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European Review For Medical and... May 2023OBJECTIVE: Neuropathic pain is regulated by several metabolites of the kynurenine pathway (KYNA-kynurenic acid, and QA-quinolinic acid). Diclofenac exerts analgesic and...
OBJECTIVE: Neuropathic pain is regulated by several metabolites of the kynurenine pathway (KYNA-kynurenic acid, and QA-quinolinic acid). Diclofenac exerts analgesic and anti-hyperalgesic effects and also alters KYNA levels, indicating a potential for therapy. We aimed to assess the nociceptive effects of different doses of diclofenac treatment in a rat model of neuropathic pain and to determine potential relationships with KYNA and QA levels (Graphical Abstract). MATERIALS AND METHODS: Twenty-eight Sprague-Dawley rats were divided into four groups: 40 mg/kg/day diclofenac (high-dose), 20 mg/kg/day diclofenac (normal-dose), non-treatment, and sham. Except for the sham group, the others underwent partial sciatic nerve ligation (left). Baseline (day 0) and post-treatment (day 3) KYNA and QA levels were measured. Allodynia and pain detection were assessed with the von Frey and hot plate tests. RESULTS: Baseline findings were similar in all groups. Compared to baseline, the non-treatment group had significantly worse allodynia on day 3. Baseline and post-treatment von Frey results (left) remained similar in the normal-dose diclofenac group (p=0.336); however, this benefit was not observed in the high-dose group. Relative to baseline, normal-dose diclofenac recipients had significantly higher KYNA concentration (p=0.046) and KYNA-to-QA ratio (p=0.028) on day 3. CONCLUSIONS: Our results show that 3-day therapy with 20 mg/kg/day diclofenac can improve nociceptive findings in neuropathic pain, and that this effect may be associated with increased KYNA or KYNA-to-QA ratio. The lack of dose-dependent effects may be associated with potential adverse influences of exceedingly high diclofenac dosage.
Topics: Rats; Animals; Diclofenac; Kynurenine; Hyperalgesia; Rats, Sprague-Dawley; Nociception; Neuralgia; Sciatic Nerve
PubMed: 37203850
DOI: 10.26355/eurrev_202305_32334 -
BMC Complementary Medicine and Therapies Dec 2022Among the most commonly consumed non-steroidal anti-inflammatory drugs (NSAID) is Diclofenac (Dic), especially in low-income countries due to its high efficiency and...
BACKGROUND
Among the most commonly consumed non-steroidal anti-inflammatory drugs (NSAID) is Diclofenac (Dic), especially in low-income countries due to its high efficiency and affordable price. However, the continuous administration of Diclofenac may induce toxic effects on various body organs including the liver and kidney. Caffeine (Caf) (1,3,7-trimethylxanthine) is a pharmacologically active alkaloid type with antioxidant and anti-inflammatory actions.
AIM
The current study aims to evaluate the ameliorative effect of Caffeine against Dic-induced hepato-renal toxicity and damage.
METHODS
Twenty-four male albino rats type were assigned randomly into four groups (n = 6): (Group 1): Control group, (Group 2): Six male rats were exposed to Dic 10 mg/kg intraperitoneally (I.P) for 28 days, (Group 3): Six male rats were exposed to Caf (15 mg/kg orally) for 28 days; (Groups 4): Six male rats were exposed to Dic (10 mg/kg, i.p) + Caf (15 mg/kg, orally) for 28 days. Histopathological study and various biological parameters were estimated among the four groups including hemoglobin (Hb%) red blood cells (RBCs), Hematocrit (HT%), total leucocyte count (WBCs), lipid peroxidation (LPO), glutathione peroxidase (GPx), alanine aminotransferase (ALT), aspartate aminotransferase (AST), urea, creatinine, tumor necrosis factor-α (TNF-α), and nitric oxide (NO).
RESULTS
The administration of Diclofenac resulted in significant deteriorations in the histopathological findings and estimated biological parameters. Whereas, daily Caffeine administration ameliorated Diclofenac-induced toxicity in the kidney and liver by three mechanisms including antioxidant, anti-inflammatory, and DNA damage inhibition.
