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In recent years, the massive use of pharmaceuticals has led to the detection of a large number of relevant residues in water. As emerging contaminants, pharmaceuticals residues in the environment pose a major threat to human health and ecosystems. Covalent organic polymers (COPs) possess high stability, uniform pore size, and easy functionalization, which have attracted great attention in water treatment. In this study, a novel covalent organic polymer was successfully studied by a simple synthesis method, combining p-phenylenediamine (Pd) and isophthalaldehyde (Is) via a Schiff-base (referred to PdIs-COP), which was used as an absorbent for the removal of indomethacin from aqueous solutions. The composite was characterized with scanning electron microscopy (SEM), Fourier transform infrared spectroscopy (FTIR), X-ray diffraction (XRD), Brunauer-Emmett-Teller (BET) specific surface area and thermogravimetric (TGA) analysis. The effect of changes in the pH values and the adsorption time on the adsorption capacity was also investigated. The results of this study indicated that the absorbent had a high adsorption capacity for indomethacin. The adsorption capacity of PdIs-COP for indomethacin is 92.86 mg g−1 at pH of five and a contact time of 2 min. This shows that PdIs-COP is a novel material with good affinity for pharmaceuticals. [ABSTRACT FROM AUTHOR]

Purpose: Some evidence that non-steroidal anti-inflammatory drugs have neuroprotective effects indicates their potential for use in a new field. However, their effects on hormone secretion have yet to be adequately discovered. Therefore, we aimed to evaluate the effects of metamizole and indomethacin on neuronal markers as well as the GnRH expression in the GT1-7 cell line. Methods: The effects of these drugs on proliferation were evaluated by MTT analysis. The effect of 10–50–250 µM concentrations of the drugs also on the expression of neuronal factors and markers, including NGF, nestin and βIII Tubulin, and additionally GnRH, was determined by the RT-qPCR method. Results: NGF and nestin mRNA expressions were increased in all concentrations of both metamizole and indomethacin. No changes were detected in βIII Tubulin. While metamizole showed an increase in GnRH mRNA expression, there was no change at 10 and 50 µM concentrations of indomethacin, but a remarkable decrease was observed at 250 µM concentrations. Conclusions: The results of our study showing an increase in the expression of neuronal factors reveal that metamizole and indomethacin may have possible neuroprotective effects. Moreover, the effects on the GnRH expression appear to be different. Animal models are required to confirm these effects of NSAIDs on neurons. [ABSTRACT FROM AUTHOR]

