Preparation and characterization of soluplus-based nanosuspension for dissolution enhancement of indomethacin using ultrasonic assisted precipitation method for formulation and Box-Behnken design for optimization.

OBJECTIVES: Nanosuspensions are increasingly recognized as a valuable technology for enhancing poorly water-soluble drugs' solubility and dissolution rate, thereby improving their bioavailability. In this study, we employed ultrasonic-assisted precipitation to fabricate nanosuspensions of indomethacin (IND), utilizing Soluplus® (Sol) as a stabilizing agent. Our objectives were driven by hypotheses centered on optimizing formulation variables and developing predictive models for optimal IND formulations. SIGNIFICANCE: This research highlights the Box-Behnken design (BBD) as a powerful tool that optimizes the properties of IND nanosuspensions, thus significantly enhancing their dissolution rate. METHODS: The impacts of the independent variables on the mean particle size (MPS), polydispersity index (PDI), and zeta potential (ZP) were investigated using BBD. The optimized nanosuspension was freeze-dried with 3% trehalose to produce a dry nanosuspension (DNS). The DNS was characterized by SEM, DSC, XRPD, solubility, and dissolution. RESULTS: The IND: Sol ratio and sonication power significantly affected the MPS and ZP of the nanosuspensions. The optimized formulation showed MPS, PDI, and ZP of 144.77 ± 6.68 nm, 0.26 ± 0.08, and -24.6 ± 1.90 mV, respectively. The DNS exhibited spherical particle morphology. The DSC and XRPD confirmed the amorphous state of IND with enhanced solubility and dissolution of IND. DNS showed a 3.7-fold increase in drug release in the first 15 min compared with raw IND. CONCLUSIONS: This study demonstrated the critical role of BBD in accurately predicting the values of independent variables essential for formulating optimal nanosuspensions. These formulations possess specific properties that can be effectively integrated into various dosage forms tailored for different routes of administration.

Preventive Measures and Risk Factors for Post-ERCP Pancreatitis: A Systematic Review and Individual Patient Data Meta-Analysis.

BACKGROUND: Post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis (PEP) is the most common complication of ERCP, with limited studies comparing combined prophylactic measures and their efficacy relative to individual patient risk profiles. This study aims to perform an individual patient data meta-analysis (IPDMA) to evaluate the contribution of patient and ERCP-related risk factors to PEP development and to identify the best prophylaxis strategies according to the patient's risk profile. METHODS: We systematically searched MEDLINE, Embase, and Cochrane databases until November 2022 for randomized controlled PEP prophylaxis trials. We invited authors to share individual patient data, including PEP risk profile and prophylaxes used. PEP incidence rates for different prophylaxis were calculated. Efficacy was compared using multilevel logistic regression and expressed as relative risk (RR). Subgroup analysis evaluated the role of patient and ERCP-related risk factors in developing PEP. RESULTS: Data from 11 studies, including 6430 patients, were analyzed. After adjusting for risk factors, rectal NSAIDs (RR 0.69, 95%CI 0.54-0.88) and peri-procedural high-volume intravenous fluid (IVF) (RR 0.40, 95%CI 0.21-0.79) were effective in reducing PEP incidence, while no benefit was noted with pancreatic duct (PD) stents (RR 1.25, 95%CI 0.91-1.73). In patients receiving rectal NSAIDs (n = 2617), difficult cannulation (RR 1.99, 1.45-2.73), contrast injection into the pancreatic duct (PD) (RR2.37, 1.68-3.32), and prior history of PEP (RR 1.90, 1.06-3.41) were associated with increased PEP risk. CONCLUSION: This IPDMA confirms that rectal NSAIDs and peri-procedural IVF are effective PEP prophylactic strategies. Further studies focusing on combination therapy or the development of personalized PEP risk calculators are needed to improve prophylactic strategies.

Neuroprotective agents ineffective in mitigating autonomic dysreflexia following experimental spinal cord injury.

