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British Journal of Pharmacology Dec 20001. Since nonsteroidal anti-inflammatory drugs (NSAIDs) may impair the ability of the chondrocyte to repair its damaged extracellular matrix, we explored the changes in...
1. Since nonsteroidal anti-inflammatory drugs (NSAIDs) may impair the ability of the chondrocyte to repair its damaged extracellular matrix, we explored the changes in the metabolism of newly synthesized proteoglycan and hyaluronan (HA) molecules produced by aceclofenac, diclofenac and meloxicam in human osteoarthritic (OA) cartilage. 2. Explants were sampled from the medial femoral condyle and were classified by use of the Mankin's histological-histochemical grading system. Cartilage specimens exhibited moderate (M) OA in 20 subjects and had severe (S) OA in 20. 3. Cartilage explants were pulsed with [-3H]-glucosamine and chased in the absence or in the presence of 0.3 - 3 microg ml(-1) of either aceclofenac, diclofenac or meloxicam. After papain digestion, the labelled chondroitin sulphate ([-3H]-proteoglycans) and [-3H]-HA molecules present in the tissue and media were purified by anion-exchange chromatography. 4. In cartilage with MOA and SOA, the metabolic balance of proteoglycan and HA was unaffected by diclofenac. In contrast, and in a dose-dependent manner, aceclofenac and meloxicam both increased the synthesis of proteoglycans and HA in explants with MOA and SOA; these two NSAIDs also reduced significantly the net loss of [-3H]-proteoglycans and [-3H]-HA molecules from cartilage explants. 5. The data obtained in short-term in vitro cultures indicate that, at the concentrations found in synovial fluid, aceclofenac and meloxicam may exert a favourable effect on the overall metabolism of proteoglycans and HA in cartilage with MOA and SOA.
Topics: Anti-Inflammatory Agents, Non-Steroidal; Cartilage, Articular; Culture Techniques; Diclofenac; Dose-Response Relationship, Drug; Extracellular Matrix; Humans; Hyaluronic Acid; Meloxicam; Osteoarthritis; Proteoglycans; Thiazines; Thiazoles
PubMed: 11090115
DOI: 10.1038/sj.bjp.0703710 -
Journal of Healthcare Engineering 2022To investigate the effects of different nonsteroidal anti-inflammatory drugs combined with platelet-rich plasma on inflammatory factor levels in patients with...
OBJECTIVE
To investigate the effects of different nonsteroidal anti-inflammatory drugs combined with platelet-rich plasma on inflammatory factor levels in patients with osteoarthritis.
METHODS
The clinic data of 120 patients with osteoarthritis who were treated in our hospital (June 2019-June 2021) were retrospectively reviewed. All the patients were given platelet-rich plasma. According to the different nonsteroidal anti-inflammatory drugs the patients received, they were equalized into diclofenac sodium group, celecoxib group, and iguratimod group, with 40 cases in each group. After treatment, the patients' clinical efficacy was compared and analyzed.
RESULTS
After treatment, the pain degrees of the patients in the three groups were gradually reduced. After 4 weeks and 8 weeks of treatment, the statistical differences in the scores of Visual Analogue Scale (VAS) were found among the three groups. Specifically, compared with the other two groups, the iguratimod group had remarkably lower VAS scores ( < 0.05) and the celecoxib group had signally lower VAS scores compared with the diclofenac sodium group ( < 0.05). After treatment, the inflammatory factor levels of interleukin-6 (IL-6), tumor necrosis factor- (TNF-), and high-sensitivity C-reactive protein (hs-CRP) in the diclofenac sodium group were observably higher compared with the celecoxib group ( < 0.05), and the inflammatory factor levels in the celecoxib group were remarkably higher compared with the iguratimod group ( < 0.05). Before treatment, no notable difference in the Lysholm scores was found among the three groups, and the patients' knee joint function was gradually improved after treatment. To be specific, after 4 and 8 weeks of treatment, the iguratimod group had observably higher Lysholm scores compared with the other two groups ( < 0.05), and the celecoxib group had signally higher Lysholm scores compared with the diclofenac sodium group ( < 0.05). The iguratimod group got markedly lower Western Ontario and McMaster Universities (WOMAC) score compared with the celecoxib group ( < 0.05); Compared with the diclofenac sodium group, the celecoxib group got remarkably lower WOMAC score ( < 0.05). During treatment, few patients suffered from mild gastrointestinal discomfort and hepatic dysfunction in the three groups, and no other severe adverse reactions were found. No statistical difference in the total incidence of adverse reactions among the three groups was observed ( > 0.05).