Non‐steroidal anti‐inflammatory drugs (NSAIDs) are extensively prescribed pharmaceutical agents worldwide. Due to their analgesic, antipyretic, and anti‐inflammatory properties, they are used in clinical practice for the treatment of numerous inflammatory diseases. The mechanism of action primarily involves the inhibition of prostaglandin synthesis mediated by cyclooxygenases (COX), key enzymes of the inflammatory cascade. Indomethacin, a non‐selective derivative of indole‐3‐acetic acid exhibits diverse mechanisms to exert its anti‐tumor effects, including angiogenesis suppression, induction of apoptosis, and reduction of tumorigenesis through immune modulation. Numerous studies suggest that derivatives of indomethacin may inhibit cell proliferation and reduce levels of anti‐apoptotic proteins through COX‐independent mechanisms. Given the diverse potential mechanisms through which indomethacin impacts cancer progression, this review provides an overview of structural analogs that possess antitumor activity and outlines future directions in developing new candidates that may have substantial efficacy in cancer therapy. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Novel biocompatible systems suitable for the controlled release of active ingredients are under the spotlight within the last few years. The present investigation focuses on the preparation of nanoparticles (NPs) based on the amphiphilic copolymer pullulan‐graft‐poly(Z‐L‐lysine) bearing different amounts of lysine (10, 20, and 30 wt%), and on the evaluation of their ensuing viability to encapsulate the hydrophobic nonsteroidal anti‐inflammatory drug indomethacin (INDO). The copolymers are synthesized by ring‐opening polymerization, characterized by NMR and FTIR, and their critical aggregation concentration is determined by fluorescence. The NPs are prepared with and without INDO using different copolymer/solvent ratios and INDO/copolymer ratios. The hydrodynamic diameter and polydispersity of the NP suspensions are monitored by dynamic light scattering for 30 days. Their sizes vary between 208 and 338 nm, and some reach the micrometric range (19–73 μm). INDO‐free NPs are identified as spherical‐shaped by atomic force microscopy. Two formulations are tested in terms of encapsulation efficiency (EE = 43%–89%), and the drug crystallinity (DC = 7%–27%) which is determined by differential scanning calorimetry, indicating a reduction with respect to pristine INDO. The results suggest that the copolymers prepared herewith have potential to be applied as carriers for new drug delivery systems of class II drugs. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Introduction: A feature of the management of extremely preterm infants in Japan is proactive circulatory management using early routine echocardiography performed by neonatologists. Methods: This study was a post hoc analysis of the Patent ductus arteriosus and Left Atrial Size Evaluation in preterm infants (PLASE) study, which is a prospective cohort study including preterm infants admitted to 34 tertiary neonatal intensive care units in Japan between October 2015 and December 2016. We described the details of the treatment strategy of patent ductus arteriosus (PDA) based on early routine echocardiography. Results: In total, 613 preterm infants were included into the analysis. Twenty percent of infants with prophylactic indomethacin were switched to therapeutic cyclooxygenase inhibitor (COX-I) before the completion of the full prophylactic indomethacin course. Therapeutic COX-I was mostly administered based on echocardiographic findings before PDA became symptomatic or hemodynamically significant. Therapeutic COX-I was frequently discontinued after one or two doses before the full course (three doses) was completed. The proportion of infants requiring additional treatment (additional therapeutic COX-I course or surgical PDA closure) after discontinued COX-I courses (<3 doses) compared to infants after completed 3 doses course was significantly lower (after the first therapeutic COX-I course 46% vs. 68%, p < 0.001) or without a significant difference (after the second or third course). Conclusions: The clinical management of PDA in Japan featured (1) COX-I administration based on echocardiographic findings before symptomatic or hemodynamically significant PDA appeared and (2) frequent discontinuation of therapeutic COX-I before completing the standard three doses course. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Interaction of diclofenac and indomethacin with lysozyme was studied using several spectroscopic and molecular docking methods. Difference UV–visible spectra showed that the absorption profile of lysozyme changed when both diclofenac and indomethacin were mixed with the former. The sequential addition of both drugs to the lysozyme solution caused the decrease of the intrinsic fluorescence of the latter, however, when the data were corrected for inner filter effect, an enhancement in the fluorescence of lysozyme was detected. Accordingly, the fluorescence enhancement data were analyzed using Benesi–Hildebrand equation. Both, diclofenac and indomethacin showed good interaction with lysozyme, although, the association constants of indomethacin were nearly two-fold higher as compared to that of diclofenac. The binding was slightly more spontaneous in case of indomethacin and the major forces involved in the binding of both drugs with lysozyme were hydrogen bonding and hydrophobic interactions. Secondary structural analysis revealed that both drugs partially unfolded lysozyme. Results obtained through molecular docking were also in good agreement with the experimental outcomes. Both, diclofenac and indomethacin, are bounded at the same site inside lysozyme which is located in the big hydrophobic cavity of the protein. [ABSTRACT FROM AUTHOR]

Uric acid is the final metabolite in humans. High level of uric acid chronically induces urate deposition, aggravates kidney damage, and concomitantly causes an increase in inflammatory factors. Alleviating acute inflammation and decreasing uric acid levels are the key points in the treatment of inflammatory diseases associated with high uric acid. However, a drug delivery system that combines anti-inflammatory and uric acid reduction functions at the same time remains a challenge to be settled. Here, we designed a nanocrystal-based co-delivery platform, IND Nplex, characterized by loading of indomethacin (IND) and uricase. Compared with free IND or uricase, IND Nplex possessed a better anti-inflammatory effect by restraining the release of inflammation-related factors in vitro. In addition, pharmacokinetic and biodistribution studies revealed that IND Nplex significantly prolonged the retention time in vivo and was more concentrated in the kidney. In acute gouty arthritis model rats, IND Nplex markedly relieved ankle joint swelling and mitigated synovial inflammation. In acute kidney injury model rats, IND Nplex indicated better biocompatibility and significant amelioration of renal fibrosis. Moreover, IND Nplex showed the effect of anti-inflammatory and improved renal function via determination of inflammatory factors and biochemical markers in the serum and kidney. In conclusion, these results indicate that IND Nplex exerts anti-inflammatory activity and uric acid–lowering effect and could become a promising candidate for the treatment of uric acid–related diseases. In this study, a stable neutral co-delivery platform (IND Nplex) was fabricated by using a co-delivery strategy, allowing for a combination of the anti-inflammation drug IND and the metabolic enzyme uricase. IND Nplex showed a good therapeutic effect on rats with acute gouty arthritis or acute kidney injury due to the dual effects of anti-inflammatory and uric acid lowering. This platform provided a novel strategy for high uric acid–related illnesses. [ABSTRACT FROM AUTHOR]

