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HPB : the Official Journal of the... Oct 2017Although many patients undergoing pancreatoduodenectomy (PD) for cancer have pancreatic exocrine insufficiency, pancreatic enzyme replacement therapy (PERT) is not... (Observational Study)
Observational Study
BACKGROUND
Although many patients undergoing pancreatoduodenectomy (PD) for cancer have pancreatic exocrine insufficiency, pancreatic enzyme replacement therapy (PERT) is not routinely used, and effects upon post-operative survival are unclear.
METHODS
This review of patients undergoing PD for periampullary malignancy sought to test for an association between PERT and overall survival, with post-hoc subgroup analysis performed after stratifying patients by the year of surgery, pancreatic duct width and tumour type.
RESULTS
Some 202/469 (43.1%) patients received PERT. After accounting for pathological variables and chemotherapy, PERT use was found to be independently associated with improved survival on multivariable analysis [HR 0.72 (95% CI: 0.52-0.99), p = 0.044] and on propensity matched analysis (p = 0.009). The effect of PERT upon improved survival was predominantly observed amongst patients with a dilated pancreatic duct (≥3 mm).
DISCUSSION
PERT use was independently associated with improved survival following PD for cancer. The validity of this observation is supported by an effect largely confined to those patients with a dilated pancreatic duct. The nutritional status of patients undergoing PD for cancer needs further investigation and the effects of PERT require verification in further clinical studies.
Topics: Aged; Bile Duct Neoplasms; Disease Progression; Disease-Free Survival; Duodenal Neoplasms; Enzyme Replacement Therapy; Exocrine Pancreatic Insufficiency; Female; Humans; Kaplan-Meier Estimate; Logistic Models; Male; Middle Aged; Multivariate Analysis; Pancreatic Neoplasms; Pancreaticoduodenectomy; Pancrelipase; Propensity Score; Proportional Hazards Models; Retrospective Studies; Risk Factors; Time Factors; Treatment Outcome
PubMed: 28711377
DOI: 10.1016/j.hpb.2017.05.009 -
Molecular Biology of the Cell Sep 2017Stress responses are highly nuanced and variable, but how this diversity is achieved by modulating receptor function is largely unknown. Corticotropin-releasing factor...
Stress responses are highly nuanced and variable, but how this diversity is achieved by modulating receptor function is largely unknown. Corticotropin-releasing factor receptors (CRFRs), class B G protein-coupled receptors, are pivotal in mediating stress responses. Here we show that the two known CRFRs interact to form heteromeric complexes in HEK293 cells coexpressing both CRFRs and in vivo in mouse pancreas. Coimmunoprecipitation and mass spectrometry confirmed the presence of both CRFR and CRFβR, along with actin in these heteromeric complexes. Inhibition of actin filament polymerization prevented the transport of CRFβR to the cell surface but had no effect on CRFR. Transport of CRFR when coexpressed with CRFR became actin dependent. Simultaneous stimulation of cells coexpressing CRFR+CRFβR with their respective high-affinity agonists, CRF+urocortin2, resulted in approximately twofold increases in peak Ca responses, whereas stimulation with urocortin1 that binds both receptors with 10-fold higher affinity did not. The ability of CRFRs to form heteromeric complexes in association with regulatory proteins is one mechanism to achieve diverse and nuanced function.
Topics: Actin Cytoskeleton; Animals; Cell Membrane; Corticotropin-Releasing Hormone; HEK293 Cells; Humans; Mice; Pancrelipase; Receptors, Corticotropin-Releasing Hormone; Signal Transduction; Stress, Physiological; Tissue Culture Techniques
PubMed: 28701349
DOI: 10.1091/mbc.E16-11-0778 -
Antimicrobial Agents and Chemotherapy Jul 2017Tenofovir disoproxil fumarate (TDF), a prodrug of tenofovir, has oral bioavailability (25%) limited by intestinal transport (P-glycoprotein), and intestinal degradation...
