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Oxymatrine (OMT) as a quinazine alkaloid extracted from matrine has been shown to exhibit anti-inflammatory and anti-tumour effects. However, the protective mechanism of OMT on NSAID-associated small bowel mucosal injury remains unreported. We found that OMT could improve the clinical symptoms and pathological inflammation scoring, reduce the secretion of proinflammatory cytokines IL-1β, IL-6 and TNF-α and cell apoptosis, promote cell proliferation and protect intestinal mucosal barrier as compared with the Diclofenac Sodium (DS) group. Further RNA-seq and KEGG analysis uncovered that the differentially expressed genes between DS and control groups were mainly enriched in immune regulation, of which MIP-1γ and its receptor CCR1 expression were validated to be repressed by OMTH. MAPK/NF-κB as the MIP-1 upstream signalling was also inactivated by OMT treatment. In this study, OMT regulated gut microbiota. Venn diagrams visualized and identified 1163 shared OTUs between DS group and OMTH group. The results showed that the α diversity index in the DS group was lower than that in the OMTH group, indicating that the complexity of the flora was reduced in the intestinal inflammatory state. β diversity mainly includes Principal Component Analysis (PCA) and Principal Co-ordinates Analysis (PCoA). The differences between groups can be observed through PCA. The more similar the composition of the flora, the closer the samples are. We found that the difference was smaller in the DS group than in the OMTH group. The results of PcoA showed that the sample similarity between OMTH groups was the highest. Moreover, gut microbiota analysis unveiled that the abundances of Ruminococcus 1, Oscillibacter and Prevotellaceae at the genus level as well as Lactobacillus SP-L-Yj at the species level were increased in OMTH group as compared with the DS group but the abundance of Allobaculum, Ruminococceos-UCG-005, Ruminococceos-NK4A214 and Clostridium associated with DS-induced small bowel mucosal injury could be decreased by OMTH. MIP-1α and CCR1 were upregulated in human small bowel injury samples as compared with the normal ileal mucosa tissues. In conclusion, our findings demonstrated that OMT could alleviate NSAID-associated small bowel mucosal injury by inhibiting MIP-1γ/CCR1 signalling and regulating gut microbiota., (Copyright © 2024 The Authors. Production and hosting by Elsevier B.V. All rights reserved.)

Background: The nephrotoxic effects of non-steroidal anti-inflammatory drugs (NSAIDs) are widely acknowledged. In particular, diclofenac is the most commonly prescribed NSAIDs, but no previous findings of electrolyte disturbances were reported following its administration., Case Report: We presented the case of a man who experienced significant weakness associated with severe deficiencies in potassium, calcium, and magnesium after misusing diclofenac because of severe back pain., Conclusions: This case emphasizes the need of awareness about the electrolyte imbalances and electrolyte disturbances associated with the misuse of diclofenac, which is a widely available drug. This is a case report which does not need a Clinical Trial Number., (© 2024. The Author(s).)

The relation between use of nonsteroidal anti-inflammatory drugs (NSAIDs) and severity of COVID-19 has been the subject to debate since the outbreak of the pandemic. Despite speculations about the possible harmful or protective effects, the position currently most supported by the scientific community is that there is no association between use of NSAIDs and COVID-19 outcomes. With the aim of contributing to increase the body of evidence on this issue, we conducted a case-control study using real-world data to investigate the association between prior use of NSAIDs, by active ingredient and type (traditional NSAIDs and selective COX-2 inhibitors), and important COVID-19-related outcomes, including susceptibility, PCR + patient progression, and hospitalisation. Our findings suggest that, in general, the use of traditional NSAIDs is not associated with any adverse COVID-19 outcome. However, we observed a possible association between diclofenac and a higher risk of PCR + patient progression. Our results also suggest that selective COX-2 inhibitors might be related with a reduction in the risk of PCR + patient progression. These results suggest that, with the possible exception of diclofenac, the use of NSAIDs should not be advised against for relief of symptoms in patients with COVID-19. In addition, they support the importance of continue to investigate the treatment potential of selective COX-2 inhibitors in the management of COVID-19, something that could have significant implications for the treatment of this disease and other viral infections., (© 2024. The Author(s).)

Objective: Tension-type headache is the most common type of primary headache and results in a huge socioeconomic burden. This network meta-analysis (NMA) aimed to compare the efficacy and safety of simple analgesics for the treatment of episodic tension-type headache (ETTH) in adults., Methods: We searched the Cochrane Library, PubMed, Web of Science, Embase, Chinese BioMedical Literature database and International Clinical Trials Registry Platform databases for eligible randomized clinical trials reporting the efficacy and/or safety of simple analgesics. A Bayesian NMA was performed to compare relative efficacy and safety. The surface under the cumulative ranking curve (SUCRA) was calculated to rank interventions. PROSPERO registration number: CRD42018090554., Results: We highlighted six studies including 3507 patients. For the 2 h pain-free rate, the SUCRA ranking was ibuprofen > diclofenac-K > ketoprofen > acetaminophen > naproxen > placebo. All drugs except naproxen reported a higher 2 h pain-free rate than placebo, with a risk ratio (RR) of 2.86 (95% credible interval, CrI: 1.62-5.42) for ibuprofen and 2.61 (1.53-4.88) for diclofenac-K. For adverse events rate, the SUCRA ranking was: metamizol > diclofenac-K > ibuprofen > lumiracoxib > placebo > aspirin > acetaminophen > naproxen > ketoprofen. The adverse event rates of all analgesics were no higher than those of placebo, except for ketoprofen. Moreover, all drugs were superior to placebo in the global assessment of efficacy. In particular, the RR of lumiracoxib was 2.47 (1.57-4.57). Global heterogeneity I 2 between the studies was low., Conclusions: Simple analgesics are considered more effective and safe as a placebo for ETTH in adults. Our results suggest that ibuprofen and diclofenac-K may be the two best treatment options for patients with ETTH from a comprehensive point of view (both high-quality evidence).

Objective: This study was conducted to investigate the mechanisms of anaphylaxis in patients with osteoarthritis of the knee and hip after diclofenac etalhyaluronate [product name: JOYCLU® (JCL)] intra-articular injection and to determine the utility of tests to investigate the mechanism involved., Methods: In this observational study in Japan, patients aged ≥20 years with knee or hip osteoarthritis who received JCL intra-articular injection experienced anaphylactic symptoms considered related to JCL ('experienced patients') or did not experience allergic symptoms considered related to JCL ('non-experienced patients'). Basophil activation tests (BATs), specific immunoglobulin E (IgE) antibody testing by enzyme-linked immunosorbent assays (ELISAs) or immunochromatographic kit, and genome-wide association studies (GWASs) were conducted using patient blood and saliva., Results: Thirteen experienced patients and 14 non-experienced patients were tested. Seven experienced patients tested positive by BAT using diclofenac etalhyaluronate-containing test substances. Diclofenac-specific IgE antibodies were detected in four of seven BAT-positive patients but not in the non-experienced patients. Specific IgE antibody testing by immunochromatographic kit and genome-wide association study showed no clear results., Conclusions: These findings suggest that anaphylaxis occurs after JCL administration via an IgE-mediated mechanism and that diclofenac etalhyaluronate may be involved in this mechanism. BAT and diclofenac -specific IgE enzyme-linked immunosorbent assay may be useful tests for investigating the mechanisms of anaphylactic reactions after JCL administration., (© Japan College of Rheumatology 2023. Published by Oxford University Press.)

Gout attacks are treated with uric-lowering and anti-inflammatory drugs. In patients with gout, non-steroidal anti-inflammatory drugs (NSAIDs) could be both cardiovascular beneficial, due to their anti-inflammatory actions, and cardiovascular hazardous, due to their prothrombotic, hypertensive, and proarrhythmic side effects. We, therefore, examined the risk of cardiovascular events associated with NSAID use in patients with gout. We conducted a nationwide, population-based case-crossover study of all Danes ≥ 18 years of age with first-time gout during 1997-2020, who experienced a cardiovascular event (myocardial infarction, ischemic stroke, congestive heart failure, atrial fibrillation/flutter, or cardiovascular death) (n = 59,150). The exposure was use of NSAIDs, overall and according to type (ibuprofen, naproxen, or diclofenac). We used the dates 300, 240, 180, and 120 before the outcome date as reference dates. We used the Mantel-Haenszel method to calculate odds ratios (ORs) with 95% confidence intervals (CIs) of the association between NSAID use and cardiovascular events. NSAID use was overall associated with 12% decreased odds of a cardiovascular event (OR = 0.88, 95% CI: 0.85-0.91). This decreased odds ratio was observed for the use of ibuprofen (OR = 0.92, 95% CI: 0.88-0.97) and naproxen (OR = 0.85, 95% CI: 0.74-0.97), but not for the use of diclofenac (OR = 0.97, 95% CI: 0.90-1.05). Overall, use of NSAIDs was associated with decreased odds of all the individual components of the composite outcome. NSAIDs were not associated with an increased cardiovascular event rate when used in gout patients. Ibuprofen and naproxen appeared to have better cardiovascular risk profiles than diclofenac., (© 2024. The Author(s).)

