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British Journal of Pharmacology Jan 2018Nonsteroidal anti-inflammatory drugs (NSAIDs) are administered to manage the pain typically found in patients suffering from pancreatitis. NSAIDs also display...
BACKGROUND AND PURPOSE
Nonsteroidal anti-inflammatory drugs (NSAIDs) are administered to manage the pain typically found in patients suffering from pancreatitis. NSAIDs also display anti-proliferative activity against cancer cells; however, their effects on normal, untransformed cells are poorly understood. Here, we evaluated whether NSAIDs inhibit the proliferation of pancreatic acinar cells during the development of acute pancreatitis.
EXPERIMENTAL APPROACH
The NSAIDs ibuprofen and diclofenac were administered to C57BL/6 mice after induction of pancreatitis with serial injections of cerulein. In addition, ibuprofen was administered concomitantly with 3,5,3-L-tri-iodothyronine (T3), which induces acinar cell proliferation in the absence of tissue inflammation. The development of pancreatic inflammation, acinar de-differentiation into metaplastic lesions and acinar proliferation were quantified by histochemical, biochemical and RT-PCR approaches.
KEY RESULTS
Therapeutic ibuprofen treatment selectively reduced pancreatic infiltration of activated macrophages in vivo, and M1 macrophage polarization and pro-inflammatory cytokine expression both in vivo and in vitro. Reduced macrophage activation was accompanied by reduced acinar de-differentiation into acinar-to-ductal metaplasia. Acinar proliferation was significantly impaired in the presence of ibuprofen and diclofenac, as demonstrated at both the level of proliferation markers and expression of cell cycle regulators. Ibuprofen also reduced acinar cell proliferation induced by mitogenic stimulation with T3, a treatment that does not elicit pancreatic inflammation.
CONCLUSIONS AND IMPLICATIONS
Our study provides evidence that the NSAIDs ibuprofen and diclofenac inhibit pancreatic acinar cell division. This suggests that prolonged treatment with these NSAIDs may negatively affect the regeneration of the pancreas and further studies are needed to confirm these findings in a clinical setting.
LINKED ARTICLES
This article is part of a themed section on Inventing New Therapies Without Reinventing the Wheel: The Power of Drug Repurposing. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.2/issuetoc.
Topics: Acinar Cells; Animals; Cell Differentiation; Cell Proliferation; Ceruletide; Cytokines; Diclofenac; Ibuprofen; Inflammation; Male; Mice; Mitogens; Neutrophil Infiltration; Pancreas; Pancreatitis; Triiodothyronine
PubMed: 28542719
DOI: 10.1111/bph.13867 -
Basic & Clinical Pharmacology &... Jan 2022Previous studies have raised serious concerns on cardiovascular safety of widely prescribed nonsteroidal anti-inflammatory drugs (NSAIDs). Therefore, the aim of this... (Comparative Study)
Comparative Study
BACKGROUND
Previous studies have raised serious concerns on cardiovascular safety of widely prescribed nonsteroidal anti-inflammatory drugs (NSAIDs). Therefore, the aim of this study was to characterize the electrophysiological effects of certain NSAIDs in an established whole heart model of proarrhythmia.
METHODS AND RESULTS
Thirty-eight hearts of New Zealand White rabbits were harvested and retrogradely perfused employing a Langendorff setup, and electrophysiology studies were performed to investigate action potential duration at 90% of repolarization (APD ), QT intervals, and effective refractory period (ERP). After generating baseline data, hearts were perfused with ibuprofen (Group 1, n = 12; 10 and 30 μM), indomethacin (Group 2, n = 13; 10 and 20 μM) and diclofenac (Group 3, n = 13; 10 and 20 μM), respectively, and the pacing protocols were repeated for each concentration. In all groups, perfusion with the NSAIDs resulted in a significant and reproducible shortening of APD and QT interval. In all groups, the arrhythmia susceptibility was significantly raised as occurrence of monomorphic ventricular tachycardia under programmed ventricular stimulation was significantly increased under perfusion with ibuprofen, indomethacin and diclofenac in all concentrations.
CONCLUSION
The perfusion with ibuprofen, indomethacin and diclofenac in commonly used doses raised the arrhythmia susceptibility in an established rabbit whole-heart model while APD shortening and shortened ERP seem to be crucial for arrhythmogenesis.