Tenofovir disoproxil fumarate (TDF), a prodrug of tenofovir, has oral bioavailability (25%) limited by intestinal transport (P-glycoprotein), and intestinal degradation (carboxylesterase). However, the influence of luminal pancreatic enzymes is not fully understood. Physiologically based pharmacokinetic (PBPK) modeling has utility for estimating drug exposure from data. This study aimed to develop a PBPK model that included luminal enzyme activity to inform dose reduction strategies. TDF and tenofovir stability in porcine pancrelipase concentrations was assessed (0, 0.48, 4.8, 48, and 480 U/ml of lipase; 1 mM TDF; 37°C; 0 to 30 min). Samples were analyzed using mass spectrometry. TDF stability and permeation data allowed calculation of absorption rates within a human PBPK model to predict plasma exposure following 6 days of once-daily dosing with 300 mg of TDF. Regional absorption of drug was simulated across gut segments. TDF was degraded by pancrelipase (half-lives of 0.07 and 0.62 h using 480 and 48 U/ml, respectively). Previously reported maximum concentration (; 335 ng/ml), time to (; 2.4 h), area under the concentration-time curve from 0 to 24 h (AUC; 3,045 ng · h/ml), and concentration at 24 h (; 48.3 ng/ml) were all within a 0.5-fold difference from the simulated (238 ng/ml), (3 h), AUC (3,036 ng · h/ml), and (42.7 ng/ml). Simulated TDF absorption was higher in duodenum and jejunum than in ileum (p<0.05). These data support that TDF absorption is limited by the action of intestinal lipases. Our results suggest that bioavailability may be improved by protection of drug from intestinal transporters and enzymes, for example, by coadministration of enzyme-inhibiting agents or nanoformulation strategies.
Topics: ATP Binding Cassette Transporter, Subfamily B, Member 1; Adolescent; Adult; Anti-HIV Agents; Carboxylesterase; HIV Infections; Humans; Lipase; Male; Middle Aged; Pancrelipase; Tenofovir; Young Adult
PubMed: 28416547
DOI: 10.1128/AAC.00105-17 -
PloS One 2017Type 1 diabetes (T1D) is an autoimmune proinflammatory disease with no effective intervention. A major obstacle in developing new immunotherapies for T1D is the lack of...
Type 1 diabetes (T1D) is an autoimmune proinflammatory disease with no effective intervention. A major obstacle in developing new immunotherapies for T1D is the lack of means for monitoring immune responsiveness to experimental therapies. The LEW1.WR1 rat develops autoimmunity following infection with the parvovirus Kilham rat virus (KRV) via mechanisms linked with activation of proinflammatory pathways and alterations in the gut bacterial composition. We used this animal to test the hypothesis that intervention with agents that block innate immunity and diabetes is associated with a shift in the gut microbiota. We observed that infection with KRV results in the induction of proinflammatory gene activation in both the spleen and pancreatic lymph nodes. Furthermore, administering animals the histone deacetylase inhibitor ITF-2357 and IL-1 receptor antagonist (Anakinra) induced differential STAT-1 and the p40 unit of IL-12/IL-23 gene expression. Sequencing of bacterial 16S rRNA genes demonstrated that both ITF-2357 and Anakinra alter microbial diversity. ITF-2357 and Anakinra modulated the abundance of 23 and 8 bacterial taxa in KRV-infected animals, respectively, of which 5 overlapped between the two agents. Lastly, principal component analysis implied that ITF-2357 and Anakinra induce distinct gut microbiomes compared with those from untreated animals or rats provided KRV only. Together, the data suggest that ITF-2357 and Anakinra differentially influence the innate immune system and the intestinal microbiota and highlight the potential use of the gut microbiome as a surrogate means of assessing anti-inflammatory immune effects in type 1 diabetes.
Topics: Animals; Biodiversity; Biomarkers; Diabetes Mellitus, Type 1; Feces; High-Throughput Nucleotide Sequencing; Hydroxamic Acids; Immunity, Innate; Interleukin 1 Receptor Antagonist Protein; Intestines; Lymph Nodes; Microbiota; Pancrelipase; Parvovirus; Principal Component Analysis; RNA, Ribosomal, 16S; Rats; Rats, Inbred Lew; Spleen
PubMed: 28301545
DOI: 10.1371/journal.pone.0173968 -
Endocrine Regulations Jan 2016Roux-en-Y gastric bypass (RYGB) is an independent risk factor for moderate hypocalcaemia and may lead to the development of resistant hypocalcaemia following thyroid...