Trigeminal autonomic cephalgias (TACs) are a well-defined subset of uncommon primary headaches that share comparable onset, pathophysiology and symptom patterns. TACs are characterised by the presentation of one-sided and high-intensity trigeminal pain together with unilateral cranial autonomic signs, which can include lacrimation, rhinorrhea, and miosis. The International Classification of Headache Disorders 3rd Edition recognises four different headache entities in this group, with cluster headache as the most recognised among them. Hemicrania continua (HC) and paroxysmal hemicrania (PH) are both distinctive cephalgias of which the diagnostic criteria include an absolute response to indomethacin. Consequently, for this reason they are often referred to as 'indomethacin-responsive' TACs. The main focus of this review was to discuss the state of knowledge regarding the pathophysiology and key characteristics of PH and HC. Given the limited understanding of these conditions, and their exceptionally uncommon prevalence, a correct diagnosis can pose a clinical challenge and the search for an effective treatment may be prolonged, which frequently has a serious impact upon patients' quality of life. The information provided in this review is meant to help physicians to differentiate indomethacin-sensitive cephalgias from other distinct headache disorders with a relatively similar clinical presentation, such as cluster headache, trigeminal neuralgia, and various migraine conditions. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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.

Vaikunthavasan Thiruchenthooran,1 Marta Espina,2,3 Marta &Sacute;witalska,4 Lorena Bonilla-Vidal,2,3 Joanna Wietrzyk,4 Maria Luisa Garcia,2,3 Eliana B Souto,5 Elena Sánchez-López,2,3,6,&ast; Anna Gliszczy&nacute;ska1,&ast; 1Department of Food Chemistry and Biocatalysis, Wroc&lstrok;aw University of Environmental and Life Sciences, Wroc&lstrok;aw, Poland; 2Department of Pharmacy, Pharmaceutical Technology and Physical Chemistry, University of Barcelona, Barcelona, Spain; 3Institute of Nanoscience and Nanotechnology (IN2UB), University of Barcelona, Barcelona, Spain; 4Department of Experimental Oncology, Ludwik Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Wroc&lstrok;aw, Poland; 5Laboratory of Pharmaceutical Technology, Department of Drug Sciences, Faculty of Pharmacy, University of Porto, Porto, Portugal; 6Unit of Synthesis and Biomedical Applications of Peptides, IQAC-CSIC, Barcelona, Spain&ast;These authors contributed equally to this workCorrespondence: Anna Gliszczy&nacute;ska; Elena Sánchez-López, Email anna.gliszczynska@upwr.edu.pl; esanchezlopez@ub.eduPurpose: 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. Keywords: lipid nanoparticles, indomethacin, antitumoral activity, tumor-targeting

Abstract Recently, there is a particular interest to utilize protic ionic liquids (PILs) in drug solubility. This study is exploring the effect of three protic ionic liquids (PILs) based on 2-hydroxyethylammonium carboxylate [2-hydroxyethylammonium acetate (MEAA), 2-hydroxyethylammonium lactate (MEAL), and 2-hydroxyethylammonium propionate (MEAP)] on the solubility of the very poorly soluble drug in water, indomethacin (IMC). The shake flask method was used to measure the experimental solubility of IMC at the different temperatures range (298.15–313.15) K. The results demonstrate significantly enhancment the solubility of IMC in PILs compared to pure water, with an approximate increase of 200 times. The experimental solubility data have been correlated using the empirical models which showed the performance as the order: Modified Apelblat–Jouyban–Acree > Van’t Hoff–Jouyban–Acree > Modified Apelblat equations and also the performance for the Wilson model indicated as the order (absolute relative deviation): 2-hydroxyethylammonium acetate (3.030) > 2-hydroxyethylammonium propionate (3.239) > 2-hydroxyethylammonium lactate (7.665). Then the thermodynamic dissolution properties were obtained by usage of Gibbs and Van’t Hoff equations to investigate the thermodynamic behavior of the IMC in the aqueous solution PILs. Eventually, the cytotoxicity of the co-solvents (PILs) under study was evaluated using a standard MTT assay. The results showed that the cell viability percentage increased in the following order: MEAA