Objective: To describe patients with NSAID-DILI, including genetic factors associated with idiosyncratic DILI., Methods: In DILIN, subjects with presumed DILI are enrolled and followed for at least 6 months. Causality is adjudicated by a Delphic approach. HLA sequencing of multiethnic NSAID-DILI patients and HLA allele imputation of matching population controls were performed following overall, class and drug-based association analysis. Significant results were tested in a non-Hispanic White (NHW) case-control replication cohort., Results: Between September 2004 and March 2022, causality was adjudicated in 2498, and 55 (41 [75%] women) were assessed as likely due to NSAIDs. Median age at onset was 55 y (range 22-83 y). Diclofenac was the causative drug in 29, celecoxib in 7, ibuprofen in 5, etodolac and meloxicam each in 4. Except for meloxicam and oxaprozin (n = 2), the liver injury was hepatocellular with median R 15-25. HLA-DRB1*04:03 and HLA-B*35:03 were significantly more frequent in NSAID-DILI patients than in non-NSAID DILI controls. Interestingly, 85% of the HLA-DRB1*04:03 carriers developed DILI due to the use of acetic acid derivative NSAIDs, supporting the hypothesis that HLA-DRB1*04:03 could be a drug and/or class risk factor. HLA-B*35:03 but not HLA-DRB1*04:03 association was confirmed in the independent NHW replication cohort, which was largely driven by diclofenac., Conclusions: Despite prevalent use, NSAID-DILI is infrequent in the United States. Diclofenac is the most commonly implicated, and adherence to warnings of risk and close observation are recommended. The increased frequency of HLA-B*35:03 and DRB1*04:03, driven by diclofenac, suggests the importance of immune-mediated responses., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Purpose: Hand-foot syndrome (HFS) is a dose-limiting side effect of capecitabine. Celecoxib prevents HFS by inhibiting cyclooxygenase-2 (COX-2) that is upregulated because of the underlying associated inflammation. However, systemic side effects of celecoxib have limited routine prescription. Topical diclofenac inhibits COX-2 locally with minimal risk of systemic adverse events. Therefore, we conducted this study to assess the efficacy of topical diclofenac in the prevention of capecitabine-induced HFS., Methods: In this single-site phase III randomized double-blind trial, we enrolled patients with breast or GI cancer who were planned to receive capecitabine-based treatment. Participants were randomly assigned in a 1:1 ratio to receive topical diclofenac or placebo gel for 12 weeks or until the development of HFS, whichever occurred earlier. The primary end point was the incidence of grade 2 or 3 HFS (Common Terminology Criteria for Adverse Events version 5), which was compared between the two groups using simple logistic regression., Results: In total, 264 patients were randomly assigned to receive topical diclofenac gel (n = 131) or placebo (n = 133). Grade 2 or 3 HFS was observed in 3.8% of participants in the diclofenac group compared with 15.0% in the placebo group (absolute difference, 11.2%; 95% CI, 4.3 to 18.1; P = .003). Grade 1-3 HFS was lower in the diclofenac group than in the placebo group (6.1% v 18.1%; absolute risk difference, 11.9%; 95% CI, 4.1 to 19.6). Capecitabine dose reductions because of HFS were less frequent in the diclofenac group (3.8%) than in the placebo group (13.5%; absolute risk difference, 9.7%; 95% CI, 3.0 to 16.4)., Conclusion: Topical diclofenac prevented HFS in patients receiving capecitabine. This trial supports the use of topical diclofenac to prevent capecitabine-associated HFS.

Objective: To investigate systemic absorption and gastrointestinal (GI) adverse effects of topical ketorolac 0.5% and diclofenac 0.1% ophthalmic solutions., Animals: 11 healthy purpose-bred Beagles., Methods: Dogs were randomly assigned to receive either ketorolac (n = 6) or diclofenac (5), 1 drop in both eyes 4 times daily for 28 days. Upper GI endoscopy was performed on days 0 and 29 with mucosal lesion scores (0 to 7) assigned to each region evaluated. Plasma samples were collected on days 14, 21, and 28 for measurement of diclofenac and ketorolac using high-performance liquid chromatography-mass spectrometry., Results: GI erosions and/or ulcers developed in all ketorolac-treated dogs and 1 of 5 diclofenac-treated dogs. Post-treatment mucosal lesion score for the antrum was higher in the ketorolac group than in the diclofenac group (P = .006) but not significantly different for any other region. Post-treatment antral mucosal lesion scores were significantly related to plasma ketorolac concentrations (P < .001). Ketorolac and diclofenac were detected in the plasma at all time points (median ketorolac day 14, 191 ng/mL; day 21, 173.5 ng/mL; and day 28, 179.5 ng/mL; and median diclofenac day 14, 21.1 ng/mL; day 21, 20.6 ng/mL; day 28, 27.5 ng/mL). Vomiting and decreased appetite events were observed uncommonly and were not significantly different between treatment groups., Clinical Relevance: GI ulceration and erosion developed after ophthalmic administration of ketorolac and diclofenac, with higher plasma concentrations and more severe GI lesions associated with ketorolac. Clients should be alerted to this potential risk with ophthalmic use and informed to watch for systemic clinical signs that would warrant veterinary reevaluation.

COX-2/NLPR3-targeted therapy might be beneficial for the inflammation diseases. To discover novel anti-inflammatory compounds with favorable safety profiles, three new series of non-carboxylic diclofenac analogues bearing various ring systems, such as oxadiazoles 4a-4w, triazoles 6a-6m, and cyclic imides 7a and 7b, were synthesized. The synthesized analogues were evaluated for their inhibitory activity against COX-2 enzyme. Among them, compound 6k exhibited potent selective COX-2 inhibition (IC 50  = 1.53 μM; selectivity ((IC 50 (COX-1)/IC 50 (COX-2) = 17.19). Treatment with compound 6k effectively suppressed the NF-κB/NLRP3 signaling pathway, resulting in reduced expression of pro-inflammatory factors. The in vivo ulcerative colitis assay demonstrated that compound 6k significantly ameliorated histological damages and showed strong protection against DSS-induced acute colitis. The collected results indicated that compound 6k displays anti-inflammatory activity through COX-2/NLRP3 inhibition. Therefore, compound 6k represents a promising candidate for further development as a new lead compound with reduced colitis side effects., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Masson SAS. All rights reserved.)

Background: Although both nonsteroidal anti-inflammatory drugs (NSAIDs) and opioids are used for analgesia in acute pancreatitis (AP), the analgesic of choice is not known. We compared buprenorphine, an opioid, and diclofenac, an NSAID, for analgesia in AP., Methods: In a double-blind randomized controlled trial, AP patients were randomized to receive intravenous diclofenac or intravenous buprenorphine. Fentanyl was used as rescue analgesia, delivered through a patient-controlled analgesia pump. Primary outcome was the difference in the dose of rescue fentanyl required. Secondary outcomes were the number of effective and ineffective demands of rescue fentanyl, pain-free interval, reduction in visual analogue scale (VAS) score, adverse events, and organ failure development., Results: Twenty-four patients were randomized to diclofenac and 24 to buprenorphine. The 2 groups were matched at baseline. The total amount of rescue fentanyl required was significantly lower in the buprenorphine group:130 μg, interquartile range (IQR), 80-255 vs 520 μg, IQR, 380-1065 (P < .001). The number of total demands was 32 (IQR, 21-69) in the diclofenac arm vs 8 (IQR, 4-15) in the buprenorphine arm (P < .001). The buprenorphine group had more prolonged pain-free interval (20 vs 4 hours; P < .001), with greater reduction in the VAS score at 24, 48, and 72 hours compared with the diclofenac group. These findings were confirmed in the subgroup of moderately severe/severe pancreatitis. Adverse events profile was similar in the 2 groups., Conclusions: Compared with diclofenac, buprenorphine appears to be more effective and equally safe for pain management in AP patients, even in the subcohort of moderately severe or severe pancreatitis (Trial Registration number: CTRI/2020/07/026914)., (Copyright © 2024 AGA Institute. Published by Elsevier Inc. All rights reserved.)