BACKGROUND AND OBJECTIVES: Loss of supraspinal cardiovascular control and secondary damage following spinal cord injury (SCI) lead to cardiovascular dysfunction, where autonomic dysreflexia (AD), triggered by stimuli below the injury, can cause uncontrolled blood pressure (BP) surges, posing severe health risks such as stroke and seizures. While anti-inflammatory neuroprotective agents have been studied for motor recovery, their impact on cardiovascular function remains under investigated. The objective was to assess the efficacy of four clinically approved neuroprotective agents in promoting cardiovascular recovery following SCI. METHODS: Male Wistar rats received contusion at the third thoracic spinal segment (T3). Fluoxetine, Glyburide, Valproic acid, and Indomethacin were first administered at 1 h or 6 h post-SCI, and every 12 h for two weeks thereafter. Four weeks following SCI, hemodynamics were measured at rest and during colorectal distension. Locomotor function was assessed prior to SCI and weekly for four weeks after SCI, using the Basso-Beattie-Bresnahan (BBB) locomotor scale. Quantitative comparisons of lesion area were performed. RESULTS: Contrary to the published literature, Indomethacin and Valproic acid resulted in high morbidity and mortality rates 60 % and 40 % respectively) within 2-3 days of administration. Fluoxetine, and Glyburide were well-tolerated. There were no differences in change in systolic BP with colorectal distension compared to control i.e., all experimental groups experienced severe episodes of AD [F(6, 67) = 0.94, p = 0.47]. There was no significant difference in BBB scores in any experimental group compared to control [F(18, 252) = 0.3, p = 0.99]. No between-group differences were observed in tissue sparing at the lesion epicentre [F(6, 422) = 6.98, p = 0.29]. DISCUSSION: Despite promising beneficial effect reported in previous studies, none of the drugs demonstrated improvement in cardiovascular or motor function. Indomethacin and Valproic acid exhibited unexpected high mortality at doses deemed safe in the literature. This emphasizes the necessity for reproducibility studies in pre-clinical research and underscores the importance of publishing null findings to guide future investigations.

Evaluation of Quinoline-Related Carboxylic Acid Derivatives as Prospective Differentially Antiproliferative, Antioxidative, and Anti-Inflammatory Agents.

The higher prevalence of cancer and the unmet need for antioxidant/anti-inflammatory chemotherapeutic compounds with little side effect are of utmost importance. In addition, the increased likelihood of failure in clinical trials along with increasing development costs may have diminished the range of choices among newer drugs for clinical use. This has dictated the necessity to seek out novel medications by repurposing as it needs less time, effort, and resources to explore new uses of a current or unsuccessful medication. In this study, we examined the biological activity of 10 potential quinoline derivatives. Given the half-maximal inhibitory concentration (IC50 value) in lipopolysaccharide (LPS) induced inflammation of RAW264.7 mouse macrophages, all commercial FQs and selected quinolines (quinoline-4-carboxlic and quinoline-3-carboxylic acids) exerted impressively appreciable anti-inflammation affinities versus classical NSAID indomethacin without related cytotoxicities in inflamed macrophages. Conversely, all 14 tested compounds lacked antioxidative DPPH radical scavenging capacities as compared to ascorbic acid. Gemifloxacin, considerably unlike markets FQs, indomethacin and quinoline derivatives, exerted exceptional and differential antiproliferation propensities in colorectum SW480, HCT116, and CACO2, pancreatic PANC1, prostate PC3, mammary T47D, lung A375, and melanoma A549 adherent monolayers using the sulforhodamine B colorimetric method versus antineoplastic cisplatin. All quinoline derivatives and gemifloxacin alike, but not levofloxacin, ciprofloxacin, or indomethacin, displayed substantially selective viability reduction affinities in prolonged tumor incubations of cervical HELA and mammary MCF7 cells. Specifically kynurenic acid (hydrate), quinoline-2-carboxylic acid, quinoline-4-carboxylic acid, quinoline-3-carboxylic acid, and 1,2-dihydro-2-oxo-4-quinoline carboxylic acids possessed the most remarkable growth inhibition capacities against mammary MCF7 cell line, while quinoline-2-carboxylic acid was the only quinoline derivative with significant cytotoxicity on cervical HELA cancer cells. It is highly speculated that chelation with divalent metals via co-planarity with close proximity of the COOH and the N atom could have the potential molecular mechanism for optimally promising repurposed pharmacologies. Conclusively, this study revealed the considerably profound repurposed duality of cytotoxicity and anti-inflammation pharmacologies of quinoline derivatives. Activity-guided structural modifications of the present nuclear scaffolds can be inherently linked to the betterment and enhancement of their repurposed pharmacologies.

