Efficacy of Diclofenac and Indomethacin for Prevention of Post-Endoscopic Cholangiopancreatography (ERCP) Pancreatitis: A Systematic Review.

Endoscopic cholangiopancreatography (ERCP) is a widely used diagnostic and therapeutic tool for pancreaticobiliary conditions. One of its major complications is pancreatitis. This study aims to understand the incidence of post-ERCP pancreatitis after using rectal diclofenac and Indomethacin as prophylactic measures. We retrieved 2870 articles from the PubMed, ScienceDirect, and Google Scholar databases. Using the Medical Subject Headings (MeSH) strategy in PubMed, we chose research articles published in the last five years. Exclusion criteria included paid full-text articles, abstracts, letters to editors, patients not undergoing ERCP, ages more than 45 years, animal studies, and non-English studies. The 2020 Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) criteria were used in the design of our systematic reviews. It was found that the medical world is still debating whether rectal diclofenac and Indomethacin are beneficial in avoiding post-ERCP pancreatitis (PEP). Rectal diclofenac is used. Although its effectiveness is debated due to mixed findings and concerns about certain outcomes, it is also considered beneficial in specific circumstances, such as before ERCP. Studies on rectal Indomethacin also yield contradictory results; while some emphasize the drug's large reduction in PEP incidence, especially in low-risk people, others question its efficacy. We need further studies to clarify the remaining uncertainties.

Development, Characterization, and Cellular Toxicity Evaluation of Solid Dispersion-Loaded Hydrogel Based on Indomethacin.

Indomethacin (IND) as a non-selective cyclooxygenase 1 and 2 inhibitor administered orally causes numerous adverse effects, mostly related to the gastrointestinal tract. Moreover, when applied exogenously in topical preparations, there are obstacles to its permeation through the stratum corneum due to its low water solubility and susceptibility to photodegradation. In this work, solid dispersions (SDs) of IND with low-substituted hydroxypropyl cellulose (LHPC) were developed. The IND-SDs were incorporated into a hydroxypropyl guar (HPG) hydrogel to enhance drug solubility on the skin. The hydrogels were characterized by scanning electron microscopy (SEM), differential scanning calorimetry (DSC), powder X-ray diffraction (XRPD), Fourier-transform infrared spectroscopy (FTIR), viscosity, drug release, and unspecific cytotoxicity in mammalian cells. SEM showed a highly porous structure for SD hydrogels. DSC and XRPD studies showed that amorphous IND species were formed; therefore, these hydrogels exhibited superior drug release in comparison with IND raw material hydrogels. FTIR evidenced the presence of the hydrogen bond in the SD hydrogel. The rheology parameter viscosity increased across gels formulated with SDs in comparison with hydrogels with pure IND. In addition, IND-SD hydrogels combine the advantages of a suitable viscosity for dermal use and no potentially hazardous skin irritation. This study suggests that the formulated IND-SD hydrogels represent a suitable candidate for topical administration.

The protective effect of benfotiamine on gastric ulcers in male rats: an experimental study.

Gastric ulcers are a common gastrointestinal disorder associated with significant morbidity and mortality. It can also increase the risk of gastric cancer. This study aimed to investigate the effect of benfotiamine on experimentally-induced gastric ulcers in male rats. In this study, 30 Wistar male rats were divided randomly into six groups: control (normal), indomethacin, omeprazole, and treatment groups, including 50, 100, and 200 mg/kg of benfotiamine. Gastric ulcer was induced by indomethacin gavage. Omeprazole and different therapeutic doses of benfotiamine were administered for three days. Twenty-four hours after the last treatment, the rats were euthanized, and samples were collected.The results demonstrated that 100 and 200 mg/kg of benfotiamine treatment significantly improved indomethacin-induced gastric tissue damage. Moreover, benfotiamine at 100 and 200 mg/kg effectively attenuated the levels of pro-inflammatory cytokines IL-6 and TNF-α and oxidative stress markers MDA and ROS while increasing the antioxidant GSH. These findings suggest that benfotiamine's gastroprotective effects are mediated through its antioxidant and anti-inflammatory properties, which help mitigate the tissue damage and inflammatory response associated with indomethacin-induced gastric ulcers.However, further research is needed to elucidate the precise molecular mechanisms underlying these beneficial effects and to evaluate the potential therapeutic application of benfotiamine in clinical settings.