In this study, an attempt was made to evaluate the relative efficacy of two important anti-gout agents, viz. allopurinol and febuxostat, in the control of hyperuricaemia/gout using a poultry model. A 21-day study was conducted on 48 Vencobb-400 broiler chicks randomly divided into four groups. In one group hyperuricaemia/gout was induced by the oral administration of diclofenac (group D); in two other groups the ameliorative effect of the two drugs under study was investigated by providing both simultaneously, i.e. diclofenac and allopurinol (group DA), diclofenac and febuxostat (group DF); and the fourth group was kept un-induced and untreated as a control (group C). Both allopurinol and febuxostat inhibit xanthine oxidase enzymes, thereby reducing the production of uric acid. The birds kept on diclofenac alone exhibited the highest level of hyperuricaemia, clinical signs of gout, and overt adverse changes in the visceral organs, whereas these changes were lesser in allopurinol- and febuxostat-treated groups. Furthermore, haematological, biochemical, patho-morphological, and ultra-structural studies using transmission electron microscopy were carried out to evaluate the pathology and, thus, the ameliorative effect of allopurinol and febuxostat. The findings proved that allopurinol and febuxostat carry definite ameliorative potential as anti-hyperuricemic and anti-gout agents in poultry, which was better expressed by febuxostat compared to allopurinol.

The present study aimed to evaluate the anti-inflammatory effects of ginger ( Zingiber officinale ) root capsule extract (GRCE) in doses of 100 mg/kg b.w. (body weight) and 200 mg/kg b.w. alone and in combination with a low dose (5 mg/kg b.w.) of diclofenac sodium (D) on carrageenan-induced acute inflammation (AI). The association of GRCE in a dose of 200 mg/kg b.w. with D offered the highest inhibition percentage for edema, reaching the maximum level of inhibition (95%) after 24 h. The association of GRCE in a dose of 200 mg/kg b.w. with D showed the ability to reduce tissue inflammatory changes when compared to D alone, while GRCE alone did not exhibit such properties. The association of both doses of GRCE with D showed significantly lower plasma and tissue levels of pro-inflammatory cytokines such as tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and interleukin-1β (IL-1β) by up to 55% ( p ≤ 0.0317), with the best results obtained by the group who received GRCE in the higher dose. These associations reduced the serum and tissue levels of prostaglandin-endoperoxide synthase 2 (COX-2) by up to 71% ( p ≤ 0.0371). In conclusion, the association of GRCE with a low dose of D could be an appropriate combination to decrease the dose used to reduce serum and tissue levels of inflammatory molecules, edema, and histological changes in acute inflammation. Further research will be necessary to achieve clinical evaluation.

Diclofenac (DIC) is one of the most commonly prescribed non-steroidal anti-inflammatory drugs and has been shown to cause oxidative stress and liver injury. The current study investigated protective effects of metformin against DIC-induced hepatic toxicity in both in vitro and in vivo models. For the in vitro study, HepG2 cells were exposed to DIC in the presence or absence of metformin. The effect of metformin on cell viability was evaluated by MTT assay. Oxidative stress parameters (malondialdehyde (MDA), total thiol molecules (TTM), and total antioxidant capacity (TAC)) were assessed. For the in vivo study, thirty-six male Wistar rats were randomly divided into 6 groups. These groups were normal saline, metformin (200 mg/kg), DIC (50 mg/kg/day), DIC + metformin (50, 100, and 200 mg/kg/day). Histopathological studies and serum levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), lactate dehydrogenase (LDH), albumin, direct and total bilirubin were measured. Also, oxidative stress parameters were assessed in liver tissue. Furthermore, expression of glutathione peroxidase (GPX)-1, -3, and -4, catalase (CAT), superoxide dismutase (SOD)-1, and -3 was examined using the real-time PCR method in hepatic tissue. In the in vitro study, metformin significantly prevented DIC-induced loss in cell viability in HepG2 cells. Metformin markedly reduced DIC-induced elevation of MDA levels and increased the TAC and TTM levels. In the in vivo study, metformin significantly prevented DIC-induced changes in hematological and histological markers. Administration of metformin significantly improved oxidative stress parameters in liver tissue. In addition, metformin increased the expression of antioxidant enzymes. Our results suggest that metformin exerts a significant protective effect against DIC-induced hepatic toxicity., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Objective: Non-steroidal anti-inflammatory drugs (NSAIDs) should be used cautiously in patients with type 2 diabetes. We examined whether the cardiovascular risks associated with NSAID use depended on HbA1c level in patients with type 2 diabetes., Methods: We conducted a population-based cohort study of all adult Danes with a first-time HbA1c measurement ≥48 mmol/mol during 2012-2020 (n = 103 308). We used information on sex, age, comorbidity burden, and drug use to calculate time-varying inverse probability of treatment weights. After applying these weights in a pooled logistic regression, we estimated hazard ratios (HRs) of the association between use of NSAIDs (ibuprofen, naproxen, or diclofenac) and cardiovascular events (a composite of myocardial infarction, ischemic stroke, congestive heart failure, atrial fibrillation or flutter, and all-cause death). We stratified all analyses by HbA1c level (<53 or ≥53 mmol/mol)., Results: For ibuprofen use, the HR of a cardiovascular event was 1.53 (95% confidence interval [CI]: 1.34-1.75) in patients with HbA1c <53 and 1.24 (95% CI: 1.00-1.53) in patients with HbA1c ≥53 mmol/mol. For naproxen use, the HR was 1.14 (95% CI: 0.59-2.21) in patients with HbA1c <53 and 1.30 (95% CI: 0.49-3.49) in patients with HbA1c ≥53 mmol/mol. For diclofenac use, the HR was 2.40 (95% CI: 1.62-3.56) in patients with HbA1c <53 and 2.89 (95% CI: 1.65-5.04) in patients with HbA1c ≥53 mmol/mol., Conclusions: In patients with type 2 diabetes, glycemic dysregulation did not affect the cardiovascular risk associated with NSAID use., (© 2023 The Authors. Pharmacoepidemiology and Drug Safety published by John Wiley & Sons Ltd.)