Feasibility of a High-Dose Inhaled Indomethacin Dry Powder with Dual Deposition for Pulmonary and Oral Delivery.

In this study we have developed a high-dose dry powder inhaler formulation of indomethacin using a novel approach to carrier-based formulations. Specifically, larger drug particles serve as the carrier for the smaller micronized drug particles, such that an inhaled dose is combined with an oral dose. To study this system, the aerosol performance of a standard indomethacin-lactose formulation was compared to carrier-free micronized indomethacin and a drug-as-carrier formulation (a micronized indomethacin-coarse indomethacin blend). Indomethacin with lactose showed a very poor aerosol performance, indicating high adhesion between the drug and carrier. The performance of the carrier-free micronized drug was significantly better, indicating low cohesion. Coarse drug particles as a carrier allowed improved powder flow and aerosol performance while also providing a potential secondary route of absorption of indomethacin, namely oral. An optimal formulation ratio of 1:1 (w/w) fine indomethacin-coarse indomethacin was developed in this study.

Neurological and Systemic Pitfalls in the Diagnosis of Cluster Headaches: A Case-Based Review.

PURPOSE OF REVIEW: To describe different pitfalls in the diagnosis of primary cluster headaches (CHs) with the guidance of seven case vignettes. RECENT FINDINGS: The question of whether primary CHs and migraines are totally different entities has been long debated. Autonomic features can be detected in as many as 60% of migraine patients. Although some genetic similarities have been found, CACNA1A mutations have not been detected among CH patients with hemimotor aura in contrast to hemiplegic migraine. Recently, functional MRI studies have shown that the left thalamic network was the most discriminative MRI feature in distinguishing migraine from CH patients. Compared to migraine, CH patients showed decreased functional interaction between the left thalamus and cortical areas mediating interception and sensory integration. However, clinically the most significant feature had been the restlessness and agitation seen during headache attacks patients with CHs. This feature is also important in distinguishing cluster patients from other patients having other trigeminal autonomic cephalalgias except for a subset of patients with hemicrania continua. CH is an important member of the group of headache disorders characterized by their association with one or more autonomic features in the trigeminal nerve distribution and termed Trigeminal Autonomic Cephalalgias (TACs). Although CH is a relatively rare condition, judged by the distress it generally causes to the affected individual, early diagnosis and institution of appropriate therapy seem mandatory. Correct diagnosis of CHs needs avoidance of pitfalls. Such pitfalls generally include differentiation from migraine, differentiation from other side locked headache disorders, from other trigeminal autonomic cephalalgias (TACs), and lastly, recognition of rare presentations of cluster-like manifestations with hemiplegic aura and simulating trigeminal and glossopharyngeal neuralgias. Differentiation between primary and symptomatic CHs related to sellar pathologies and systemic medical conditions is of equal importance. In the present review such issues are discussed with the assistance of seven case vignettes.

Heterotopic ossification (HO) prophylaxis after distal biceps repair.

