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The Science of the Total Environment Jan 2020Diclofenac, a nonsteroidal anti-inflammatory drug has turned into a contaminant of emerging concern; hence, it was included in the previous Watch List of the EU Water... (Review)
Review
Diclofenac, a nonsteroidal anti-inflammatory drug has turned into a contaminant of emerging concern; hence, it was included in the previous Watch List of the EU Water Framework Directive. This review paper aims to highlight the metabolism of diclofenac at different trophic levels, its occurrence, ecological risks, and interactive effects in the water cycle and biota over the past two decades. Increased exposure to diclofenac not only raises health concerns for vultures, aquatic organisms, and higher plants but also causes serious threats to mammals. The ubiquitous nature of diclofenac in surface water (river, lake canal, estuary, and sea) is compared with drinking water, groundwater, and wastewater effluent in the environment. This comprehensive survey from previous studies suggests the fate of diclofenac in wastewater treatment plants (WWTPs) and may predict its persistence in the environment. This review offers evidence of fragmentary available data for the water environment, soil, sediment, and biota worldwide and supports the need for further data to address the risks associated with the presence of diclofenac in the environment. Finally, we suggest that the presence of diclofenac and its metabolites in the environment may represent a high risk because of their synergistic interactions with existing contaminants, leading to the development of drug-resistant strains and the formation of newly emerging pollutants.
Topics: Biota; Diclofenac; Environmental Monitoring; Environmental Pollutants
PubMed: 31783460
DOI: 10.1016/j.scitotenv.2019.134057 -
Ecotoxicology and Environmental Safety Nov 2022Diclofenac is an emerging surface water contaminant, yet the environmental impact of its degradation products remains elusive. The current study focuses on...
Diclofenac is an emerging surface water contaminant, yet the environmental impact of its degradation products remains elusive. The current study focuses on mineralogy-controlled diclofenac photo-degradation and its potential health impacts. Under irradiated conditions, we studied the effects of kaolinite, hematite, and anatase on diclofenac degradation. Our results showed that kaolinite doubled the diclofenac degradation rate, which can be attributed to the high catalytic effect, mediated via increased surface area and pore size of mineral surface in the low pH. Conversely, anatase, a crystal phase of titanium dioxide (TiO), diminished the diclofenac degradation compared to treatments without TiO. Hematite, on the other hand, showed no effect on diclofenac degradation. Photo-degradation products also varied with the mineral surface. We further assessed in vitro toxicological effects of photo-degraded products on two human cell lines, HEK293T and HepG2. Biological assays confirmed that photo-degraded compound 6 (1-(2,6-dichlorophenyl)indolin-2-one) decreased HEK293T cell survival significantly (p < 0.05) when compared to diclofenac in all concentrations. At lower concentrations, inhibition of HEK293T cells caused by compounds 4 (2-(8-chloro-9H-carbazol-1-yl)acetic acid), and 5 (2-(9H-carbazol-1-yl)acetic acid) was greater than diclofenac. Compound 7 (1-phenylindolin-2-one) was toxic only at 250 µM. Additionally, compound 6 decreased HepG2 cell viability significantly when compared to diclofenac. Overall, our data highlighted that mineralogy plays a vital role in environmental diclofenac transformation and its photo-degraded products. Some photo-degraded compounds can be more cytotoxic than the parent compound, diclofenac.
Topics: Humans; Diclofenac; Kaolin; HEK293 Cells; Titanium; Water Pollutants, Chemical
PubMed: 36201921
DOI: 10.1016/j.ecoenv.2022.114138 -
Environmental Science & Technology Aug 2022Diclofenac (DCF) is a pharmaceutically active contaminant frequently found in aquatic ecosystems. The transformation pathways and microbiology involved in the...
Diclofenac (DCF) is a pharmaceutically active contaminant frequently found in aquatic ecosystems. The transformation pathways and microbiology involved in the biodegradation of DCF, particularly under anoxic conditions, remain poorly understood. Here, we demonstrated microbially mediated reductive dechlorination of DCF in anaerobic enrichment culture derived from contaminated river sediment. Over 90% of the initial 76.7 ± 3.6 μM DCF was dechlorinated at a maximum rate of 1.8 ± 0.3 μM day during a 160 days' incubation. Mass spectrometric analysis confirmed that 2-(2-((2-chlorophenyl)amino)phenyl)acetic acid (2-CPA) and 2-anilinophenylacetic acid (2-APA) were formed as the monochlorinated and nonchlorinated DCF transformation products, respectively. A survey of microbial composition and Sanger sequencing revealed the enrichment and dominance of a new population, designated as sp. strain DCF, in the DCF-dechlorinating community. Following the stoichiometric conversion of DCF to 2-CPA (76.0 ± 2.1 μM) and 2-APA (3.7 ± 0.8 μM), strain DCF cell densities increased by 24.4 ± 4.4-fold with a growth yield of 9.0 ± 0.1 × 10 cells per μmol chloride released. Our findings expand the metabolic capability in the genus and highlight the relevant roles of organohalide-respiring bacteria for the natural attenuation of halogenated contaminants of emerging concerns (e.g., DCF).
