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Clinical Drug Investigation Jan 2022A topical formulation of diclofenac (FLECTOR diclofenac epolamine topical system (FDETS)) is approved in adults for the treatment of acute pain due to minor strains,...
BACKGROUND AND OBJECTIVE
A topical formulation of diclofenac (FLECTOR diclofenac epolamine topical system (FDETS)) is approved in adults for the treatment of acute pain due to minor strains, sprains, and contusions; however, its safety and efficacy have not been investigated in a pediatric population. This study assessed the safety and efficacy of the FLECTOR (diclofenac epolamine) topical system in children.
METHODS
This was an open-label, single-arm, phase IV study at ten USA-based family medicine or pediatric practices in children aged 6-16 years with a clinically significant minor soft tissue injury sustained within the preceding 96 h and at least moderate spontaneous pain on the Wong-Baker FACES Pain Rating Scale. The FLECTOR topical system was applied twice daily until pain resolution or Day 14. The primary endpoint was local tolerability and systemic safety. Key secondary endpoints were diclofenac plasma concentrations and analgesic efficacy.
RESULTS
104 patients were enrolled; 52 were 6-11 years old, and 52 were 12-16 years old (mean age 11.6 years). The maximum tolerability score experienced by any patient was 1 (faint redness). Fourteen adverse events (none serious) in nine patients (8.7%) were considered possibly treatment-related. Reduction in pain during the study was somewhat greater for patients aged 6-11 versus 12-16 years (p < 0.011). The diclofenac plasma concentration tended to be higher in the younger age group compared with older patients: 1.83 versus 1.46 ng/mL at the first assessment and 2.49 versus 1.11 ng/mL at the last assessment (p = 0.002).
CONCLUSION
The FLECTOR topical system safely and effectively provided pain relief for minor soft tissue injuries in the pediatric population, with minimal systemic nonsteroidal anti-inflammatory drug exposure and low potential risk of local or systemic adverse events.
CLINICAL TRIAL REGISTRATION
ClinicalTrials.gov identifier NCT02132247.
Topics: Acute Pain; Administration, Topical; Adolescent; Anti-Inflammatory Agents, Non-Steroidal; Child; Diclofenac; Humans; Pyrrolidines; Soft Tissue Injuries
PubMed: 34826122
DOI: 10.1007/s40261-021-01101-x -
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 -
International Journal of Molecular... May 2021A series of diclofenac N-derivatives (, , , , , -) were synthesized in order to test their anti-cancer and anti-inflammatory effects. The anticarcinogen activity has...
A series of diclofenac N-derivatives (, , , , , -) were synthesized in order to test their anti-cancer and anti-inflammatory effects. The anticarcinogen activity has been assayed against three cancer cell lines: HT29, human colon cancer cells; Hep-G2, human hepatic cells; and B16-F10, murine melanoma cells. First, we determined the cytotoxicity of the different compounds, finding that the most effective compound was compound against all cell lines and both compounds and in human Hep-G2 and HT29 cell lines. Compounds and were selected for the percentage of apoptosis determination, cell cycle distribution, and mitochondrial membrane potential measure because these products presented the lowest IC values in two of the three cancer cell lines assayed (B16-F10 and HepG2), and were two of the three products with lowest IC in HT29 cell line. Moreover, the percentages of apoptosis induction were determined for compounds and , showing that the highest values were between 30 to 60%. Next, the effects of these two compounds were observed on the cellular cycle, resulting in an increase in the cell population in G2/M cell cycle phase after treatment with product , whereas compound increased the cells in phase G0/G1, by possible differentiation process induction. Finally, to determine the possible apoptosis mechanism triggered by these compounds, mitochondrial potential was evaluated, indicating the possible activation of extrinsic apoptotic mechanism. On the other hand, we studied the anti-inflammatory effects of these diclofenac (DCF) derivatives on lipopolysaccharide (LPS) activated RAW 264.7 macrophages-monocytes murine cells by inhibition of nitric oxide (NO) production. As a first step, we determined the cytotoxicity of the synthesized compounds, as well as DCF, against these cells. Then, sub-cytotoxic concentrations were used to determine NO release at different incubation times. The greatest anti-inflammatory effect was observed for products and at 20 µg·mL concentration after 48 h of treatment, with inhibition of produced NO between 60 to 75%, and a concentration that reduces to the 50% the production of NO (IC) between 2.5 to 25 times lower than that of DCF. In this work, we synthesized and determined for the first time the anti-cancer and anti-inflammatory potential of eight diclofenac N-derivatives. In agreement with the recent evidences suggesting that inflammation may contribute to all states of tumorigenesis, the development of these new derivatives capable of inducing apoptosis and anti-inflammatory effects at very low concentrations represent new effective therapeutic strategies against these diseases.
