Nonselective Nonsteroidal Anti-inflammatory Drugs Research Articles

Individual trombocity reactivity in hematuria associated with nephrolitiasis: the role of purinergic signalisation in the treatment of nesteroid protective preparations

Aim of the study was to establish the significance of TR-receptor, P2X1-receptor and P2Y-receptor synergism for the efficiency of TC aggregation in patients with different sensitivity to non-selective NSAIDs, which will allow us to approach an understanding the causes of the variability of hematuria associated with NLT. Material and methods. The study was prospective and included 60 patients with nephrolithiasis who were treated with high doses of NSAIDs for analgesia. The cohort of patients was divided into two groups: with effective (group 1. n=30) and ineffective (group 2. n=30) COX inhibition. The severity of hematuria was assessed during 7 days of drug therapy. The activity of TR receptors, purine P2X1- and P2Y- receptors of platelets (Tc) was analysed by turbidimetric method on ChronoLog analyser (USA). Agonists (ATP, ADP and Arachidonic acid) were used at EC50 and EC10 concentrations. Results. In the 1 group of patients, hyporeactivity of the TP receptor was established within 72 hours, which was restored to the level of normoreactivity on the 5th day of therapy. Optimal modulation of the compensatory reaction of Pl in response to hematuria was provided through the synergism of purine P2X1 and P2Y receptors. Optimal modulation of the compensatory reaction of Tc in response to hematuria was provided through the synergism of purine P2X1 and P2Y receptors. On the 7th day, a residual level of COX activity was reached, while intracellular signaling associated with stimulation of the TP receptor and purine P2 receptors did not provide the limitation of hematuria. In the 2 group, when patients were prescribed NSAIDs for 7 days, hyperreactivity of the TP receptor, P2 receptors and a stable level of microhematuria remained. In the case of COX resistance and increased production of TxA2, the maximum increase in proaggregant Tc activity was ensured through the stereotypical mechanism of intracellular signaling associated with stimulation of P2Y receptors (through Gi- and Gq- proteins) and the TP receptor (through Gq- and Gq12/13- proteins). Conclusion. Further study of the mechanisms of crosstalk signaling pathways with different COX activity will allow us to establish promising directions for pharmacological correction aimed at preventing hematuria and ensuring hemostasis in nephrolithiasis.

Non-steroidal anti-inflammatory drugs, renin-angiotensin system blockade or diuretics and risk of acute kidney injury: A case-crossover study

BackgroundAging-related physiological changes, such as decline in renal function, not only exacerbates pre-existing comorbidities but also escalate the susceptibility to adverse events. Previous studies have shown that non-steroidal anti-inflammatory drugs (NSAIDs) are associated with an increased risk of acute kidney injury (AKI), and the concomitant use of renin-angiotensin system blockade or diuretics may further potentiate the risk. However, studies evaluating the risk of AKI associated with NSAIDs (including routes, concomitant use of different NSAIDs, categories (traditional NSAIDs or COX-2 inhibitors), and cumulative doses of NSAIDs) are limited, particularly the risk of AKI associated with the dual or triple combination of NSAIDs with renin-angiotensin system blockade (RAS blockades) and/or diuretics. MethodsA case-crossover study utilized two sets of longitudinal data from Taiwan's National Health Insurance Research Database (NHIRD). Newly admitted patients with a primary AKI diagnosis were included, with the index date defined as the first admission date. The 1–7 days and 181–187 days prior to the index date served as the case and control periods. Exposure to NSAIDs and co-exposures of RAS blockade and/or diuretics were assessed in both periods. Multivariable conditional logistic regression models, adjusting for potential confounders, estimated adjusted odds ratios (aORs) and 95 % confidence intervals (CIs) for AKI associated with NSAIDs, dual, or triple combinations. Sensitivity analyses explored result robustness by varying case and control period lengths. ResultsThe study included 1,284 newly diagnosed AKI patients. NSAIDs showed a 3.55-fold increased risk of AKI (aOR: 3.55; 95 % CI 2.70–4.65), with similar risks for traditional NSAIDs and COX-2 inhibitors. Use of multiple NSAIDs, parenteral dosage forms, and higher cumulative doses increased AKI risk. Dual combination with either RAS blockade or diuretics resulted in a 2.90-fold (aOR: 2.90; 95 %CI 1.47–5.70) and 12.68-fold (aOR: 12.68; 95 %CI 6.15–26.12) risk, respectively. The highest risk occurred with triple combination (aOR: 29.22; 95 %CI 12.82–66.64). ConclusionsNSAIDs, including both non-selective NSAIDs and COX2 inhibitors, elevate the risk of AKI. Increased AKI risk is linked to using multiple NSAIDs, the parenteral dosage form, and higher cumulative doses. Dual combination of RAS blockade with NSAIDs or diuretics with NSAIDs, as well as triple therapy, heightens the risk, with the latter associated with the highest risk of AKI.

