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Basic & Clinical Pharmacology &... Apr 2022Several studies investigated diclofenac tissue concentrations using microdialysis (MD). However, thorough evaluations of the optimal MD set-up for diclofenac are...
Several studies investigated diclofenac tissue concentrations using microdialysis (MD). However, thorough evaluations of the optimal MD set-up for diclofenac are unavailable. Thus, this in vitro MD study aimed to compare different set-ups to improve quantitative recovery of diclofenac. In forward and reverse in vitro MD experiments with diclofenac at two concentrations (1 and 100 ng/ml), the perfusion solutions physiological saline 0.9% (PS) and human albumin 1% (HSA) were compared using tissue probes (10-mm membrane) and customized intravenous (iv) probes (30-mm membrane). Using PS, the mean relative recovery of diclofenac at 1 ng/ml was 1.6% ± 0.04% and 3.12% ± 0.00% with the tissue probe and the iv probe, respectively. The respective mean relative recovery for diclofenac at 100 ng/ml was 0.02% ± 0.01% and 0.21% ± 0.11%. Using HSA, the mean relative recovery was 314% ± 25% (tissue probe) and 1064% ± 97% (iv probe) for diclofenac at 1 ng/ml and 444% ± 91% and 1415% ± 217% for diclofenac at 100 ng/ml. In reverse dialysis using PS, the mean relative loss of diclofenac was 99.2% ± 0.5% (tissue probe) and 95.8% ± 1.7% (iv probe). Using HSA, the mean relative loss was -4.4% ± 7.2% and 0.2% ± 7.5%, respectively. PS and HSA were not suitable perfusion solutions for quantification of absolute diclofenac concentrations. Despite methodological challenges, HSA may be used for comparative experiments or bioequivalence studies.
Topics: Administration, Cutaneous; Diclofenac; Humans; Microdialysis; Perfusion
PubMed: 35048557
DOI: 10.1111/bcpt.13709 -
Mutation Research. Genetic Toxicology... Jun 2021Diclofenac is a non-steroidal anti-inflammatory drug discovered several decades ago, which has since been used by an estimated one billion patients and has demonstrated...
Diclofenac is a non-steroidal anti-inflammatory drug discovered several decades ago, which has since been used by an estimated one billion patients and has demonstrated an acceptable safety profile. In support of its marketing approval, a comprehensive set of genotoxicity studies were conducted in vitro and in vivo. Despite the fact that these studies preceded both Good Laboratory Practice (GLP) requirements and International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) guidelines on genotoxicity testing, they were conducted using the best scientific principles and are considered appropriate by contemporary standards. In addition to bacterial mutagenicity and mammalian in vitro assays, repeat-dose somatic, germ cell and dominant lethal assays were conducted. These data are made available for the first time to offer researchers an opportunity to review the existing data set that unequivocally demonstrates that diclofenac sodium is not genotoxic. This is further substantiated by long-term bioassay data demonstrating that diclofenac sodium has no carcinogenic potential in rodents. However, more recently, new studies have been published showing a genotoxic potential for diclofenac in novel or modified in vitro test systems. These new publications are discussed in the context of the existing comprehensive data package.
Topics: Animals; Carcinogens; Cell Line, Tumor; Cricetulus; Diclofenac; Female; Germ Cells; Male; Mammals; Mice; Mutagenicity Tests; Mutagens; Rats
PubMed: 33985691
DOI: 10.1016/j.mrgentox.2021.503347 -
Journal of Hazardous Materials Oct 2021Diclofenac is an anti-inflammatory drug used as an analgesic. It is often detected in various environmental sources around the world and is considered as one of the... (Review)
Review
Diclofenac is an anti-inflammatory drug used as an analgesic. It is often detected in various environmental sources around the world and is considered as one of the emerging contaminants (ECs). This paper reviews the distribution of diclofenac at high concentrations in diverse environments and its adverse ecological impact. Recent studies observed strong evidence of the hazardous effect of diclofenac on mammals, including humans. Diclofenac could cause gastrointestinal complications, neurotoxicity, cardiotoxicity, hepatotoxicity, nephrotoxicity, hematotoxicity, genotoxicity, teratogenicity, bone fractures, and skin allergy in mammals even at a low concentration. Collectively, this comprehensive review relates the mode of toxicity, level of exposure, and route of administration as a unique approach for addressing the destructive consequence of diclofenac in mammalian systems. Finally, the mitigation strategy to eradicate the diclofenac toxicity through green remediation is critically discussed. This review will undoubtedly shed light on the toxic effects of pseudo-persistent diclofenac on mammals as well as frame stringent guidelines against its common usage.
Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Diclofenac; Environment; Humans; Mammals
PubMed: 34157463
DOI: 10.1016/j.jhazmat.2021.126135 -
Water Research May 2021With questions emerging on the presence and risks associated with metabolites and transformation products (TPs) of organic contaminants in the aquatic environment,...
With questions emerging on the presence and risks associated with metabolites and transformation products (TPs) of organic contaminants in the aquatic environment, progress has been made in terms of monitoring and regulation of pesticide metabolites. However, less interest is shown for pharmaceutical residues, although their pseudo-persistence and adverse effects on non-target organisms are proven. This study provides original knowledge about the contamination of ten sites located along three French rivers (water, sediments, biofilms, clams) by pharmaceutical metabolites and TPs, as well as a preliminary environmental risk assessment. Studied compounds included carbamazepine with five metabolites and TPs, and diclofenac with three metabolites and TPs. Results show that metabolites and TPs are present in all studied compartments, with mean concentrations up to 0.52 µg L in water, 229 ng g in sediments, 2153 ng g in biofilms, and 1149 ng g in clams. QSAR estimations (OECD toolbox) were involved to predict the studied compounds ecotoxicities. QSAR models showed that diclofenac and its metabolites and TPs could be more toxic than carbamazepine and its metabolites and TPs to three aquatic species representing green algae, invertebrates, and fish. However, real ecotoxicological effects are still to be determined. The environmental risk assessment showed that hydroxydiclofenac, 2-[(2-chlorophenyl)-amino]-benzaldehyde and dibenzazepine could present a greater risk than other studied compounds for aquatic organisms. In addition, the risk associated with a mixture of diclofenac and its related metabolites and TPs has been found to be greater than that of the compounds considered individually.
Topics: Animals; Carbamazepine; Diclofenac; Environmental Monitoring; Pharmaceutical Preparations; Risk Assessment; Rivers; Water Pollutants, Chemical
PubMed: 33774347
DOI: 10.1016/j.watres.2021.117052 -
PeerJ 2023Amultigenerational study on was carried out by exposing three subsequent generations to pharmaceuticals chlorpromazine (CPZ) and diclofenac (DCF), and two lanthanide...
Amultigenerational study on was carried out by exposing three subsequent generations to pharmaceuticals chlorpromazine (CPZ) and diclofenac (DCF), and two lanthanide chlorides, gadolinium as GdCl and europium as EuCl. As the treatments, environmentally relevant concentrations were chosen (0.001, 0.01 and 0.1 mg/L for CPZ; 0.1, 1 and 10 mg/L for DCF; 0.425, 4.25 and 42.5 µg/L for Gd and 0.41, 4.1 and 41 µg/L for Eu). Survival, population growth and reproduction success were evaluated at 21 and 30 days of exposure, and the whole observation period lasted 40 days. The least sensitive to all selected substances was the first daphnid generation (F1). Within 21-day exposure, no significant effects of the psychotropic drug CPZ on survival were observed in generations F1-F3. The anti-inflammatory drug DCF did not affect survival in the F1 generation; however, it significantly reduced survival in the F3 generation at 1-10 mg/L. Both lanthanides did not affect survival in the F1 and F2 generations of but considerably decreased survival in the F3 at 4-42 µg/L. Both pharmaceuticals stimulated the reproduction of in the F1 generation, while inhibition occurred at the highest tested concentrations in generations F2 and F3. The inhibitory effect on the reproductive success of lanthanides in the F2 generation resembled that for CPZ but not for DCF. The dynamics of adverse effects during the 21-30-day period revealed that despite increased mortality in the controls (up to 30%), concentrations used in the study minified, in most instances, the survival and aggravated population growth and reproduction success of . Our data suggest that as a test organism can be used for 21 days in multigenerational investigations, especially when testing close to environmental concentrations. In this respect, the standard chronic toxicity assay seems limited since prolonged observations and several generations of daphnids are required to obtain reliable information for the risk assessment of potentially aggressive chemicals.