Topics: Action Potentials; Animals; Anti-Inflammatory Agents, Non-Steroidal; Arrhythmias, Cardiac; Cardiac Electrophysiology; Diclofenac; Dose-Response Relationship, Drug; Electrocardiography; Female; Ibuprofen; Indomethacin; Isolated Heart Preparation; Rabbits; Tachycardia, Ventricular
PubMed: 34634184
DOI: 10.1111/bcpt.13671 -
The Science of the Total Environment Sep 2022Organic micropollutants (OMPs) need to be removed from wastewater as they can negatively affect aquatic organisms. It has been demonstrated that microalgae-based...
Organic micropollutants (OMPs) need to be removed from wastewater as they can negatively affect aquatic organisms. It has been demonstrated that microalgae-based technologies are efficient in removing OMPs from wastewater. In this study, the removal processes and kinetics of six persistent OMPs (diclofenac, clarithromycin, benzotriazole, metoprolol, carbamazepine and mecoprop) were studied during cultivation of Scenedesmus obliquus in batch mode. These OMPs were added as individual compounds and in a mixture. Short experiments (8 days) were performed to avoid masking of OMP removal processes by light and nutrient limitation. The results show that diclofenac, clarithromycin, and benzotriazole were mainly removed by photodegradation (diclofenac), biodegradation (benzotriazole), or a combination of these two processes (clarithromycin). Peroxidase was involved in intracellular and extracellular biodegradation when benzotriazole was present as individual compound. Carbamazepine, metoprolol and mecoprop showed no biodegradation or photodegradation, and neglectable removal (<5%) by bioadsorption and bioaccumulation. Using an OMP mixture had an adverse effect on the photodegradation of clarithromycin and diclofenac, with reduced first-order kinetic constants compared to the individual compounds. Benzotriazole biodegradation was inhibited by the presence of the OMP mixture. This indicates that the presence of OMPs inhibits the photodegradation and biodegradation of some individual OMPs. These results will improve our understanding of removal processes of individual and mixtures of OMPs by microalgae-based technologies for wastewater treatment.
Topics: Carbamazepine; Chlorophyceae; Clarithromycin; Diclofenac; Metoprolol; Microalgae; Scenedesmus; Wastewater; Water Pollutants, Chemical
PubMed: 35679938
DOI: 10.1016/j.scitotenv.2022.156526 -
The Cochrane Database of Systematic... Aug 2018Postoperative administration of non-steroidal anti-inflammatory drugs (NSAIDs) reduces patient opioid requirements and, in turn, reduces the incidence and severity of... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Postoperative administration of non-steroidal anti-inflammatory drugs (NSAIDs) reduces patient opioid requirements and, in turn, reduces the incidence and severity of opioid-induced adverse events (AEs).
OBJECTIVES
To assess the analgesic efficacy and adverse effects of single-dose intravenous diclofenac, compared with placebo or an active comparator, for moderate to severe postoperative pain in adults.
SEARCH METHODS
We searched the following databases without language restrictions: the Cochrane Central Register of Controlled Trials (Cochrane Register of Studies Online), MEDLINE, and Embase on 22 May 2018. We checked clinical trials registers and reference lists of retrieved articles for additional studies.
SELECTION CRITERIA
We included randomized trials that compared a single postoperative dose of intravenous diclofenac with placebo or another active treatment, for treating acute postoperative pain in adults following any surgery.
DATA COLLECTION AND ANALYSIS
We used standard methodological procedures expected by Cochrane. Two review authors independently considered trials for review inclusion, assessed risk of bias, and extracted data.Our primary outcome was the number of participants in each arm achieving at least 50% pain relief over a four- and six-hour period.Our secondary outcomes were time to, and number of participants using rescue medication; withdrawals due to lack of efficacy, AEs, and for any cause; and number of participants experiencing any AE, serious AEs (SAEs), and NSAID-related AEs. We performed a post hoc analysis of opioid-related AEs, to enable indirect comparisons with other analyses of postoperative analgesics.For subgroup analysis, we planned to analyze different doses and formulations of parenteral diclofenac separately.We assessed the overall quality of the evidence for each outcome using GRADE and created two 'Summary of findings' tables.