Ibuprofen delays ovulation by several hours – a prospective controlled study in spontaneous cycles with hCG triggered ovulation

Research question Does ibuprofen, a non-steroidal anti-inflammatory drug (NSAID), delay ovulation? Design Two-stage proof of concept controlled study, assessing the percentage of non-ovulated follicles 42h after hCG injection in patients taking ibuprofen. The intervention group consisted of women undergoing natural cycle IVF treatment cycles taking ibuprofen 3×400g/day. The control group consisted of women undergoing timed sexual intercourse or intrauterine insemination. The proportion of patients with non-ovulated follicles in the ibuprofen group was first compared against a reference of 50% using a one-sample binomial test, and second against the proportion observed in the control group using an adjusted logistic regression. Results A total of 26 women were recruited in the ibuprofen intervention group. 25 patients were recruited in the control group. The proportion of patients with delayed ovulation observed (22/26, 85%; CI: 65% - 96%) was significantly higher than the reference of 50% (Pvalue = <0.001). In the control group the proportion of patients with delayed ovulation observed was 20% (5/25, 95% CI: 6.8% - 41%). Comparing this proportion to the one observed in the ibuprofen group a significant increase of probability of a delayed ovulation was found in the ibuprofen intervention group (aOR=22.72 [5.77,115], Pval ≤0.001). Of the 22 women with delayed ovulation, oocytes were retrieved in 20 women (91%) and all oocytes were mature (Metaphase II). Conclusions Women trying to conceive should take care to avoid non-selective NSAIDs around time of ovulation. Ibuprofen or other NSAID can be used to delay ovulation for several hours in ART and other infertility treatments if required.

Indomethacin-omeprazole as therapeutic hybrids? Salt and co-amorphous systems enhancing physicochemical and pharmacological properties

Multidrug therapeutic hybrids constitute a promising proposal to overcome problems associated with traditional formulations containing physical mixtures of drugs, potentially improving pharmacological and pharmaceutical performance. Indomethacin (IND) is a non-selective non-steroidal anti-inflammatory drug (NSAIDs) that acts by inhibiting normal processes of homeostasis, causing a series of side effects, such as gastrointestinal symptoms. Proton pump inhibitors, such as omeprazole (OME), have been used to treat such gastrointestinal tract symptoms. In this work, two new multidrug therapeutic hybrids were prepared (an IND:OME salt and an IND:OME co-amorphous system) by ball mill grinding crystalline IND and OME under different conditions, i.e., liquid assisted grinding (LAG) with ethanol and dry grinding, respectively. The crystalline salt returned to a neutral state co-amorphous system when submitted to ball mill grinding in the absence of solvent (dry grinding), but the reverse process (LAG of the IND:OME co-amorphous system) showed partial decomposition of OME. The IND:OME co-amorphous system showed a higher physical stability than the neat IND and OME amorphous materials (with an amorphous stability longer than 100 days, compared to 4 and 16 h for the neat amorphous drugs, respectively, when stored at dry conditions at room temperature). Furthermore, OME presented a higher chemical stability in solution when dissolved from a salt form than from the pure crystalline form. The dissolution studies showed a dissolution enhancement for IND in both salt (1.8-fold after 8 h of dissolution) and co-amorphous (2.5-fold after 8 h of dissolution) forms. Anti-inflammatory activity using a mice paw oedema model showed an increase of the pharmacological response to IND at a lower dose (∼5mg/kg) for both IND:OME salt (2.8-fold) and IND:OME co-amorphous system (3.2-fold) after 6 h, when compared to the positive control group (IND, administered at 10 mg/kg). Additionally, the anti-inflammatory activity of both salt and co-amorphous form was faster than for the crystalline IND. Finally, an indomethacin-induced gastric ulceration assay in mice resulted in a higher mucosal protection at the same dose (40 mg/kg) for both IND:OME salt and IND:OME co-amorphous system when compared with crystalline OME.