OBJECTIVE
Roux-en-Y gastric bypass (RYGB) is an independent risk factor for moderate hypocalcaemia and may lead to the development of resistant hypocalcaemia following thyroid surgery. Subject and Results. A 35-year old female patient was referred to our hospital by her family physician for treatment of resistant hypocalcaemia. The patient underwent RYGB three years ago and a total thyroidectomy for a benign thyroid nodule one year ago. Calcitriol, calcium carbonate, magnesium oxide, and ergocalciferol therapeutic dosages were incremented. Despite dosage increments, the desired calcium levels were not achieved. In the sixth month after admission to our hospital, pancrelipase was added to patient's treatment scheme. On the following visit, a good calcium increase had been achieved.
CONCLUSION
This report presents a case history of RYGB and resistant hypocalcaemia, which developed after thyroid surgery and positively responded to pancrelipase treatment.
Topics: Adult; Calcium, Dietary; Female; Gastric Bypass; Humans; Hypocalcemia; Intestinal Absorption; Pancrelipase; Thyroidectomy
PubMed: 27560634
DOI: 10.1515/enr-2016-0006 -
Journal of Cystic Fibrosis : Official... Sep 2016Despite guidelines suggesting pancreatic enzyme replacement therapy (PERT) should be taken before or during a meal, it is currently unknown whether this has benefits... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Despite guidelines suggesting pancreatic enzyme replacement therapy (PERT) should be taken before or during a meal, it is currently unknown whether this has benefits over administration after a meal in individuals with cystic fibrosis (CF).
METHODS
18 children with pancreatic insufficient CF were randomised to two (13)C-mixed triglyceride ((13)C-MTG) breath tests to assess lipase activity with PERT administered 10min before and 10min after a meal. Results were expressed as percentage cumulative dose recovered (PCDR) of (13)CO2 and were compared with established values in healthy subjects. Gastric half emptying time (T½) was also assessed by a (13)C-octanoate breath test.
RESULTS
There was no difference in mean PCDR of (13)CO2 between taking PERT before versus after the meal (p=0.68). Eleven subjects had a greater PCDR when PERT was taken before and 7 when PERT was taken after the meal. 6/8 subjects (75%) with a lower than normal PCDR at one time point normalised PCDR when PERT timing was changed. When PERT was taken after the meal, PCDR was higher in normal vs. fast T½ (p=0.04).
CONCLUSIONS
Changing PERT timing can result in normalised lipase activity. Gastric emptying rate may influence optimal timing of PERT. Clinical Trial Registration Number - This study was undertaken prior to the registration process being a commonly required practice.
Topics: Adolescent; Breath Tests; Child; Cystic Fibrosis; Dietary Fats; Drug Administration Schedule; Enzyme Replacement Therapy; Female; Gastric Emptying; Gastrointestinal Agents; Humans; Lipase; Male; Pancreas; Pancreatic Function Tests; Pancrelipase; Time Factors; Triglycerides
PubMed: 27102891
DOI: 10.1016/j.jcf.2016.03.008 -
Journal of Cystic Fibrosis : Official... Sep 2016Zenpep (APT-1008) is a pancreatic enzyme product for the treatment of exocrine pancreatic insufficiency (EPI) associated with cystic fibrosis (CF). (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Zenpep (APT-1008) is a pancreatic enzyme product for the treatment of exocrine pancreatic insufficiency (EPI) associated with cystic fibrosis (CF).
METHODS
Zenpep and Kreon, both containing 25,000 lipase units, were compared in a randomised, double-blind, crossover, non-inferiority study for CF-associated EPI in patients aged ≥12years. Patients on a standardised diet and stabilised treatment were randomised to two treatment sequences: Zenpep/Kreon or Kreon/Zenpep. The primary efficacy endpoint was the coefficient of fat absorption over 72h (CFA-72h).