Topics: Biodegradation, Environmental; Chloroflexi; Diclofenac; Ecosystem; Respiration
PubMed: 35921385
DOI: 10.1021/acs.est.1c08824 -
Physiological Reports Sep 2023The aim of our study is to investigate the electrophysiological and anti-inflammatory effects of diclofenac potassium on epileptiform activity, which is the liquid form...
The aim of our study is to investigate the electrophysiological and anti-inflammatory effects of diclofenac potassium on epileptiform activity, which is the liquid form of diclofenac, and frequently used clinically for inflammatory process by inhibiting cyclooxygenase enzyme (COX). Wistar rats aged 2-4 months were divided into Epilepsy, Diazepam, Diclofenac potassium, and Diazepam+diclofenac potassium groups. Diazepam and diclofenac potassium were administered intraperitoneally 30 min after the epileptiform activity was created with penicillin injected intracortically under anesthesia. After the electrophysiological recording was taken in the cortex for 125 min, interleukin-1β (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) were evaluated by the ELISA in the serums. No change was observed between the groups in serum IL-1β, IL-6, and TNF-α values. It was observed that the co-administration of diclofenac potassium and diazepam at 51-55, 56-60, 61-65, 111-115, and 116-120 min was more effective in reducing spike amplitude than diclofenac potassium alone (p < 0.05). Single-dose diclofenac potassium did not have an anti-inflammatory effect in epileptiform activity but both diazepam and diclofenac potassium reduced the epileptiform activity.
Topics: Rats; Animals; Rats, Wistar; Diclofenac; Interleukin-6; Tumor Necrosis Factor-alpha; Cyclooxygenase 2; Diazepam; Anti-Inflammatory Agents
PubMed: 37688418
DOI: 10.14814/phy2.15800 -
Environmental Science and Pollution... Mar 2023Diclofenac, ibuprofen, and carbamazepine are three of the most widely detected and most concerning pharmaceutical residues in aquatic ecosystems. The aim of this study...
Diclofenac, ibuprofen, and carbamazepine are three of the most widely detected and most concerning pharmaceutical residues in aquatic ecosystems. The aim of this study was to identify bacteria that may be involved in their degradation from a bacterial biofilm. Selective enrichment cultures in mineral salt solution containing pharmaceutical compounds as sole source of carbon and energy were set up, and population dynamics were monitored using shotgun metagenome sequencing. Bacterial genomes were reconstructed using genome-resolved metagenomics. Thirty bacterial isolates were obtained, identified at species level, and tested regarding pharmaceutical biodegradation at an initial concentration of 1.5 mg l. The results indicated that most probably diclofenac biodegrading cultures consisted of members of genera Ferrovibrio, Hydrocarboniphaga, Zavarzinia, and Sphingopyxis, while in ibuprofen biodegradation Nocardioides and Starkeya, and in carbamazepine biodegradation Nocardioides, Pseudonocardia, and Sphingopyxis might be involved. During the enrichments, compared to the initial state the percentage relative abundance of these genera increased up to three orders of magnitude. Except Starkeya, the genomes of these bacteria were reconstructed and annotated. Metabolic analyses of the annotated genomes indicated that these bacteria harbored genes associated with pharmaceutical biodegradation. Stenotrophomonas humi DIC_5 and Rhizobium daejeonense IBU_18 isolates eliminated diclofenac and ibuprofen during the tests in the presence of either glucose (3 g l) or in R2A broth. Higher than 90% concentration reduction was observed in the case of both compounds.
Topics: Ibuprofen; Diclofenac; Ecosystem; Carbamazepine; Bacteria; Biodegradation, Environmental; Groundwater; Biofilms; Pharmaceutical Preparations
PubMed: 36690856
DOI: 10.1007/s11356-022-24975-6 -
European Journal of Medicinal Chemistry Nov 2023A series of diclofenac hybrid molecules were synthesized and evaluated for their NO-inhibitory ability in LPS-induced RAW 264.7 macrophage cells. Among them, compound 1...