Aim: Sepsis is a common cause of acute kidney injury (AKI). Lipopolysaccharides (LPS) are the main gram-negative bacterial cell wall component with a well-documented inflammatory impact. Diclofenac (DIC) is a non-steroidal anti-inflammatory drug with a potential nephrotoxic effect. Curcumin (CUR) and silymarin (SY) are natural products with a wide range of pharmacological activities, including antioxidant and anti-inflammatory ones. The objective of this study was to examine the protective impact of CUR and SY against kidney damage induced by LPS/DIC co-exposure., Materials and Methods: Four groups of rats were used; control; LPS/DIC, LPS/DIC + CUR, and LPS/DIC + SY group. LPS/DIC combination induced renal injury at an LPS dose much lower than a nephrotoxic one., Key Finding: Nephrotoxicity was confirmed by histopathological examination and significant elevation of renal function markers. LPS/DIC induced oxidative stress in renal tissues, evidenced by decreasing reduced glutathione and superoxide dismutase, and increasing lipid peroxidation. Inflammatory response of LPS/DIC was associated with a significant increase of renal IL-1β and TNF-α. Treatment with either CUR or SY shifted measured parameters to the opposite side. Moreover, LPS/DIC exposure was associated with upregulation of mTOR and endoplasmic reticulum stress protein (CHOP) and downregulation of podocin These effects were accompanied by reduced gene expression of cystatin C and KIM-1. CUR and SY ameliorated LPS/DIC effect on the aforementioned genes and protein significantly., Significance: This study confirms the potential nephrotoxicity; mechanisms include upregulation of mTOR, CHOP, cystatin C, and KIM-1 and downregulation of podocin. Moreover, both CUR and SY are promising nephroprotective products against LPS/DIC co-exposure., Competing Interests: Declaration of competing interest The authors declare no potential conflicts of interest related to the research, authorship, and/or publication of this article., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Aims: It is unknown whether the cardiovascular risks associated with the use of non-steroidal anti-inflammatory drugs (NSAIDs) shortly after first-time myocardial infarction (MI) or heart failure (HF) differ between patients continuing and initiating use., Methods and Results: Using nationwide health registries, we conducted a cohort study of all patients with first-time MI or HF during 1996-2018 (n = 273 682). NSAID users (n = 97 966) were categorized as continuing (17%) and initiating (83%) users according to prescription fillings < 60 days before index diagnosis. The primary outcome was a composite of new MI, HF admission, and all-cause death. Follow-up started 30 days after the index discharge date. We used Cox regression to compute hazard ratios (HRs) with 95% confidence intervals (CIs) comparing NSAID users vs. non-users. The most commonly filled NSAIDs were ibuprofen (50%), diclofenac (20%), etodolac (8.5%), and naproxen (4.3%). The composite outcome HR of 1.25 (CI: 1.23-1.27) was driven by initiators (HR = 1.39, 1.36-1.41) and not continuing users (HR = 1.03, 1.00-1.07). The lack of association among continuing users was also observed for individual NSAIDs (ibuprofen and naproxen), except diclofenac (HR = 1.11, 95% CI: 1.05-1.18). Among initiators, the HR was 1.63 (CI: 1.57-1.69) for diclofenac, 1.31 (CI: 1.27-1.35) for ibuprofen, and 1.19 (CI: 1.08-1.31) for naproxen. The results were consistent for both MI and HF patients, the individual components of the composite outcome, and various sensitivity analyses., Conclusion: NSAID initiators were more susceptible to adverse cardiovascular outcomes after first-time MI or HF than continuing users., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Study Design: This is a basic science, animal research study., Objective: This study aims to explore, in rodent models, the effectiveness of systemic nonsteroidal anti-inflammatory drugs in reducing recombinant human bone morphogenetic protein-2 (rhBMP-2) induced neuroinflammation., Summary of Background Data: rhBMP-2 is increasingly used to augment fusion in lumbar interbody fusion surgeries, although it can cause complications including postoperative radiculitis., Materials and Methods: Eighteen 8-week-old Sprague-Dawley rats underwent Hargreaves testing to measure the baseline thermal withdrawal threshold before undergoing surgical intervention. The L5 nerve root was exposed and wrapped with an Absorbable Collagen Sponge containing rhBMP-2. Rats were randomized into 3 groups: (1) Low dose (LD), (2) high dose (HD) diclofenac sodium, and (3) saline, receiving daily injection treatment. Hargreaves testing was performed postoperatively on days 5 and 7. Seroma volumes were measured by aspiration and the nerve root was then harvested for hematoxylin and eosin, immunohistochemistry, Luxol Fast Blue staining, and real-time quantitative polymerase chain reaction. The Student t test was used to evaluate the statistical significance among groups., Results: The intervention groups showed reduced seroma volume, and a general reduction of inflammatory markers (MMP12, MAPK6, GFAP, CD68, and IL18) compared with controls, with the reduction in MMP12 being statistically significant ( P = 0.02). Hematoxylin and eosin and immunohistochemistry of the nerve roots showed the highest macrophage density in the saline controls and the lowest in the HD group. Luxol Fast Blue staining showed the greatest extent of demyelination in the LD and saline groups. Lastly, Hargreaves testing, a functional measure of neuroinflammation, of the HD group demonstrated a minimal change in thermal withdrawal latency. In contrast, the thermal withdrawal latency of the LD and saline groups showed a statistically significant decrease of 35.2% and 28.0%, respectively ( P < 0.05)., Conclusion: This is the first proof-of-concept study indicating that diclofenac sodium is effective in alleviating rhBMP-2-induced neuroinflammation. This can potentially impact the clinical management of rhBMP-2-induced radiculitis. It also presents a viable rodent model for evaluating the effectiveness of analgesics in reducing rhBMP-2-induced inflammation., Competing Interests: H.K.W. has received personal fees from Spineguard, outside the submitted work. The remaining authors report no conflicts of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Aims: To examine the dose dependency of diclofenac's cardiovascular risks., Methods and Results: Using Danish health registries and the target trial emulation design, we conducted a series of 300 nationwide cohort studies during 1996-2020, each mimicking the strict design criteria of a clinical trial. Adults eligible for inclusion had no recent non-steroidal anti-inflammatory drug prescriptions, contraindications (gastrointestinal diseases, thrombocytopenia, or heart failure), or conditions with low adherence (dementia or psychiatric disease). Diclofenac initiators were compared to healthcare-seeking non-initiators and head-to-head using an approximated high dose of ≥150 mg/day vs. low dose of <150 mg/day. Cox regression was used to compute the incidence rate ratio (IRR) of major adverse cardiovascular events (MACE) within 30 days following initiation. We adjusted for age, sex, calendar period, comorbidity, comedication, and socioeconomic position. Compared with non-initiators (n = 3 789 617), diclofenac initiators (n = 1 894 834) had an approximately 50% increased rate of MACE (IRR 1.53, 95% confidence interval [CI]: 1.43-1.63), reflecting IRRs of 1.54 (95% CI: 1.40-1.69) for myocardial infarction, 1.29 (1.14-1.45) for ischaemic stroke, and 1.92 (1.71-2.16) for cardiac death. The risk increase was observed for most conditions with chronic pain, in particular headache (IRR 5.10, 95% CI: 1.46-17.85). The risk increase was similar for initiators of high- (IRR 1.55, 95% CI: 1.40-1.71) and low-dose diclofenac (IRR 1.52, 1.41-1.63), which was confirmed in a head-to-head analysis (IRR 1.01, 95% CI: 0.90-1.12)., Conclusions: Initiators of high- and low-dose diclofenac had comparably increased cardiovascular risks. This finding provides evidence against the assumption that low-dose diclofenac is risk-neutral., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Although the United States and Europe have shifted to the prescription use of oral diclofenac due to several serious incidences of cardiotoxicity, it is one of the most commonly used over-the-counter (OTC) pain medicines in major parts of the world. We elucidated the quantitative and tissue-specific contribution of uridine diphosphate-glucuronosyltransferases 17 (UGT2B17) in diclofenac metabolism and pharmacokinetics (PK). UGT2B17 is one of most deleted genes in humans with the gene deletion frequency ranging from ~ 20% in White population to 90% in Japanese population. The human intestinal and liver microsomes isolated from the high-UGT2B17 expressing individuals showed 21- and 4-fold greater rate of diclofenac glucuronide (DG) formation than in the null-UGT2B17 carriers, respectively. The greater contribution of intestinal UGT2B17 was confirmed by a strong correlation (R = 0.78, P < 0.001) between UGT2B17 abundance and DG formation in individual intestinal microsomes (n = 14). However, because UGT2B17 is a minor UGT isoform in the liver, DG formation rate correlated better with the expression of UGT2B7. The proteomics-informed physiologically-based pharmacokinetic (PBPK) model explains the reported higher exposure of diclofenac in women consistent with ~ 3-fold lower expression of UGT2B17. Similarly, our in silico predictions also corroborate with the reported higher exposure and lower standard clinical dose of diclofenac in Japanese population. Therefore, variable UGT2B17 mediated metabolism of oral diclofenac is a cause of concern, especially in the developing countries where it is still used as an OTC drug. The ontogeny data of UGTs in human hepatocytes can be utilized in developing PBPK models for predicting PK in the pediatric population., (© 2023 The Authors. Clinical Pharmacology & Therapeutics © 2023 American Society for Clinical Pharmacology and Therapeutics.)

The impacts of polymorphic cytochrome P450 (P450 or CYP) 2C9 on drug interactions and the pharmacokinetics of cyclooxygenase inhibitors have attracted considerable attention. In this survey, the prescribed dosage was reduced or discontinued in 150 and 56 patients, respectively, receiving celecoxib and diclofenac prescribed alone, as recorded in a Japanese database of adverse drug events. Among the factors underlying adverse events, intrinsic drug clearance rates may be a contributing factor. The pharmacokinetically modeled plasma concentrations of celecoxib after an oral 200-mg dose increased in CYP2C9*3 homozygotes: the area under the plasma concentration curve was 4.7-fold higher than that in CYP2C9*1 homozygotes. In patients with CYP2C9*3/*3, the virtual hepatic concentrations of diclofenac after three daily 25-mg doses for a week were 11-fold higher than the plasma concentrations in subjects with CYP2C9*1/*1. The in vivo and in vitro fractions of the victim drug metabolized by a specific polymorphic P450 form is an important determining factor for estimating drug-drug interactions. Virtual hepatic and plasma exposures estimated by pharmacokinetic modeling in patients harboring the impaired CYP2C9*3 allele could represent a causal factor for adverse events induced by celecoxib or diclofenac in a manner similar to that for drug interactions.

Introduction: It is unknown whether the cardiovascular risks associated with non-steroidal anti-inflammatory drug (NSAID) use differ according to lifestyle and socioeconomic position., Objective: We examined the association between NSAID use and major adverse cardiovascular events (MACE) within subgroups defined by lifestyle and socioeconomic position., Methods: We conducted a case-crossover study of all adult first-time respondents to the Danish National Health Surveys of 2010, 2013, or 2017, without previous cardiovascular disease, who experienced a MACE from survey completion through 2020. We used a Mantel-Haenszel method to obtain odds ratios (ORs) of the association between NSAID use (ibuprofen, naproxen, or diclofenac) and MACE (myocardial infarction, ischemic stroke, heart failure, or all-cause death). We identified NSAID use and MACE via nationwide Danish health registries. We stratified the analyses by body mass index, smoking status, alcohol consumption, physical activity level, marital status, education, income, and employment., Results: Compared with non-use, the OR of MACE was 1.34 (95% confidence interval: 1.23-1.46) for ibuprofen, 1.48 (1.04-2.43) for naproxen, and 2.18 (1.72-2.78) for diclofenac. When comparing NSAID use with non-use or the individual NSAIDs with each other, we observed no notable heterogeneity in the ORs within subgroups of lifestyle and socioeconomic position for any NSAID. Compared with ibuprofen, diclofenac was associated with increased risk of MACE in several subgroups with high cardiovascular risk, e.g., individuals with overweight (OR 1.52, 1.01-2.39) and smokers (OR 1.54, 0.96-2.46)., Conclusions: The relative increase in cardiovascular risk associated with NSAID use was not modified by lifestyle or socioeconomic position., (© 2023. The Author(s).)