Regulation of platelet proaggregant activity in cyclooxygenase inhibition in patients with nephrolithiasis

Aim of the study was to establish the possibility of synergism between the TP receptor for TxA2 and purinergic P2 receptors during COX inhibition, and the effect of the resulting remodeling of signaling pathways on aggregometry parameters in patients with nephrolithiasis (NLT). Materials and Methods. The study was prospective and included 30 patients with imaging evidence of urinary tract calculi who were treated with high doses of non-selective NSAIDs for analgesia. The severity of hematuria was assessed at the time of hospitalization and during 7 days of lithokinetic therapy (LKT). Analysis of functional activity of TR-receptors, purine P2X1and P2Yreceptors of platelets (Tc) was performed by turbidimetric method on ChronoLog analyzer (USA). Agonists (ATP, ADP and Arachidonic acid) were used at concentrations of EC50 and EC10. Statistical analysis was performed using MedCalc package. Results. Two waves of COX activity decrease were revealed 24h and 72h after the beginning of NSAID administration. On the 5th day of LKT, the compensatory reaction of Tc was switched on, which was reproduced at restoration of normoreactivity of TR-receptor. Purine P2X1 – and P2Y-receptor synergism had a more pronounced inducing effect on aggregation parameters compared with the interaction between P2Y-receptor and TR-receptor or TR-receptor and P2X -receptor. On the 7th day, the residual level of COX activity was reached and hyporeactivity of TR-receptor was registered; at the same time the preserved level of TxA2 synthesis did not provide limitation of hematuria. Conclusion. Upon COX inhibition, potentiation of Tc proaggregant activity is reproduced by purine P2-receptor and TR-receptor interaction due to an increase in the rate of intracellular signalling (Slope) and the number of aggregates formed (AUC).

Comparison of different nonsteroidal anti-inflammatory drugs for cesarean section: a systematic review and network meta-analysis.

Cesarean section is associated with moderate to severe pain and nonsteroidal anti-inflammatory drugs (NSAIDs) are commonly employed. The optimal NSAID, however, has not been elucidated. In this network meta-analysis and systematic review, we compared the influence of control and individual NSAIDs on the indices of analgesia, side effects, and quality of recovery. CDSR, CINAHL, CRCT, Embase, LILACS, PubMed, and Web of Science were searched for randomized controlled trials comparing a specific NSAID to either control or another NSAID in elective or emergency cesarean section under general or neuraxial anesthesia. Network plots and league tables were constructed, and the quality of evidence was evaluated with Grading of Recommendations Assessment, Development and Evaluation (GRADE) analysis. We included 47 trials. Cumulative intravenous morphine equivalent consumption at 24 h, the primary outcome, was examined in 1,228 patients and 18 trials, and control was found to be inferior to diclofenac, indomethacin, ketorolac, and tenoxicam (very low quality evidence owing to serious limitations, imprecision, and publication bias). Indomethacin was superior to celecoxib for pain score at rest at 8-12 h and celecoxib + parecoxib, diclofenac, and ketorolac for pain score on movement at 48 h. In regard to the need for and time to rescue analgesia COX-2 inhibitors such as celecoxib were inferior to other NSAIDs. Our review suggests the presence of minimal differences among the NSAIDs studied. Nonselective NSAIDs may be more effective than selective NSAIDs, and some NSAIDs such as indomethacin might be preferable to other NSAIDs.

Co-administered oral anticoagulants with nonsteroidal anti-inflammatory drugs and the risk of bleeding: A systematic review and meta-analysis