The primary goal of the investigation was to analyse the anti-inflammatory and antioxidant properties of Gamma-linolenic acid (GLA) on rats with indomethacin (IND)-induced gastric ulcers. Thirty rats were divided into five groups: Control, IND (50 mg/kg, p.o.), IND pretreated with GLA 100 mg/kg (p.o. for 14 d), IND pretreated with GLA 150 mg/kg (p.o. for 14 d) and IND pretreated with omeprazole (20 mg/kg, p.o. for 14 d). The stomach tissues were examined to calculate the ulcer index and pH and analyse biochemical markers (prostaglandin E2 (PGE2), cyclooxygenase 1 (COX1), TNF-1, IL-6 and intercellular adhesion molecule-1 (ICAM1)) and oxidative stress parameters (malondialdehyde: (MDA), superoxide dismutase (SOD), glutathione (GSH) and CAT (catalase)) as well as undergo histopathological assessment. GLA 100 and 150 mg/kg showed a protective effect against IND-induced gastric damage. It reduced levels of COX1, TNF-1, IL-6 and ICAM and increased PGE2 levels. GLA also normalised antioxidant function by modulating MDA, SOD, GSH and CAT. GLA intervention protects against IND-induced gastric ulcers by restoring oxidant/antioxidant balance and reducing inflammation. [ABSTRACT FROM AUTHOR]

The use of indomethacin to delay delivery in preterm labor (PTL) is widely accepted; however, the optimal dosage of indomethacin in pregnancy is unknown. Here, we perform population pharmacokinetic (PK) and pharmacodynamic (PD) analyses, characterize the plasma disposition of indomethacin in pregnant women with PTL, and relate indomethacin exposure to delayed delivery and maternal/neonatal safety. We analyzed plasma and urine samples collected from a multicenter, prospective, opportunistic PK/PD study of indomethacin in pregnant women 12‐32 weeks gestation admitted with PTL. Ninety‐four participants with 639 plasma concentrations for indomethacin were included in the analysis. The final population PK (popPK) model for indomethacin was a 2‐compartment structural model with first‐order absorption and elimination and a covariate effect of body mass index on apparent oral clearance. We observed a 21%‐60% increase in apparent oral clearance observed during pregnancy. There was no clear association between indomethacin exposure and maternal or neonatal safety outcomes, or with the magnitude of delayed delivery; however, 96.7% of women treated with indomethacin had a delivery that was delayed at least 48 hours. Given the changes to indomethacin apparent oral clearance during pregnancy, and the lack of relationship between indomethacin exposure and safety, dose‐finding studies of indomethacin in pregnant women with PTL may help clarify the most safe and efficacious dosage and duration of indomethacin. [ABSTRACT FROM AUTHOR]

Gout arthritis is an inflammatory arthritis characterized by increased serum uric acid and accumulation of monosodium urate (MSU) crystals in soft tissues. The treatment for gout arthritis is centered on reducing uric acid agents with long-term and anti-inflammatory agents during attack times. In recent studies, it is noteworthy that Indomethacin and Dexamethasone have positive effects in the treatment of gout. Dimethyl sulfoxide (DMSO) is a lipophilic solvent and has an anti-inflammatory effect at appropriate doses. Based on this information, for this study, the effects of these three agents were investigated in rats using a gut model to compare their efficacy. In the study, a total of 48 female 3–4-month rats were divided equally into 8 groups: Control, Indomethacin, DMSO, Dexamethasone, Gout, Gout+Indomethacin, Gout+DMSO, Gout +Dexamethasone. During the eight-week study, a gout arthritis model was used that included 10 mg MSU given intra-articularly in the right foot. Indomethacin 12.5 mg/kg intragastric, DMSO 0.1 ml intraperitoneally and dexamethasone 0.2 mg/kg were administered subcutaneously to the related groups once a day for seven days. At the end of the study, collected articular tissues were stained with haematoxylin and eosin after the fixation and decalcification processes were done. The findings obtained showed that inflammation was reduced in treatment groups compared to the Control groups (all p values 0.002). Also, synovial proliferation was remarkably decreased in the Gout+Dexamethasone group compared to the Gout group (p = 0.019). As a result of these findings, although the three agents all reduced inflammation in gout arthritis, DMSO was shown to be more advantageous due to its having fewer side-effects. [ABSTRACT FROM AUTHOR]

