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BMC Genomics Nov 2021Despite proven therapeutic effects in inflammatory conditions, the specific mechanisms of phytochemical therapies are not well understood. The transcriptome effects of...
BACKGROUND
Despite proven therapeutic effects in inflammatory conditions, the specific mechanisms of phytochemical therapies are not well understood. The transcriptome effects of Traumeel (Tr14), a multicomponent natural product, and diclofenac, a non-selective cyclooxygenase (COX) inhibitor, were compared in a mouse cutaneous wound healing model to identify both known and novel pathways for the anti-inflammatory effect of plant-derived natural products.
METHODS
Skin samples from abraded mice were analyzed by single-molecule, amplification-free RNAseq transcript profiling at 7 points between 12 and 192 h after injury. Immediately after injury, the wounds were treated with either diclofenac, Tr14, or placebo control (n = 7 per group/time). RNAseq levels were compared between treatment and control at each time point using a systems biology approach.
RESULTS
At early time points (12-36 h), both control and Tr14-treated wounds showed marked increase in the inducible COX2 enzyme mRNA, while diclofenac-treated wounds did not. Tr14, in contrast, modulated lipoxygenase transcripts, especially ALOX12/15, and phospholipases involved in arachidonate metabolism. Notably, Tr14 modulated a group of cell-type specific markers, including the T cell receptor, that could be explained by an overarching effect on the type of cells that were recruited into the wound tissue.
CONCLUSIONS
Tr14 and diclofenac had very different effects on the COX/LOX synthetic pathway after cutaneous wounding. Tr14 allowed normal autoinduction of COX2 mRNA, but suppressed mRNA levels for key enzymes in the leukotriene synthetic pathway. Tr14 appeared to have a broad 'phytocellular' effect on the wound transcriptome by altering the balance of cell types present in the wound.
Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Biomarkers; Diclofenac; Inflammation; Mice; Wound Healing
PubMed: 34823472
DOI: 10.1186/s12864-021-08083-2 -
Journal of Cellular and Molecular... Nov 2023The most prominent adverse effects of nonsteroidal anti-inflammatory drugs (NSAIDs) such as diclofenac (DF) are hepato-renal damage. Natural antioxidants can be...
The most prominent adverse effects of nonsteroidal anti-inflammatory drugs (NSAIDs) such as diclofenac (DF) are hepato-renal damage. Natural antioxidants can be preferred as an alternative and/or combination to improve this damage. This present study was conducted to evaluate the protective effect of Tubuloside A (TA) against diclofenac (DF)-induced hepato-renal damage. TA (1 mg/kg, ip) was administered to male Sprague-Dawley rats for 5 days, and DF (50 mg/kg, ip) was administered on Days 4 and 5. Plasma aspartate amino transferase, alanine amino transferase, alkaline phosphatase, blood urea nitrogen and creatinine were measured to evaluate liver and kidney functions. Additionally, oxidative stress parameters (malondialdehyde, glutathione, superoxide dismutase, catalase, and 8-oxo-7,8-dihydro-2'-deoxyguanosine) in blood, liver, and kidney tissues, changes in mRNA expression of genes involved in the Nrf2/HO-1 signalling pathway (Nrf2, HO-1, NQO-1, IL-6, iNOS, Cox-2, TNF-α, IL1-β and NFκB) and apoptotic process (Bcl-2, Cas-3 and Bax) in liver and kidney tissues were determined. Additionally, tissue sections were evaluated histopathologically. Biochemical, histopathological, and molecular results demonstrated the hepato-renal toxic effects of DF, and TA treatment protected the liver and kidney from DF-induced damage. This provides an explanation for the hepato-nephro damage caused by DF and offers new ideas and drug targets together with TA for the prevention and treatment of DF injury.
Topics: Rats; Animals; Male; Diclofenac; NF-E2-Related Factor 2; Glycosides; Rats, Sprague-Dawley; Oxidative Stress; Antioxidants; Kidney; Apoptosis
PubMed: 37772986
DOI: 10.1111/jcmm.17968 -
Arhiv Za Higijenu Rada I Toksikologiju Jun 2021Concomitant treatment with drugs that inhibit drug metabolising enzymes and/or transporters, such as commonly prescribed statins and nonsteroidal anti-inflammatory drugs... (Review)
Review
Concomitant treatment with drugs that inhibit drug metabolising enzymes and/or transporters, such as commonly prescribed statins and nonsteroidal anti-inflammatory drugs (NSAIDs), has been associated with prolonged drug exposure and increased risk of adverse drug reactions (ADRs) due to drug-drug interactions. The risk is further increased in patients with chronic diseases/comorbidities who are more susceptible because of their genetic setup or external factors. In that light, we present a case of a 46-year-old woman who had been experiencing acute renal and hepatic injury and myalgia over two years of concomitant treatment with diclofenac, atorvastatin, simvastatin/fenofibrate, and several other drugs, including pantoprazole and furosemide. Our pharmacogenomic findings supported the suspicion that ADRs, most notably the multi-organ toxicity experienced by our patient, may be owed to drug-drug-gene interactions and increased bioavailability of the prescribed drugs due to slower detoxification capacity and decreased hepatic and renal elimination. We also discuss the importance of CYP polymorphisms in the biotransformation of endogenous substrates such as arachidonic acid and their modulating role in pathophysiological processes. Yet even though the risks of ADRs related to the above mentioned drugs are substantially evidenced in literature, pre-emptive pharmacogenetic analysis has not yet found its way into common clinical practice.