A series of diclofenac hybrid molecules were synthesized and evaluated for their NO-inhibitory ability in LPS-induced RAW 264.7 macrophage cells. Among them, compound 1 showed the highest NO-inhibitory ability (approximately 66%) and no significant cytotoxicity. Compound 1 exhibited superior NF-κB-inhibitory ability compared to diclofenac through the activation of Nrf2/HO-1 signaling pathway in RAW 264.7. 20 mg/kg compound 1 resulted in remarkable colitis improvement in dextran sulfate sodium (DSS)-induced mice model by up-regulating HO-1 and down-regulating phosphorylation level of NF-κB p65. Moreover, 50 mg/kg dose of compound 1 showed a lower ulcerogenic potential compared to diclofenac in rats. The diclofenac-eugenol hybrid (compound 1) may serve as a novel anti-inflammatory agent based on its role in inhibiting the NF-κB signaling pathway and activating HO-1 expression with no toxicity in vitro and in vivo.
Topics: Animals; Mice; Rats; Anti-Inflammatory Agents; Diclofenac; Eugenol; Heme Oxygenase-1; Lipopolysaccharides; NF-E2-Related Factor 2; NF-kappa B; RAW 264.7 Cells
PubMed: 37517204
DOI: 10.1016/j.ejmech.2023.115669 -
British Journal of Cancer Aug 2023B-raf inhibitors (BRAFi) are effective for BRAF-mutated papillary (PTC) and anaplastic (ATC) thyroid carcinomas, although acquired resistance impairs tumour cells'...
BACKGROUND
B-raf inhibitors (BRAFi) are effective for BRAF-mutated papillary (PTC) and anaplastic (ATC) thyroid carcinomas, although acquired resistance impairs tumour cells' sensitivity and/or limits drug efficacy. Targeting metabolic vulnerabilities is emerging as powerful approach in cancer.
METHODS
In silico analyses identified metabolic gene signatures and Hif-1α as glycolysis regulator in PTC. BRAF-mutated PTC, ATC and control thyroid cell lines were exposed to HIF1A siRNAs or chemical/drug treatments (CoCl, EGF, HGF, BRAFi, MEKi and diclofenac). Genes/proteins expression, glucose uptake, lactate quantification and viability assays were used to investigate the metabolic vulnerability of BRAF-mutated cells.
RESULTS
A specific metabolic gene signature was identified as a hallmark of BRAF-mutated tumours, which display a glycolytic phenotype, characterised by enhanced glucose uptake, lactate efflux and increased expression of Hif-1α-modulated glycolytic genes. Indeed, Hif-1α stabilisation counteracts the inhibitory effects of BRAFi on these genes and on cell viability. Interestingly, targeting metabolic routes with BRAFi and diclofenac combination we could restrain the glycolytic phenotype and synergistically reduce tumour cells' viability.
CONCLUSION
The identification of a metabolic vulnerability of BRAF-mutated carcinomas and the capacity BRAFi and diclofenac combination to target metabolism open new therapeutic perspectives in maximising drug efficacy and reducing the onset of secondary resistance and drug-related toxicity.
Topics: Humans; Diclofenac; Proto-Oncogene Proteins B-raf; Mutation; Protein Kinase Inhibitors; Thyroid Neoplasms; Glycolysis; Phenotype; Glucose; Cell Line, Tumor
PubMed: 37198319
DOI: 10.1038/s41416-023-02282-2 -
International Journal of Pharmaceutics Feb 2022An important question in the development of a dermatological drug product is whether a target concentration has been achieved in, for example, the viable epidermis...
An important question in the development of a dermatological drug product is whether a target concentration has been achieved in, for example, the viable epidermis following topical administration. When attempting to address this challenge, it is essential to consider the role of excipients in the formulation that may influence drug partitioning and diffusion in the different layers of the skin. The objective, therefore, was to correlate, in human subjects, the skin pharmacokinetics of diclofenac (specifically, its uptake into and clearance from the stratum corneum (SC)) from an approved drug product (Voltaren® medicated plaster) with the in vivo co-uptake of two key excipients, namely propylene glycol and butylene glycol. SC sampling was used to assess diclofenac input into the skin during patch application, and its subsequent clearance post-removal of the delivery system. In parallel the uptake of the two glycol excipients was also measured. Drug and excipient amounts in the SC increased with time of application up to 6 h and, for diclofenac, no further increase was observed when the administration was prolonged to 12 h. When the plaster was removed after 6 h of wear, diclofenac cleared relatively slowly from the SC suggesting that drug binding with a slow off-rate had occurred. The results indicate that the optimisation of drug delivery from a topical formulation must take into account the disposition of key excipients and their impact on dermato-pharmacokinetics in general.