From formulation to structure: 3D electron diffraction for the structure solution of a new indomethacin polymorph from an amorphous solid dispersion.

3D electron diffraction (3DED) is increasingly employed to determine molecular and crystal structures from micro-crystals. Indomethacin is a well known, marketed, small-molecule non-steroidal anti-inflammatory drug with eight known polymorphic forms, of which four structures have been elucidated to date. Using 3DED, we determined the structure of a new ninth polymorph, σ, found within an amorphous solid dispersion, a product formulation sometimes used for active pharmaceutical ingredients with poor aqueous solubility. Subsequently, we found that σ indomethacin can be produced from direct solvent evaporation using dichloromethane. These results demonstrate the relevance of 3DED within drug development to directly probe product formulations.

Incidence of Post-ERCP Pancreatitis in Patients Receiving Rectal Indomethacin vs. Compounded Rectal Diclofenac Prophylaxis.

BACKGROUND AND AIMS: Endoscopic retrograde cholangiopancreatography (ERCP) carries a 3-15% risk of post-ERCP pancreatitis (PEP). Rectal indomethacin reduces the risk of PEP, but its cost has increased more than 20-fold over the past decade. Rectal diclofenac is also used to prevent PEP but is not commercially available in the United States. The aim of this study is to compare the incidence of PEP after administration of commercially available rectal indomethacin versus compounded rectal diclofenac and assess financial implications. METHODS: ERCP cases at our institution with administration of 100 mg rectal indomethacin or 100 mg compounded rectal diclofenac between May 2018 and January 2022 were retrospectively reviewed. The incidence and severity of PEP was compared between the indomethacin (n = 728) and diclofenac (n = 304) groups. Risk factors (young age, female sex, history of pancreatitis or PEP, sphincterotomy during procedure, pancreatic indication, trainee involvement) and protective factors (prior sphincterotomy, pancreatic duct stenting) for PEP were compared between groups. RESULTS: 60 patients (8.2%) in the rectal indomethacin group and 25 patients (8.2%) in the compounded rectal diclofenac group developed PEP, resulting in moderate or severe PEP in 9 (15.0%) and 2 (8.0%) patients, respectively. The compounded rectal diclofenac group had more trainee involvement (46.1% vs. 32.8%, p = 0.0001) and more prior sphincterotomy cases (15.8% vs. 10.6%, p = 0.0193) compared to the rectal indomethacin group; no statistically significant differences were observed in all other risk and protective factors. Following switch to compounded rectal diclofenac, institutional annual cost savings amounted to $441,460.62 and patient charge decreased 45-fold. CONCLUSION: This retrospective single-center real-world analysis showed similar efficacy of rectal indomethacin and compounded rectal diclofenac in preventing PEP but demonstrates substantial cost savings after switching to compounded rectal diclofenac.

Acute indomethacin exposure impairs cardiac development by affecting cardiac muscle contraction and inducing myocardial apoptosis in zebrafish (Danio rerio).

The accumulation of the active pharmaceutical chemical in the environment usually results in environmental pollution to increase the risk to human health. Indomethacin is a non-steroidal anti-inflammatory drug that potentially causes systemic and developmental toxicity in various tissues. However, there have been few studies for its potential effects on cardiac development. In this study, we systematically determined the cardiotoxicity of acute indomethacin exposure in zebrafish at different concentrations with morphological, histological, and molecular levels. Specifically, the malformation and dysfunction of cardiac development, including pericardial oedema, abnormal heart rate, the larger distance between the venous sinus and bulbus arteriosus (SV-BA), enlargement of the pericardial area, and aberrant motor capability, were determined after indomethacin exposure. In addition, further investigation indicated that indomethacin exposure results in myocardial apoptosis in a dose-dependent manner in zebrafish at early developmental stage. Mechanistically, our results revealed that indomethacin exposure mainly regulates key cardiac development-related genes, especially genes related to the cardiac muscle contraction-related signaling pathway, in zebrafish embryos. Thus, our findings suggested that acute indomethacin exposure might cause cardiotoxicity by disturbing the cardiac muscle contraction-related signaling pathway and inducing myocardial apoptosis in zebrafish embryos.