BackgroundThe bleeding risk of individuals taking nonsteroidal anti-inflammatory drugs (NSAIDs) concomitantly with oral anticoagulants (OACs) compared to OACs alone remains controversial. This meta-analysis aims to evaluate the bleeding risk of concomitant use of OACs and NSAIDs, and to make comparisons between different OACs types. MethodsPubMed, Embase, Cochrane Library and Web of Science were searched systematically until 11 August 2023 for studies reporting the bleeding risk of combined use of OACs and NSAIDs. Summary estimates with 95 % confidence interval (CI) were calculated by meta-analysis. Heterogeneity was assessed by I2 statistics. We performed subgroup analyses according to the types of NSAIDs, the types of OACs, the indication for therapy and the types of research. ResultsA total of 27 studies were included. Taking vitamin K antagonist (VKAs) concurrently with NSAIDs was associated with a higher risk of any bleeding [odds ratio (OR) = 1.55; 95 % CI, 1.21 to 2.00; P = 0.0007), gastrointestinal bleeding (OR = 2.66; 95 % CI, 1.96 to 3.62; P < 0.00001) as well as major bleeding (OR = 1.55; 95 % CI, 1.04 to 2.30; P = 0.03). Concomitant exposure to direct OACs (DOACs) and NSAIDs increased the risks of any bleeding (OR = 1.54; 95 % CI, 1.33 to 1.80; P < 0.00001) and gastrointestinal bleeding (OR = 2.18; 95 % CI, 1.02 to 4.69; P = 0.05), but was nonsignificant for major bleeding (OR = 1.42; 95 % CI, 0.84 to 2.40; P = 0.19). Without considering other confounding factors, concomitant exposure to DOACs and NSAIDs was associated with a lower risk of bleeding compared to VKAs plus NSAIDs (OR = 0.55; 95 % CI, 0.34 to 0.90; P = 0.02) in atrial fibrillation and venous thromboembolism patients. Subgroup analyses showed that compared to VKAs only, concurrent administration of VKAs and nonselective NSAIDs was associated with a heightened risk of bleeding (OR = 3.06; 95%CI, 1.99 to 4.71; P < 0.00001). However, inconsistent result was observed when it comes to selective NSAIDs (OR = 1.99; 95%CI, 0.87 to 4.51; P = 0.10). Compared to DOACs only, combined use of rivaroxaban and NSAIDs increased bleeding risk (OR = 1.61; 95 % CI, 1.21 to 2.14; P = 0.001), while dabigatran co-administered with NSAIDs showed no significant association with bleeding (OR = 1.40; 95 % CI, 0.80 to 2.44; P = 0.24). Regardless of indication, concomitant administration of NSAIDs and DOACs increased the risk of bleeding. ConclusionsCo-administered OACs with NSAIDs significantly increased the risk of any bleeding and gastrointestinal bleeding compared to OACs alone. Without considering other confounding factors, DOACs were associated with a lower risk of bleeding compared to VKAs in atrial fibrillation and venous thromboembolism patients.

Indomethacin Induces Spermidine/Spermine-N1-Acetyltransferase-1 via the Nucleolin-CDK1 Axis and Synergizes with the Polyamine Oxidase Inhibitor Methoctramine in Lung Cancer Cells.

Indomethacin is a non-selective NSAID used against pain and inflammation. Although cyclooxygenase (COX) inhibition is considered indomethacin's primary action mechanism, COX-independent ways are associated with beneficial effects in cancer. In colon cancer cells, the activation of the peroxisome proliferator-activated receptor-γ (PPAR-γ) is related to the increase in spermidine/spermine-N1-acetyltransferase-1 (SSAT-1), a key enzyme for polyamine degradation, and related to cell cycle arrest. Indomethacin increases the SSAT-1 levels in lung cancer cells; however, the mechanism relying on the SSAT-1 increase is unclear. Thus, we asked for the influence of the PPAR-γ on the SSAT-1 expression in two lung cancer cell lines: H1299 and A549. We found that the inhibition of PPAR-γ with GW9662 did not revert the increase in SSAT-1 induced by indomethacin. Because the mRNA of SSAT-1 suffers a pre-translation retention step by nucleolin, a nucleolar protein, we explored the relationship between indomethacin and the upstream translation regulators of SSAT-1. We found that indomethacin decreases the nucleolin levels and the cyclin-dependent kinase 1 (CDK1) levels, which phosphorylates nucleolin in mitosis. Overexpression of nucleolin partially reverts the effect of indomethacin over cell viability and SSAT-1 levels. On the other hand, Casein Kinase, known for phosphorylating nucleolin during interphase, is not modified by indomethacin. SSAT-1 exerts its antiproliferative effect by acetylating polyamines, a process reverted by the polyamine oxidase (PAOX). Recently, methoctramine was described as the most specific inhibitor of PAOX. Thus, we asked if methoctramine could increase the effect of indomethacin. We found that, when combined, indomethacin and methoctramine have a synergistic effect against NSCLC cells in vitro. These results suggest that indomethacin increases the SSAT-1 levels by reducing the CDK1-nucleolin regulatory axis, and the PAOX inhibition with methoctramine could improve the antiproliferative effect of indomethacin.