Background: Hemicrania continua is a primary unilateral headache characterized by ipsilateral parasympathetic and sympathetic autonomic features. A key diagnostic criterion is its dramatic response to indomethacin treatment; however, various vascular or structural abnormalities have been reported to cause secondary hemicrania continua, presenting with clinical features similar to those of the primary headache presentation. Objective: We reviewed the literature to compile secondary hemicrania continua cases, highlighting the importance of imaging during the evaluation. Additionally, we also contributed our three cases to the existing studies. Methods: We conducted a review of articles from the PubMed and EMBASE databases that described reported cases of secondary hemicrania continua, covering the period from 1993 to 2021. Our review included detailed patient information, signs, and symptoms of hemicrania continua, as well as information on indomethacin usage and headache resolution (if pertinent). Results: Secondary hemicrania continua can result from a remarkably diverse range of structural and vascular lesions, yet clinical reports on long‐term follow‐up are lacking. Notably, cases may exhibit a classical response to indomethacin, emphasizing the importance of neuroimaging in excluding secondary cases. Our search yielded 41 cases meeting our criteria. We excluded six cases that were not treated with indomethacin or were unresponsive to it. Additionally, we present three cases that highlight the necessity of neuroimaging in evaluating hemicrania continua, along with short‐ and long‐term clinical outcomes following indomethacin and lesion‐directed treatments. Case 1 presented with daily right‐sided headaches and cranial autonomic symptoms. Her pain completely resolved with indomethacin use. Neuroimaging of the brain revealed a laterally directed saccular aneurysm of the right internal carotid artery. Case 2 presented with continuous left‐sided unilateral headaches with superimposed exacerbations. She complained of left‐sided photophobia with a dull sensation in the left ear. Her symptoms decreased after 2 weeks of indomethacin use. Neuroimaging of the head indicated a benign tumor with mass effect into the left lateral medulla and inferior cerebellar peduncle. Case 3 presented with a right side‐locked headache with daily, severe superimposed exacerbations. She had photophobia in the right eye and a right‐sided Horner's syndrome, along with tearing during her exacerbations. Neuroimaging of the brain revealed a pituitary tumor and her pain completely resolved with indomethacin. Conclusion: Hemicrania continua is a rare headache disorder that can be either primary or secondary. Importantly, response to indomethacin can still occur in secondary hemicrania continua. Thus, neuroimaging should be considered to rule out underlying structural etiology in all cases, regardless of their clinical responsiveness to indomethacin therapy. Plain Language Summary: Hemicrania continua is a primary headache disorder, but in some patients the headache phenotype can be due to a secondary cause. We reviewed 46 published cases of patients with this headache phenotype and added three patients of our own; scans revealed additional serious, often treatable, problems in many of the cases. Clinicians should consider imaging studies when patients present with symptoms consistent with hemicrania continua, even if they respond to medication. [ABSTRACT FROM AUTHOR]

Background: The term "gout" refers to a broad clinical spectrum of diseases, including common and complex forms of arthritis, that affect multiple joints in a patient due to an elevated serum urate concentration. Purpose: The study aims to compare the efficacy and safety of selective cyclooxygenase-2 (COX-2) inhibitors and non-selective nonsteroidal anti-inflammatory drugs (NSAIDs) in the treatment of acute gout, as well as to conduct a meta-analysis on safety. Methodology: As of December 2021, the literature search was conducted using authorised electronic databases such as PubMed, Embase, Web of Science, and the Cochrane Library. Results: There were seven investigations included in this study's findings. Three COX-2 inhibitors, etoricoxib, celecoxib, and meloxicam, were reportedly compared to indomethacin or diclofenac. Four hours after the initial dose, 120 mg of etoricoxib reduces pain and inflammation by diminishing erythema. At higher dosages, celecoxib is more effective than at lower doses. Meloxicam has the same efficacy as NSAIDs. The subgroup analysis revealed that the risk of adverse events was 8.0% lower in the COX-2 inhibitors group than in the non-selective NSAIDs group (risk ratio = 0.92, 95% confidence interval = 0.60 to 0.40, p -value = 0.5). Conclusion: Etoricoxib, a COX-2 inhibitor, has a more potent effect and may be more effective than non-selective NSAIDs. COX-2 inhibitors are more well tolerated and reduce the risk of adverse gastrointestinal events more effectively than non-selective NSAIDs. In the treatment of gout, non-selective NSAIDs may be a suitable alternative to COX-2 inhibitors. [ABSTRACT FROM AUTHOR]