Objective: The aim of the present study was to assess the safety and efficacy of Diclofenac sodium (DS) 140 mg medicated plaster vs. Diclofenac epolamine (DIEP) 180 mg medicated plaster and placebo plaster, for the treatment of painful disease due to traumatic events of the limbs., Patients and Methods: This was a multicenter, phase III study involving 214 patients, aged 18-65 years, affected by painful conditions due to soft tissue injuries. Patients were randomized to DS, DIEP or placebo arms and treated with once-daily application of the plaster for a total treatment period of 7 days. The primary objective was first to demonstrate the non-inferior efficacy of the DS treatment when compared to the reference DIEP treatment and second that both, test and reference treatments, were superior with respect to placebo. The secondary objectives included the evaluation of efficacy, adhesion, safety, and local tolerability of DS in comparison to both DIEP and placebo., Results: The mean visual analog scale (VAS) score decrease for pain at rest was higher in the DS (-17.65 mm) and the DIEP group (-17.5 mm) than in the placebo (-11.3 mm). Both active formulation plasters were associated with a statistically significant pain reduction compared to placebo. No statistically significant differences were observed between DIEP and DS plasters efficacy in relieving pain. Secondary endpoint evaluations supported the primary efficacy results. No serious adverse events (SAEs) were registered, and the most commonly detected adverse events were skin reactions at the application site., Conclusions: The results showed that both the DS 140 mg plaster and the reference DIEP 180 mg plaster are effective in relieving pain and present a good safety profile.

Context: Diclofenac is commonly used as pain relief. Hypoglycemia has rarely been reported due to aspirin and indomethacin use but not of any other nonsteroidal anti-inflammatory drugs., Case Report: A 69-years old endocrinologist participated as a control in a glucagon-like peptide-1 (GLP-1) study. He decreased his plasma glucose to 1.8 mmol/L and developed full-blown hypoglycemic symptoms during an oral glucose tolerance test (OGTT). He had taken a 50 mg diclofenac tablet at 10 pm the evening before for a harmless muscle stretch in the lower back. Apart from well-controlled hypothyroidism he was healthy. During medical school he often had reactive hypoglycemia which came after intake of a carbohydrate rich but otherwise poor breakfast followed by bicycling. However, he had never experienced problems later in life after more decent meals containing slower absorbable carbohydrates. A 3-day continuous glucose monitoring (CGM) was performed three weeks after the OGTT test. A glucose value of 3.1 mmol/L was registered on the third CGM day in the afternoon after intake of 500 mg aspirin in the early morning the same day. Otherwise, all values were normal. A second OGGT where no medications apart from levothyroxine had been taken during at least a 2-week period adjacent was normal. Detailed analyses of the OGTTs showed that the GLP-1 levels before the test were higher after diclofenac exposure while the insulin levels increased after the glucose challenge which suggesting uncoupling., Conclusion: With this case report we would like to draw attention to that diclofenac may cause hypoglycemia., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Postoperative intravenous diclofenac reduces patient opioid demand and is commonly used in surgical units. Orphenadrine is mainly used in combination with diclofenac for musculoskeletal injuries and postoperative pain control. The objective of this study was to compare the analgesic efficacy of diclofenac-orphenadrine, diclofenac alone and saline., Methods: We performed a double-blind, randomized, placebo-controlled, parallel-group, single-center clinical study investigating the opioid-sparing effect of a combination of diclofenac and orphenadrine versus diclofenac alone versus isotonic saline solution. Initially 72 patients were included and received total intravenous anesthesia during cruciate ligament surgery. All patients were postoperatively treated with a patient-controlled analgesia (PCA) device containing hydromorphone. Pharmacological safety was assessed by laboratory parameters, vital signs, and delirium detection scores., Results: There was no significant difference between the groups in cumulative dose of PCA analgesics required after 24 h postsurgery, with 5.90 mg (SD ± 2.90 mg) in the placebo group, 5.73 mg (SD ± 4.75 mg) in the diclofenac group, and 4.13 mg (SD ± 2.57 mg) in the diclofenac-orphenadrine group. Furthermore, there was no significant difference between the groups in cumulative dose of PCA analgesics required 2 h postsurgery (n = 65). Mean dose of hydromorphone required after 2 h was 1.54 mg (SD ± 0.57 mg) in the placebo group, 1.56 mg (SD ± 1.19 mg) in the diclofenac-only group, and 1.37 mg (SD ± 0.78 mg) in the diclofenac-orphenadrine group. However, when comparing the diclofenac-orphenadrine group and the diclofenac group combined to placebo there was a significant reduction in PCA usage in the first 24 h postsurgery. In total, there were 25 adverse events reported, none of which were rated as severe., Conclusion: Orphenadrine-diclofenac failed to significantly reduce postoperative opioid requirements. However, in an exploratory post hoc analysis the diclofenac-orphenadrine and the diclofenac group combined versus placebo showed a tendency to reduce opioid demand in postoperative pain control. Further research is required to determine the value of orphenadrine as an adjuvant in a multimodal approach for postoperative pain management., (© 2022. The Author(s).)

Introduction: In the present study, we aimed to investigate the extraction and identification of the potential phytochemicals from the Methanolic Extract of Dryopteris ramosa (MEDR) using GC-MS profiling for validating the traditional uses of MEDR its efficacy in inflammations by using in-vitro, in-vivo and in silico approaches in anti-inflammatory models., Methods: GC-MS analysis confirmed the presence of a total of 59 phytochemical compounds. The human red blood cells (HRBC) membrane stabilization assay and heat-induced hemolysis method were used as in-vitro anti-inflammatory activity of the extract. The in-vivo analysis was carried out through the Xylene-induced mice ear oedema method. It was found that MEDR at a concentration of 20 μg, 30 μg, and 40 μg showed 35.45%, 36.01%, and 36.33% protection to HRBC in a hypotonic solution, respectively. At the same time, standard Diclofenac at 30 μg showed 45.31% protection of HRBC in a hypotonic solution., Results: The extract showed inhibition of 25.32%, 26.53%, and 33.31% cell membrane lysis at heating at 20 μg, 30 μg, and 40 μg, respectively. In comparison, standard Diclofenac at 30 μg showed 50.49% inhibition of denaturation to heat. Methanolic extract of the plant exhibited momentous inhibition in xylene-induced ear oedema in mice treated with 30 μg extract were 47.2%, 63.4%, and 78.8%, while inhibition in mice ear oedema treated with 60 μg extract was 34.7%, 43.05%, 63.21% and reduction in ear thickness of standard drug were 57.3%, 59.54%, 60.42% recorded at the duration of 1, 4 and 24 hours of inflammation. Molecular docking and simulations were performed to validate the anti-inflammatory role of the phytochemicals that revealed five potential phytochemicals i.e. Stigmasterol,22,23dihydro, Heptadecane,8methyl, Pimaricacid, Germacrene and 1,3Cyclohexadiene,&#95;5(1,5dimethyl4hexenyl)-2methyl which revealed potential or significant inhibitory effects on cyclooxygenase-2 (COX-2), tumour necrosis factor (TNF-α), and interleukin (IL-6) in the docking analysis., Conclusion: The outcome of the study signifies that MEDR can offer a new prospect in the discovery of a harmonizing and alternative therapy for inflammatory disease conditions., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Background: Exercise is a known trigger of the inhibitory pain modulation system and its analgesic effect is termed exercise-induced hypoalgesia (EIH). Previous studies have demonstrated that rats with deficient analgesic response following exercise develop more significant hypersensitivity following nerve injury compared to rats with substantial analgesic response following exercise., Objectives: A rat model of EIH as an indicator of the pain inhibitory system's efficiency was used to explore the association between EIH profiles and the effect of pharmacotherapy on rat's neuropathic pain., Methods: EIH profiles were assessed by evaluating paw responses to mechanical stimuli before and after exercise on a rotating rod. Rats with a reduction of ≤33% in responses were classified as low EIH and those with ≥67% as high EIH. Low and high EIH rats underwent sciatic nerve chronic constriction injury (CCI). Paw responses to mechanical stimuli were measured at baseline, following CCI, and after treatment with diclofenac, duloxetine or pregabalin. In a different group of low and high EIH rats, EIH was measured before and following treatment with the same medications., Results: Low EIH rats developed more significant hypersensitivity following CCI. Duloxetine and pregabalin successfully reduced hypersensitivity, although significantly more so in low EIH rats. Diclofenac had limited effects, and only on low EIH rats. Four days of duloxetine administration transformed low EIH rats' profiles to high EIH., Conclusions: The findings of this study suggest that EIH profiles in rats can not only predict the development of hypersensitivity following injury but may also support targeted pharmacological treatment., Significance: Exercise is a known trigger of the inhibitory pain modulation. Rats with deficient analgesic response following exercise develop more significant hypersensitivity following nerve injury. Pain modulation profiles in rats can also support targeted pharmacological treatment; rats with deficient analgesic response following exercise benefit more from treatment with duloxetine and gabapentin. Treatment with duloxetine can improve pain modulation profile., (© 2022 European Pain Federation - EFIC ®.)

