S-diclofenac (2-(2,6-dichlorophenyl)aminobenzeneacetic acid 4-(3
H-1,2,dithiol-3-thione-5-yl)phenyl ester; ACS 15) is a novel molecule comprising a hydrogen sulfide (H
2S)-releasing dithiol-thione ...moiety attached by an ester linkage to diclofenac. S-diclofenac administration inhibited lipopolysaccharide-induced inflammation (as evidenced by reduced lung and liver myeloperoxidase activity) and caused significantly less gastric toxicity than diclofenac. S-diclofenac did not affect blood pressure or heart rate of the anesthetized rat. S-diclofenac administration downregulated expression of genes encoding enzymes which synthesize nitric oxide, prostanoids, and H
2S; reduced plasma IL-1β/TNF-α; and elevated plasma IL-10. Reduced liver NF-κB p65 and AP-1/c-fos DNA-binding activity was also observed. These effects were mimicked in large part by a combination of diclofenac plus an H
2S-releasing moiety (ADT-OH). Incubation of S-diclofenac (100 μM) with rat plasma or liver homogenate caused a time-dependent release of H
2S, which was inhibited by sodium fluoride (10 mM). Administration of S-diclofenac (47.2 μmol/kg, ip) to conscious rats significantly increased plasma H
2S concentration (at 45 min and 6 h). We propose that H
2S release from S-diclofenac in vivo contributes to the observed effects.
Diclofenac instillation is useful in preventing intraoperative miosis and macular edema caused by postoperative inflammation in cataract surgery; however, optimum efficacy is not attained when the ...instilled diclofenac strongly binds to albumin in patients’ aqueous humor. Therefore, a method that inhibits diclofenac binding and increases the concentration of its free fraction is needed. We conducted a basic study regarding the effects of inhibitors on the binding of instilled diclofenac to albumin and endogenous substances in aqueous humor. Aqueous humor samples from 16 patients were pooled together for analysis. The free fraction of diclofenac was measured using ultrafiltration methods in various experiments with pooled and mimic aqueous humor. Free fraction of diclofenac, a site II drug, in pooled aqueous humor was 0.363 ± 0.013. The binding of diclofenac in the presence of phenylbutazone (PB), a site I inhibitor, was significantly inhibited (free fraction = 0.496 ± 0.013); however, no significant inhibition by ibuprofen, a site II inhibitor, (free fraction = 0.379 ± 0.004), was observed. The unexpected result was due to free fatty acids (FFAs; palmitic acid (PA)) and L-tryptophan (Trp). The inhibition of diclofenac binding by PB in the mimic aqueous humor containing these endogenous substances revealed significant binding inhibition in the presence of PA and Trp. Diclofenac is strongly rebound from site II to site I in the presence of FFAs and Trp in the aqueous humor because FFAs and Trp induce a conformational change in albumin. Therefore, PB significantly inhibits the binding of diclofenac to albumin.
Diclofenac (DCF) is a prevalent anti-inflammatory drug used throughout the world. Intensive researches carried out in the past few decades have confirmed the global ubiquity of DCF in various ...environmental compartments. Its frequent occurrence in freshwater environments and its potential toxicity towards several organisms such as fish and mussels makes DCF an emerging environmental contaminant. At typical detected environmental concentrations, the drug does not exhibit toxic effects towards living organisms, albeit chronic exposure may lead to severe effects. For DCF, about 30–70% removal has been obtained through the conventional treatment system in wastewater treatment plant being the major primary sink. Thus, the untreated DCF will pass to surface water. DCF can interact with other inorganic contaminants in the environment particularly in wastewater treatment plant, such as metals, organic contaminants and even with DCF metabolites. This process may lead to the creation of another possible emerging contaminant. In the present context, environmental fate of DCF in different compartments such as soil and water has been addressed with an overview of current treatment methods. In addition, the toxicity concerns regarding DCF in aquatic as well as terrestrial environment along with an introduction to the metabolites of DCF through consumption as well as abiotic degradation routes are also discussed. Further studies are required to better assess the fate and toxicological effects of DCF and its metabolites and must consider the possible interaction of DCF with other contaminants to develop an effective treatment method for DCF and its traces.
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•A review on the occurrence, toxicity and metabolites of diclofenac•Current status of diclofenac in environment is discussed with treatment methods.•Legislative measures to control the drug are briefly covered with toxicity studies.•The toxicity of diclofenac metabolites in the environment is poorly understood.•Potential interactions of diclofenac with other pollutants are briefly discussed.