CONCLUSION
The current study demonstrated the promising ameliorative and protective effects of Caffeine against Diclofenac-induced hepatic and renal injury.
Topics: Male; Rats; Animals; Diclofenac; Caffeine; Liver; Chromosome Aberrations; Anti-Inflammatory Agents
PubMed: 36482339
DOI: 10.1186/s12906-022-03802-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 -
CPT: Pharmacometrics & Systems... May 2021Establishing bioequivalence (BE) for dermatological drug products by conducting comparative clinical end point studies can be costly and the studies may not be... (Review)
Review
Establishing bioequivalence (BE) for dermatological drug products by conducting comparative clinical end point studies can be costly and the studies may not be sufficiently sensitive to detect certain formulation differences. Quantitative methods and modeling, such as physiologically-based pharmacokinetic (PBPK) modeling, can support alternative BE approaches with reduced or no human testing. To enable PBPK modeling for regulatory decision making, models should be sufficiently verified and validated (V&V) for the intended purpose. This report illustrates the US Food and Drug Administration (FDA) approval of a generic diclofenac sodium topical gel that was based on a totality of evidence, including qualitative and quantitative sameness and physical and structural similarity to the reference product, an in vivo BE study with PK end points, and, more importantly, for the purposes of this report, a virtual BE assessment leveraging dermal PBPK modeling and simulation instead of a comparative clinical end point study in patients. The modeling approach characterized the relationship between systemic (plasma) and local (skin and synovial fluid) diclofenac exposure and demonstrated BE between the generic and reference products at the presumed site of action. Based on the fit-for-purpose modeling principle, the V&V process involved assessing observed data of diclofenac concentrations in skin tissues and plasma, and the overall performance of the modeling platform for relevant products. Using this case as an example, this report provides current scientific considerations on good practices for model V&V and the establishment of BE for dermatological drug products when leveraging PBPK modeling and simulation for regulatory decision making.
Topics: Administration, Cutaneous; Anti-Inflammatory Agents, Non-Steroidal; Diclofenac; Humans; Models, Biological; Skin; Therapeutic Equivalency
PubMed: 33547863
DOI: 10.1002/psp4.12600 -
British Medical Journal (Clinical... May 1982
Topics: Chemical and Drug Induced Liver Injury; Diagnosis, Differential; Diclofenac; Hepatitis; Humans; Male; Middle Aged; Phenylacetates
PubMed: 6805622
DOI: 10.1136/bmj.284.6329.1605 -
Molecules (Basel, Switzerland) Apr 2022The use of enterosorbents-materials which can be administered orally and eliminate toxic substances from the gastrointestinal tract (GIT) by sorption-offers an...
The use of enterosorbents-materials which can be administered orally and eliminate toxic substances from the gastrointestinal tract (GIT) by sorption-offers an attractive complementary protection of humans against acute and chronic poisoning. In this study, we report the results of developing a microgranulated binary biomedical preparation for oral use. It was designed with a core-shell structure based on pectin with low degree of esterification as the core, and nanoporous activated carbon produced from rice husk, AC-RH, as the shell, designated as AC-RH@pectin. The adsorption properties of the synthesized materials were studied in aqueous solutions for the removal of lead (II) nitrate as a representative of toxic polyvalent metals and sodium diclofenac as an example of a medicinal drug. The composite enterosorbent demonstrated high adsorption capacity for both adsorbates studied. Adsorption kinetics of lead and diclofenac adsorption by AC-RH, pectin, and AC-RH@pectin, fitted well a pseudo-second-order model. According to the Langmuir adsorption isotherm model, the best fitted isotherm model, the maximum adsorption capacity, q, of AC-RH@pectin for diclofenac and for lead (II) was 130.9 mg/g and 227.8 mg/g, respectively. Although q of AC-RH for diclofenac, 537.6 mg/g, and q of pectin for lead (II), 245.7 mg/g, were higher, the maximum adsorption capacity of AC-RH for lead (II), 52.7 mg/g, was much lower than that of the composite AC-RH@pectin and the adsorption capacity of pectin for diclofenac was negligible. Therefore, the composite material AC-RH@pectin demonstrated substantial efficiency of removing both species which potentially defines it as a more universal enterosorbent suitable for treating poisoning caused by substances of different chemical nature.