Hypothesis and Background: A potential complication of distal biceps repair is heterotopic ossification (HO), which impacts both limb function and overall patient outcomes. Common HO prophylaxis methods include nonsteroidal anti-inflammatory drugs or localized radiation therapy. The purpose of this systematic review was to determine an effective means of providing HO prophylaxis following distal biceps repair. Methods: A systematic review of the literature was performed according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The following databases were searched for studies published after 1998: PubMed, Embase, and Cochrane Library. Studies were included if they compared patients who were placed on HO prophylaxis following distal biceps repair compared to those that were not placed on HO prophylaxis, were prospective randomized controlled trials or retrospective case-control studies, and evaluated HO prophylaxis regimens. Studies that were not written in English, analyzed animals or cadavers, and did not directly evaluate patients undergoing distal biceps repair, did not study HO rophylaxis, or had alternative study designs were excluded. Results: The initial search identified 134 studies, 4 of which met the inclusion criteria and were included in the study. Each of these 4 (100%) studies evaluated indomethacin, and 1 (25%) study evaluated both indomethacin and meloxicam. The included studies evaluated HO prophylaxis in the setting of both one- and two-incision distal biceps repairs. Overall, 2 of the 4 (50%) studies supported the use of indomethacin as HO prophylaxis, 1 of 4 (25%) did not support the use of indomethacin for HO prophylaxis, and 1 of 4 (25%) studies reported that indomethacin and meloxicam are similarly effective HO prophylaxis drugs. None of the studies meeting the inclusion criteria analyzed radiation therapy as a potential method for HO prophylaxis. Discussion and Conclusion: Indomethacin is commonly used as a prophylactic measure for HO following distal biceps repair; however, based on the results of this study, it is not necessary to use this routinely due to its limited efficacy in preventing HO and potential risks (eg, gastrointestinal upset, bleeding) associated with the medication. Future randomized studies should evaluate the use of other nonsteroidal anti-inflammatory drugs (eg, meloxicam) for HO prophylaxis in addition to not using any HO prophylaxis following either one- or two-incision distal biceps repairs.

ß-Citronellol: a potential anti-inflammatory and gastro-protective agent-mechanistic insights into its modulatory effects on COX-II, 5-LOX, eNOS, and ICAM-1 pathways through in vitro, in vivo, in silico, and network pharmacology studies.

BACKGROUND: The current study aimed to evaluate the anti-inflammatory, anti-oxidant, and pronounced gastro-protective activities of ß- Citronellol using in vitro, in vivo assays and in silico approaches. METHODS: In vitro assays, denaturation of bovine serum albumin, egg protein, and human Red Blood Cells (RBCs) membrane stabilization were performed, using Piroxicam as standard. For in vivo assessment, Histamine (0.1 ml from 1% w/v) and Formaldehyde (0.1 ml from 2% v/v) were used to mediate inflammation. In silico molecular docking and network pharmacology were employed to probe the possible target genes mediating gastroprotective effect of ß-Citronellol at 25, 50, and 100 mg/kg, using indomethacin-induced (25 mg/kg i.p) gastric ulcer in rats. Moreover, Gastric tissues were evaluated for morphological, histopathological, and bio-chemical analysis of PGE2, COX-I, COX-II, 5-LOX, eNOS, ICAM-1, oxygen-free radical scavengers (SOD, CAT), and oxidative stress marker (MDA). RESULTS: ß-Citronellol prevented denaturation of proteins and RBCs membrane stabilization with maximum effect observed at 6,400 µg/mL. Citronellol decreased rat's paw edema. Network pharmacology and docking studies revealed gastro-protective potential of Citronellol possibly mediated through arachidonic acid pathways by targeting COX-I, COX-II, PGE2, and 5-LOX. Citronellol reduced the ulcer indices, and histopathological changes. Further, ß-Citronellol (50 and 100 mg/kg) increased gastric PGE2, COX-1, and eNOS; while suppressing COX-2, 5-LOX and ICAM-1. Citronellol markedly enhanced the oxidative balance in isolated rat stomach tissues. CONCLUSIONS: The anti-inflammatory, anti-oxidant, and gastro-protective effects of ß-Citronellol against indomethacin-induced gastric ulcer model in rats through mediating COX-I, COX-II, PGE2, 5-LOX, eNOS, and ICAM-1 inflammatory markers.