Topics: Diclofenac; Drug Interactions; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Middle Aged; Pharmaceutical Preparations
PubMed: 34187111
DOI: 10.2478/aiht-2021-72-3549 -
Journal of Nanobiotechnology May 2022Despite attracting increasing attention in clinic, non-invasive high-intensity focused ultrasound (HIFU) surgery still commonly suffers from tumor recurrence and even...
Three birds with one stone: co-encapsulation of diclofenac and DL-menthol for realizing enhanced energy deposition, glycolysis inhibition and anti-inflammation in HIFU surgery.
Despite attracting increasing attention in clinic, non-invasive high-intensity focused ultrasound (HIFU) surgery still commonly suffers from tumor recurrence and even matastasis due to the generation of thermo-resistance in non-apoptotic tumor cells and adverse therapy-induced inflammation with enhanced secretion of growth factors in irradiated region. In this work, inspired by the intrinsic property that the expression of thermo-resistant heat shock proteins (HSPs) is highly dependent with adenosine triphosphate (ATP), dual-functionalized diclofenac (DC) with anti-inflammation and glycolysis-inhibition abilities was successfully co-encapsulated with phase-change dl-menthol (DLM) in poly(lactic-co-glycolic acid) nanoparticles (DC/DLM@PLGA NPs) to realize improved HIFU surgery without causing adverse inflammation. Both in vitro and in vivo studies demonstrated the great potential of DC/DLM@PLGA NPs for serving as an efficient synergistic agent for HIFU surgery, which can not only amplify HIFU ablation efficacy through DLM vaporization-induced energy deposition but also simultaneously sensitize tumor cells to hyperthermia by glycolysis inhibition as well as diminished inflammation. Thus, our study provides an efficient strategy for simultaneously improving the curative efficiency and diminishing the harmful inflammatory responses of clinical HIFU surgery.
Topics: Diclofenac; Glycolysis; High-Intensity Focused Ultrasound Ablation; Humans; Inflammation; Menthol
PubMed: 35524259
DOI: 10.1186/s12951-022-01437-2 -
Biomedicine & Pharmacotherapy =... Aug 2021Tibetan traditional medicine CheeZheng Pain-Relieving Plaster (CZPRP) is frequently used as an over-the-counter external analgesic for musculoskeletal pain; however, its... (Meta-Analysis)
Meta-Analysis
ETHNOPHARMACOLOGICAL RELEVANCE
Tibetan traditional medicine CheeZheng Pain-Relieving Plaster (CZPRP) is frequently used as an over-the-counter external analgesic for musculoskeletal pain; however, its evidence for low back pain (LBP) has not been evaluated.
AIM OF THE STUDY
This study aims to assess the efficacy and safety of CZPRP for both acute, subacute and chronic LBP through a systematic review and meta-analysis of clinical trials.
MATERIALS AND METHODS
PubMed, CENTRAL, CNKI, CQVIP, and Wanfang databases were searched through April 20, 2020 for randomized controlled trials of CZPRP for LBP. Eligible comparators were placebo, active treatment, or usual care. Clinical outcomes included pain severity, lower back function score, pain-free rate, and adverse events (AEs). Qualitative evaluations were conducted using the Cochrane risk of bias assessment tools. Quantitative analyses were conducted using a random-effects model.
RESULTS
This study includes 1674 LBP patients from nine clinical studies. Pooled analyses among subjects with acute LBP show 1) significant pain reductions (mean difference -0.84, 95% confidence interval[CI] -1.31, -0.37) in CZPRP plus diclofenac versus diclofenac, 2) significant improvements in lower back function (standard mean difference -1.50, 95% CI -2.16, -0.85) in CZPRP versus diclofenac, and 3) a higher pain-free rate in CZPRP alone (risk ratio 1.48, 95% CI 1.16, 1.89; I = 61%) or CZPRP plus nonsteroidal anti-inflammatory drugs (NSAIDs) (risk ratio 1.66, 95% CI 1.14, 2.40; I = 0%) versus NSAIDs. However, in a heterogeneous population with mixed LBP subtypes, there was no significant difference in pain outcomes between CZPRP and diclofenac. Additionally, CZPRP use did not increase AEs compared with no CZPRP (p = 0.40). All nine studies are associated with moderate to high risk of bias.