Therapeutic effect of non-steroidal anti-inflammatory drugs (NSAIDs) has been related with gastrointestinal injury. Docosahexaenoic acid (DHA), an omega-3 polyunsaturated fatty acid (PUFA), can prevent gastric and small intestinal damage. Nonetheless, contribution of antioxidative action in the protective effect of DHA has not been evaluated before in the small intestine injury after indomethacin treatment. Pathogenesis of NSAID-induced small intestinal injury is multifactorial, and reactive oxidative species have been related to indomethacin's small intestinal damage. The present work aimed to evaluate antioxidative activity in the protective action of DHA in the indomethacin-induced small intestinal damage. Female Wistar rats were gavage with DHA (3 mg/kg) or omeprazole (3 mg/kg) for 10 days. Each rat received indomethacin (3 mg/kg, orally) daily to induce small intestinal damage. The total area of intestinal ulcers and histopathological analysis were performed. In DHA-treated rats, myeloperoxidase and superoxide dismutase activity, glutathione, malondialdehyde, leukotriene, and lipopolysaccharide (LPS) levels were measured. Furthermore, the relative abundance of selective bacteria was assessed. DHA administration (3 mg/kg, p.o.) caused a significant decrease in indomethacin-induced small intestinal injury in Wistar rats after 10 days of treatment. DHA's enteroprotection resulted from the prevention of an increase in myeloperoxidase activity, and lipoperoxidation, as well as an improvement in the antioxidant defenses, such as glutathione levels and superoxide dismutase activity in the small intestine. Furthermore, we showed that DHA's enteroprotective effect decreased significantly LPS levels in indomethacin-induced injury in small intestine. Our data suggest that DHA's enteroprotective might be attributed to the prevention of oxidative stress. [ABSTRACT FROM AUTHOR]

Indomethacin (INDO) is an NSAID with remarkable efficacy and widespread utilization for alleviating pain. Nevertheless, renal function impairment is an adverse reaction linked to INDO usage. Nifuroxazide (NFX), an oral nitrofuran antibiotic, is frequently employed as an intestinal anti-infective agent. Our study aimed to investigate the renoprotective effects of NFX against INDO-induced nephrotoxicity and explore the protection mechanisms. Four groups of rats were allocated to (I) the normal control, (II) the NFX-treated (50 mg/kg), (III) INDO control (20 mg/kg), and (IV) NFX + INDO. NFX attenuates renal impairment in INDO-induced renal injury, proved by decreasing serum levels of urea, creatinine, uric acid, and NGAL while the albumin was elevated. NFX mitigates renal oxidative stress by decreasing MDA levels and restoring the antioxidants' GSH and SOD levels mediated by upregulating Nrf2, HO-1, and cytoglobin pathways. NFX mitigated renal inflammation and effectively decreased MPO, IL-1β, and TNF-α levels in the rat's kidney mediated by significant downregulation of NADPH-oxidase and NF-κB expression and suppression of JAK-1 and STAT3 phosphorylation. NFX mitigates renal apoptosis by decreasing the expression of cleaved caspase-3 expression. In conclusion, NFX treatment prevents INDO nephrotoxicity by regulating Nrf2/HO-1, cytoglobin, NADPH-oxidase, NF-κB, and JAK-1/STAT3 signals. [ABSTRACT FROM AUTHOR]

The aim of this experiment was to investigate the ameliorative effect and molecular mechanism of tilapia head glycolipid (TH-GL) on indomethacin (IDM)-induced gastric ulcer in male Sprague Dawley (SD) rats. The gastric ulcer model was established by oral administration of 30 mg kg−1 IDM after 7 days of TH-GL or omeprazole (OME) administration in rats. Then the macroscopic gastric injury symptoms, gastric mucosa protective factor cyclooxygenase 1 (COX-1), cyclooxygenase 2 (COX-2), prostaglandin E2 (PGE2), the levels of oxidative stress, and inflammatory cytokine expression levels in the rats were analyzed. The experimental results showed that multiple ulcers appeared on the gastric surface of the rats in the model group. Compared to the model group, TH-GL significantly alleviated gastric ulcers and reduced the gastric damage index in rats. In addition, TH-GL significantly promoted the expression of constitutive enzyme COX-1 while inhibited the expression of inducible enzyme COX-2, and make PGE2 maintain at normal levels. TH-GL also inhibited oxidative stress and inflammatory responses, increased superoxide dismutase (SOD) activity and glutathione (GSH) content, decreased the level of malondialdehyde (MDA) and the content of pro-inflammatory factor. In conclusion, these results suggested that TH-GL could maintain the expression levels of COX-1 and PGE2 while inhibit the expression of COX-2 in the gastric of rat and then prevent IDM-induced gastric ulcer, which may be related to the regulation of oxidative stress and inflammatory response. Therefore, TH-GL might be a new option for the prevention of gastric diseases induced by IDM. [ABSTRACT FROM AUTHOR]