Topics: Adsorption; Charcoal; Diclofenac; Humans; Hydrogen-Ion Concentration; Kinetics; Lead; Pectins; Water Pollutants, Chemical; Xenobiotics
PubMed: 35408695
DOI: 10.3390/molecules27072296 -
Environmental Science & Technology Jun 2021The exposure of ecologically critical invertebrate species to biologically active pharmaceuticals poses a serious risk to the aquatic ecosystem. Yet, the fate and toxic...
The exposure of ecologically critical invertebrate species to biologically active pharmaceuticals poses a serious risk to the aquatic ecosystem. Yet, the fate and toxic effects of pharmaceuticals on these nontarget aquatic invertebrates and the underlying mechanisms are poorly studied. Herein, we investigated the toxicokinetic (TK) processes (i.e., uptake, biotransformation, and elimination) of the pharmaceutical diclofenac and its biotransformation in the freshwater invertebrate . We further employed mass spectrometry-based metabolomics to assess the toxic effects of diclofenac on the metabolic functions of . exposed to environmentally relevant concentrations (10 and 100 μg/L). The TK results showed a quick uptake of diclofenac by . (maximum internal concentration of 1.9 μmol/kg) and rapid formation of the conjugate diclofenac taurine (maximum internal concentration of 80.6 μmol/kg), indicating over 40 times higher accumulation of diclofenac taurine than that of diclofenac in . . Depuration kinetics demonstrated that the elimination of diclofenac taurine was 64 times slower than diclofenac in . . Metabolomics results suggested that diclofenac inhibited prostaglandin synthesis and affected the carnitine shuttle pathway at environmentally relevant concentrations. These findings shed light on the significance of the TK process of diclofenac, especially the formation of diclofenac taurine, as well as the sublethal effects of diclofenac on the bulk metabolome of . . Combining the TK processes and metabolomics provides complementary insights and thus a better mechanistic understanding of the effects of diclofenac in aquatic invertebrates.
Topics: Amphipoda; Animals; Diclofenac; Ecosystem; Invertebrates; Metabolomics; Pharmaceutical Preparations; Toxicokinetics; Water Pollutants, Chemical
PubMed: 34086445
DOI: 10.1021/acs.est.0c07887 -
Environmental Pollution (Barking, Essex... Dec 2022Although the presence of pharmaceuticals in the environment is an issue widely addressed in research over the past two decades, still little is known about their...
Although the presence of pharmaceuticals in the environment is an issue widely addressed in research over the past two decades, still little is known about their transformation products. However, there are indications that some of these chemicals may be equally or even more harmful than parent compounds. Diclofenac (DCF) is among the most commonly detected pharmaceuticals in the aquatic environment, but the potential effects of its metabolites on organisms are poorly understood. Therefore, the present study aimed to evaluate and compare the toxicity of DCF and its metabolite, 4-hydroxy diclofenac (4-OH DCF), in mussels using a multi-biomarker approach. Mytilus trossulus mussels were exposed to DCF and 4-OH DCF at 68.22 and 20.85 μg/L (measured concentrations at day 0), respectively, for 7 days. In our work, we showed that both tested compounds have no effect on most of the enzymatic biomarkers tested. However, it has been shown that their action can affect the protein content in gills and also be reflected through histological markers. ENVIRONMENTAL IMPLICATION: Studies in recent years clearly prove that pharmaceuticals can negatively affect aquatic organisms. In addition to parent compounds, metabolites of pharmaceuticals can also be a significant environmental problem. In the present work, the effects of diclofenac and its main metabolite, 4-hydroxy diclofenac, on marine mussels were evaluated. Both compounds showed negative effects on mussels, which was primarily observed through histological changes. The present study therefore confirms that not only diclofenac, but also its main metabolite can have negative effects on aquatic organisms.