CONCLUSION
The combination of nonsteroidal anti-inflammatory drugs with platelet-rich plasma can further reduce the inflammatory reactions of the patients with osteoarthritis and improve their knee joint function. Significantly, the iguratimod, with high safety, has observably better effects on inhibiting inflammatory factors and improving knee joint function compared with diclofenac sodium and celecoxib.
Topics: Anti-Inflammatory Agents, Non-Steroidal; Celecoxib; Diclofenac; Humans; Osteoarthritis, Knee; Platelet-Rich Plasma; Retrospective Studies; Treatment Outcome
PubMed: 35399859
DOI: 10.1155/2022/1979892 -
Acta Poloniae Pharmaceutica 2015The delayed release and mucoadhesive properties of Cedrela gum and hydroxypropylmethylcellulose blend in diclofenac sodium tablet formulations were evaluated. Tablets...
The delayed release and mucoadhesive properties of Cedrela gum and hydroxypropylmethylcellulose blend in diclofenac sodium tablet formulations were evaluated. Tablets were prepared by direct compression and the crushing strength and detachment force were found to increase from 74.49 ± 1.22 to 147.25 ± 2.57 N and 0.302 ± 0.36 to 1.141 ± 0.05 N from low to high level of polymers, respectively. The release kinetics followed Korsmeyer-Peppas release and the n varied between 0.834 and 1.273, indicating that the release mechanism shifts from Fickian to super case I (anomalous release). The drug release profile fits a pulsatile-release pattern characterized by a lag time followed by a more or less rapid and complete drug release. The Cedrela gum-hydroxypropylmethylcelluse blend tablets delayed diclofenac release for 2 h and sustained the release for 12 h. The polymer blend delayed drug release in the 0.1 M HCl simulating gastric environment and subsequent release pH 6.8 phosphate buffer.
Topics: Adhesiveness; Delayed-Action Preparations; Diclofenac; Hypromellose Derivatives; Plant Gums; Polymers; Solubility; Tablets
PubMed: 26642664
DOI: No ID Found -
International Journal of Biological... May 2024This study involved creating oligomeric conjugates of 3-hydroxy fatty acids and diclofenac, named Dic-oligo(3HAs). Advanced NMR techniques confirmed no free diclofenac...
Physicochemical, structural and biological characterisation of poly(3-hydroxyoctanoate) supplemented with diclofenac acid conjugates - Harnessing the potential in the construction of materials for skin regeneration processes.
This study involved creating oligomeric conjugates of 3-hydroxy fatty acids and diclofenac, named Dic-oligo(3HAs). Advanced NMR techniques confirmed no free diclofenac in the mix. We tested diclofenac release under conditions resembling healthy and chronic wound skin. These oligomers were used to make P(3HO) blends, forming patches for drug delivery. Their preparation used the solvent casting/porogen leaching (SCPL) method. The patches' properties like porosity, roughness, and wettability were thoroughly analysed. Antimicrobial assays showed that Dic-oligo(3HAs) exhibited antimicrobial activity against reference (S. aureus, S. epidermis, S. faecalis) and clinical (Staphylococcus spp.) strains. Human keratinocytes (HaCaT) cell line tests, as per ISO 10993-5, showed no toxicity. A clear link between material roughness and HaCaT cell adhesion was found. Deep cell infiltration was verified using DAPI and phalloidin staining, observed under confocal microscopy. SEM also confirmed HaCaT cell growth on these scaffolds. The strong adhesion and proliferation of HaCaT cells on these materials indicate their potential as wound dressing layers. Additionally, the successful diclofenac release tests point to their applicability in treating both normal and chronic wounds.