MAIN RESULTS
We included eight studies, involving 1756 participants undergoing various surgeries (dental, mixed minor, abdominal, and orthopedic), with 20 to 175 participants receiving intravenous diclofenac in each study. Mean study population ages ranged from 24.5 years to 54.5 years. Intravenous diclofenac doses varied among and within studies, ranging from 3.75 mg to 75 mg. Five studies assessed newer formulations of parenteral diclofenac that could be administered as an undiluted intravenous bolus. Most studies had an unclear risk of bias for several domains and a high risk of bias due to small sample size. The overall quality of evidence for each outcome was generally low for reasons including unclear risk of bias in studies, imprecision, and low event numbers.Primary outcomeThree studies (277 participants) produced a number needed to treat for an additional beneficial outcome (NNTB) for at least 50% of maximum pain relief versus placebo of 2.4 (95% confidence interval (CI) 1.9 to 3.1) over four hours (low-quality evidence). Four studies (436 participants) produced an NNTB of 3.8 versus placebo (95% CI 2.9 to 5.9) over six hours (low-quality evidence). No studies provided data for the comparison of intravenous diclofenac with another NSAID over four hours. At six hours there was no difference between intravenous diclofenac and another NSAID (low-quality evidence).Secondary outcomesFor secondary efficacy outcomes, intravenous diclofenac was generally superior to placebo and similar to other NSAIDs.For time to rescue medication, comparison of intravenous diclofenac versus placebo demonstrated a median of 226 minutes for diclofenac versus 80 minutes for placebo (5 studies, 542 participants, low-quality evidence). There were insufficient data for pooled analysis for comparisons of diclofenac with another NSAID (very low-quality evidence).For the number of participants using rescue medication, two studies (235 participants) compared diclofenac with placebo. The number needed to treat to prevent one additional harmful event (NNTp) (here, the need for rescue medication) compared with placebo was 3.0 (2.2 to 4.5, low-quality evidence). The comparison of diclofenac with another NSAID included only one study (98 participants). The NNTp was 4.5 (2.5 to 33) for ketorolac versus diclofenac (very low-quality evidence).The numbers of participants withdrawing were generally low and inconsistently reported (very low-quality evidence). Participant withdrawals were: 6% (8/140) diclofenac versus 5% (7/128) placebo, and 9% (8/87) diclofenac versus 7% (6/82) another NSAID for lack of efficacy; 2% (4/211) diclofenac versus 0% (0/198) placebo, and 3% (4/138) diclofenac versus 2% (2/129) another NSAID due to AEs; and 11% (21/191) diclofenac versus 17% (30/179) placebo, and 18% (21/118) diclofenac versus 15% (17/111) another NSAID for any cause.Overall adverse event rates were similar between intravenous diclofenac and placebo (71% in both groups, 2 studies, 296 participants) and between intravenous diclofenac and another NSAID (55% and 58%, respectively, 2 studies, 265 participants) (low-quality evidence for both comparisons). Serious and specific AEs were rare, preventing meta-analysis.There were sufficient data for a dose-effect analysis for our primary outcome for only one alternative dose, 18.75 mg. Analysis of the highest dose employed in each study demonstrated a relative benefit compared with placebo of 1.9 (1.4 to 2.4), whereas for the group receiving 18.75 mg, the relative benefit versus placebo was 1.6 (1.2 to 2.1, 2 studies). Compared to another NSAID, the high-dose analysis demonstrated a relative benefit of 0.9 (0.8 to 1.1), for the group receiving 18.75 mg, the relative benefit was 0.78 (0.65 to 0.93). For direct comparison of high dose versus 18.75 mg, the proportion of participants with at least 50% pain relief was 66% (90/137) for the high-dose arm versus 57% (77/135) in the low-dose arm. There were insufficient data for subgroup meta-analysis of different diclofenac formulations.
AUTHORS' CONCLUSIONS
The amount and quality of evidence for the use of intravenous diclofenac as a treatment for postoperative pain is low. The available evidence indicates that postoperative intravenous diclofenac administration offers good pain relief for the majority of patients, but further research may impact this estimate. Adverse events appear to occur at a similar rate to other NSAIDs. Insufficient information is available to assess whether intravenous diclofenac has a different rate of bleeding, renal dysfunction, or cardiovascular events versus other NSAIDs. There was insufficient information to evaluate the efficacy and safety of newer versus traditional formulations of intravenous diclofenac. There was a lack of studies in major and cardiovascular surgeries and in elderly populations, which may be at increased risk for adverse events.
Topics: Acute Pain; Adult; Analgesics, Opioid; Anti-Inflammatory Agents, Non-Steroidal; Diclofenac; Humans; Injections, Intravenous; Pain, Postoperative; Placebos; Randomized Controlled Trials as Topic
PubMed: 30153336
DOI: 10.1002/14651858.CD012498.pub2 -
International Journal of Molecular... Jan 2023Free drug concentration in the blood sera is crucial for its appropriate activity. Serum albumin, the universal blood carrier protein, is responsible for transporting...