Decrease in the Internal Cerebral Vein Pulsation With Improvement of Patent Ductus Arteriosus in Premature Infants at the Risk of Intraventricular Hemorrhage: Two Interesting Case Reports.

Recently, augmenting the pulsation of the internal cerebral vein (ICV) has been reported to be a predictor of premature intraventricular hemorrhage (IVH); however, prophylaxis for IVH has not yet been established. Venous pulsation is a marker of central venous pressure elevation and may be improved after heart failure treatment. Herein, we report two cases of low-birth-weight infants (29 weeks and 31 weeks of gestational age), who exhibited improvements in ICV pulsation with relief of hemodynamically significant patent ductus arteriosus (hs-PDA) following indomethacin administration. ICV flow patterns were continuously flat early after birth. Thereafter, both patients demonstrated ICV pulsation augmentation with PDA progression and brain natriuretic peptide (BNP) elevation at 52 h and 39 h after birth (in infants born at 29 and 31 weeks of gestational age, respectively). After relieving PDA with indomethacin administration, both infants exhibited an improvement in ICV pulsation with decreased BNP levels. In both cases, ICV pulsation increased when PDA became hemodynamically significant with BNP elevation, and the pulsation improved by reduction in ductal flow with decreasing BNP when PDA was relieved by indomethacin administration. The association between hs-PDA and elevated ICV pulsation indicates that hs-PDA likely leads to heightened central venous pressure. Additionally, indomethacin treatment was effective in reducing the exacerbated ICV pulsation caused by heart failure due to hs-PDA. These cases suggest that treatment for heart failure might improve the augmented ICV pulsation, which is related to the development of premature IVH. However, further studies are needed to confirm this association.

Perinatal Factors Associated with Successful Pharmacologic Closure of the Patent Ductus Arteriosus in Premature Infants.

The patent ductus arteriosus (PDA) is associated with significant morbidity and mortality in preterm infants. While pharmacologic closure of the PDA is common and effective, it can be difficult to identify which patients will respond. As such, the objective of this study was to identify factors associated with successful pharmacologic closure of the PDA. We hypothesized that clinical factors such as gestational age, birth weight, and hypertensive disorders of pregnancy would be associated with successful closure. We performed a retrospective cohort study of preterm infants who received pharmacologic treatment for a PDA at two large neonatal intensive care units in Boston, MA between January 2016 and December 2021. Infants were excluded if they received prophylactic indomethacin, had early termination of therapy, did not have an echocardiogram prior to therapy, or had congenital heart disease. The primary outcome was closure after initial course. Relevant perinatal data were collected on enrolled infants. Of the 215 enrolled infants, 131 (61%) had successful closure. Older gestational age (OR, 1.23; 95% CI,1.03-1.47), male sex (OR, 2.17; 95% CI,1.18-3.99), and maternal preeclampsia (OR, 2.75; 95% CI,1.07-7.02) were associated with successful closure. Infants who received postnatal steroids (OR, 0.49; 95% CI,0.25-0.96) were less likely to have had successful closure. In this study, we identified previously established associations of gestational age and male sex with successful pharmacologic closure. However, the associations with maternal preeclampsia and postnatal steroids are novel. While further investigation is warranted, these associations can help inform decision-making around management of the PDA.

Hydrogen Bonding in Amorphous Indomethacin.