Topics: Animals; Chlorpromazine; Cladocera; Diclofenac; Lanthanoid Series Elements
PubMed: 38025671
DOI: 10.7717/peerj.16472 -
Asian Pacific Journal of Cancer... Apr 2022To examine the effects of ibuprofen, naproxen and diclofenac, non-steroidal anti-inflammatory drugs (NSAIDs) on cell proliferation activity of the human CCA cell lines.
OBJECTIVE
To examine the effects of ibuprofen, naproxen and diclofenac, non-steroidal anti-inflammatory drugs (NSAIDs) on cell proliferation activity of the human CCA cell lines.
METHODS
KKU-M139 and KKU-213B cell lines were used in this study. The cell viability was assessed by the MTT assay. Lipid synthesis determined by Oil red O staining and colorimetric assay. An inverted phase-contrast light microscope was used to investigate the histological change of the cells. Caspases 3/7 activity and AnnexinV/PI were used to assess apoptosis by multiple microplate reader.
RESULTS
The results showed that ibuprofen, naproxen and diclofenac suppressed the viability of the KKU-M139 and KKU-213B cells in a dose-dependent manner, as measured especially diclofenac. However, these three NSAIDs slightly decreased lipid synthesis determined by Oil red O staining and colorimetric assay. The histological change observations showed the shrinking cell and become star-shaped in high dose treated groups. Interestingly, these NSAIDs exhibited in both of KKU-M139 and KKU-213B cell lines, the diclofenac-treated cells had the most injury cells. The cells exhibited cell injury features. In addition, the detection of caspase 3/7 and AnnexinV/PI in this investigation revealed early cell apoptotic characteristics.
CONCLUSION
These finding suggest that ibuprofen, naproxen and diclofenac suppress cell viability. The results reveal that ibuprofen, naproxen and diclofenac, which induce the histological change and apoptosis. This study indicates that these NSAIDs may be used as an anti-proliferation agent for the treatment of CCA in the future.
Topics: Anti-Inflammatory Agents, Non-Steroidal; Apoptosis; Bile Duct Neoplasms; Bile Ducts, Intrahepatic; Cell Line, Tumor; Cell Proliferation; Cholangiocarcinoma; Diclofenac; Humans; Ibuprofen; Lipids; Naproxen
PubMed: 35485696
DOI: 10.31557/APJCP.2022.23.4.1351 -
Chemosphere Nov 2022Topical diclofenac gels are frequently applied on human skin and, consequently are exposed to sunlight during outdoor activities. The degradation of diclofenac (DCF)...
Topical diclofenac gels are frequently applied on human skin and, consequently are exposed to sunlight during outdoor activities. The degradation of diclofenac (DCF) with sunlight exposure is known to occur but the detailed transformation characteristics and biological concerns have not been comprehensively investigated. In the present work, the transformation products during diclofenac photolysis were identified with the aid of ultra-performance liquid chromatography coupled with triple time-of-flight mass spectrometry (UPLC-TripleTOF). Biological concerns, including microtoxicity, genotoxicity, cytotoxicity and antiestrogenicity were examined with multiple in-vitro bioassays. Spearman correlation analysis was conducted to obtain further insight into the contributions of photolysis products to overall biological concerns. The results demonstrated that diclofenac was readily degraded under sunlight to form five main photolysis products via substitution, dechlorination, dehydroxylation, homodimerization and heterodimerization. Products P1, P2 and P5 were reported previously, while two dimer products (P3 and P4) are innovative products and have not been found in prior studies. A significant elevation in the microtoxicity was found during the photolysis of diclofenac, resulting mainly from the carbazole-containing photolysis products P2, P3, P4 and P5. Genotoxicity and antiestrogenicity declined along with the reduction of diclofenac, indicating that no photolysis products were genotoxic or anti-estrogenic. Modest cytotoxicity to the human skin epidermis cell line was observed and attributed to the formation of intermediate species. This outcome highlighted the biological concerns of diclofenac to human health when exposed to sunlight.