Free drug concentration in the blood sera is crucial for its appropriate activity. Serum albumin, the universal blood carrier protein, is responsible for transporting drugs and releasing them into the bloodstream. Therefore, a drug's binding to SA is especially important for its bioavailability and it is a key problem in the drug design process. In this paper, we present crystal structures of three animal serum albumin complexes: ovine, caprine, and leporine, with diclofenac, a popular non-steroidal anti-inflammatory drug that is used in therapy of chronic and acute pain. Details of diclofenac binding mode by the presented serum albumins are compared with analogous complexes of human and equine serum albumins. The analysis of the occupied binding pockets in crystal structures of the investigated serum albumins from different mammals shows that they have two common and a number of unique diclofenac binding sites. The most intriguing is the fact that the albumins from the described species are able to bind different numbers of molecules of this popular anti-inflammatory drug, but none of the binding sites overlap with ones in the human serum albumin.
Topics: Animals; Sheep; Horses; Humans; Diclofenac; Serum Albumin; Goats; Anti-Inflammatory Agents, Non-Steroidal; Binding Sites; Albumins; Protein Binding
PubMed: 36675044
DOI: 10.3390/ijms24021534 -
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 -
Pain Medicine (Malden, Mass.) Feb 2021To compare the efficacy and safety of celecoxib and diclofenac sodium in patients with knee osteoarthritis (KOA). (Meta-Analysis)
Meta-Analysis
OBJECTIVE
To compare the efficacy and safety of celecoxib and diclofenac sodium in patients with knee osteoarthritis (KOA).
METHODS
Clinical controlled trials (CCTs) and randomized controlled trials (RCTs) from online databases comparing the efficacy of celecoxib and diclofenac sodium in the treatment of KOA were retrieved. The main outcomes included the treatment effect, C-reactive protein (CRP) level, erythrocyte sedimentation rate (ESR), visual analog scale (VAS) score, and complication rate. The Cochrane risk of bias (ROB) tool in Review Manager 5.3.5 was used to assess methodological quality.
RESULTS
Twelve studies (N = 2,350) were included in this meta-analysis. The meta-analysis indicated that celecoxib reduced pain more effectively than diclofenac sodium in patients with KOA, as evaluated by the VAS score. In addition, celecoxib has certain advantages in terms of better treatment effects and greater reductions in the ESR, CRP level, and complication rate.
CONCLUSIONS
Celecoxib is superior to diclofenac sodium in the treatment of KOA. However, well-designed and high-quality RCTs are still needed.
Topics: Celecoxib; Diclofenac; Humans; Osteoarthritis, Knee; Pain; Treatment Outcome
PubMed: 32797224
DOI: 10.1093/pm/pnaa230 -
Primary Health Care Research &... Dec 2021The most frequently prescribed analgesic drugs in primary care centers in Turkey are diclofenac and paracetamol, respectively. In this study, we aimed to compare...
INTRODUCTION
The most frequently prescribed analgesic drugs in primary care centers in Turkey are diclofenac and paracetamol, respectively. In this study, we aimed to compare paracetamol-included prescriptions (PIP) and diclofenac-included prescriptions (DIP) generated for adult patients in primary care.
METHODS
In this cross-sectional study, PIPs (n = 280 488) and DIPs (n = 337 935) created for adults by systematic sampling among primary care physicians working in Istanbul in 2016 (n = 1431) were examined. The demographic characteristics, diagnoses, and additional drugs in PIPs and DIPs were compared.
RESULTS
Women constituted the majority in both groups (69.8% and 67.9%, respectively; P < 0.05), and mean age at PIP (52.6 ± 18.8 years) was lower compared to DIP (56.3 ± 16.1 years), (P < 0.05). In single-diagnosis prescriptions, 11 of the 15 most common diagnoses in PIP were respiratory tract infections (47.9%); three pain-related diagnoses formed 4.6% of all these prescriptions. In DIP, the number of pain-related diagnoses, mostly of musculoskeletal origin, was eight (28.5%); four diagnoses (7.8%) were upper respiratory tract infections. While hypertension was the third most common diagnosis in PIP (6.1%), it was ranked first in DIP (8.0%). The percentage of prescriptions with additional analgesic (14.0% versus 18.3%, P < 0.001), proton-pump inhibitor (13.8% versus 18.4%; P < 0.001), and antihypertensive (22.0% versus 24.8%, P < 0.001) was lower in PIP compared to DIP. However, the percentage of prescriptions with antibiotics (31.3% versus 14.7%, P < 0.001) was higher in PIP.