Topics: Diclofenac; Humans; Skin; Regeneration; Keratinocytes; HaCaT Cells; Wound Healing; Cell Proliferation; Chemical Phenomena; Cell Line; Polymers; Porosity; Biocompatible Materials
PubMed: 38614181
DOI: 10.1016/j.ijbiomac.2024.131476 -
Environmental Pollution (Barking, Essex... Oct 2023This study assessed the eco-genotoxic impact of diclofenac (DCF) in sentinel species of the freshwater ecosystem. DCF residues are found in freshwater from few ng/L to...
This study assessed the eco-genotoxic impact of diclofenac (DCF) in sentinel species of the freshwater ecosystem. DCF residues are found in freshwater from few ng/L to tens of μg/L due to the inability of conventional wastewater treatment plants to ensure removal efficiency of the drug. An ample body of literature reports on the acute toxicity of DCF in non-target organisms without addressing potential chronic long-term effects on organisms at actual, environmental concentrations. Herein, assessment for acute and chronic toxicity was performed on organisms in vivo exposed to DCF, specifically on the green alga Raphidocelis subcapitata, the rotifer Brachionus calyciflorus and the crustacean Ceriodaphnia dubia. Furthermore, potential DNA damage and expression of antioxidant genes (MnSOD, Cu/ZnSOD and CAT) were evaluated in crustacean neonates. The toxicological risk of DCF was assessed as well as its. GENOTOXIC RISK: The acute toxicity was observed at concentrations far from those of environmental concern. Rotifers and crustaceans were much more chronically sensitive than the algae to DCF, observing besides, the median effect concentrations at tens of μg/L. In crustaceans, DNA damage was noted at units of μg/L, revealing concentrations of environmental concern. The dysregulated activity of SOD and CAT also showed the ability of DCF to provoke oxidative stress. On assessment of environmental risk, the chronic Risk Quotient (RQ) was above the threshold value of 1. Nevertheless, the genotoxic RQ was significantly greater than the chronic RQ, thus, the need of regulatory bodies to acknowledge the genotoxic impact as an environmental risk factor. To our knowledge, this study is the first investigation to perform environmental genotoxic risk assessment of DCF.
Topics: Animals; Humans; Infant, Newborn; Diclofenac; Ecosystem; Rotifera; Crustacea; Fresh Water; Water Pollutants, Chemical
PubMed: 37506803
DOI: 10.1016/j.envpol.2023.122251 -
Drug Metabolism and Disposition: the... Oct 2019In the present work, in vivo transporter knockout (KO) mouse models were used to characterize the disposition of diclofenac (DCF) and its primary metabolites following a...
In the present work, in vivo transporter knockout (KO) mouse models were used to characterize the disposition of diclofenac (DCF) and its primary metabolites following a single subtoxic dose in mice lacking breast cancer resistance protein (Bcrp) or multidrug resistance-associated protein (Mrp)3. The results indicate that Bcrp acts as a canalicular efflux mediator for DCF, as wild-type (WT) mice had biliary excretion values that were 2.2- to 2.6-fold greater than Bcrp KO mice, although DCF plasma levels were not affected. The loss of Bcrp resulted in a 1.8- to 3.2-fold increase of diclofenac acyl glucuronide (DCF-AG) plasma concentrations in KO animals compared with WT mice, while the biliary excretion of DCF-AG increased 1.4-fold in WT versus KO mice. Furthermore, Mrp3 was found to mediate the basolateral transport of DCF-AG, but not DCF or 4'-hydroxy diclofenac. WT mice had DCF-AG plasma concentrations 7.0- to 8.6-fold higher than Mrp3 KO animals; however, there were no changes in biliary excretion of DCF-AG. Vesicular transport experiments with human MRP3 demonstrated that MRP3 is able to transport DCF-AG via low- and high-affinity binding sites. The low-affinity MRP3 transport had a and of 170 pmol/min/mg and 98.2 M, respectively, while the high-affinity and parameters were estimated to be 71.9 pmol/min/mg and 1.78 M, respectively. In summary, we offer evidence that the disposition of DCF-AG can be affected by both Bcrp and Mrp3, and these findings may be applicable to humans.