Topics: Carbazoles; Diclofenac; Gels; Humans; Kinetics; Sunlight; Water Pollutants, Chemical
PubMed: 35868525
DOI: 10.1016/j.chemosphere.2022.135775 -
Methods in Molecular Biology (Clifton,... 2021The potential for new chemical entities to inhibit the major cytochrome P450 (CYP) isoforms is routinely evaluated to minimize the risk of developing drugs with... (Comparative Study)
Comparative Study
The potential for new chemical entities to inhibit the major cytochrome P450 (CYP) isoforms is routinely evaluated to minimize the risk of developing drugs with drug-drug interaction liabilities. CYP inhibition assays are routinely performed in a high-throughput format to efficiently screen large numbers of compounds. In evaluating a time-saving assay using diclofenac as the CYP2C9 probe substrate, a discrepancy was observed in which minimal inhibition was detected using diclofenac whereas using (S)-warfarin resulted in potent inhibition, supporting the presence of dual-binding sites in the relatively large CYP2C9 active site cavity.These observations provided further insights into explaining the reported ineffective inactivation of CYP2C9 for the pan-CYP inactivator 1-aminobenzotriazole (ABT). Mechanistic reversible and time-dependent inhibition experiments revealed that the ineffective CYP2C9 inactivation by ABT was also probe-dependent, with utilization of (S)-warfarin as the probe substrate resulting in more potent CYP2C9 inhibition by ABT compared to diclofenac. Addition of (S)-warfarin to the reversible and time-dependent inhibition experiments between ABT and diclofenac resulted in an attenuation of the inhibitory effects of ABT on CYP2C9-mediated diclofenac metabolism. Molecular docking studies further confirmed that (S)-warfarin and diclofenac preferentially bind in different regions of the CYP2C9 active site, with (S)-warfarin occupying a distal "warfarin-binding pocket" and diclofenac occupying a binding site close to the active heme moiety. ABT preferentially binds in the distal warfarin-binding pocket, supporting that diclofenac is minimally deterred from access to the CYP2C9 active site in the presence of ABT, thus resulting in minimal inactivation. Simultaneously docking of (S)-warfarin and ABT revealed that (S)-warfarin outcompetes ABT for the distal binding site and results in the binding of ABT to the CYP2C9 active site, supporting the observations of potent inactivation of CYP2C9 when (S)-warfarin is the probe substrate.These results highlight that probe selection is crucial when evaluating CYP inhibition potential, and it is recommended that multiple probes be utilized for CYP2C9, similar to the approach routinely employed for CYP3A4. Further, utilization of ABT as a pan-inhibitor of CYP activity for investigational compounds, both in vitro and in vivo, should be accompanied with the understanding that residual CYP-mediated oxidative metabolism could potentially be observed for CYP2C9 substrates and should not necessarily be attributed to non-P450-mediated metabolism.
Topics: Binding Sites; Crystallography, X-Ray; Cytochrome P-450 CYP2C9; Diclofenac; Drug Interactions; Gene Silencing; Humans; Models, Molecular; Molecular Docking Simulation; Protein Conformation; Time Factors; Triazoles; Warfarin
PubMed: 34272716
DOI: 10.1007/978-1-0716-1554-6_28 -
Pain Medicine (Malden, Mass.) Feb 2021To compare the efficacy and safety of celecoxib and diclofenac sodium in patients with knee osteoarthritis (KOA). (Meta-Analysis)
Meta-Analysis
OBJECTIVE
To compare the efficacy and safety of celecoxib and diclofenac sodium in patients with knee osteoarthritis (KOA).