Literature data are reviewed regarding the scientific advisability of allowing a waiver of in vivo bioequivalence (BE) testing for the approval of immediate release (IR) solid oral dosage forms ...containing either diclofenac potassium and diclofenac sodium. Within the biopharmaceutics classification system (BCS), diclofenac potassium and diclofenac sodium are each BCS class II active pharmaceutical ingredients (APIs). However, a biowaiver can be recommended for IR drug products of each salt form, due to their therapeutic use, therapeutic index, pharmacokinetic properties, potential for excipient interactions, and performance in reported BE/bioavailability (BA) studies, provided: (a) test and comparator contain the same diclofenac salt; (b) the dosage form of the test and comparator is identical; (c) the test product contains only excipients present in diclofenac drug products approved in ICH or associated countries in the same dosage form, for instance as presented in this paper; (d) test drug product and comparator dissolve 85% in 30min or less in 900mL buffer pH6.8, using the paddle apparatus at 75rpm or the basket apparatus at 100rpm; and (e) test product and comparator show dissolution profile similarity in pH1.2, 4.5, and 6.8.
Abstract
Background:
Diclofenac is a proven, commonly prescribed nonsteroidal anti-inflammatory drug (NSAID) that has analgesic, anti-inflammatory, and antipyretic properties, and has been shown to ...be effective in treating a variety of acute and chronic pain and inflammatory conditions. As with all NSAIDs, diclofenac exerts its action via inhibition of prostaglandin synthesis by inhibiting cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) with relative equipotency. However, extensive research shows the pharmacologic activity of diclofenac goes beyond COX inhibition, and includes multimodal and, in some instances, novel mechanisms of action (MOA).
Data sources:
Literature retrieval was performed through PubMed/MEDLINE (through May 2009) using combinations of the terms diclofenac, NSAID, mechanism of action, COX-1, COX-2, and pharmacology. Reference citations resulting from publications identified in the literature search were reviewed when appropriate.
Methods:
This article reviews the established, putative, and emerging MOAs of diclofenac; compares the drug’s pharmacologic and pharmacodynamic properties with other NSAIDs to delineate its potentially unique qualities; hypothesizes why it has been chosen for further recent formulation enhancement; and evaluates the potential effect of its MOA characteristics on safety.
Discussion:
Research suggests diclofenac can inhibit the thromboxane-prostanoid receptor, affect arachidonic acid release and uptake, inhibit lipoxygenase enzymes, and activate the nitric oxide-cGMP antinociceptive pathway. Other novel MOAs may include the inhibition of substrate P, inhibition of peroxisome proliferator activated receptor gamma (PPARγ), blockage of acid-sensing ion channels, alteration of interleukin-6 production, and inhibition of N-methyl-D-aspartate (NMDA) receptor hyperalgesia. The review was not designed to compare MOAs of diclofenac with other NSAIDs. Additionally, as the highlighted putative and emerging MOAs do not have clinical data to demonstrate that these models are correct, further research is necessary to ascertain if the proposed pathways will translate into clinical benefits. The diversity in diclofenac’s MOA may suggest the potential for a relatively more favorable profile compared with other NSAIDs.
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Oral Thin Film (OTF) is a newly emerging drug delivery system which has many benefits for patients. Although there has been some formulation of OTF products, these have mainly been as ...confectionary or dental health products. The most significant benefit of this dosage format will only be realised once more pharmaceutical products become available. Within this paper, OTF strips containing Diclofenac Sodium were prepared using the solvent casting method and then characterised to ensure the method could conform to acceptable levels of uniformity, the mean (SD) diclofenac sodium content was 25.43 (1.39) mg, range 22.84–27.44 mg. Bioburden was tested against coliforms, yeasts and moulds and all results were confirmed to be <10 CFU/g, also similar dissolution profile when compared to a commercial product to ensure biowaiver. An acceptable level of uniformity of mass was produced. K-F titration was employed to reduce the water content of the strips and it was found to be acceptable, this represented a level of water which would not be viable for microbial growth. The technique employed here in the production of OTF resulted in high quality products and amenability to being up scaled. Furthermore, the characterisation method was also sufficient to assess the quality of the products and may be used for future analysis of OTF pharmaceuticals.
Diclofenac (DCF) is a common anti-inflammatory pharmaceutical that is often detected in waste wasters, effluents and surface waters. Recently, DCF was included in the watch list of substances in EU ...that requires its environmental monitoring in the member states. DCF is also known to harmfully affect several environmental species already at concentrations of ≤1μg/l. This review focuses on the occurrence and fate of DCF in conventional wastewater treatment processes. Research done in this area was gathered and analyzed in order to find out the possibilities to enhance DCF elimination during biological wastewater treatment. More precisely, human metabolism, concentrations in wastewater influents and effluents, elimination rates in the treatment train, roles of sorption and biotransformation mechanisms during the treatment as well as formation of transformation products are reported. Additionally, the effect of process configuration, i.e. conventional activated sludge (CAS), biological nutrient removal (BNR), membrane bioreactor (MBR) and attached-growth bioreactor, and process parameters, i.e. solids retention time (SRT) and hydraulic retention time (HRT) are presented. Generally, DCF is poorly biodegradable which often translates into low elimination rates during biological wastewater treatment. Only a minor portion is sorbed to sludge. MBR and attached-growth bioreactors may result in higher elimination of DCF over CAS or BNR. Long SRTs (>150d) favor the DCF elimination due to sludge adaptation. Longer HRTs (>2–3d) could significantly increase the elimination of DCF during biological wastewater treatment. Bioaugmentation could be used to enhance DCF elimination, however, this requires more research on microbial communities that are able to degrade DCF. Also, further research is needed to gain more information about the deconjugation processes and biotic and abiotic transformation and the nature of transformation products.