Amorphous Indomethacin has enhanced bioavailability over its crystalline forms, yet amorphous forms can still possess a wide variety of structures. Here, Empirical Potential Structure Refinement (EPSR) has been used to provide accurate molecular models on the structure of five different amorphous Indomethacin samples, that are consistent with their high-energy X-ray diffraction patterns. It is found that the majority of molecules in amorphous Indomethacin are non-bonded or bonded to one neighboring molecule via a single hydrogen bond, in contrast to the doubly bonded dimers found in the crystalline state. The EPSR models further indicate a substantial variation in hydrogen bonding between different amorphous forms, leading to a diversity of chain structures not found in any known crystal structures. The majority of hydrogen bonds are associated with the carboxylic acid group, although a significant number of amide hydrogen bonding interactions are also found in the models. Evidence of some dipole-dipole interactions are also observed in the more structurally ordered models. The results are consistent with a distribution of Z-isomer intramolecular type conformations in the more disordered structures, that distort when stronger intermolecular hydrogen bonding occurs. The findings are supported by 1H and 2H NMR studies of the hydrogen bond dynamics in amorphous Indomethacin.

Synthesis of Quarternized Chitosans and Their Potential Applications in the Solubility Enhancement of Indomethacin by Solid Dispersion.

This study was designed to synthesize quarternized chitosans (Q-CS) and explore their potential application in aqueous solubility enhancement of indomethacin (IND), a BCS class-II drug. Three different Q-CS; N,N,N-trimethyl chitosan chloride (TMC), N-(4-N'-methylpyridinylmethyl) chitosan chloride (mPyCS), and N-(4-N',N',N'-trimethylaminobenzyl) chitosan chloride (TmBzCS) were synthesized and characterized through various spectroscopic analysis. Q-CS-based solid-dispersion (SD) composites of IND (Q-CS-IND) were prepared using the spray-drying method and characterized through Fourier transform infrared (FTIR), scanning electron microscopy (SEM), differential-scanning calorimetry (DSC), and powder X-ray diffraction (P-XRD). The solubility and dissolution profiles of SD-composites of IND were evaluated and compared with physical mixtures (PM). The IND contents were quantified and validated in the composites using UV-Vis spectrophotometer. FTIR and NMR analysis showed the successful preparation of Q-CS. TMC was found with the highest yield (55.13%) and mPyCS with the highest degree of quaternization (DQ) (63.37%). FT-IR analysis of IND-Q-CS composites demonstrated chemical interaction between carbonyl moieties of IND with functional groups of Q-CS. DSC and PXRD analyses demonstrated the transformation of IND in SD composites from crystalline to an amorphous form. All the IND-Q-CS composites were observed with a significant increase in the solubility and dissolution rate of the drug (1996.0 µg/min) compared to PM (1306.8 µg/min), which is higher than pure IND (791.6 µg/min). The contents of IND in TMC, mPyCS, and TmBzCS composites were 97.69-99.92%, 97.66-100.25%, and 97.18-100.11% respectively. Overall, the findings encourage the applications of Q-CS derivatives for increasing IND water solubility and warrant further in vivo biological profiling of IND composites.

In vitro and in vivo assessment of indomethacin-induced genotoxicity: protection by curcumin.

Background and purpose: Indomethacin is one of the most widely used non-steroidal anti-inflammatory drugs. This study aimed to investigate the protective effects of curcumin against indomethacin-induced genotoxicity. Experimental approach: For in vitro studies, human peripheral blood lymphocytes were obtained from a healthy volunteer and treated for 24 h as follows: vehicle control, indomethacin at 100 and 200 µΜ, indomethacin (100 µM and 200 µM) plus curcumin (27 µM). For in vivo experiments, mice received a single i.p dose of curcumin (100 mg/kg) and after 30 min genotoxicity induction was carried out by a single i.p injection of indomethacin at 10, 20, and 40 mg/kg. After 24 h, bone marrow cells were obtained from mice femurs. Genotoxicity was evaluated using a micronucleus assay. Oxidative damage was also inspected both in vitro and in vivo. Findings/Results: In-vitro studies indicated that co-treatment with curcumin caused a significant decrease in the average micronuclei percentage and MDA level, and a significant increase in GSH concentration compared to the groups treated only with indomethacin. In-vivo findings revealed that pretreatment with curcumin induced a significant increase in the average ratio of polychromatic erythrocyte/normochromic erythrocyte, GSH concentration and caused a significant decrease in the average percentage of micronuclei and MDA level, in comparison with the group treated only with indomethacin. Conclusion and implications: Curcumin attenuated indomethacin-induced genotoxicity both in vitro and in vivo. These effects might be partially exerted by decreasing oxidative stress. Further studies are required to elucidate the exact genoprotective mechanism of curcumin against indomethacin.