METHODS
Clinical controlled trials (CCTs) and randomized controlled trials (RCTs) from online databases comparing the efficacy of celecoxib and diclofenac sodium in the treatment of KOA were retrieved. The main outcomes included the treatment effect, C-reactive protein (CRP) level, erythrocyte sedimentation rate (ESR), visual analog scale (VAS) score, and complication rate. The Cochrane risk of bias (ROB) tool in Review Manager 5.3.5 was used to assess methodological quality.
RESULTS
Twelve studies (N = 2,350) were included in this meta-analysis. The meta-analysis indicated that celecoxib reduced pain more effectively than diclofenac sodium in patients with KOA, as evaluated by the VAS score. In addition, celecoxib has certain advantages in terms of better treatment effects and greater reductions in the ESR, CRP level, and complication rate.
CONCLUSIONS
Celecoxib is superior to diclofenac sodium in the treatment of KOA. However, well-designed and high-quality RCTs are still needed.
Topics: Celecoxib; Diclofenac; Humans; Osteoarthritis, Knee; Pain; Treatment Outcome
PubMed: 32797224
DOI: 10.1093/pm/pnaa230 -
Primary Health Care Research &... Dec 2021The most frequently prescribed analgesic drugs in primary care centers in Turkey are diclofenac and paracetamol, respectively. In this study, we aimed to compare...
INTRODUCTION
The most frequently prescribed analgesic drugs in primary care centers in Turkey are diclofenac and paracetamol, respectively. In this study, we aimed to compare paracetamol-included prescriptions (PIP) and diclofenac-included prescriptions (DIP) generated for adult patients in primary care.
METHODS
In this cross-sectional study, PIPs (n = 280 488) and DIPs (n = 337 935) created for adults by systematic sampling among primary care physicians working in Istanbul in 2016 (n = 1431) were examined. The demographic characteristics, diagnoses, and additional drugs in PIPs and DIPs were compared.
RESULTS
Women constituted the majority in both groups (69.8% and 67.9%, respectively; P < 0.05), and mean age at PIP (52.6 ± 18.8 years) was lower compared to DIP (56.3 ± 16.1 years), (P < 0.05). In single-diagnosis prescriptions, 11 of the 15 most common diagnoses in PIP were respiratory tract infections (47.9%); three pain-related diagnoses formed 4.6% of all these prescriptions. In DIP, the number of pain-related diagnoses, mostly of musculoskeletal origin, was eight (28.5%); four diagnoses (7.8%) were upper respiratory tract infections. While hypertension was the third most common diagnosis in PIP (6.1%), it was ranked first in DIP (8.0%). The percentage of prescriptions with additional analgesic (14.0% versus 18.3%, P < 0.001), proton-pump inhibitor (13.8% versus 18.4%; P < 0.001), and antihypertensive (22.0% versus 24.8%, P < 0.001) was lower in PIP compared to DIP. However, the percentage of prescriptions with antibiotics (31.3% versus 14.7%, P < 0.001) was higher in PIP.
CONCLUSION
Paracetamol appears to be preferred mostly in upper respiratory tract infections compared to the preference of diclofenac rather in painful/inflammatory musculoskeletal conditions. The presence of hypertension among the most commonly encountered diagnoses for these analgesic drugs points to challenges in establishing the diagnosing-treatment match and indicates potential irrational prescribing practice, especially for interactions.
Topics: Acetaminophen; Adult; Cross-Sectional Studies; Diclofenac; Female; Humans; Practice Patterns, Physicians'; Primary Health Care; Respiratory Tract Infections
PubMed: 34852871
DOI: 10.1017/S1463423621000797