Diclofenac [HRP]

Background: 100 mg rectal nonsteroidal anti-inflammatory drugs (NSAIDs) and pancreatic stents both significantly reduce the incidence of post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis. Direct comparison of randomized controlled trials (RCTs) between them in high-risk patients is absent. We conducted this network meta-analysis to indirectly compare the efficacies of 100 mg rectal NSAIDs and pancreatic stents in preventing post-ERCP pancreatitis (PEP) in high-risk patients and help us decide which is preferred in clinical practice. Methods: A comprehensive search was done to identify RCTs published in English full-text. Interventions included 100 mg rectal NSAIDs (diclofenac or indomethacin) and pancreatic stents. Only studies with high-risk patients of PEP were included. Meta-analyses of NSAIDs and pancreatic stents were conducted respectively. A network meta-analysis using the Bayesian method was performed. Results: We included 14 RCTs, 8 on pancreatic stents and 6 on 100 mg rectal NSAIDs in high-risk patients. There was no direct comparison between them. After excluding an outlier study on NSAIDs (n = 144), meta-analyses showed they both significantly and statistically reduced the incidence of PEP in high-risk patients (pancreatic stents: n = 8 studies, random-effects risk ratio (RR)0.41, 95%CI 0.30-0.56, I-2 = 0%; NSAIDs: n = 5 studies, random-effects RR 0.37, 95%CI 0.25-0.54, I-2 = 0%). And network meta-analysis showed efficacy of 100 mg rectal NSAIDs was equal to pancreatic stents (random-effects RR 0.94, 95%CI 0.50-1.8). Conclusions: The efficacy of 100 mg rectal NSAIDs (diclofenac or indomethacin) seems equally significant to pancreatic stents in preventing PEP in high-risk patients. Considering the cost-effectiveness and safety, 100 mg diclofenac or indomethacin may be preferred.

A major parameter controlling the extent and rate of oral drug absorption is permeability through the lipid bilayer of intestinal epithelial cells. Here, a biomimetic artificial membrane permeability assay (Franz-PAMPA Pampa) was validated using a Franz cells apparatus. Both high and low permeability drugs (metoprolol and mannitol, respectively) were used as external standards. Biomimetic properties of Franz-PAMPA were also characterized by electron paramagnetic resonance spectroscopy (EPR). Moreover, the permeation profile for eight Biopharmaceutic Classification System (BCS) model drugs cited in the FDA guidance and another six drugs (acyclovir, cimetidine, diclofenac, ibuprofen, piroxicam, and trimethoprim) were measured across Franz-PAMPA. Apparent permeability (Papp) Franz-PAMPA values were correlated with fraction of dose absorbed in humans (Fa%) from the literature. Papp in Caco-2 cells and Corti artificial membrane were likewise compared to Fa% to assess Franz-PAMPA performance. Mannitol and metoprolol Papp values across Franz-PAMPA were lower (3.20 x 10(-7) and 1.61 x 10(-5) cm/s, respectively) than those obtained across non-impregnated membrane (2.27 x 10(-5) and 2.55 x 10(-5) cm/s, respectively), confirming lipidic barrier resistivity. Performance of the Franz cell permeation apparatus using an artificial membrane showed acceptable log-linear correlation (R-2 = 0.664) with Fa%, as seen for Papp in Caco-2 cells (R-2 = 0.805). Data support the validation of the Franz-PAMPA method for use during the drug discovery process.