investigation to Google Scholar. Of 739 screened publications, 26 were included in the final assessment. Contrary to current guideline recommendations, no scientific evidence was found to support a 2 mm diameter threshold for gastric emptying of indigestible particles. There is no documented advantage of ≤2 mm spheres regarding duodenal delivery and restoring maldigestion. The evolving picture is that of a gradation of sizes, over which gastric emptying becomes slower and more variable as particle size increases. Even 7 mm particles may be emptied from the stomach in conjunction with nutrient uptake. In conclusion sphere size of PP is not the essential parameter for selecting an effective PP fitting all patients. A variety of brands offer different lipase contents and sphere sizes that allow the physician to tailor treatment to the individual patient`s needs.

PURPOSE: The purpose of this study was to systematically review the literature of esophageal carcinosarcomas (ECS) and report epidemiologic and clinicopathologic data for this rare entity. We also attempted to shed light to the biologic behavior of ECSs with special reference to factors that may affect disease-free (DES) and overall survival (OS). METHODS: A systematic literature review was performed using MEDLINE, EMBASE and the Cochrane Library databases (Search date: 12 May 2017). The search strategy referred to carcinosarcoma OR pseudosarcoma OR polypoid carcinoma OR sarcomatoid carcinoma OR spindle-cell squamous cell carcinoma OR metaplastic carcinoma OR pseudosarcomatous carcinoma AND esophagus. A total number of 103 ECS patients was identified. Results: ECs most frequently occur in middle-aged as well as elderly men with a history of smoking or drinking. Middle and/or lower esophagus remains the most common location. Imaging plays a pivotal role in the management of ECS by delineating the anatomic extent of the tumor and thereby determining the appropriate therapeutic strategy. Nevertheless, immunohistochemistry is the gold standard for the diagnosis of carcinosarcomas, since it has been demonstrated that CEA, EMA, pancreatin, chromogranin A, CD56 and synaptophysin staining are highly specific markers for the carcinomatous components, while desmin, vimentin and smooth muscle/sarcomeric actin show affinity for the sarcomatous elements. Esophagectomy has been traditionally considered the treatment modality of choice. Endoscopic procedures, including mucosal resection and submucosal dissection have also been proposed. Alternative therapies, such as radio- and chemotherapy proved insufficient. CONCLUSION: ECS is a rare tumor. Immunohistochemistry is the gold standard for the diagnosis of this disease. Esophagectomy has been traditionally considered the treatment modality of choice. Endoscopic procedures have also been proposed while potential benefit of alternative therapies, such as radiotherapy and chemotherapy remains controversial.