CONCLUSION
Paracetamol appears to be preferred mostly in upper respiratory tract infections compared to the preference of diclofenac rather in painful/inflammatory musculoskeletal conditions. The presence of hypertension among the most commonly encountered diagnoses for these analgesic drugs points to challenges in establishing the diagnosing-treatment match and indicates potential irrational prescribing practice, especially for interactions.
Topics: Acetaminophen; Adult; Cross-Sectional Studies; Diclofenac; Female; Humans; Practice Patterns, Physicians'; Primary Health Care; Respiratory Tract Infections
PubMed: 34852871
DOI: 10.1017/S1463423621000797 -
Genes Jan 2023Nonsteroidal anti-inflammatory drugs (NSAIDs) and glucocorticoids (GCs) are often used to treat articular-skeletal disorders. The extended use of NSAIDs and GCs have...
Nonsteroidal anti-inflammatory drugs (NSAIDs) and glucocorticoids (GCs) are often used to treat articular-skeletal disorders. The extended use of NSAIDs and GCs have adverse effects on bone metabolism, reducing bone quality and impairing fracture healing. In the present study, we used mouse pre-osteoblast cells MC3T3-E1 to demonstrate the effects of diclofenac (DF) and methylprednisolone (MP) on cell proliferation and gene expression. Cells were incubated with three doses of DF or MP: 0.5 µM, 5 µM, and 50 µM. MP decreased cell viability even after 24 h, but DF inhibited cell viability after only seven days of treatment. The cells were lysed after one, two, three, and seven days of treatment, and gene expression was analyzed by reverse transcription and quantitative PCR (RT-qPCR) assays. DF did not significantly affect the expression of the osteogenic marker genes. MP modified the expression of , , and . We concluded that MP is a more potent inhibitor of mouse pre-osteoblast differentiation and viability than is DF. Our results suggest that prolonged DF treatment could be less harmful to osteoblasts than MP treatment.
Topics: Animals; Mice; Methylprednisolone; Diclofenac; Cell Differentiation; Glucocorticoids; Gene Expression; Anti-Inflammatory Agents, Non-Steroidal
PubMed: 36672925
DOI: 10.3390/genes14010184 -
Archives of Toxicology Jun 2018The pharmacokinetics of diclofenac were investigated following single oral doses of 10 mg/kg to chimeric liver humanized and murinized FRG and C57BL/6 mice. In...
The pharmacokinetics of diclofenac were investigated following single oral doses of 10 mg/kg to chimeric liver humanized and murinized FRG and C57BL/6 mice. In addition, the metabolism and excretion were investigated in chimeric liver humanized and murinized FRG mice. Diclofenac reached maximum blood concentrations of 2.43 ± 0.9 µg/mL (n = 3) at 0.25 h post-dose with an AUC of 3.67 µg h/mL and an effective half-life of 0.86 h (n = 2). In the murinized animals, maximum blood concentrations were determined as 3.86 ± 2.31 µg/mL at 0.25 h post-dose with an AUC of 4.94 ± 2.93 µg h/mL and a half-life of 0.52 ± 0.03 h (n = 3). In C57BL/6J mice, mean peak blood concentrations of 2.31 ± 0.53 µg/mL were seen 0.25 h post-dose with a mean AUC of 2.10 ± 0.49 µg h/mL and a half-life of 0.51 ± 0.49 h (n = 3). Analysis of blood indicated only trace quantities of drug-related material in chimeric humanized and murinized FRG mice. Metabolic profiling of urine, bile and faecal extracts revealed a complex pattern of metabolites for both humanized and murinized animals with, in addition to unchanged parent drug, a variety of hydroxylated and conjugated metabolites detected. The profiles in humanized mice were different to those of both murinized and wild-type animals, e.g., a higher proportion of the dose was detected in the form of acyl glucuronide metabolites and much reduced amounts as taurine conjugates. Comparison of the metabolic profiles obtained from the present study with previously published data from C57BL/6J mice and humans revealed a greater, though not complete, match between chimeric humanized mice and humans, such that the liver humanized FRG model may represent a model for assessing the biotransformation of such compounds in humans.
Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Area Under Curve; Bile; Biotransformation; Chimera; Diclofenac; Feces; Half-Life; Humans; Male; Mice; Mice, Inbred C57BL; Species Specificity
PubMed: 29721588
DOI: 10.1007/s00204-018-2212-1