A Preliminary Study on the Relationship between Gastric Lesions and Anti-Inflammatory Drug Usage in Heavy Pigs.

Gastric lesions in pigs cause welfare and economic losses. Their prevalence in heavy pigs reared for premium products (e.g., Parma ham) requires further investigation. Stress, nutrition, and farm management are known risk factors, but the effects of steroidal and non-steroidal anti-inflammatory drugs (NSAIDs) are largely unknown. The aim of this study was to evaluate the prevalence of gastric lesions in Italian heavy pigs and their possible association with the use of anti-inflammatory drugs. A total of 9371 pig stomachs from 76 farms were evaluated. Among these, 20.3% showed no lesions, while 30.7%, 42.1%, and 6.8% were scored 1, 2 and 3, respectively. A tendency for an inverse relationship with farm size emerged. The use of steroids and NSAIDs was estimated by calculating a treatment incidence per 1000 (TI1000) in a subset of 36 farms. At least one prescription for NSAIDs and/or steroids was found in 80.6% of the farms (55.6% used NSAIDs and 63.9% used steroids). Median TI1000 was 0.07 (range: 0-30.1) and 0.18 (range: 0-6.2) for NSAIDs and steroids, respectively. Gastric scores were positively associated with NSAID use, but not with steroid use. Although the role of these drugs in gastric lesions needs to be further clarified, these findings suggest a cautious use of non-selective NSAIDs.

Selective COX-2 inhibitors after bariatric surgery: Celecoxib, etoricoxib and etodolac post-bariatric solubility/dissolution and pharmacokinetics

Anatomical/physiological gastrointestinal changes after bariatric surgery may influence the fate of orally administered drugs.Since non-selective NSAIDs are not well-tolerated post-surgery, selective cyclooxygenase-2 (COX-2) inhibitors may be important for these patients. In this work we investigated celecoxib, etoricoxib and etodolac, for impaired post-bariatric solubility/dissolution and absorption. Solubility was studied in-vitro, and ex-vivoin aspirated gastric contents from patients pre- vs. post-surgery. Dissolution was studied in conditions simulating pre- vs. post-surgery stomach. Finally, the experimental solubility data were used in physiologically-based biopharmaceutics model (PBBM) (GastroPlus®) to simulate pre- vs. post-surgery celecoxib/etoricoxib/etodolac pharmacokinetic (PK) profiles.For etoricoxib and etodolac (but not celecoxib), pH-dependent solubility was demonstrated: etoricoxib solubility decreased ∼1000-fold, and etodolac solubility increased 120-fold, as pH increased from 1 to 7, which was also confirmed ex-vivo. Hampered etoricoxib dissolution and improved etodolac dissolution post-surgery was revealed. Tablet crushing, clinically recommended after surgery, failed to improve post-bariatric dissolution. PBBM simulations revealed significantly impaired etoricoxib absorption post-surgery across all conditions; for instance, 79% lower Cmax and 53% decreased AUC was simulated post-gastric bypass procedure, after single 120 mg dose. Celecoxib and etodolac maintained unaffected absorption after bariatric surgery.This mechanistically-based analysis suggests to prefer the acidic drug etodolac or the neutral celecoxib as selective COX-2 inhibitors, over the basic drug etoricoxib, after bariatric surgery.

Pericardial diseases in pregnancy.

Pericardial effusion is the most common manifestation of pericardial diseases during pregnancy. This effusion is benign, mild, or moderate, well tolerated, and with spontaneous resolution after delivery; no specific treatment is required. Acute pericarditis is the second most common condition, usually requiring medical therapy during pregnancy. Cardiac tamponade and constrictive pericarditis are rare in pregnancy. Pre-pregnancy counselling is essential in women of childbearing age with recurrent pericarditis to plan pregnancy in a phase of disease quiescence and to review therapy. High-dose aspirin or non-selective nonsteroidal anti-inflammatory drugs, such as ibuprofen and indomethacin, can be used up to the 20th week of gestation. Low-dose prednisone (2.5 to 10 mg/day) can be administered throughout pregnancy. All of these medications, apart from high-dose aspirin, may be used during lactation. Colchicine is compatible with pregnancy and breastfeeding, and it can be continued throughout pregnancy in order to prevent recurrences. Appropriate follow-up with a multidisciplinary team with experience in the field is recommended throughout pregnancy to ensure good materno-fetal outcomes.