CONCLUSIONS
The use of CZPRP is associated with improved acute LBP outcomes compared to diclofenac. However, due to the moderate to high risk of bias of the studies, future rigorous randomized controlled trials are needed to evaluate the effects of CZPRP for acute and chronic LBP.
Topics: Analgesics; Animals; Diclofenac; Humans; Low Back Pain; Medicine, Traditional; Plant Preparations; Randomized Controlled Trials as Topic; Tibet
PubMed: 34015584
DOI: 10.1016/j.biopha.2021.111727 -
International Journal of Molecular... Aug 2022Non-steroidal anti-inflammatory drugs (NSAIDs) such as diclofenac (DIC) frequently induce drug-induced liver injury (DILI). It is unclear whether macrophages such as M1...
Non-steroidal anti-inflammatory drugs (NSAIDs) such as diclofenac (DIC) frequently induce drug-induced liver injury (DILI). It is unclear whether macrophages such as M1 and M2 participate in NSAID-associated DILI; elucidating this relationship could lead to a better understanding of the detailed mechanism of DILI. We co-cultured human hepatoma HepG2 cells with M1 or M2 derived from human monocytic leukemia THP-1 cells to examine the roles of M1 and M2 in DIC-induced cytotoxicity. DIC was added to the direct or indirect co-cultures of HepG2 cells with M1 or M2 (HepG2/M1 or HepG2/M2, respectively) at cell ratios of (1:0, 1:0.1, 1:0.4, and 1:1). In both direct and indirect HepG2/M2 co-cultures (1:0.4), there was lower lactate dehydrogenase release compared with HepG2/M1 co-cultures. Other NSAIDs as well as DIC showed similar protective effects of DIC-induced cytotoxicity. There were only slight differences in mRNA levels of apoptosis- and endoplasmic reticulum stress-associated factors between M1 and M2 after DIC treatment, suggesting that other factors determined the protective effects of M2 on DIC-induced cytotoxicity. Levels of high mobility group box 1 (HMGB1) in the medium and the mRNA expression levels of HMGB1 receptors were different between M1 and M2 after DIC treatment. Increased HMGB1 concentrations and expression of toll-like receptor 2 mRNA in M1 were observed compared with M2 after DIC treatment. In conclusion, these results suggested that the HMGB1/TLR2 signaling axis can be suppressed in M2 but not M1, leading to the different roles of M1 and M2 in NSAID-induced cytotoxicity.
Topics: Anti-Inflammatory Agents, Non-Steroidal; Chemical and Drug Induced Liver Injury; Coculture Techniques; Diclofenac; HMGB1 Protein; Hep G2 Cells; Humans; RNA, Messenger; THP-1 Cells
PubMed: 35955793
DOI: 10.3390/ijms23158660 -
Postgraduate Medical Journal Jan 1986Two patients developed clinical, biochemical and histopathological signs of a liver hypersensitivity reaction following treatment with diclofenac. Hepatic side effects...
Two patients developed clinical, biochemical and histopathological signs of a liver hypersensitivity reaction following treatment with diclofenac. Hepatic side effects of this drug are very rare. The relevant literature is reviewed.
Topics: Aged; Chemical and Drug Induced Liver Injury; Diclofenac; Female; Humans; Liver
PubMed: 3797366
DOI: 10.1136/pgmj.62.723.63 -
Drug Design, Development and Therapy 2018Since electroporation (EP) can increase the permeability of biological membranes, we hypothesized that it offers an opportunity to enhance the transdermal delivery of...
PURPOSE
Since electroporation (EP) can increase the permeability of biological membranes, we hypothesized that it offers an opportunity to enhance the transdermal delivery of drugs for intra-articular indications. Our aim was to compare the anti-inflammatory and analgesic efficacy of EP-combined topical administration of diclofenac sodium hydrogel (50 mg mL in 230 µL volume) with that of an equivalent dose of oral (75 mg kg) and simple topical administration.
METHODS
Arthritis was induced with the injection of 2% λ-carrageenan and 4% kaolin into the right knee joints of male Sprague Dawley rats. EP was applied for 8 min with 900 V high-voltage pulses for 5 ms followed by a 20 ms break. Drug penetration into the synovial fluid and plasma was detected by high-performance liquid chromatography. Leukocyte-endothelial interactions were visualized by intravital videomicroscopy on the internal surface of the synovium. Inflammation-induced thermal and mechanical hyperalgesia reactions, knee joint edema, and inflammatory enzyme activities were assessed at 24 and 48 h after arthritis induction.