RESULTS
96 patients (mean age 19.2years, 60.4% males) were randomised with 83 completers of both sequences comprising the efficacy population. Zenpep demonstrated non-inferiority and equivalence to Kreon in fat absorption (LS mean CFA-72h: Zenpep, 84.1% [SE 1.1] vs. Kreon, 85.3% [SE 1.1]; p=0.297). Safety and tolerability were similar.
CONCLUSIONS
Zenpep is comparable with Kreon in efficacy and safety for the treatment of adolescents and adults with CF-associated EPI. NCT01641393.
Topics: Adolescent; Adult; Cystic Fibrosis; Double-Blind Method; Drug Monitoring; Enzyme Replacement Therapy; Exocrine Pancreatic Insufficiency; Female; Gastrointestinal Agents; Humans; Intestinal Absorption; Male; Pancreas; Pancreatic Function Tests; Pancrelipase; Treatment Outcome
PubMed: 27013382
DOI: 10.1016/j.jcf.2016.02.010 -
Internal Medicine (Tokyo, Japan) 2016
PubMed: 26726093
DOI: 10.2169/internalmedicine.55.5729 -
International Journal of Surgery Case... 2015Gastric outlet obstruction is characterized by the retention of gastric contents. Removal of gastric contents is an important part of the treatment strategy. The use of...
INTRODUCTION
Gastric outlet obstruction is characterized by the retention of gastric contents. Removal of gastric contents is an important part of the treatment strategy. The use of a nasogastric tube alone can result in inadequate removal of gastric contents. We treated a patient with advanced gastric cancer and gastric outlet obstruction with pancrelipase to aid in the removal of gastric contents.
PRESENTATION OF CASE
The patient is an 81-year-old man with a Type 3 gastric cancer nearly circumferentially involving the antrum, resulting in gastric outlet obstruction. A nasogastric tube was placed for four days, but drainage of gastric contents was inadequate. Pancrelipase was then given orally for four days, and gastric contents were evacuated. The patient underwent distal gastrectomy with Roux-en-Y reconstruction and was discharged from the hospital on postoperative day 14.
DISCUSSION
This report suggests that pancrelipase may be beneficial in the treatment of patients with gastric outlet obstruction.
CONCLUSION
Pancrelipase allowed gastric contents to be evacuated in a short period of time in a patient with gastric outlet obstruction.
PubMed: 26036459
DOI: 10.1016/j.ijscr.2015.05.023 -
PloS One 2014The molecular interactions between pancreatic lipase (PL) and four tea polyphenols (EGCG analogs), like (-)-epigallocatechin gallate (EGCG), (-)-gallocatechin gallate...
The molecular interactions between pancreatic lipase (PL) and four tea polyphenols (EGCG analogs), like (-)-epigallocatechin gallate (EGCG), (-)-gallocatechin gallate (GCG), (-)-epicatechin gallate (ECG), and (-)-epigallocatechin (EC), were studied from PL activity, conformation, kinetics and thermodynamics. It was observed that EGCG analogs inhibited PL activity, and their inhibitory rates decreased by the order of EGCG>GCG>ECG>EC. PL activity at first decreased rapidly and then slowly with the increase of EGCG analogs concentrations. α-Helix content of PL secondary structure decreased dependent on EGCG analogs concentration by the order of EGCG>GCG>ECG>EC. EGCG, ECG, and EC could quench PL fluorescence both dynamically and statically, while GCG only quenched statically. EGCG analogs would induce PL self-assembly into complexes and the hydrodynamic radii of the complexes possessed a close relationship with the inhibitory rates. Kinetics analysis showed that EGCG analogs non-competitively inhibited PL activity and did not bind to PL catalytic site. DSC measurement revealed that EGCG analogs decreased the transition midpoint temperature of PL enzyme, suggesting that these compounds reduced PL enzyme thermostability. In vitro renaturation through urea solution indicated that interactions between PL and EGCG analogs were weak and non-covalent.
Topics: Animals; Catechin; Enzyme Activation; Hydrodynamics; Kinetics; Molecular Structure; Pancrelipase; Protein Binding; Protein Structure, Secondary; Swine; Thermodynamics
PubMed: 25365042
DOI: 10.1371/journal.pone.0111143