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.

A comparison of the effects of nifedipine and indomethacin used in preterm labor tocolytic treatment on feto-maternal Doppler ultrasonography flow.

OBJECTIVE: To compare the effects of nifedipine and indomethacin, used for tocolytic purposes in the treatment of preterm labor (PTL), on fetal-maternal Doppler blood flows and perinatal outcomes. MATERIALS AND METHODS: Eighty pregnant women between weeks 24 and 32 of gestation who used nifedipine (n = 40) and indomethacin (n = 40) as tocolytic treatments due to PTL were prospectively and consecutively included in the study. Sociodemographic, obstetric, and laboratory and Doppler flow parameters were compared between the groups. RESULTS: Statistically significant differences were observed between the groups in terms of gestational age at delivery and birth weight, Doppler flows (umbilical artery (UA) Pulsatility Index (PI), and UA Resistance Index (RI)) at 12, 24, and 48 h, middle cerebral artery RI at 12 h, and ductus venosus (DV) PI and DV-RI at 12, 24, and 48 h (p < 0.05). CONCLUSIONS: The findings of this study showed that nifedipine and indomethacin used in the treatment of PTL had significant effects on UA-PI and UA-RI Doppler flows at 12, 24, and 24 h, MCA-RI Doppler flows at 12 h, and DV-PI and DV-RI Doppler flows at 12, 24, and 48 h. Further studies involving larger numbers of participants are now needed to support these results.

Furosemide for patent ductus arteriosus during cyclooxygenase inhibitor therapy: A systematic review.

BACKGROUND: Although furosemide is used during cyclooxygenase (COX) inhibitor therapy for patent ductus arteriosus (PDA), there are concerns regarding increased ductal closure failure and acute renal failure (ARF). This systematic review explores the effects of furosemide during COX inhibitor therapy. METHODS: We searched MEDLINE, Embase, Cumulative Index to Nursing and Allied Health Literature, Cochrane Central Register of Controlled Trials, and Igaku Chuo Zasshi databases for randomized clinical trials that assessed furosemide during COX inhibitor therapy for PDA in preterm infants. The primary outcome measure was PDA closure failure. Mortality and other complications were also assessed. The risk of bias was assessed using the Cochrane risk-of-bias tool for randomized control trials, and the certainty of evidence was assessed using the Grading of Recommendations Assessment, Development, and Evaluation criteria. RESULTS: Overall, three trials involving 121 patients were included in the analysis. The overall incidence of PDA closure failure was 28%. Although the result of PDA closure failure, mortality, and ARF were obtained, other outcomes were not described in any of the studies. The risk of bias was high. The risk of PDA closure failure did not increase with furosemide administration. Furosemide was not associated with decreased mortality but was associated with an increased risk of ARF (risk ratio, 4.96 [95% confidence interval: 1.80-13.6]). The certainty of evidence for all outcomes was very low. CONCLUSION: Although furosemide is not associated with an increased risk of PDA closure failure or mortality, the risk of ARF increases after furosemide administration during COX inhibitor therapy.

Design and Synthesis of an Azo Reductase Responsive Flavonol-Indomethacin Hybrid Used for the Diagnosis and Treatment of Colitis.

