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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 -
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 -
Current Topics in Medicinal Chemistry 2017Non-steroidal anti-inflammatory drugs (NSAIDs) are the group of drugs prescribed in various pain related disorders and inflammatory conditions. Diclofenac (DI) is widely... (Review)
Review
Non-steroidal anti-inflammatory drugs (NSAIDs) are the group of drugs prescribed in various pain related disorders and inflammatory conditions. Diclofenac (DI) is widely prescribed drug for chronic inflammatory conditions like osteoarthritis (OA), a highly prevalent musculoskeletal disorder of adults, projected to affect about 60 million people of total world population by 2020. The chronic oral administration of diclofenac is linked with many gastrointestinal complications like ulceration, bleeding and perforation. These issues paved the way for the development of a structurally similar drug Aceclofenac, which proved to be a safer and more efficient alternative. In spite of better tolerability of Aceclofenac, the oral use of it is not completely free from typical NSAID like side effects. Thus in this context, it becomes mandatory to explore the potential of newer delivery approaches. Amongst the varied newer carrier-systems, microemulsion systems, lipidic colloidal carrier systems and many other supramolecular systems promise to improve the delivery. They tend to place the molecules to the desired target site or in the vicinity without disturbing the unaffected normal surrounding tissues and also ensure enhanced permeation into the skin. The current investigation highlights and deals with the different conventional and novel approaches used thus far in oral delivery of Aceclofenac, their limitations and recent shift towards non oral routes.
Topics: Administration, Oral; Animals; Anti-Inflammatory Agents, Non-Steroidal; Diclofenac; Drug Administration Routes; Drug Carriers; Drug Stability; Humans; Solubility; Species Specificity
PubMed: 27237333
DOI: 10.2174/1568026616666160530152958 -
The Science of the Total Environment Nov 2018The incomplete elimination of pharmaceuticals and personal care products (PPCPs) during wastewater treatment has resulted in their detection in the environment. PPCP...
The incomplete elimination of pharmaceuticals and personal care products (PPCPs) during wastewater treatment has resulted in their detection in the environment. PPCP biodegradation is a potential removal mechanism; however, the microorganisms and pathways involved in soils are generally unknown. Here, the biodegradation of diclofenac (DCF), carbamazepine (CBZ) and triclocarban (TCC) in four agricultural soils at concentrations typically detected in soils and biosolids (50 ng g) was examined. Rapid DCF removal (<7 days) was observed under aerobic conditions, but only limited biodegradation was noted under other redox conditions. CBZ and TCC degradation under aerobic conditions was slow (half-lives of 128-241 days and 165-190 days for CBZ and TCC). Phylotypes in the Proteobacteria, Gemmatimonadales and Actinobacteria were significantly more abundant during DCF biodegradation compared to the controls (no DCF). For CBZ, those in the Bacteroidetes, Actinobacteria, Proteobacteria and Verrucomicrobia were enriched compared to the controls. Actinobacteria and Proteobacteria were also enriched during TCC biodegradation. Such differences could indicate these microorganisms are associated with the biodegradation of these compounds, as they appear to be benefiting from their removal. The impact of these PPCPs on the KEGG pathways associated with metabolism was also examined. Four pathways were positively impacted during DCF biodegradation (propanoate, lysine, fatty acid & benzoate metabolism). These pathways are likely common in soils, explaining the rapid removal of DCF. There was limited impact of CBZ on the metabolic pathways. TCC removal was linked to genes associated with the degradation of simple and complex substrates. The results indicate even low concentrations of PPCPs significantly affect soil communities. The recalcitrant nature of TCC and CBZ suggests soils receiving biosolids could accumulate these chemicals, representing risks concerning crop uptake.
Topics: Biodegradation, Environmental; Carbamazepine; Carbanilides; Diclofenac; Metabolic Networks and Pathways; Soil; Soil Microbiology; Soil Pollutants
PubMed: 30021306
DOI: 10.1016/j.scitotenv.2018.05.403 -
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 -
ACS Applied Materials & Interfaces Jun 2024A novel therapeutic approach combining acupuncture and diclofenac sodium (DS) administration was established for the potential treatment for rheumatoid arthritis (RA)....
A novel therapeutic approach combining acupuncture and diclofenac sodium (DS) administration was established for the potential treatment for rheumatoid arthritis (RA). DS is a commonly used anti-inflammatory and analgesic drug but has short duration and adverse effects. Acupoints are critical linkages in the meridian system and are potential candidates for drug delivery. Herein, we fabricated a DS-loaded multilayer-modified acupuncture needle (DS-MMAN) and investigated its capacity for inhibiting RA. This DS-MMAN possesses sustained release properties and anti-inflammatory effects. Experimental results showed that the DS-MMAN with microdoses can enhance analgesia and efficiently relieve joint swelling compared to the oral or intra-articular administration of DS with gram-level doses. Moreover, the combination of acupoint and DS exerts a synergistic improvement in inflammation and joint damage. Cytokine and T cell analyses in the serum indicated that the application of DS-MMAN suppressed the levels of pro-inflammatory factors and increased the levels of anti-inflammatory factors. Furthermore, the acupoint administration via DS-MMAN could decrease the accumulation of DS in the liver and kidneys, which may express better therapeutic efficiency and low toxicity. The present study demonstrated that the acupuncture needle has the potential to build a bridge between acupuncture and medication, which would be a promising alternative to the combination of traditional and modern medicine.