Combination of Indomethacin with Nanostructured Lipid Carriers for Effective Anticancer Therapy.

Purpose: The anticancer potential of indomethacin and other nonsteroidal anti-inflammatory drugs (NSAIDs) in vitro, in vivo, and in clinical trials is well known and widely reported in the literature, along with their side effects, which are mainly observed in the gastrointestinal tract. Here, we present a strategy for the application of the old drug indomethacin as an anticancer agent by encapsulating it in nanostructured lipid carriers (NLC). We describe the production method of IND-NLC, their physicochemical parameters, and the results of their antiproliferative activity against selected cancer cell lines, which were found to be higher compared to the activity of free indomethacin. Methods: IND-NLC were fabricated using the hot high-pressure homogenization method. The nanocarriers were physicochemically characterized, and their biopharmaceutical behaviour and therapeutic efficacy were evaluated in vitro. Results: Lipid nanoparticles IND-NLC exhibited a particle size of 168.1 nm, a negative surface charge (-30.1 mV), low polydispersity index (PDI of 0.139), and high encapsulation efficiency (over 99%). IND-NLC were stable for over 60 days and retained integrity during storage at 4 °C and 25 °C. The potential therapeutic benefits of IND-NLC were screened using in vitro cancer models, where nanocarriers with encapsulated drug effectively inhibited the growth of breast cancer cell line MDA-MB-468 at dosage 15.7 µM. Conclusion: We successfully developed IND-NLC for delivery of indomethacin to cancer cells and confirmed their antitumoral efficacy in in vitro studies. The results suggest that indomethacin encapsulated in lipid nanoparticles possesses high anticancer potential. Moreover, the presented strategy is highly promising and may offer a new alternative for future therapeutic drug innovations.

Dietary Walnuts Prevented Indomethacin-Induced Gastric Damage via AP-1 Transcribed 15-PGDH, Nrf2-Mediated HO-1, and n-3 PUFA-Derived Resolvin E1.

Non-steroidal anti-inflammatory drugs (NSAIDs), the most highly prescribed drugs in the world for the treatment of pain, inflammation, and fever, cause gastric mucosal damage, including ulcers, directly or indirectly, by which the development of GI-safer (-sparing) NSAIDs relates to unmet medical needs. This study aimed to document the preventive effects of walnut polyphenol extracts (WPEs) against NSAID-induced gastric damage along with the molecular mechanisms. RGM-1 gastric mucosal cells were administered with indomethacin, and the expressions of the inflammatory mediators between indomethacin alone or a combination with WPEs were compared. The expressions of the inflammatory mediators, including COX-1 and COX-2, prostaglandin E2, 15-hydroxyprostaglandin dehydrogenase (15-PGDH), and antioxidant capacity, were analyzed by Western blot analysis, RT-PCR, and ELISA, respectively. HO-1, Nrf-2, and keap1 were investigated. The in vivo animal models were followed with in vitro investigations. The NSAIDs increased the expression of COX-2 and decreased COX-1 and 15-PGDH, but the WPEs significantly attenuated the NSAID-induced COX-2 expression. Interestingly, the WPEs induced the expression of 15-PGDH. By using the deletion constructs of the 15-PGDH promoter, we found that c-Jun is the most essential determinant of the WPE-induced up-regulation of 15-PGDH expression. We confirmed that the knockdown of c-Jun abolished the ability of the WPEs to up-regulate the 15-PGDH expression. In addition, the WPEs significantly increased the HO-1 expression. The WPEs increased the nuclear translocation of Nrf2 by Keap-1 degradation, and silencing Nrf2 markedly reduced the WPE-induced HO-1 expression. We found that the WPE-induced HO-1 up-regulation was attenuated in the cells harboring the mutant Keap1, in which the cysteine 151 residue was replaced by serine. These in vitro findings were exactly validated in indomethacin-induced gastric rat models. Daily walnut intake can be a promising nutritional supplement providing potent anti-inflammatory, antioxidative, and mucosa-protective effects against NSAID-induced GI damage.