Human intestinal bacteria are the primary producers of azo reductase, and the content of azo reductase is closely associated with various intestinal diseases, including ulcerative colitis (UC). The rapid detection of changes in azo reductase levels is crucial for diagnosing and promptly intervening in UC. In this study, a therapeutic agent, FAI, specifically targeting UC, was designed and synthesized. This agent was developed by linking the anti-inflammatory drug indomethacin to flavonols with antioxidant activity via an azo bond (off-on). Breakage of the azo bond breaks results in the release of both fluorophores and drugs, achieving targeted tracing and integrated treatment effects. In vivo and in vitro fluorescence imaging experiments were used to demonstrate the potential of FAI in the diagnosis of UC, together with synergistic therapeutic effects through the release of both fluorophores and anti-inflammatory agents. Therefore, this diagnostic agent shows promise as a potential tool for diagnosing and treating UC.

Effectiveness of indomethacin in preventing Heterotopic Ossification: a systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: Heterotopic ossification (HO) is a frequent complication of joint trauma or surgery, commonly occurring after hip replacements, acetabular or other joint injuries, or surgeries. Indomethacin has long been used to prevent HO and is considered the first-line therapy. However, its effectiveness and necessity for HO prevention are still debated due to mixed evidence about its efficacy and potential side effects. METHODS: Following PRISMA guidelines, this systematic review and meta-analysis evaluated randomized controlled trials using the PICO framework. Searches were conducted across PubMed, Embase, Cochrane Library, and Web of Science. Data were extracted and assessed based on the evidence levels of the selected articles. This study was registered with the International Platform of Registered Systematic Review and Meta-analysis Protocols (INPLASY). RESULTS: This analysis included 665 patients, with 347 in the Indomethacin group and 318 in the No Indomethacin group. The outcomes analyzed-HO, Gastrointestinal Side Effects, and Bone Ununion-indicated that indomethacin effectively prevents HO. The meta-analysis revealed that the Indomethacin group experienced a significant reduction in the occurrence of grade I-II HO compared to the No Indomethacin group, but not for grade III-IV HO. Gastrointestinal side effects were notably higher in the Indomethacin group. The incidence of bone nonunion was higher in the Indomethacin group, although not statistically significant. CONCLUSIONS: The meta-analysis suggests that indomethacin is effective in preventing HO, particularly for Brooker grade I-II, rather than Brooker grade III-IV. Special attention should be given to gastrointestinal complications when using indomethacin. Further prospective randomized controlled studies are required to confirm these findings.

Effect of central administration of indomethacin on anandamide-induced GnRH/LH secretion in the hypothalamus of anoestrous ewes.

Introduction: It is suggested that cannabinoids (CBs) may disturb reproduction through action on hypothalamic gonadotropin-releasing hormone (GnRH) neurons directly or indirectly through intermediates such as prostaglandins. The study aimed to determine the influence of intracerebroventricular (i.c.v.) injection of the endogenous cannabinoid anandamide (N-arachidonoylethanolamine - AEA), alone or with the prostaglandin synthesis inhibitor indomethacin (IND), on GnRH/luteinising hormone (LH) secretion. The purpose of the research was to clarify the role of endocannabinoids and their interaction with prostaglandins in the regulation of reproduction at the level of the hypothalamus and pituitary in anoestrous sheep. Material and Methods: The study was performed on 24 anoestrous ewes divided into four experimental groups: a control group receiving i.c.v. injection of Ringer-Locke solution, an AEA group that received i.c.v. injection of 30 µM of AEA, an IND group receiving i.c.v. injection of 5 µM of IND and an AEA + IND group that received i.c.v. injections of 30 µM of AEA and 5 µM of IND. Results: Anandamide stimulated GnRH protein and gene expression in the median eminence and protein expression in the preoptic area without influencing GnRH messenger RNA (mRNA) in this structure. Indomethacin reversed the changes in GnRH secretion after AEA administration. It was also found that AEA stimulated LH mRNA in the pituitary without influencing LH release. Conclusion: Our results support the role of endogenous cannabinoids in the regulation of reproductive processes at the central nervous system level. They may act directly on the hypothalamic GnRH neurons or indirectly through intermediates such as prostaglandins.

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.

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.

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.

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.

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.