Topics: ATP Binding Cassette Transporter, Subfamily B; ATP Binding Cassette Transporter, Subfamily G, Member 2; Animals; Diclofenac; Glucuronides; Male; Mice; Mice, Knockout; Tissue Distribution
PubMed: 31399506
DOI: 10.1124/dmd.119.086603 -
Environment International Jan 2022Three steroidal estrogens, 17α-ethinylestradiol (EE2), 17β-estradiol (E2), estrone (E1), and the non-steroidal anti-inflammatory drug (NSAID), diclofenac have been...
Biological effect and chemical monitoring of Watch List substances in European surface waters: Steroidal estrogens and diclofenac - Effect-based methods for monitoring frameworks.
Three steroidal estrogens, 17α-ethinylestradiol (EE2), 17β-estradiol (E2), estrone (E1), and the non-steroidal anti-inflammatory drug (NSAID), diclofenac have been included in the first Watch List of the Water Framework Directive (WFD, EU Directive 2000/60/EC, EU Implementing Decision 2015/495). This triggered the need for more EU-wide surface water monitoring data on these micropollutants, before they can be considered for inclusion in the list of priority substances regularly monitored in aquatic ecosystems. The revision of the priority substance list of the WFD offers the opportunity to incorporate more holistic bioanalytical approaches, such as effect-based monitoring, alongside single substance chemical monitoring. Effect-based methods (EBMs) are able to measure total biological activities (e.g., estrogenic activity or cyxlooxygenase [COX]-inhibition) of specific group of substances (such as estrogens and NSAIDs) in the aquatic environment at low concentrations (pg/L). This makes them potential tools for a cost-effective and ecotoxicologically comprehensive water quality assessment. In parallel, the use of such methods could build a bridge from chemical status assessments towards ecological status assessments by adressing mixture effects for relevant modes of action. Our study aimed to assess the suitability of implementing EBMs in the WFD, by conducting a large-scale sampling and analysis campaign of more than 70 surface waters across Europe. This resulted in the generation of high-quality chemical and effect-based monitoring data for the selected Watch List substances. Overall, water samples contained low estrogenicity (0.01-1.3 ng E2-Equivalent/L) and a range of COX-inhibition activity similar to previously reported levels (12-1600 ng Diclofenac-Equivalent/L). Comparison between effect-based and conventional analytical chemical methods showed that the chemical analytical approach for steroidal estrogens resulted in more (76%) non-quantifiable data, i.e., concentrations were below detection limits, compared to the EBMs (28%). These results demonstrate the excellent and sensitive screening capability of EBMs.
Topics: Diclofenac; Ecosystem; Environmental Monitoring; Estradiol; Estrogens; Water Pollutants, Chemical
PubMed: 34979407
DOI: 10.1016/j.envint.2021.107033 -
Actas Dermo-sifiliograficas 2016To perform a cost-effectiveness and cost-utility analysis of ingenol mebutate in the treatment of actinic keratosis in Spain. (Comparative Study)
Comparative Study
OBJECTIVE
To perform a cost-effectiveness and cost-utility analysis of ingenol mebutate in the treatment of actinic keratosis in Spain.
METHODS
We used an adapted Markov model to simulate outcomes in a cohort of patients (mean age, 73 years) with actinic keratosis over a 5-year period. The comparators were diclofenac 3% and imiquimod 5%. The analysis was performed from the perspective of the Spanish National Health System based on direct costs (2015 retail price plus value added tax less the mandatory discount). A panel of experts estimated resources, taking unit costs from national databases. An annual discount rate of 3% was applied. Deterministic and probabilistic sensitivity analyses were performed.