Medicinal and toxicological investigation of some common NSAIDs; A computer-aided drug design approach

Nonsteroidal anti-inflammatory drugs (NSAIDs) are commonly used for the treatment of pain, fever, and inflammation. Their consumption rises some crucial side effects like gastrointestinal, cardiovascular, and renal injury because of the non-selective reduction of prostaglandin synthesis, with differences in the extent of inhibition of the cyclooxygenase. Attempts have been taken for a comparative biochemical, medicinal, and toxicological investigation to raise awareness of the consumption of NSAIDs. In-silico methods were incorporated to investigate their physicochemical, spectral, medicinal, pharmacological, and toxicological properties. Molecular docking and non-bonding calculations were performed against the human prostaglandin synthase protein to reveal their binding affinity and interactions with the amino acid residues of the receptor protein. Further, molecular dynamics simulation was conducted to validate the binding mode and drug-protein stability at the inhibiting binding pocket. The physical and chemical analysis supports their geometries and spectral results confirming the presence of essential functional groups at the core structure. From ADMET and PASS prediction, all the drugs are non-carcinogenic (except IBP), and nonselective NSAIDs showed relatively higher adverse effects compared to selective agents. Based on the above studies, this report can be helpful to understand more deeply the medicinal, and toxicological effects of the reported NSAIDs.

Comparative structural study of selective and non-selective NSAIDs against the enzyme cyclooxygenase-2 through real-time molecular dynamics linked to post-dynamics MM-GBSA and e-pharmacophores mapping.

Inflammation-provoked disorders including cancer are arbitrated by cyclooxygenase-2 (COX-2). Celecoxib and niflumic acid are amongthe potent and selective inhibitors of this enzyme while aspirin (acetylsalicylic acid) and sodium salicylate are its non-selective and lesser potent inhibitors. Despite these proven studies, the comparative structural study of these selective and non-selective molecules at atomistic scale in complex state with COX-2 that may answer this differential inhibitory behavior has not been accomplished spotlighting the imperative need of additional research in this area. Thus, this study was framed to provide a strong explanation for the enigma of higher inhibitory activity of celecoxib-niflumic acid duo in comparison to aspirin and sodium salicylate towards COX-2. A contemporary approach including advanced molecular docking against COX2, molecular dynamics of receptor-ligand complexes, simulation-trajectory-backed MMGBSA for different time points, radius of gyration (Rg) calculations, and e-pharmacophores approach was employed to attain a rational conclusion. Our findings demonstrated the higher binding affinity of celecoxib and niflumic acid over aspirin and sodium salicylate against COX-2. Although both selective and non-selective COX-2 inhibitors manifested nearly the same stability in the active site of this enzyme but the e-pharmocophoric features found in the case of selective inhibitors scored over non-selective ones. Thus, our findings excluded the differential stability to be the cause of stronger potency of selective inhibitors but attributed their potency to greater number of complementary features present in these inhibitors against the active site of inflammation engendering COX-2.

Effect of Firocoxib and Flunixin Meglumine on Large Colon Mural Thickness of Healthy Horses

Nonsteroidal anti-inflammatory drug (NSAID) administration carries risks of gastrointestinal toxicity. Selective COX-2 inhibitors (“coxibs”) were designed to reduce risks of adverse effects but are still associated with gastrointestinal complications in humans. The effect of coxibs on colonic inflammation and integrity in horses is unknown. The study objective was to compare the effects of the coxib firocoxib and the nonselective NSAID flunixin meglumine on ultrasonographic indicators of colonic inflammation in healthy horses. Twelve healthy adult horses were administered flunixin meglumine (1.1 mg/kg IV q12h) and omeprazole (1 mg/kg PO q24h) for 5 days, allowed a 6-month washout period, then administered firocoxib (0.3 mg/kg PO once, then 0.1 mg/kg PO q24h for 4 days) and omeprazole. Transabdominal ultrasonographic examination and serum chemistry profiles were performed at the beginning and end of each treatment week. Colon wall thickness increased over time when horses received firocoxib (median post treatment 5.8 mm, interquartile range 2.8 mm; P < .001), but not flunixin (median 3 mm, interquartile range 1.2 mm; P = .7) and was significantly greater following firocoxib compared to flunixin (P = .003). Subjectively, colonic edema was noted more frequently following treatment with firocoxib (11/12 horses), compared to flunixin (1/12 horses). There were no clinically significant alterations in hematologic parameters after administration of either drug. The increase in colon wall thickness following treatment with the COX-2 selective NSAID firocoxib may suggest a risk of subclinical colitis in healthy horses. Monitoring colonic health when NSAIDs are used in a clinical setting is warranted.