Background: Indomethacin is an anti-inflammatory drug that causes ulcers on the gastric mucosa due to its use. Probiotic bacteria are live microorganisms, and it has been stated by various studies that these bacteria have antioxidant and anti-inflammatory effects. In this study, we investigated the possible protective effect of various types of probiotic bacteria (Lactobacillus rhamnosus, Lactobacillus fermentum, and Lactobacillus brevis) against acute gastric mucosal damage caused by indomethacin. Methods: Control group - Physiological saline was administered daily for 10 days. Indo group-Physiological saline was administered daily for 10 days. Ranitidine + Indo group 5 mg/kg ranitidine dose was administered daily for 5 days. On day 11, a single dose of 100 mg/kg of indomethacin was given to the same group. Probiotic + Indo group 1 ml/kg of oral probiotic bacteria was administered daily for 10 days. On day 11, a single 100 mg/kg dose of indomethacin was given. After the application, the rats were anesthetized with ketamine xylazine, killed under appropriate conditions, the abdominal cavity was opened and the stomach tissues were removed. The obtained gastric tissues were used in the biochemical and histopathological analyses discussed below. All data were statistically evaluated by one-way ANOVA using SPSS 20.00, followed by Duncan Post hoc test. The data were expressed as mean ± SD. P < 0.05 was considered statistically significant. Results: As a result, the administration of indomethacin caused gastric damage, stimulating oxidative stress, inflammation, and apoptosis. We found that the use of probiotic bacteria reduces oxidative stress (TOC), increases the activity of antioxidant enzymes (TAC), suppresses inflammation (IL-6 and Tnf-α), and inhibits apoptosis (Bax and Bcl-2) (P < 0.05). Conclusion: Probiotic treatment can mitigate gastric damage and apoptosis caused by indomethacin-induced gastric damage in rats. Probiotic also enhances the restoration of biochemical oxidative enzymes as it has anti-inflammatory, antioxidant, and antiapoptotic properties. [ABSTRACT FROM AUTHOR]

Four alkaline earth metal complexes of ketoprofen (Hket) and indomethacin (Hind) were synthesized and characterized: [Ca(ket)2(H2O)2]n (1), [Mg(ket)2(H2O)2] (2), [Ca(ind)2(EtOH)2]n (3), and [Mg(ind)2(EtOH)2] (4). All compounds were studied by elemental analysis (EA), flame atomic absorption spectrometry (FAAS), Fourier transform infrared spectroscopy (FTIR), and thermogravimetric analysis (TGA). Crystal structures of 1 and 3 were determined by single crystal X‐ray diffraction technique T=100 K. The structure of 1 is dominated by a one‐dimensional coordination polymer, while 3 is formed by a two‐dimensional layer stabilized by the calcium zig‐zag chains and π⋅⋅⋅π stacking interactions. Crystal packing arrangements were characterized by fingerprint plots (FPs) that were derived from the Hirshfeld surfaces (HSs). The antioxidant and antimicrobial activities of complexes were evaluated against Gram‐positive and Gram‐negative bacteria as well as yeasts. [ABSTRACT FROM AUTHOR]

Osteoarthritis (OA) remains a chronic incurable condition, presenting substantial challenges in treatment. This study explores a novel strategy by investigating the concurrent use of cuminaldehyde, a natural compound, with indomethacin in animal models of MIA-induced OA. Our results demonstrate that the co-administration of cuminaldehyde and indomethacin does indeed produce a superior effect when compared to these compounds individually, significantly enhancing therapeutic outcomes. This effect is evidenced by a marked reduction in pro-inflammatory cytokines IL-6 and IFN-γ, alongside a significant increase in the anti-inflammatory cytokine IL-10, compared to treatments with each compound alone. Radiographic analyses further confirm the preservation of joint integrity and a reduction in osteoarthritic damage, highlighting the association's efficacy in cartilage-reducing damage. These findings suggests that the association of cuminaldehyde and indomethacin not only slows OA progression but also offers enhanced cartilage-reducing damage and fosters the production of protective cytokines. This study underscores the potential benefits of integrating natural products with pharmaceuticals in OA management and stresses the importance of further research to fully understand the mechanisms underlying the observed potentiated effects. [ABSTRACT FROM AUTHOR]