Objective: To evaluate the efficacy and safety of using a fixed combination of diclofenac and orphenadrine for early postoperative pain relief in orthopedic patients following hip prosthetics., Material and Methods: A prospective comparative study enrolled 65 patients with primary total hip replacement in the setting of spinal bupivacaine anesthesia. Patients were divided into 2 groups - study (39 patients) and control (26 people). The study group underwent Neodolpasse infusion (orphenadrine 30 mg + diclofenac 75 mg) after the end of surgery and morphine infusion in a patient-controlled analgesia (PKA) regimen. The control group underwent morphine monotherapy in the PKA regimen. The intensity of pain syndrome was compared on a visual-analog scale (VAS) from 0 to 100, the total amount of morphine administered, the number of bolus requests, the change in kidney function and the side effect were assessed., Results: In the control group, the duration of the intervention was shorter and amounted to 70 [59; 82] minutes, in the study group - 83 [65; 94] minutes ( p =0.05). No significant difference was found in the number of bolus requests (32 [22; 38] and 23 [15; 36], p =0.085 and pain intensity 2 and 12 hours after the start of therapy (5 [4; 6] and 3 [2; 4] and 5 [4; 6] and 2 [2; 3] points) in the control group and in the study group. When assessing the intensity of pain syndrome 24 hours after the start of therapy, differences were found in the groups - in the control group 30 [2; 3] mm, in the study group 20 [2; 3] mm ( p =0.05). There was no nephrotoxic effect on Neodolpasse. Complications of analgesic therapy in the form of nausea, vomiting, pruritus were recorded in both groups in equal amounts, which is explained by the administration of morphine in both groups., Conclusion: 1. The use of a fixed combination of orphenadrine 30 mg + diclofenac 75 mg as part of postoperative pain relief after operations of primary hip prosthetics improves the quality of postoperative pain relief according to the subjective assessment of patients. 2. The use of a fixed combination of orphenadrine 30 mg + diclofenac 75 mg did not lead to the development of side effects and complications.

Background: Renal transplants are often prescribed non-steroidal anti-inflammatory drugs (NSAIDs) for analgesic purposes., Objective: Considering the dearth of data, we carried out the present study to evaluate the use of various NSAIDs and the incidence of acute kidney injury (AKI) in transplant patients., Methods: A retrospective study amongst renal transplant patients prescribed at least one dose of NSAID was carried between January and December 2020 at the Department of Nephrology, Salmaniya Medical Complex, Kingdom of Bahrain. The patients' demographic details, serum creatinine values, and drug-related details were obtained. The Kidney Disease Improving Global Outcomes (KDIGO) criteria were used for defining AKI., Results: Eighty-seven patients were included. Forty-three patients were prescribed diclofenac, 60 received ibuprofen, six received indomethacin, 10 were administered mefenamic acid, and 11 received naproxen. Due to multiple courses of NSAID prescription, a total of 70 prescriptions were identified for diclofenac, 80 for ibuprofen, six for indomethacin, 11 for mefenamic acid, and 16 for naproxen. No significant differences were observed in the absolute (p = 0.08) and percent changes in serum creatinine (p = 0.1) between the NSAIDs. Twenty-eight (15.2%) courses of NSAID therapy met the KDIGO criteria for AKI. Age (OR: 1.1, 95% CI: 1.007, 1.2; p = 0.02), concomitant everolimus (OR: 483, 95% CI: 4.3, 54407; p = 0.01), and mycophenolate + cyclosporine + azathioprine (OR: 63.4E+006, 95% CI: 203.2157 to 19.8E+012; p = 0.005) administration were observed with significant risk of NSAID-induced AKI., Conclusion: We observed possible NSAID-induced AKI to an extent of around 15.2% in our renal transplant patients. No significant differences were observed in the incidence of AKI between various NSAIDs and none of them had either graft failure or death.

Background: Diclofenac is a widely used analgesic, anti-inflammatory, antipyretic drug. In several case reports, its use was associated with the occurrence of Kounis syndrome. The aim of this review was to investigate and summarize published cases of Kounis syndrome suspected to be associated with the use of diclofenac., Methods: Electronic searches were conducted in PubMed/MEDLINE, Scopus, Web of Science, Google Scholar, and the Serbian Citation Index., Results: Twenty publications describing the 20 patients who met inclusion criteria were included in the systematic review. Specified patient ages ranged from 34 to 81 years. Eighteen (90.0%) patients were male. Five patients (25.0%) reported a previous reaction to diclofenac. Reported time from the used dose of diclofenac to onset of the first reaction symptoms ranged from immediately to 5 hours. Diclofenac caused both type I and type II Kounis syndrome, with the presence of various cardiovascular, gastrointestinal, dermatologic, and respiratory signs and symptoms. Most patients experienced hypotension (n = 15 [75.0%]) and chest pain (n = 12 [60.0%]). The most frequently reported finding on electrocardiogram was ST-segment elevations (n = 17 [85.0%]). Coronary angiogram showed normal coronary vessels in 9 patients (45.0%), with some pathologic findings in 8 patients (40.0%)., Conclusion: Clinicians should be aware that Kounis syndrome may be an adverse effect of diclofenac. Prompt recognition and withdrawal of the drug, with treatment of both allergic and cardiac symptoms simultaneously, is important., (© 2023 by the Texas Heart® Institute, Houston.)

Background and Aim: Nonsteroidal anti-inflammatory drugs and proton pump inhibitors are known to affect the diagnostics of gastrointestinal disorders. The aim of this study was to investigate to what extent omeprazole, diclofenac or co-administration of these affects faecal calprotectin levels and the normalisation interval after cessation., Methods: Participants received 20 mg omeprazole daily for 2 weeks in the first sequence, 50 mg oral diclofenac three times daily for 2 weeks in the second and co-administration of these for 2 weeks in the third, with washout periods in between. The first two sequences were randomised to a different order. Faecal calprotectin was measured on days 0, 4, 7, 14, 21, 28 and 35 and thereafter at 7-day intervals until normalisation in each sequence., Results: Thirty-two healthy volunteers were included. During drug intake, 39% on diclofenac (median 70.8 µg/g; range 50.2-1080 µg/g), 53% on omeprazole (median 85.3 µg/g; range 51.1-249 µg/g) and 69% on omeprazole + diclofenac (median 101.5 µg/g; range 51.5-532 µg/g) had faecal calprotectin levels above normal. In the diclofenac sequence, faecal calprotectin returned to normal in all participants within 2 weeks of cessation and in the omeprazole and co-administration sequences, within 3 weeks of cessation. No statistical significant difference was found with respect to drug order., Conclusion: Short-term intake of omeprazole, diclofenac or co-administration appears to increase faecal calprotectin levels. In patients with increased faecal calprotectin on omeprazole alone or in combination with diclofenac, a repeated faecal calprotectin test is recommended at least 3 weeks after cessation. On diclofenac alone, it is sufficient to repeat the faecal calprotectin test 2 weeks after cessation., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Aims: Studies have found an increased risk of myocardial infarction (MI) in association with some non-steroidal anti-inflammatory drugs (NSAIDs). We evaluated this association in patients without major cardiovascular risk factors and assessed potential reverse causality bias., Methods and Results: In this nested case-control study of patients aged 40-79 in Clinical Practice Research Datalink GOLD who received at least one NSAID prescription between 2006 and 2019, we found 8639 MI cases and 34 556 matched controls. We calculated odds ratios (ORs) and 95% confidence intervals (CIs) for MI comparing NSAID users to non-exposed according to the number and timing of NSAID prescriptions and proton-pump inhibitor (PPI) use. Current diclofenac use was associated with a two-fold increased risk of MI regardless of duration of use (adjusted OR, 2.08; 95% CI, 1.82-2.38). ORs ranged from 3 to 5 among current and recent diclofenac users newly exposed to PPIs. There was no spike in risk in new current diclofenac users not exposed to PPIs, but ORs rose with increasing prescriptions. The risk of MI in ibuprofen users was concentrated in new PPI users. There was no material increased risk in naproxen users, nor in past users of most NSAIDs in the absence of PPIs., Conclusion: The risk of MI was elevated in current diclofenac users, particularly in new concomitant PPI users. ORs increased in new users of ibuprofen and PPIs but declined with extended use and were lower in non-PPI users. This suggests that some of the findings may be explained by reverse causality bias., (© The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background: Cytokine release syndrome (CRS) is a major complication after chimeric-antigen receptor T-cell treatment, characterized by an uncontrolled systemic inflammatory reaction. We investigated the potential role of diclofenac in the management of CRS in five pediatric patients treated for relapsed/refractory B-lineage acute lymphoblastic leukemia., Methods: In case of persistent fever with fever-free intervals shorter than 3 hours, diclofenac continuous infusion was initiated, at the starting dose of 0.5 mg/Kg/day, the lowest effective pediatric dose in our experience, possibly escalated up to 1 mg/Kg/day, as per institutional guidelines., Results: CRS occurred at a median of 20 hours (range 8-27) after tisagenlecleucel infusion. Diclofenac was started at a median of 20 hours (range 13-33) after fever onset. A mean of 3.07 febrile peaks without diclofenac and 0.95 with diclofenac were reported ( p = 0.02). Clinical benefit was achieved by hampering the progression of tachypnea and tachycardia. Despite fever control, CRS progressed in four of the five patients, and hypotension requiring vasopressors and fluid retention, as well as hypoxia, occurred. Vasopressors were followed by 1-2 doses of tocilizumab (one in patient 2 and two in patients 3, 4, and 5), plus steroids in patients 4 and 5., Conclusion: Based on a limited number of patients, diclofenac leads to better fever control, which translates into symptom relief and improvement of tachycardia, but could not prevent the progression of CRS.