The Safety of Celecoxib as an Acute Treatment for Migraine: A Narrative Review.

Nonsteroidal anti-inflammatory drugs (NSAIDs) have been the first-line choice for the acute treatment of migraine attacks for decades; however, the safety of a particular NSAID is related to its treatment dose, duration, and mechanism of action. Although adverse event (AE) risks differ substantially among individual migraine treatments, increased or prolonged exposure to any NSAID elevates risks and severity of AEs. For this narrative review, we conducted a literature search of PubMed until July 2022, focusing on the history, mechanism of action, and treatment guidelines informing the safety and efficacy of celecoxib oral solution for the acute treatment of migraine attacks. Here we discuss the mechanisms of action of nonselective NSAIDs vs. cyclooxygenase-2 (COX-2) inhibitors, and how these mechanisms underlie the AEs associated with these treatments. We review the clinical trials that influenced the regulatory history of NSAIDs, specifically COX-2 inhibitors, the role of traditional and new formulations of NSAIDs including celecoxib oral solution, and special considerations in the acute treatment of migraine attacks. Low-dose formulations of NSAIDs, such as celecoxib oral solution, provide acute migraine analgesia with similar or fewer associated cardiovascular and gastrointestinal events than previous formulations.

Invited Commentary: A Step Toward Safer and More Precise Management of Osteoarthritis Pain.

In this issue of the Journal, Wei et al. (Am J Epidemiol. 2023;192(9):1432-1448); demonstrate the modification of effect of nonselective nonsteroidal antiinflammatory drugs in the setting of aspirin use for the outcome of cardiovascular events. This study is distinctive in its aim to compare 2 similar therapies in the setting of 2 clinical scenarios (aspirin use vs. not) based on some mechanistic rationale. The use of an active comparator design with a prehypothesized evaluation of treatment heterogeneity can provide compelling evidence to support relevant clinical decisions for which clinical trial evidence is not likely or possible.

Proton pump inhibitors increase the risk of nonsteroidal anti-inflammatory drug-related small bowel injury: A Systematic Review with Meta-analysis.

Conflicting results exist on the association between proton-pump inhibitor (PPI) and nonsteroidal anti-inflammatory drug (NSAID)-related small bowel damage. Aims: To determine whether PPIs increased the risk of NSAID-related small bowel damage by meta-analysis. Methods: A systematic electronic search in PubMed, Embase, and Web of Science was conducted from the time the database was created until 31 March 2022 for studies reporting associations between PPI use and outcomes, including the endoscopy-verified prevalence of small bowel injury, mean number of small bowel injuries per patient, change in hemoglobin level, and risk of small bowel bleeding in subjects taking NSAIDs. Meta-analytical calculations for odds ratio (OR) and mean difference (MD) were performed with the random-effects model and interpreted with 95% confidence intervals (CIs). Results: Fourteen studies comprising 1996 subjects were included. Pooled analysis demonstrated that concomitant use of PPIs significantly increased the prevalence and number of endoscopy-verified small bowel injuries (prevalence: OR=3.00; 95% CI: 1.74-5.16; number: MD=2.30; 95% CI: 0.61-3.99) and decreased hemoglobin levels (MD=-0.50 g/dL; 95% CI: -0.88 to -0.12) in NSAID users but did not change the risk of small bowel bleeding (OR=1.24; 95% CI: 0.80-1.92). Subgroup analysis demonstrated that PPIs significantly increased the prevalence of small bowel injury in subjects taking nonselective NSAIDs (OR=7.05; 95% CI: 4.70-10.59, 4 studies, I2=0) and COX-2 inhibitors (OR=4.00; 95% CI: 1.18-13.60, 1 study, no calculated I2) when compared to COX-2 inhibitors alone.Conclusion: PPIs increased the risk of NSAID-related small bowel damage, and the clinical significance of higher prevalence of small bowel injuries should be studied in future.

Preeclampsia and aspirin.