•Diclofenac (DCF) is poorly biodegraded and sorbed into sludge.•Biotic elimination of DCF could be enhanced by the following techniques.•Use of MBR or attached-growth biomass process•Increase the hydraulic retention time to >2–3days•Enrich DCF degrading bacteria into the reactor (i.e. long SRTs or bioaugmentation)
The degradation of diclofenac sodium (DCF) in pre-magnetization Fe.sup.0/persulfate (Pre-Fe.sup.0/PS) and Fe.sup.0/PS systems were studied in detail in this study. The influencing operational ...conditions (initial PS dosage, Fe.sup.0 dosage, and pH) were studied for their effects on the DCF degradation. The removal rate constant for DCF by the Pre-Fe.sup.0/PS system was 2.1-6.2 times higher than that of the Fe.sup.0/PS system. A higher TOC removal efficiency (81.5%) was observed during the mineralization of DCF in the Pre-Fe.sup.0/PS process than that of the Fe.sup.0/PS process (70%). The results of electron paramagnetic resonance (EPR) confirmed that the Pre-Fe.sup.0/PS system could produce much more .sup.*OH and SO.sub.4.sup.-* at a faster rate than the Fe.sup.0/PS system. Moreover, the degradation mechanism of DCF by the Pre-Fe.sup.0/PS process was elucidated. This work would provide a perspective on the Pre-Fe.sup.0/PS process for efficient degradation of DCF, exhibiting advantages to removing DCF, such as broaden the range of working pH and reduce the amount of chemicals. So, it is an efficient and potential method to remove DCF from wastewater by the Pre-Fe.sup.0/PS process.
Diclofenac (DCF) is the frequently detected non-steroidal pharmaceuticals in the aquatic environment. In this study, the degradation of DCF was evaluated by UV-254nm activated persulfate (UV/PS). The ...degradation of DCF followed the pseudo first-order kinetics pattern. The degradation rate constant (kobs) was accelerated by UV/PS compared to UV alone and PS alone. Increasing the initial PS dosage or solution pH significantly enhanced the degradation efficiency. Presence of various natural water constituents had different effects on DCF degradation, with an enhancement or inhibition in the presence of inorganic anions (HCO3− or Cl−) and a significant inhibition in the presence of NOM. In addition, preliminary degradation mechanisms and major products were elucidated using LC-MS/MS. Hydroxylation, decarbonylation, ring-opening and cyclation reaction involving the attack of SO4•− or other substances, were the main degradation mechanism. TOC analyzer and Microtox bioassay were employed to evaluate the mineralization and cytotoxicity of solutions treated by UV/PS at different times, respectively. Limited elimination of TOC (32%) was observed during the mineralization of DCF. More toxic degradation products and their related intermediate species were formed, and the UV/PS process was suitable for removing the toxicity. Of note, longer degradation time may be considered for the final toxicity removal.
•UV-activated persulfate induced diclofenac oxidation was studied.•Two different reaction pathways contributed to degradation.•Microtox bioassay was employed to evaluate toxicity of reaction solutions.
The present study was aimed to coencapsulate methotrexate (MTX) and aceclofenac (ACL) in fucose anchored lipid–polymer hybrid nanoparticles (Fu-LPHNPs) to achieve target specific and controlled ...delivery for developing therapeutic interventions against breast cancer. The effective combination therapy requires coadministration of drugs to achieve synergistic effect on tumor with minimum adverse effects. Present study investigates the potential of codelivery of MTX and ACL through LPHNPs in MCF-7 and triple negative breast cancer cells (MDA-MB-231). We obtained LPHNPs in the nanosize range (<150 nm) with better particle size distribution (<0.3). The entrapment and loading efficiency of MTX and ACL was calculated as 85–90% and 10–12%, respectively. The coumarin-6 LPHNP formulations showed rapid internalization within 2 h incubation with MCF-7 and MDA-MB-231 cells. With 8–10 times, greater bioavailability of drug-loaded LPHNPs than free MTX and ACL was obtained. Also, antitumor efficacy of MTX- and ACL-loaded LPHNPs was determined on DMBA-induced experimental breast cancer mouse model. This model showed better control over tumor growth with MTX- and ACL-loaded LPHNPs than the combination of MTX and ACL or MTX alone. ACL-loaded LPHNPs showed prophylactic and anticancer activity in DMBA-induced mouse model at higher dose (10 mg/kg). ACL-LPHNPs confer synergistic anticancer effect when administered in combination with MTX. In conclusion, ACL enhances the therapeutic and anticancer efficacy of MTX, when coencapsulated into fucose-anchored LPHNPs, as confirmed by cell viability and serum angiogenesis (IL-6, TNF-α, IL-1β, COX2, and MMP1) at both transcript and proteome level.
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