The aim of this study was to evaluate patient satisfaction and usability scores of different tape treatments and examine the scores in relation to the mechanical characteristics of the tape formulation. A questionnaire for the assessment of comfort level and satisfaction with two brand-name (Naboal, Voltaren) and four generic tapes (Yutoku, Teikoku, Rakool, Towa) containing sodium diclofenac was developed and then applied to 12 healthy volunteers. Results showed that Voltaren was difficult to apply to the skin and easier to peel off the skin than Naboal (p < 0.01). Moreover, Rakool was easier to peel than Naboal (p < 0.05). The mechanically measured peeling force was associated with pain during peeling off (r = -0.65), and the measured value of bending rigidity was associated with ease of peeling off (r = -0.97). The knowledge obtained regarding the influence of pharmaceutical properties on the degree of satisfaction with and usability of different tape formulations may be useful for supporting the selection of generic tapes tailored to individual needs or pharmacist preferences, and thus improve treatment adherence and clinical outcomes.

Introduction: Primary care provides an opportunity to prevent community acquired, medicine or drug-induced acute kidney injury. One of the barriers to proactive prevention of medicine-induced kidney injury in primary care is the lack of a list of nephrotoxic medicines that are most problematic in primary care, particularly one that provides a comparison of risks across medicines., Objective: The aim of this study was to consolidate evidence on the risks associated with medicines and acute kidney injury, with a focus on medicines used in primary care., Method: We searched the MEDLINE and EMBASE databases to identify published studies of all medicines associated with acute kidney injury identified from spontaneous report data. For each medicine positively associated with acute kidney injury, as identified from spontaneous reports, we implemented a sequence symmetry analysis (SSA) and a case-control design to determine the association between the medicine and hospital admission with a primary diagnosis of acute kidney injury (representing community-acquired acute kidney injury). Administrative claims data held by the Australian Government Department of Veterans' Affairs for the study period 2005-2019 were used., Results: We identified 89 medicines suspected of causing acute kidney injury based on spontaneous report data and a reporting odds ratio above 2, from Japan, France and the US. Spironolactone had risk estimates of 3 or more based on spontaneous reports, SSA and case-control methods, while furosemide and trimethoprim with sulfamethoxazole had risk estimates of 1.5 or more. Positive association with SSA and spontaneous reports, but not case control, showed zoledronic acid had risk estimates above 2, while candesartan telmisartan, simvastatin, naproxen and ibuprofen all had risk estimates in SSA between 1.5 and 2. Positive associations with case-control and spontaneous reports, but not SSA, were found for amphotericin B, omeprazole, metformin, amlodipine, ramipril, olmesartan, ciprofloxacin, valaciclovir, mycophenolate and diclofenac. All with the exception of metformin and omeprazole had risk estimates above 2., Conclusion: This research highlights a number of medicines that may contribute to acute injury; however, we had an insufficient sample to confirm associations of some medicines. Spironolactone, furosemide, and trimethoprim with sulfamethoxazole are medicines that, in particular, need to be used carefully and monitored closely in patients in the community at risk of acute kidney injury., (© 2022. The Author(s).)

Competing Interests: Competing interests: None declared.

Background: Routine rectal administration of 100 mg of diclofenac or indomethacin was demonstrated to be an effective prevention method to prevent post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis. The systematic review and meta-analysis aimed to estimate the incidence and severity of post-ERCP pancreatitis (PEP) and explore the discrepancies of PEP incidences among different subgroups., Methods: The PubMed, Web of Science, and Ovid EMBASE databases were searched for studies published until December 2020. Only randomized controlled trials (RCTs) reported rectal administration of 100 mg or higher doses of diclofenac or indomethacin, with PEP as the primary outcomes were eligible for inclusion. The overall and severity of PEP were estimated. Subgroup analysis was performed based on geographic regions, risk level, study beginning time, type of NSAIDs, administration time, and sample size., Results: There were 26 randomized controlled trials (RCTs) with 7954 patients in 31 NSAIDs arms. The pooled incidences were 7.2% for overall PEP (95% confidence interval (CI) 5.9-8.5%), 5.0% for mild PEP (95% CI, 4.0-6.0%), and 1.5% for moderate and severe PEP (0.8-2.3%). PEP rate were higher in patients receiving rectal indomethacin than that of patients receiving rectal diclofenac (7.8% (95% CI, 6.4-9.3%) vs 3.8% (95% CI, 2.2-5.3%), p = 0.009). The PEP rates of high-risk patients and average-risk patients were 8.9% (95% CI, 5.6-12.2%) and 6.4% (95% CI, 5.1-7.6%), respectively (p = 0.160)., Conclusions: The incidence of PEP was higher in patients receiving 100 mg rectal indomethacin than patients receiving 100 mg diclofenac. The effect of 100 mg diclofenac versus indomethacin on preventing PEP requires further study., (© 2022. The Society for Surgery of the Alimentary Tract.)

Aceclofenac controlled-release (CR) is a once-a-day tablet with 200 mg of aceclofenac, and is bioequivalent to conventional aceclofenac. However, its safety in humans has not been well studied in Korea. Therefore, we aimed to evaluate the overall incidence and patterns of adverse events (AEs), the effectiveness of aceclofenac CR, and the differences in incidence rates of the AEs based on each patient's baseline charateristics. This study was conducted on patients receiving aceclofenac CR in clinical practice at each investigational institution to treat musculoskeletal pain and inflammation. The subjects were administered one tablet of aceclofenac CR (200 mg once-a-day) and were observed for 4 weeks post-administration. Factors affecting the occurrence of AEs were evaluated, and the Visual Analogue Scale (VAS) was used to measure the pain intensity. Among 14,543 subjects, the incidence rate of AEs was 0.86%, and that of adverse drug reactions was 0.74%. No serious AEs and unexpected adverse drug reactions were monitored. The incidence rates of AEs were significantly higher in females, inpatient treatment, individuals with concurrent disorders, and those receiving concomitant medications, respectively (all P < 0.05). Four weeks post-using aceclofenac CR, the mean changes in VAS was significantly decreased compared to prior administration. The overall clinical efficacy rate was 91.63%. This study confirmed that no severe adverse reactions were observed for aceclofenac CR exceeding those previously reported for safety results of conventional formulation of this drug in routine clinical practice settings. The use of aceclofenac CR might not violate the previously reported information on the safety and effectiveness of aceclofenac., (© 2022. The Author(s).)

Nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit the enzyme cyclooxygenase (COX), which forms prostaglandins involved in pain and inflammation. COX inhibitors have analgesic and anti-inflammatory effects, but also increase risks for gastrointestinal ulcers, bleeding, and renal and cardiovascular adverse events. Identification of two isoforms of COX, COX-1 and COX-2, led to the development of selective COX-2 inhibitors, which were launched as having fewer gastrointestinal side effects since gastroprotective prostaglandins produced via COX-1 are spared. The balance between COX-1 mediated prothrombotic thromboxane and COX-2 mediated antithrombotic prostacyclin is important for thrombotic risk. An increased risk of suffering myocardial infarction and death with COX-2 inhibitor treatment is well established from clinical trials and observational research. Rofecoxib (Vioxx) was withdrawn from the market for this reason, but the equally COX-2 selective etoricoxib has replaced it in Europe but not in the United States. The "traditional" NSAID diclofenac is as COX-2 selective as celecoxib and increases cardiovascular risk dose dependently. COX inhibitor dosages should be lower in osteoarthritis than in rheumatoid arthritis. Randomized trials comparing COX-2 inhibitors with NSAIDs have exaggerated their gastrointestinal benefits by using maximal NSAID doses regardless of indication, and/or hidden the cardiovascular risk by comparing with COX-2 selective diclofenac instead of low-dose ibuprofen or naproxen. Observational studies show increased cardiovascular risks within weeks of treatment with COX-2 inhibitors and high doses of NSAIDs other than naproxen, which is the safest alternative. COX inhibitors are symptomatic drugs that should be used intermittently at the lowest effective dosage, especially among individuals with an increased cardiovascular risk., (© 2022 The Association for the Publication of the Journal of Internal Medicine.)