Topics: Diclofenac; Arthritis, Rheumatoid; Needles; Animals; Acupuncture Therapy; Mice; Male; Drug Delivery Systems; Humans; Anti-Inflammatory Agents, Non-Steroidal; Rats
PubMed: 38829728
DOI: 10.1021/acsami.4c04815 -
Drug Metabolism and Pharmacokinetics Dec 2021Cisplatin (CDDP) is a well-known anticancer agent, and CDDP-induced nephrotoxicity (CIN) is one of the most serious adverse effects. Previously, we revealed that while...
Diclofenac potentiates the antitumor effect of cisplatin in a xenograft mouse model transplanted with cisplatin-resistant cells without enhancing cisplatin-induced nephrotoxicity.
Cisplatin (CDDP) is a well-known anticancer agent, and CDDP-induced nephrotoxicity (CIN) is one of the most serious adverse effects. Previously, we revealed that while celecoxib reduces CIN, diclofenac does not appear to enhance it. Furthermore, we reported that diclofenac additively enhances the cytotoxic effect of CDDP on CDDP-resistant A549 cells (A549/DDP cells) and their spheroids. In addition, celecoxib reduces the cytotoxic effect of CDDP on A549/DDP cells while demonstrating an anticancer effect; however, it enhanced the effect of CDDP cytotoxicity on spheroids. Therefore, we evaluated the effects of diclofenac or celecoxib on CIN and the antitumor effect of CDDP in a xenograft mouse model transplanted with A549/DDP cells. Although CDDP did not decrease tumor size and tumor weight, these parameters were significantly reduced following co-administration with diclofenac when compared with the control group. Conversely, celecoxib marginally suppressed the antitumor effect of CDDP. Moreover, CDDP increased the mRNA levels of kidney injury molecule 1 (Kim-1), a renal disorder marker, in the kidneys of xenograft mice; treatment with celecoxib and diclofenac did not impact Kim-1 mRNA levels increased by CDDP. In conclusion, diclofenac potentiated the antitumor effect of CDDP without enhancing CIN.
Topics: A549 Cells; Animals; Antineoplastic Agents; Cisplatin; Diclofenac; Heterografts; Humans; Mice
PubMed: 34619549
DOI: 10.1016/j.dmpk.2021.100417 -
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 -
CNS Drugs Aug 2014Diclofenac potassium powder for oral solution (Voltfast(®), Catafast(®), Cambia(®); hereafter referred to as diclofenac potassium powder) is a non-steroidal... (Review)
Review
Diclofenac potassium powder for oral solution (Voltfast(®), Catafast(®), Cambia(®); hereafter referred to as diclofenac potassium powder) is a non-steroidal anti-inflammatory drug (NSAID), and is indicated for the acute treatment of migraine. This article reviews the pharmacological properties of diclofenac potassium powder and its efficacy and tolerability in patients with acute migraine. Diclofenac potassium powder was clinically efficacious and generally well tolerated in placebo-controlled trials in patients with this indication; it was more effective than diclofenac potassium tablets with regard to the primary endpoint of 2-h pain relief as well as in several important secondary endpoints, such as time to onset of analgesic action. The oral powder-for-solution formulation of diclofenac potassium is a useful option in the acute treatment of migraine with or without aura.
Topics: Administration, Oral; Anti-Inflammatory Agents, Non-Steroidal; Controlled Clinical Trials as Topic; Diclofenac; Humans; Migraine Disorders; Powders
PubMed: 25034250
DOI: 10.1007/s40263-014-0186-y -
Journal of Pharmacy & Pharmaceutical... 2018The objective of this study was to determine: 1) the incidence and the risk factors of diclofenac/acetaminophen combination as a single agent induced Acute Kidney Injury...
PURPOSE
The objective of this study was to determine: 1) the incidence and the risk factors of diclofenac/acetaminophen combination as a single agent induced Acute Kidney Injury (AKI) in postoperative pain relief 2) the average cost and length of hospital stay for patients in AKI group and non-AKI group.
METHODS
All patients with no prior history of chronic kidney disease (CKD) and normal serum creatinine [44~130 μmol /l] who received diclofenac and acetaminophen combination as a single agent intramuscularly (IM) between January and December 2015 in The Second Xiangya Hospital, Changsha, Hunan, China were included in this retrospective own-control study. Baseline serum creatinine (SCr) and SCr during NSAID use were collected. AKI is defined as an increased of Scr over 1.5 times the baseline. Multivariate analyses were performed with a logistic regression model to assess the significant risk factors of AKI.
RESULTS
A total of 821 patients were included in the study with 63 [7.7%] patients had diclofenac/acetaminophen combination single agent induced AKI. Multivariate analysis confirmed that using diclofenac/acetaminophen combination after surgeries within 24 h were significantly associated with AKI [odds ratio, OR, 2.173; 95% CI, 1.113-4.243; P=0.023]. The average cost and length of hospitalization in AKI group was 1.87 times [p=0.000] and 1.2 times [p=0.043] comparison than non-AKI group, respectively.
CONCLUSIONS
The incidence of diclofenac/acetaminophen combination single agent induced AKI in postoperative pain relief was 7.7%. Patients with hypertension or liver cirrhosis was more likely to develop AKI and using diclofenac/acetaminophen combination after surgeries within 24 h was significant risk factors for AKI. AKI prolonged the cost and length of hospitalization. This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page.
Topics: Acetaminophen; Acute Kidney Injury; Adolescent; Adult; Aged; Aged, 80 and over; Child; Child, Preschool; Diclofenac; Drug Therapy, Combination; Female; Humans; Injections, Intramuscular; Male; Middle Aged; Pain, Postoperative; Retrospective Studies; Risk Factors; Young Adult
PubMed: 29382434
DOI: 10.18433/J3SH21