LDH-Indomethacin Nanoparticles Antitumoral Action: A Possible Coadjuvant Drug for Cancer Therapy.

Indomethacin (INDO) has a mechanism of action based on inhibiting fatty acids cyclooxygenase activity within the inflammation process. The action mechanism could be correlated with possible anticancer activity, but its high toxicity in normal tissues has made therapy difficult. By the coprecipitation method, the drug carried in a layered double hydroxides (LDH) hybrid matrix would reduce its undesired effects by promoting chemotherapeutic redirection. Therefore, different samples containing INDO intercalated in LDH were synthesized at temperatures of 50, 70, and 90 °C and synthesis times of 8, 16, 24, and 48 h, seeking the best structural organization. X-ray diffraction (XRD), vibrational Fourier transform infrared spectroscopy (FT-IR), scanning electron microscopy (SEM), spectrophotometric analysis in UV-VIS, and differential thermogravimetric analysis (TGA/DTA) were used for characterization. Our results indicate that higher temperatures and longer synthesis time through coprecipitation reduce the possibility of INDO intercalation. However, it was possible to establish a time of 16 h and a temperature of 50 °C as the best conditions for intercalation. In vitro results confirmed the cell viability potential and anticancer activity in the LDH-INDO sample (16 h and 50 °C) for gastric cancer (AGP01, ACP02, and ACP03), breast cancer (MDA-MB-231 and MCF-7), melanoma (SK-MEL-19), lung fibroblast (MRC-5), and non-neoplastic gastric tissue (MN01) by MTT assay. Cell proliferation was inhibited, demonstrating higher and lower toxicity against MDA-MB-231 and SK-MEL-19. Thus, a clinical redirection of INDO is suggested as an integral and adjunctive anticancer medication in chemotherapy treatment.

Licofelone, a Dual COX/LOX Inhibitor, Ameliorates Paclitaxel-Induced Mechanical Allodynia in Rats in a Cannabinoid Receptor-Dependent Manner.

The use of paclitaxel as a chemotherapeutic drug is limited by the development of dose-dependent paclitaxel-induced neuropathic pain (PINP). Recently, we observed that the combination of indomethacin plus minocycline (IPM) attenuates PINP in a mouse model in a cannabinoid (CB) receptor-dependent manner. Indomethacin inhibits cyclooxygenase (COX) activity, and minocycline inhibits 5-lipoxygenase (5-LOX) activity. Male Sprague Dawley rats with paclitaxel-induced mechanical allodynia were treated with indomethacin, minocycline, IPM combination, licofelone (a dual COX/LOX inhibitor), or their vehicles. AM251, a CB1 receptor antagonist, and AM630, a CB2 receptor antagonist, were administered before the IPM combination or licofelone. Mechanical allodynia was measured using a dynamic plantar aesthesiometer. Molecular docking was performed using CB-Dock2. Licofelone and IPM combination had antiallodynic effects, which were significantly higher than either indomethacin or minocycline alone. AM251 and AM630 blocked the antiallodynic effects of IPM combination and licofelone. Molecular docking showed that licofelone binds to both CB1 and CB2 receptors with a high affinity similar to the phytocannabinoid 1-trans-delta-9-tetrahydrocannabinol and the synthetic cannabinoid WIN 55,212-2. Licofelone inhibits COX and LOX and/or directly interacts with CB receptors to produce antiallodynic effects in a rat model of PINP. The findings further suggest that licofelone could be a therapeutic agent for managing PINP.

Modulation of adipogenesis and lipogenesis by indomethacin and pantoprazole.