Topics: Animals; Mytilus; Diclofenac; Water Pollutants, Chemical; Aquatic Organisms; Biomarkers; Pharmaceutical Preparations
PubMed: 36223851
DOI: 10.1016/j.envpol.2022.120384 -
Journal of Nanobiotechnology Oct 2020Magnetic nanocomposites with a core-shell nanostructure have huge applications in different sciences especially in the release of the drugs, because of their exclusive...
BACKGROUND
Magnetic nanocomposites with a core-shell nanostructure have huge applications in different sciences especially in the release of the drugs, because of their exclusive physical and chemical properties. In this research, magnetic@layered double hydroxide multicore@shell nanostructure was synthesized by the facile experiment and is used as novel drug nanocarrier.
METHODS
Magnetic nanospheres were synthesized by a facile one-step solvothermal route, and then, layered double hydroxide nanoflakes were prepared on the magnetic nanospheres by coprecipitation experiment. The synthesized nanostructures were characterized by FTIR, XRD, SEM, VSM, and TEM, respectively. After intercalation with Ibuprofen and Diclofenac as anti-inflammatory drugs and using exchange anion experiment, the basal spacing of synthesized layered double hydroxides was compared with brucite nanosheets from 0.48 nm to 2.62 nm and 2.22 nm, respectively.
RESULTS
The results indicated that Ibuprofen and Diclofenac were successfully intercalated into the interlay space of LDHs via bridging bidentate interaction. In addition, in-vitro drug release experiments in pH 7.4, phosphate-buffered saline (PBS) showed constant release profiles with Ibuprofen and Diclofenac as model drugs with different lipophilicity, water solubility, size, and steric effect.
CONCLUSION
The FeO@LDH-ibuprofen and FeO@LDH-diclofenac had the advantage of the strong interaction between the carboxyl groups with higher trivalent cations by bridging bidentate, clarity, and high thermal stability. It is confirmed that FeO@LDH multicore-shell nanostructure may have potential application for constant drug delivery.
Topics: Animals; Anti-Inflammatory Agents; Delayed-Action Preparations; Diclofenac; Drug Carriers; Drug Compounding; Drug Liberation; Humans; Hydroxides; Ibuprofen; Intercalating Agents; Magnetic Iron Oxide Nanoparticles; Mice; Myoblasts; Nanocomposites; Particle Size; Solubility; Surface Properties
PubMed: 33121499
DOI: 10.1186/s12951-020-00718-y -
International Journal of Pharmaceutics Mar 2016The aim of this in vivo study was to assess the ability of the prodrug conjugate diclofenac-β-cyclodextrin to release diclofenac in the colon following oral...
The aim of this in vivo study was to assess the ability of the prodrug conjugate diclofenac-β-cyclodextrin to release diclofenac in the colon following oral administration, using sulfapyridine (a metabolite of sulfasalazine) as a marker of colonic absorption. Two groups of rats were used; the test rats received a suspension containing the two prodrugs, diclofenac-β-cyclodextrin and sulfasalazine, while the control rats received a suspension containing the corresponding free drugs, sodium diclofenac and sulfapyridine. The rats were fasted overnight with free access to water before and throughout the first 12h of the study. Blood was collected from the tail vein at pre-determined time points and the plasma analyzed for the concentrations of diclofenac and sulfapyridine. Following the oral administration of the two prodrugs, a more extended absorption profile was observed and Cmax was achieved 10h post-dose, in contrast to rapid absorption of the free drugs (tmax of diclofenac being 1.3h, and that of sulfapyridine being 2.1h). In addition to a later tmax, conjugation of diclofenac to β-cyclodextrin also resulted in a reduced Cmax and a reduced AUC. The same tmax for diclofenac-β-cyclodextrin as for sulfasalazine confirms the colonic metabolism of diclofenac-β-cyclodextrin. This study shows the potential of this new cyclodextrin-based prodrug to target and release diclofenac specifically in the colon following oral administration.
Topics: Administration, Oral; Animals; Anti-Inflammatory Agents, Non-Steroidal; Colon; Diclofenac; Drug Delivery Systems; Drug Liberation; Intestinal Absorption; Male; Prodrugs; Rats, Wistar; Sulfasalazine; beta-Cyclodextrins
PubMed: 26784980
DOI: 10.1016/j.ijpharm.2016.01.024