Topics: Animals; Anti-Inflammatory Agents; Antineoplastic Agents; Apoptosis; Cell Cycle; Cell Proliferation; Diclofenac; Edema; Humans; Molecular Structure; Neoplasms; Rats; Tumor Cells, Cultured
PubMed: 34064702
DOI: 10.3390/ijms22105067 -
Clinical Pharmacology in Drug... Feb 2018Given their established analgesic properties, nonsteroidal anti-inflammatory drugs (NSAIDs) represent an important postoperative pain management option. This study...
Pharmacokinetics of Diclofenac and Hydroxypropyl-β-Cyclodextrin (HPβCD) Following Administration of Injectable HPβCD-Diclofenac in Subjects With Mild to Moderate Renal Insufficiency or Mild Hepatic Impairment.
Given their established analgesic properties, nonsteroidal anti-inflammatory drugs (NSAIDs) represent an important postoperative pain management option. This study investigated: (1) the effects of mild or moderate renal insufficiency and mild hepatic impairment on the pharmacokinetics (PK) of diclofenac and hydroxypropyl-β-cyclodextrin (HPβCD) following administration of the injectable NSAID HPβCD-diclofenac; and (2) the PK of HPβCD following administration of HPβCD-diclofenac and intravenous itraconazole formulated with HPβCD in healthy adults. Diclofenac clearance (CL) and volume of distribution (V ) tended to increase with decreasing renal function (moderate insufficiency versus mild insufficiency or healthy controls). Regression analysis demonstrated a significant relationship between V (but not CL or elimination half-life, t ) and renal function. HPβCD CL was significantly decreased in subjects with renal insufficiency, with a corresponding increase in t . There were no significant differences in diclofenac or HPβCD PK in subjects with mild hepatic impairment versus healthy subjects. Exposure to HPβCD in healthy subjects following HPβCD-diclofenac administration was ∼12% of that with intravenous itraconazole, after adjusting for dosing schedule and predicted accumulation (<5% without adjustment). With respect to PK properties, these results suggest that HPβCD-diclofenac might be administered to patients with mild or moderate renal insufficiency or mild hepatic impairment without dose adjustment (NCT00805090).
Topics: 2-Hydroxypropyl-beta-cyclodextrin; Adult; Aged; Anti-Inflammatory Agents, Non-Steroidal; Diclofenac; Female; Humans; Injections, Intravenous; Liver Diseases; Male; Middle Aged; Renal Insufficiency
PubMed: 29197175
DOI: 10.1002/cpdd.417 -
Molecules (Basel, Switzerland) Jun 2024An RP-HPLC method with a UV detector was developed for the simultaneous quantification of diclofenac diethylamine, methyl salicylate, and capsaicin in a pharmaceutical...
An RP-HPLC method with a UV detector was developed for the simultaneous quantification of diclofenac diethylamine, methyl salicylate, and capsaicin in a pharmaceutical formulation and rabbit skin samples. The separation was achieved using a Thermo Scientific ACCLAIM 120 C column (Waltham, MA, USA, 4.6 mm × 150 mm, 5 µm). The optimized elution phase consisted of deionized water adjusted to pH = 3 using phosphoric acid mixed with acetonitrile in a 35:65% (/) ratio with isocratic elution. The flow rate was set at 0.7 mL/min, and the detection was performed at 205 nm and 25 °C. The method exhibits good linearity for capsaicin (0.05-70.0 µg/mL), methyl salicylate (0.05-100.0 µg/mL), and diclofenac diethylamine (0.05-100.0 µg/mL), with low LOD values (0.0249, 0.0271, and 0.0038 for capsaicin, methyl salicylate, and diclofenac diethylamine, respectively). The RSD% values were below 3.0%, indicating good precision. The overall greenness score of the method was 0.61, reflecting its environmentally friendly nature. The developed RP-HPLC method was successfully applied to analyze Omni Hot Gel pharmaceutical formulation and rabbit skin permeation samples.