Endocrine disruptors are suggested to act as potential "obesogens" by interacting with various metabolic processes in adipose tissue. Besides industrial chemicals that are blamed for acting as endocrine disruptors as well as obesogens, pharmaceuticals can also cause obesogenic effects as unintended adverse effects. However, limited studies evaluated the obesogenic adverse effects of pharmaceuticals. Based on this information, the present study aimed to investigate the possible in vitro adipogenic/lipogenic potential of indomethacin and pantoprazole that are prescribed during pregnancy. Their effects on lipid accumulation, adiponectin level, glycerol-3-phosphate dehydrogenase (G3PDH) activity, and expression of adipogenic genes and proteins were investigated in 3 T3-L1 cell line. The range of concentrations of the pharmaceuticals was selected according to their Cmax values. Lipid accumulation was increased dependently with indomethacin dose and with pantoprazole at its highest concentration. Both pharmaceuticals also increased adiponectin levels, which was thought to play a role in stimulating the adipogenesis pathway. Moreover, both pharmaceuticals altered the gene and/or protein expression of some adipogenic/lipogenic transcriptional factors, which may lead to disruption of metabolic pathways during the fetal period. In conclusion, indomethacin and pantoprazole may have obesogenic effects through different mechanisms and their potential to cause obesity should be investigated by further in vivo and epidemiological studies.

Indomethacin Does Not Reduce Post-ERCP Pancreatitis in High-Risk Patients Receiving Pancreatic Stenting.

BACKGROUND: Rectal indomethacin reduces pancreatitis following endoscopic retrograde cholangiopancreatography (ERCP). However, there is insufficient evidence regarding its added benefits in patients already receiving prophylactic pancreatic stenting. Our goal was to evaluate the impact of indomethacin in high-risk patients undergoing pancreatic stenting. METHODS: A cohort study was conducted on all patients who underwent the rescue cannulation technique for challenging bile duct cannulation (selected high-risk patients). Patients were split into two groups based on the prophylaxis method for post-ERCP pancreatitis (PEP): one receiving a combination of indomethacin and pancreatic stenting, while the other received pancreatic stenting alone. Comparative analyses were carried out on PEP, hyperamylasemia, gastrointestinal bleeding, and postoperative hospital stay among post-ERCP pancreatitis patients. RESULTS: Between November 2017 and May 2023, a total of 607 patients with native papillae were enrolled, with 140 grouped into the indomethacin plus stent group and 467 into the stent alone group. The overall PEP rate was 4.4% in the entire cohort, with no statistical differences observed between the groups in terms of PEP rates (P = 0.407), mild PEP (P = 0.340), moderate to severe PEP (P = 1.000), hyperamylasemia (P = 0.543), gastrointestinal bleeding (P = 0.392), and postoperative hospital stay (P = 0.521). Furthermore, sensitivity analysis using multivariable analysis also validated these findings. CONCLUSIONS: Indomethacin did not reduce the incidence or severity of PEP in high-risk patients who routinely received prophylactic pancreatic stent placement. Therefore, the additional administration of rectal indomethacin to further mitigate PEP appears to be not necessary.

Novel Dual COX-2/5-LOX Inhibitory Activity by Chalcone Derivatives: A Safe and Efficacious Anti-Inflammatory Agent.

BACKGROUND: Non-communicable diseases are chronic systemic inflammation in humans that occurs because of enhanced inflammatory mediators of the arachidonic acid cas-cade. We aimed to explore whether the lead chalcone compounds could exhibit anti-inflam-matory activity via dual blockage of COX-2/5-LOX enzymes and their regulatory mechanism. METHODS: RAW 264.7 macrophages were collected from NCC, Pune, for in-vitro experiments. The IC50 values of chalcone compounds C45 and C64 were calculated. RAW 264.7 macro-phages were treated with C45 and C64 (10%, 5%, 2.5%, 0.125%, and 0.0625% concentration). The cell viability was carried out with an MTT assay. The COX-1, COX-2, 5-LOX, PGE2, and LTB4 levels were detected by ELISA-based kits. The in-vivo evaluation was carried out in Male Wistar rats (250-300 g, 7-8 weeks old) with acute and chronic anti-inflammatory models and histopathological studies on the stomach, liver, and kidney. RESULTS: The present study described the in-vitro and in-vivo biological evaluation of dual COX-2/5-LOX inhibitors in chalcone derivatives (C45 and C64) compounds showed the most effective COX-2 and 5-LOX inhibition with IC50 values 0.092 and 0.136µM respectively. Simultaneously, compound C64 showed comparable selectivity towards COX-2 with a Selec-tivity Index (SI) of 68.43 compared to etoricoxib, with an SI of 89.32. In-vivo carrageenan-induced rat paw oedema activity, the compound C64 showed a significant reduction in oedema with 78.28% compared to indomethacin with 88.07% inhibition. Furthermore, cotton pellet-induced granuloma activity revealed that compound C64 significantly reduced 32.85% com-pared with standard 40.13% granuloma inhibition. CONCLUSION: The chalcone compound C64, (E)-1-(4-Amino-2-hydroxyphenyl)-3-(3,4,5-tri-methoxyphenyl)-prop-2-en-1-one was proved to be a potent and novel Dual COX-2/5-LOX inhibitor with improved gastric safety profiling.