Background: A novel formulation of diclofenac, complexed with hydroxypropyl-β-cyclodextrin (HPβCD) as a solubility enhancer, in a prefilled syringe for self-administered subcutaneous injection may overcome the limitations of acute migraine treatments administered by oral, rectal, intramuscular, or intravenous routes., Methods: This multicentre, phase 2, double-blind, randomized, placebo-controlled, dose-finding pilot study evaluated the efficacy, safety and tolerability of three different doses (25/50/75 mg/1 mL) of subcutaneous diclofenac sodium in the treatment of an acute migraine attack in 122 subjects. The primary efficacy endpoint was the percentage of patients pain-free at 2 hours after the study drug injection., Results: A significantly higher percentage of patients in the 50 mg diclofenac group 14 (46.7%) were pain-free at 2 hours when compared with placebo: 9 (29.0%) ( p  = 0.01). The 50 mg dose proved superior to placebo also in the majority of the secondary endpoints. The overall global impression favoured diclofenac vs placebo. There were no adverse events leading to study withdrawal. The majority of treatment-emergent adverse events were mild., Conclusions: The 50 mg dose of this novel formulation of diclofenac represents a valuable self-administered option for the acute treatment of migraine attacks. Trial registration: EudraCT Registration No. 2017-004828-29.

Introduction: Diclofenac has increased cardiovascular risks, but its risk profile compared with other COX-2 inhibitors remains unknown., Aims: The aim of this study was to compare the cardiovascular risks of diclofenac versus other older and newer COX-2 inhibitors (coxibs)., Methods: Using Danish nationwide health registries (1999-2020), we conducted a series of emulated trials (n = 264). Eligible adults had no recent NSAID prescriptions, contraindications or conditions with low adherence. We included initiators of diclofenac (n = 1,600,202), meloxicam (n = 10,903), etodolac (n = 238,538), celecoxib (n = 77,591), and etoricoxib (n = 12,122). We computed the adjusted intention-to-treat incidence rate ratio (aIRR) with 95% confidence interval (CI) of major adverse cardiovascular events (MACE) within 30 days of initiation (5562 events)., Results: MACE was 20% increased among initiators of diclofenac compared with other older COX-2 inhibitors (aIRR 1.19, 95% CI 1.10-1.28), driven by cardiac death (aIRR 1.57, 95% CI 1.21-2.03). The effect appeared strongest for women (aIRR 1.28, 95% CI 1.15-1.43), individuals with high baseline cardiovascular risk (aIRR 1.32, 95% CI 1.05-1.66), and when comparing high-dose diclofenac with low doses of the other older COX-2 inhibitors (aIRR 1.31, 95% CI 1.13-1.52). The results reflected increased rates compared with both meloxicam (aIRR 1.46, 95% CI 0.94-2.26) and etodolac (aIRR 1.18, 95% CI 1.09-1.28). Diclofenac initiators had similar increased rates of MACE compared with coxibs (aIRR 0.96, 95% CI 0.85-1.08), consistent for celecoxib (aIRR 1.02, 95% CI 0.88-1.19) and etoricoxib (aIRR 0.85, 95% CI 0.66-1.10)., Conclusions: The increased cardiovascular risks associated with diclofenac initiation were higher than for other older COX-2 inhibitors (meloxicam/etodolac) and comparable to coxibs (celecoxib/etoricoxib)., (© 2022. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Objective: Non-steroidal anti-inflammatory drugs (NSAIDs) are widely used drugs. However, numerous studies have shown that non-selective cyclooxygenase (COX) inhibitors can also significantly increase the risk of cardiovascular side effects. Diclofenac has the highest risk, while naproxen has the lowest risk of developing these complications. The aim of the study was to analyze the structure and amount of NSAIDs consumed in Montenegro, Finland and Croatia in the last 10 years., Materials and Methods: In our study, we used 90% drug use (DU90) and ATC/DDD methodology. Drug consumption is shown in DDD/1000 inhabitants/day, and drug prices per DDD in Euros (€). Pearson's correlation test was used to examine the correlation between the number of drugs consumed and their price., Results: Diclofenac consumption is 3 to 4 times higher in Montenegro compared to Croatia, and 9 to 10 times higher than in Finland. The average price of diclofenac in Montenegro was around € 0.07 per DDD, in Finland around € 0.26 per DDD and in Croatia € 0.19 per DDD. In Montenegro, the Pearson correlation test did not show a statistically significant association between high diclofenac consumption and its DDD price but showed a positive strong correlation between DDD price growth and naproxen consumption growth., Conclusions: The situation in Montenegro regarding the consumption of diclofenac is unfavorable and it is necessary to change the attitude and awareness of doctors and patients about the use of diclofenac. It is also necessary to replace diclofenac with naproxen, which is a slightly more expensive but safer drug.

Background: Non-steroidal anti-inflammatory drugs (NSAIDs) are one of the most frequently used medications for pain, even though they increase the risk for adverse cardiovascular events., Objectives: The objective of this study was to determine cardiovascular, cerebrovascular, and renal event rates between NSAIDs versus NSAIDs plus misoprostol., Methods: A population-based historical cohort of U.S. veterans receiving prescription NSAIDs (1,681,609) versus NSAIDs plus misoprostol (5972 misoprostol users) was followed for 5 years. In an intent-to-treat analysis, NSAID and NSAID plus misoprostol groups were compared using propensity score-weighted Poisson regression models to estimate incident rate ratio (IRR) and Cox regression to estimate hazard ratio (HR)., Results: The most prescribed NSAIDs were diclofenac and ibuprofen. The mean follow-up was 35.2 ± 14.5 months. There were 439 total cardio-renal events (5.62/1000 patient-months) in the NSAID group and 419 patients (5.01/1000 patient-months) in the NSAID plus misoprostol group (Hazard Ratio (HR): 0.89; 95% confidence interval [CI]: 0.78-1.019; p = 0.09). The risk of cardiovascular event was lower in the NSAID plus misoprostol group (HR: 0.56; 95% CI: 0.34-0.93; p < 0.0001). Cerebrovascular event rates were lower in the NSAID plus misoprostol group (HR: 0.74; 95% CI: 0.60-0.94, p < 0.0001) and for renal (HR: 0.67; 95% CI: 0.49-0.89, p < 0.0001) events. All-cause mortality rate was not different between the two groups (HR: 1.05; 95% CI: 0.88-1.25, p = 0.61)., Conclusion: Compared with NSAID use alone, the concomitant use of NSAID plus misoprostol is associated with a reduced risk of NSAID-induced cardiovascular, cerebrovascular, and renal adverse events. These data support the development of a safer NSAID when combined with misoprostol., (© 2022 Pharmacotherapy Publications, Inc.)

Introduction: Hand-foot syndrome (HFS) is a common cutaneous side effect of capecitabine therapy. Apart from oral cyclooxygenase-2 (COX-2) inhibitor (celecoxib), there are no proven strategies for the prevention of HFS. However, celecoxib is associated with significant cardiotoxicity. To date, no study has evaluated the role of topical COX inhibitor, diclofenac. In this study, we aim to compare topical 1% diclofenac gel with placebo in the prevention of capecitabine-induced HFS., Methods: This is a randomized, placebo-controlled, double-blind, parallel-group superiority trial: the Diclofenac Topical in Reducing Capecitabine induced HFS (D-TORCH) study. A total of 264 patients with breast and gastrointestinal malignancies will be randomly allocated (stratified by sex and type of therapy [monotherapy or combination regimen with capecitabine]) to receive either 1% topical diclofenac or placebo that will be applied over the palmar and dorsal surface of the hands twice daily whilst taking capecitabine for 12 weeks. The patients will be followed up until the end of four cycles. The primary objective of this study is to compare the effect of topical diclofenac with placebo in preventing HFS (incidence of NCI CTCAEv5.0 grade 2 or higher HFS). The secondary objective is to compare the effect of topical diclofenac with placebo on preventing all grades of HFS (incidence of NCI CTCv5.0 all grade HFS), time to develop HFS (from the start of capecitabine), patient-reported outcomes (PROs) (HF-HRQoL questionnaire), adherence with the application (self-reported), capecitabine dose changes (number of patients with dose modifications due to HFS) and safety profile (NCICTCv5.0 all grade HFS) DISCUSSION: The D-TORCH study aims to determine if 1% topical diclofenac reduces the incidence of grade 2 or higher HFS in patients receiving capecitabine. To date, there have been a lot of trials for hand-foot syndrome prevention using agents like pyridoxine, vitamin E, carvedilol, and various polyherbal formulations, but none has been found successful. If the trial meets the primary end point, 1% topical diclofenac will be the new standard of care for HFS prevention., Trial Registration: Clinical Trials Registry of India  CTRI/2021/01/030592 . Prospectively registered on January 19, 2021., (© 2022. The Author(s).)