Topics: Capsaicin; Diclofenac; Chromatography, High Pressure Liquid; Salicylates; Skin; Animals; Rabbits; Chromatography, Reverse-Phase; Diethylamines
PubMed: 38930798
DOI: 10.3390/molecules29122732 -
Ecotoxicology (London, England) Sep 2023Soil contamination with micropollutants is an important global problem and the impact of these pollutants on living organisms cannot be underestimated. The effects of...
Soil contamination with micropollutants is an important global problem and the impact of these pollutants on living organisms cannot be underestimated. The effects of diclofenac (DCF) and sulfamethoxazole (SMX), their mixture (MIX), and wastewater containing these drugs on the mortality and reproduction of Eisenia fetida were investigated. The impact on the activities of antioxidant enzymes in earthworm cells was also assessed. Furthermore, the influence of the following parameters of the vertical flow constructed wetlands on wastewater toxicity was investigated: the dosing system, the presence of pharmaceuticals and the plants Miscanthus giganteus. The compounds and their mixture significantly affected the reproduction and mortality of earthworms. The calculated values of LC values were 3.4 ± 0.3 mg kg for DCF, 1.6 ± 0.3 mg kg for SMX, and 0.9 ± 0.1 mg kg for MIX. The EC (reproduction assay) for DCF was 1.2 ± 0.2 mg kg, whereas for SMX, it was 0.4 ± 0.1 mg kg, and for MIX, it was 0.3 ± 0.1 mg kg, respectively. The mixture toxicity index (MTI) was calculated to determine drug interactions. For both E. fetida mortality (MTI = 3.29) and reproduction (MTI = 3.41), the index was greater than 1, suggesting a synergistic effect of the mixture. We also observed a negative effect of wastewater (raw and treated) on mortality (32% for raw and 8% for treated wastewater) and fertility (66% and 39%, respectively) of E. fetida. It is extremely important to analyze the harmfulness of microcontaminants to organisms inhabiting natural environments, especially in the case of wastewater for irrigation of agricultural fields.
Topics: Animals; Diclofenac; Wastewater; Sulfamethoxazole; Oligochaeta; Wetlands; Fertility; Soil; Oxidative Stress; Soil Pollutants
PubMed: 37633869
DOI: 10.1007/s10646-023-02690-3 -
Environmental Science and Pollution... Apr 2023Chemicals from anthropogenic activities such as domestic sewage, pesticide leaching, and improper chemical disposal have caused groundwater contamination. The presence...
Chemicals from anthropogenic activities such as domestic sewage, pesticide leaching, and improper chemical disposal have caused groundwater contamination. The presence of these emerging contaminants in the aquatic environment can change water quality and biota composition. Thus, this study investigates the effect of two emerging contaminants, anti-inflammatory drug diclofenac (DCF) and antibiotic sulfamethoxazole (SMX), on the aquatic environment, evaluating the phytoplankton community structure. A microcosm experiment was conducted with 16 sampling units, each one with 500 mL of water sample containing phytoplankton exposed to these drugs at different concentrations (0.1, 0.5, and 1.0 mg L). The experiment lasted 15 days, and samples were collected on days 0, 3, 5, 7, and 14 to evaluate the phytoplankton community, the concentrations of the drugs, and the nutrients in the samples. Six phytoplankton groups were identified, and diatoms and green algae were the most diverse and abundant groups. For the entire community, we identified differences between the days of the experiment, varying in the diversity and density of organisms, but not between the concentrations of the two drugs. Evaluating the groups separately, we identified differences in the abundance of cyanobacteria for the treatment with diclofenac and desmids for the treatment with sulfamethoxazole. We demonstrated that the presence of pharmaceuticals in freshwater ecosystems can somehow affect the phytoplankton community, especially the diversity and abundance of cyanobacteria and desmids. Therefore, our study indicates the importance of evaluating the presence of pharmaceuticals in freshwater ecosystems and their influence on aquatic organisms, as well as pharmaceuticals may be changing the structure of the aquatic environment.
Topics: Diclofenac; Phytoplankton; Sulfamethoxazole; Ecosystem; Water Pollutants, Chemical; Cyanobacteria; Pharmaceutical Preparations
PubMed: 36719587
DOI: 10.1007/s11356-023-25589-2 -
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 -
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