Preeclampsia (PE) is a multisystem disorder that is an important cause of maternal and perinatal deaths. Currently, delivery is the only final treatment for PE. This practice is usually accompanied by premature birth, which inevitably increases neonatal morbidities. Aspirin is a non-selective NSAID that irreversibly inhibits cyclooxygenase enzymes involved in converting arachidonic acid to prostaglandins and thromboxane. Aspirin inhibits thromboxane A2 production via platelet aggregation, thereby increasing the prostacyclin/thromboxane A2 ratio and reducing platelet aggregation. Since the first case report of aspirin's potential use during pregnancy was reported in 1978, many studies have attempted to confirm the effect of aspirin on preeclampsia, and the results have been controversial. However, this preventive strategy is generally accepted in clinical practice. As evidence for aspirin's prevention of pre-eclampsia has been accumulating, a recent study investigated the effectiveness of aspirin at high doses of 150 mg, which is higher than before. However, there is an ongoing debate about how much aspirin should be used during pregnancy and when to start aspirin therapy. Guidelines for the use of prophylactic aspirin during pregnancy vary slightly among countries and groups. In this article, we review and summarize the evidence regarding the use of aspirin for PE prevention.

Development of Delayed-Release Matrix Tablets Comprising Solid Dispersion of Mefenamic Acid

Mefenamic acid (MA), a member of nonselective nonsteroidal anti-inflammatory drugs (NSAIDs), has been widely use to relief pain and inflammation. Its medical uses are limited by poor aqueous solubility resulting in low bioavailability and gastric irritation. The aim of this study was to develop a mefenamic acid delayed-release matrix tablet formulation using solid dispersion (SD). Delayed-release drug delivery systems were designed to retard drug release in upper gastrointestinal tract avoiding gastrointestinal (GI) adverse reactions. SDs of MA were successfully prepared by solvent evaporation method employing methanol as a solvent. SDs incorporated surfactant and super disintegrant gave much higher rates of dissolution than SDs with combined carriers (PEG and surfactant), SD containing PEG and pure drug, respectively. The optimal SD containing MA:PEG4000:poloxamer188:crospovidone in the ratio 1:8:1:3 exhibited higher amount of drug release up to 8-fold compared with pure MA. FTIR and DSC were performed to identify the physicochemical interaction between drug and polymers. The resulting data justified that no change in the chemical structure of MA and the crystalline MA transformed into the amorphous state after preparation. The formulation F4 delayed-release tablet comprising SD of MA dissolved less than 4 % in artificial gastric fluid in the initial 2 h and released more than 95 % at 3 h in the artificial intestinal fluid. Accordingly, formulation F4 containing polyethylene oxide as a time-controlled matrix-forming polymer was a promising delayed-release solid dispersion system of MA. HIGHLIGHTS The present study demonstrated a mefenamic acid delayed-release matrix tablet formulation using solid dispersion (SD) The optimal SD of mefenamic acid exhibited higher amount of drug release (8-fold) compared with that of the pure drug The tablet formulation F4 containing polyethylene oxide is capable of releasing mefenamic acid in a typical delayed-release profile GRAPHICAL ABSTRACT

Derivation and validation of a risk prediction score for nonsteroidal anti-inflammatory drug-related serious gastrointestinal complications in the elderly.

Few studies have quantified the impact of risk factors on GI complications in elderly nonsteroidal anti-inflammatory drug (NSAID) users. This study aimed to develop and validate a risk prediction score for severe GI complications to identify high-risk elderly patients using NSAID. We used the following two Korean claims datasets: customized data with an enrolment period 2016-2017 for model development, and the sample data in 2019 for external validation. We conducted a nested case-control study for model development and validation. NSAID users were identified as the elderly (≥65 years) who received NSAIDs for more than 30 days. Serious GI complications were defined as hospitalizations or emergency department visits, with a main diagnosis of GI bleeding or perforation. We applied the logistic least absolute shrinkage and selection operator (LASSO) regression model for variable selection and model fitting. We identified 8176 cases and 81 760 controls with a 1:10 matched follow-up period in the derivation cohort. In the external validation cohort, we identified 372 cases from 254 551 patients. The risk predictors were high-dose NSAIDs, nonselective NSAID, complicated GI ulcer history, male sex, concomitant gastroprotective agents, relevant co-medications, severe renal disease and cirrhosis. Area under the receiver operating characteristic curve was 0.79 (95% confidence interval, 0.77-0.81) in the external validation dataset. The prediction model may be a useful tool for reducing the risk of serious GI complications by identifying high-risk elderly patients.