Protective effect of astaxanthin on indomethacin-induced gastric ulcerations in mice.

Gastric ulcer disease remains one of the common medical burdens affecting millions worldwide due to its prevalent risk factors with the chronic usage of non-steroidal anti-inflammatory drugs at the top, reportedly through the stimulation of oxidative stress and triggering of inflammatory and apoptotic cascades in the gastric mucosa. Astaxanthin, a dietary keto-carotenoid derived from marine organisms is gaining a wide interest as a nutraceutical for its pronounced antioxidant properties. Here, we aim to examine the potential modulatory role of astaxanthin on indomethacin-induced gastric ulceration in experimental mice. Twenty-four Swiss albino mice were randomly distributed into four groups: a control group, an indomethacin group, and two groups pre-treated with either omeprazole or astaxanthin. The gastric tissues were assessed using gross morphology, ulcer scoring, gastric juice acidity, as well as reduced glutathione (GSH) and malondialdehyde (MDA) levels. Histopathological examination and immunostaining for nuclear factor-kappa B (NF-κB) and caspase-3 levels were also employed. Indomethacin group tended to show a higher number of mucosal ulcerations relative to control and pre-treated groups. The indomethacin group also showed significantly lower GSH levels and higher MDA levels relative to control. Immunostaining of gastric tissue sections showed a higher reactivity to NF-κB and caspase-3 in indomethacin group. Astaxanthin pre-treatment significantly elevated gastric juice pH, normalized GSH levels, and lowered the indomethacin-induced elevations in MDA, NF-κB, and caspase-3 levels. These results indicate that astaxanthin exhibits a comparable protective effect to omeprazole, against indomethacin-induced gastric ulceration. This anti-ulcerogenic effect could be mediated through its antioxidant, anti-inflammatory, and anti-apoptotic modulatory activities.

Atractylenolide I Alleviates Indomethacin-Induced Gastric Ulcers in Rats by Inhibiting NLRP3 Inflammasome Activation.

Atractylodes macrocephala Koidz, a traditional Chinese medicine, contains atractylenolide I (ATR-I), which has potential anticancer, anti-inflammatory, and immune-modulating properties. This study evaluated the therapeutic potential of ATR-I for indomethacin (IND)-induced gastric mucosal lesions and its underlying mechanisms. Noticeable improvements were observed in the histological morphology and ultrastructures of the rat gastric mucosa after ATR-I treatment. There was improved blood flow, a significant decrease in the expression of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), IL-1ß, and IL-18, and a marked increase in prostaglandin E2 (PGE2) expression in ATR-I-treated rats. Furthermore, there was a significant decrease in the mRNA and protein expression levels of NOD-like receptor thermal protein domain associated protein 3 (NLRP3), apoptosis-associated speck-like protein (ASC), cysteinyl aspartate specific proteinase-1 (caspase-1), and nuclear factor-κB (NF-κB) in rats treated with ATR-I. The results show that ATR-I inhibits the NLRP3 inflammasome signaling pathway and effectively alleviates local inflammation, thereby improving the therapeutic outcomes against IND-induced gastric ulcers in rats.