RESULTS
The effectiveness of ingenol mebutate-with 0.192 and 0.129 more clearances gained in treatments for face and scalp lesions and trunk and extremity lesions, respectively-was superior to diclofenac's. The total costs of treatment with ingenol mebutate were lower at € 551.50 (face and scalp) and € 622.27 (trunk and extremities) than the respective costs with diclofenac (€ 849.11 and € 844.93). The incremental cost-effectiveness and cost-utility ratios showed that ingenol mebutate was a dominant strategy vs diclofenac. Ingenol mebutate also proved to be more effective than imiquimod, based on 0.535 and 0.503 additional clearances, and total costs of € 551.50 and € 527.89 for the two drugs, respectively. The resulting incremental cost-effectiveness ratio was € 728.64 per clearance gained with ingenol mebutate vs imiquimod.
CONCLUSIONS
Ingenol mebutate was a dominant treatment option vs diclofenac and was efficient vs imiquimod (i.e., more effective at a higher cost, achieving an incremental cost-utility ratio of<€30000/quality-adjusted life-years).
Topics: Aged; Aminoquinolines; Cost-Benefit Analysis; Diclofenac; Diterpenes; Humans; Imiquimod; Keratosis, Actinic; Spain
PubMed: 27130804
DOI: 10.1016/j.ad.2016.03.004 -
Journal of Pharmaceutical Sciences Apr 2009Literature data are reviewed regarding the scientific advisability of allowing a waiver of in vivo bioequivalence (BE) testing for the approval of immediate release (IR)...
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 30 min or less in 900 mL buffer pH 6.8, using the paddle apparatus at 75 rpm or the basket apparatus at 100 rpm; and (e) test product and comparator show dissolution profile similarity in pH 1.2, 4.5, and 6.8.
Topics: Administration, Oral; Animals; Anti-Inflammatory Agents, Non-Steroidal; Biological Availability; Chemical Phenomena; Diclofenac; Excipients; Humans; Solubility; Tablets; Therapeutic Equivalency
PubMed: 18752289
DOI: 10.1002/jps.21525 -
Topical bioequivalence: Experimental and regulatory considerations following formulation complexity.International Journal of Pharmaceutics May 2022Documenting topical bioequivalence can be an extremely complex process, which is intrinsically dependent on the formulation technological features. According to EMA...
Documenting topical bioequivalence can be an extremely complex process, which is intrinsically dependent on the formulation technological features. According to EMA guideline, for simple formulations, BE may be demonstrated by documenting the qualitative (Q1), quantitative (Q2), microstructure (Q3) and performance (Q4) equivalence. Nevertheless, when addressing complex semisolids, equivalence regarding local availability should also be demonstrated. The purpose of this study is to pursue this strategy using two opposite scenarios: a simple dimetindene maleate 1 mg/g gel formulation and a diclofenac diethylammonium 23.2 mg/g emulgel, representing a complex formulation. For both formulations, Q1/Q2 test (TP) and reference products (RP) were used. Rheology, in vitro release (IVRT) and in vitro permeation methods (IVPT) were developed and validated for both products. For the dimetindene formulation, equivalence pertaining to Q4 was established. However, high variability was observed for some rheology endpoints, especially for the different RP batches. Therefore, equivalence could not be established for Q3 as per EMA requirements. Can some rheology endpoints be waived? Can we establish reasonable criteria that are overall feasible for generic manufacturers and at the same time safe for the patient? An attempt was made to propose a wider acceptance range based on the inter-batch variability of the RP. For that, the rationale presented in the EMA guideline on bioequivalence for highly variable products was used. For the diclofenac formulation, Q3 equivalence was likewise not established. Q4 equivalence was only found for some batch combinations and when applying a wider acceptance criterion (75-133%). Furthermore, IVPT equivalence also failed to be demonstrated. Nevertheless, since the TP displays an equivalent pharmacokinetic profile compared to the RP, the observed Q3, Q4 and local availability differences are not expected to be clinically significant. This study draws attention to an effective search to determine the most appropriate strategy for assessing topical bioequivalence on a case-by-case basis.
Topics: Diclofenac; Dimethindene; Drugs, Generic; Humans; In Vitro Techniques; Therapeutic Equivalency
PubMed: 35358644
DOI: 10.1016/j.ijpharm.2022.121705