RESULTS
EP significantly increased the plasma level of diclofenac as compared with the topical controls 10 min after the 2% λ-carrageenan and 4% kaolin injection. Increased leukocyte-endothelial interactions were accompanied by joint inflammation, which was significantly reduced by oral and EP diclofenac (by 45% and by 30%, respectively) and only slightly ameliorated by simple topical diclofenac treatment (by 18%). The arthritis-related secondary hyperalgesic reactions were significantly ameliorated by oral and EP-enhanced topical diclofenac treatments. The knee cross-section area (which increased by 35%) was also reduced with both approaches. However, simple topical application did not influence the development of joint edema and secondary hyperalgesia.
CONCLUSION
The study provides evidence for the first time of the potent anti-inflammatory and analgesic effects of EP-enhanced topical diclofenac during arthritis. The therapeutic benefit provided by EP is comparable with that of oral diclofenac; EP is a useful alternative to conventional routes of administration.
Topics: Administration, Cutaneous; Animals; Anti-Inflammatory Agents, Non-Steroidal; Arthritis, Experimental; Cell Communication; Cytokines; Diclofenac; Electrochemotherapy; Knee Joint; Male; Peroxidase; Rats; Rats, Sprague-Dawley
PubMed: 29983546
DOI: 10.2147/DDDT.S161703 -
BioMed Research International 2013In vitro analysis of drug release and antimicrobial activity of the coblended crosslinked polymeric fibre device (PFD) were investigated. The fibre loaded with...
In vitro analysis of drug release and antimicrobial activity of the coblended crosslinked polymeric fibre device (PFD) were investigated. The fibre loaded with ciprofloxacin and diclofenac sodium was comprised of alginate and glycerol crosslinked with barium cations. The pH dependent drug release was evident with ciprofloxacin and diclofenac sodium diffusing from the fibre at pH 4.0 compared to pH 6.8, where the fibre swelled and eroded resulting in zero-order drug release. Agar diffusion studies followed by minimum inhibitory assays were conducted to determine the antimicrobial activity of the device against Escherichia coli, Enterococcus faecalis, and Streptococcus mutans. The antimicrobial activity of the PFD was confirmed in both test assays against all test pathogens. The MIC ranges at pH 4.0 for E. coli, E. faecalis, and S. mutans were 0.5-0.8, 0.4-1.1, and 0.7-2.1 μg/mL, respectively. At pH 6.8, similar efficacies (0.3-0.5 μg/mL for E. coli and E. faecalis and 0.6-1.0 μg/mL for S. mutans) were observed. The effect of varying the plasticizer and crosslinking ion concentration on drug release profile of the fibers was further elucidated and conceptualized using molecular mechanics energy relationships (MMER) and by exploring the spatial disposition of geometrically minimized molecular conformations.
Topics: Anti-Bacterial Agents; Ciprofloxacin; Diclofenac; Drug Delivery Systems; Enterococcus faecalis; Escherichia coli; Humans; Hydrogen-Ion Concentration; Microbial Sensitivity Tests; Periodontal Diseases; Polymers; Streptococcus mutans
PubMed: 24324962
DOI: 10.1155/2013/460936 -
BMC Research Notes Jun 2020Musculoskeletal pain is often caused by injury to the bones, muscles, tendons, ligaments or nerves. Symptoms can be localized or generalized. Mild-moderate symptoms... (Observational Study)
Observational Study
OBJECTIVE
Musculoskeletal pain is often caused by injury to the bones, muscles, tendons, ligaments or nerves. Symptoms can be localized or generalized. Mild-moderate symptoms are treated with topical/oral over the counter drugs. Microemulsion delivery formulations are thermodynamically stable, have superior bioavailability and better penetration of lipophilic and hydrophilic drug into the dermis. A prospective observational study in patients: 18 years or older, with mild-moderate musculoskeletal pain; with severe pain without adequate pain control; with severe pain and could not tolerate oral agents; with renal impairment were invited to try diclofenac 2% in microemulsion foam. They were followed up at 2 and 4 weeks. A 50% reduction on a visual analog pain scale was considered success. Adverse events were defined as irritation, gastrointestinal upset/bleed, rectal bleed, and hematemesis. The objective was to determine the efficacy and toxicity of diclofenac 2% in microemulsion foam.
RESULTS
Thirteen consecutive patients with musculoskeletal pain consented to participate. Two patients were lost to follow up. Two of the 11 patients reported minimal improvement, while nine patients reported minimum 50% reduction. No adverse effects were reported. Diclofenac 2% in microemulsion foam is effective in the treatment of mild to moderate musculoskeletal pain and well tolerated.
Topics: Administration, Topical; Aged; Aged, 80 and over; Anti-Inflammatory Agents, Non-Steroidal; Diclofenac; Drug Compounding; Emulsions; Female; Humans; Male; Middle Aged; Musculoskeletal Pain; Outcome Assessment, Health Care; Prospective Studies
PubMed: 32532323
DOI: 10.1186/s13104-020-05120-3