Topics: Administration, Cutaneous; Diclofenac; Excipients; Humans; Skin; Skin Absorption
PubMed: 35031414
DOI: 10.1016/j.ijpharm.2022.121469 -
Advanced Science (Weinheim,... Jul 2021Implant infections caused by methicillin-resistant (MRSA) can cause major complications during the perioperative period. Diclofenac, one of the most widely used...
Implant infections caused by methicillin-resistant (MRSA) can cause major complications during the perioperative period. Diclofenac, one of the most widely used nonsteroidal anti-inflammatory drugs, is often used to relieve pain and inflammation. In this study, it is found that high-dose diclofenac can inhibit the growth of MRSA, and does not easily induce drug-resistant mutations after continuous passage. However, low-doses diclofenac can resensitize bacteria to -lactams, which help to circumvent drug resistance and improve the antibacterial efficacy of conventional antibiotics. Further, low-dose diclofenac in combination with -lactams inhibit MRSA associated biofilm formation in implants. Transcriptomic and proteomic analyses indicate that diclofenac can reduce the expression of genes and proteins associated with -lactam resistance: mecA, mecR, and blaZ; peptidoglycan biosynthesis: murA, murC, femA, and femB; and biofilm formation: altE and fnbP. Murine implant infection models indicate that diclofenac combined with -lactams, can substantially alleviate MRSA infections in vivo. In addition, it is investigated that low dose diclofenac can inhibit MRSA antibiotic resistance via the mecA/blaZ pathway and related biofilms in implants. The synergistic effect of diclofenac and -lactams might have promising applications for preventing perioperative infection, considering its multitarget effects against MRSA.
Topics: Animals; Anti-Bacterial Agents; Anti-Inflammatory Agents, Non-Steroidal; Diclofenac; Disease Models, Animal; Female; Methicillin-Resistant Staphylococcus aureus; Mice; Prostheses and Implants; beta-Lactams
PubMed: 34258168
DOI: 10.1002/advs.202100681 -
Environmental Science and Pollution... Jul 2023Bioremediation of pharmaceuticals has gained large research efforts, but there is still a need to improve the performance of bioremediation systems by selecting...
Bioremediation of pharmaceuticals has gained large research efforts, but there is still a need to improve the performance of bioremediation systems by selecting effective organisms. In this study, we characterized the capability to remove clarithromycin (CLA) and diclofenac (DCF) by the bacterium Streptomyces rochei, and the fungi Phanerochaete chrysosporium and Trametes versicolor. The macrolide antibiotic CLA and the non-steroid anti-inflammatory DCF were selected because these are two of the most frequently detected drugs in water bodies. Growth and content of the PhCs and a DCF metabolite (MET) by the energy crop Arundo donax L. were also evaluated under hydroponic conditions. The removal rate (RR) by S. rochei increased from 24 to 40% at 10 and 100 µg CLA L, respectively, averaged over incubation times. At 144 h, the RR by P. chrysosporium was 84%, while by T. versicolor was 70 and 45% at 10 and 100 CLA µg L. The RR by S. rochei did not exceed 30% at 1 mg DCF L and reached 60% at 10 mg DCF L, whereas approached 95% and 63% by P. chrysosporium and T. versicolor, respectively, at both doses. Root biomass and length of A. donax were strongly affected at 100 µg CLA L. CLA concentration in roots and shoots increased with the increase of the dose and translocation factor (TF) was about 1. DCF severely affected both shoot fresh weight and root length at the highest dose and concentration in roots and shoots increased with the increase of the dose. DCF concentrations were 16-19 times higher in roots than in shoots, and TF was about 0.1. MET was detected only in roots and its proportion over the parent compound decreased with the increase of the DCF dose. This study highlights the potential contribution of A. donax and the tested microbial inoculants for improving the effectiveness of bioremediation systems for CLA and DCF removal.
Topics: Diclofenac; Wastewater; Clarithromycin; Biodegradation, Environmental; Trametes; Poaceae
PubMed: 37249765
DOI: 10.1007/s11356-023-27660-4