The research about α-methylene-γ-lactams is scarce; however, their synthesis has emerged in recent years mainly because they are isosters of α-methylene-γ-lactones. This last kind of compound is structurally most common in some natural products' nuclei, like sesquiterpene lactones that show biological activity such as anti-inflammatory, anticancer, antibacterial, etc., effects. In this work, seven α-methylene-γ-lactams were evaluated by their inflammation and α-glucosidase inhibition. Thus, compounds 3-methylene-4-phenylpyrrolidin-2-one (1), 3-methylene-4-(p-tolyl)pyrrolidin-2-one (2), 4-(4-chlorophenyl)-3-methylenepyrrolidin-2-one (3), 4-(2-chlorophenyl)-3-methylenepyrrolidin-2-one (4), 5-ethyl-3-methylene-4-phenylpyrrolidin-2-one (5), 5-ethyl-3-methylene-4-(p-tolyl)pyrrolidin-2-one (6) and 4-(4-chlorophenyl)-5-ethyl-3-methylenepyrrolidin-2-one (7) were evaluated via in vitro α-glucosidase assay at 1 mM concentration. From this analysis, 7 exerts the best inhibitory effect on α-glucosidase compared with the vehicle, but it shows a low potency compared with the reference drug at the same dose. On the other side, inflammation edema was induced using TPA (12-O-tetradecanoylphorbol 13-acetate) on mouse ears; compounds 1–7 were tested at 10 µg/ear dose. As a result, 1, 3, and 5 show a better inhibition than indomethacin, at the same doses. This is a preliminary report about the biological activity of these new α-methylene-γ-lactams. [ABSTRACT FROM AUTHOR]

Cyclooxygenase (COX) products of arachidonic acid metabolism, specifically prostaglandins, play a role in evoking and transmitting the exercise pressor reflex in health and disease. Individuals with type 2 diabetes mellitus (T2DM) have an exaggerated exercise pressor reflex; however, the mechanisms for this exaggerated reflex are not fully understood. We aimed to determine the role played by COX products in the exaggerated exercise pressor reflex in T2DM rats. The exercise pressor reflex was evoked by static muscle contraction in unanesthetized, decerebrate, male, adult University of California Davis (UCD)-T2DM (n = 8) and healthy Sprague-Dawley (n = 8) rats. Changes (Δ) in peak mean arterial pressure (MAP) and heart rate (HR) during muscle contraction were compared before and after intra-arterial injection of indomethacin (1 mg/kg) into the contracting hindlimb. Data are presented as means ± SD. Inhibition of COX activity attenuated the exaggerated peak MAP (Before: Δ32 ± 13 mmHg and After: Δ18 ± 8 mmHg; P = 0.004) and blood pressor index (BPi) (Before: Δ683 ± 324 mmHg·s and After: Δ361 ± 222 mmHg·s; P = 0.006), but not HR (Before: Δ23 ± 8 beats/min and After Δ19 ± 10 beats/min; P = 0.452) responses to muscle contraction in T2DM rats. In healthy rats, COX activity inhibition did not affect MAP, HR, or BPi responses to muscle contraction. Inhibition of COX activity significantly reduced local production of prostaglandin E2 in T2DM and healthy rats. We conclude that peripheral inhibition of COX activity attenuates the pressor response to muscle contraction in T2DM rats, suggesting that COX products partially contribute to the exaggerated exercise pressor reflex in those with T2DM. NEW & NOTEWORTHY: We compared the pressor and cardioaccelerator responses to static muscle contraction before and after inhibition of cyclooxygenase (COX) activity within the contracting hindlimb in decerebrate, unanesthetized type 2 diabetic mellitus (T2DM) and healthy rats. The pressor responses to muscle contraction were attenuated after peripheral inhibition of COX activity in T2DM but not in healthy rats. We concluded that COX products partially contribute to the exaggerated pressor reflex in those with T2DM. [ABSTRACT FROM AUTHOR]

The article focuses on the anti-inflammatory properties of sodium cromolyn in rats induced by carrageenan and its impact on IL-6 levels. It discusses the method of inducing carrageenan paw edema, administration of sodium cromolyn, and IL-6 levels evaluation.It highlights sodium cromolyn as an alternative to nonsteroidal anti-inflammatory drugs (NSAIDs) due to its anti-inflammatory properties.

The purpose of this study was to evaluate the effects of syringic acid, an anti-oxidant, on indomethacin induced gastric ulcers in rats. Experimental groups were control, ulcer, ulcer treated with 20 mg/kg esomeprazole (a proton pump inhibitor that reduces acid secretion), and ulcer treated with 100 mg/kg syringic acid. Rats were pretreated with esomeprazole or syringic acid two weeks before ulcer induction. Our histopathological observations showed that either syringic acid or esomeprazole attenuated the severity of gastric mucosal damage. Moreover, syringic acid and esomeprazole pretreatments alleviated indomethacin-induced damage by regulating oxidative stress, inflammatory response, the level of transforming growth factor-β (TGF-β), expressions of COX and prostaglandin E2, cell proliferation, apoptosis and regulation of the NF-κB signaling pathway. We conclude that either esomeprazole or syringic acid administration protected the gastric mucosa from harmful effects of indomethacin. Syringic acid might, therefore be a potential therapeutic agent for preventing and treating indomethacin-induced gastric damage. [ABSTRACT FROM AUTHOR]