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Advanced Science (Weinheim,... Feb 2023CD73, a cell surface-bound nucleotidase, facilitates extracellular adenosine formation by hydrolyzing 5'-AMP to adenosine. Several studies have shown that CD73 plays an...
CD73, a cell surface-bound nucleotidase, facilitates extracellular adenosine formation by hydrolyzing 5'-AMP to adenosine. Several studies have shown that CD73 plays an essential role in immune escape, cell proliferation and tumor angiogenesis, making it an attractive target for cancer therapies. However, there are limited clinical benefits associated with the mainstream enzymatic inhibitors of CD73, suggesting that the mechanism underlying the role of CD73 in tumor progression is more complex than anticipated, and further investigation is necessary. In this study, CD73 is found to overexpress in the cytoplasm of pancreatic ductal adenocarcinoma (PDAC) cells and promotes metastasis in a nucleotidase-independent manner, which cannot be restrained by the CD73 monoclonal antibodies or small-molecule enzymatic inhibitors. Furthermore, CD73 promotes the metastasis of PDAC by binding to the E3 ligase TRIM21, competing with the Snail for its binding site. Additionally, a CD73 transcriptional inhibitor, diclofenac, a non-steroidal anti-inflammatory drug, is more effective than the CD73 blocking antibody for the treatment of PDAC metastasis. Diclofenac also enhances the therapeutic efficacy of gemcitabine in the spontaneous KPC (LSL-Kras , LSL-Trp53 , and Pdx-1-Cre) pancreatic cancer model. Therefore, diclofenac may be an effective anti-CD73 therapy, when used alone or in combination with gemcitabine-based chemotherapy regimen, for metastatic PDAC.
Topics: Humans; Carcinoma, Pancreatic Ductal; Diclofenac; Gemcitabine; Pancreatic Neoplasms; Nucleotidases
PubMed: 36563135
DOI: 10.1002/advs.202206335 -
Drugs in R&D Jun 2016According to health technology assessment, patients deserve the best medicine. The development of drugs associated with solubility enhancers, such as cyclodextrins,... (Review)
Review
BACKGROUND
According to health technology assessment, patients deserve the best medicine. The development of drugs associated with solubility enhancers, such as cyclodextrins, represents a measure taken in order to improve the management of patients. Different drugs, such as estradiol, testosterone, dexamethasone, opioids, non-steroidal anti-inflammatories (NSAIDs; i.e. diclofenac), and progesterone are associated with cyclodextrins. Products containing the association of diclofenac/cyclodextrins are available for subcutaneous, intramuscular, and intravenous administration in doses that range from 25 to 75 mg. Medicinal products containing the association of progesterone/cyclodextrins are indicated for intramuscular and subcutaneous injection at a dose equal to 25 mg.
OBJECTIVES AND METHODS
The effects of cyclodextrins have been discussed in the solubility profile and permeability through biological membranes of drug molecules. A literature search was performed in order to give an overview of the pharmacokinetic characteristics, and efficacy and safety profiles of diclofenac/hydroxypropyl-β-cyclodextrin (HPβCD) and progesterone/HPβCD associations.
RESULTS
The results of more than 20 clinical studies were reviewed. It was suggested that the new diclofenac/HPβCD formulation gives a rapid and effective response to acute pain and, furthermore, has pharmacokinetic and efficacy/safety profiles comparable to other medicinal products not containing cyclodextrins. One of the principal aspects of these new diclofenac formulations is that in lowering the dose (lower than 50 mg) the drugs could be more tolerable, especially in patients with comorbid conditions. Moreover, results of studies investigating the characteristics of progesterone and cyclodextrins showed that the new formulation (progesterone/HPβCD 25 mg solution) has the same bioavailability as other products containing progesterone. It is more rapidly absorbed and allows the achievement of peak plasma concentrations in a shorter time. Finally, the new formulation of progesterone was shown to be safe and not inferior to other products already on the market, with the exception of progesterone administered vaginally.
CONCLUSIONS
As shown by the results of clinical studies presented in this review, the newly approved medicines containing cyclodextrins have been found to be as effective and as well-tolerated as other medicinal products that do not contain cyclodextrins. Moreover, the newly approved lower dose of diclofenac associated with cyclodextrins is consistent with the European Medicines Agency recommendations reported in the revision of the Assessment Report for Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) and Cardiovascular Risk. Finally, the use of cyclodextrins led to significant increases in solubility and bioavailability of drugs, such as diclofenac and progesterone, and improvement in the efficacy and safety of these drugs.
Topics: 2-Hydroxypropyl-beta-cyclodextrin; Biological Availability; Cyclodextrins; Diclofenac; Drug Compounding; Drug Therapy, Combination; Female; Humans; Male; Pain; Permeability; Pregnancy; Progesterone; Solubility; Treatment Outcome; beta-Cyclodextrins
PubMed: 26939533
DOI: 10.1007/s40268-016-0123-2 -
Molecules (Basel, Switzerland) Oct 2019The presence of pharmaceutical compounds in the environment is a reality that calls for more efficient water treatment technologies. Photocatalysis is a powerful... (Review)
Review
The presence of pharmaceutical compounds in the environment is a reality that calls for more efficient water treatment technologies. Photocatalysis is a powerful technology available but the high energy costs associated with the use of UV irradiation hinder its large scale implementation. More sustainable and cheaper photocatalytic processes can be achieved by improving the sunlight harvesting and the synthesis of semiconductor/carbon composites has proved to be a promising strategy. Carbamazepine, diclofenac, and sulfamethoxazole were selected as target pharmaceuticals due to their recalcitrant behavior during conventional wastewater treatment and persistence in the environment, as properly reviewed. The literature data on the photocatalytic removal of carbamazepine, diclofenac, and sulfamethoxazole by semiconductor/carbon materials was critically revised to highlight the role of the carbon in the enhanced semiconductor performance under solar irradiation. Generally it was demonstrated that carbon materials induce red-shift absorption and they contribute to more effective charge separation, thus improving the composite photoactivity. Carbon was added as a dopant (C-doping) or as support or doping materials (i.e nanoporous carbons, carbon nanotubes (CNTs), graphene, and derived materials, carbon quantum dots (CQDs), and biochars) and in the large majority of the cases, TiO was the semiconductor tested. The specific role of carbon materials is dependent on their properties but even the more amorphous forms, like nanoporous carbons or biochars, allow to prepare composites with improved properties compared to the bare semiconductor. The self-photocatalytic activity of the carbon materials was also reported and should be further explored. The removal and mineralization rates, as well as degradation pathways and toxicity of the treated solutions were also critically analyzed.
Topics: Carbamazepine; Catalysis; Diclofenac; Graphite; Photochemical Processes; Semiconductors; Sulfamethoxazole; Sunlight; Water Pollutants, Chemical
PubMed: 31618947
DOI: 10.3390/molecules24203702 -
Ecotoxicology and Environmental Safety Nov 2022Diclofenac is an emerging surface water contaminant, yet the environmental impact of its degradation products remains elusive. The current study focuses on...
Diclofenac is an emerging surface water contaminant, yet the environmental impact of its degradation products remains elusive. The current study focuses on mineralogy-controlled diclofenac photo-degradation and its potential health impacts. Under irradiated conditions, we studied the effects of kaolinite, hematite, and anatase on diclofenac degradation. Our results showed that kaolinite doubled the diclofenac degradation rate, which can be attributed to the high catalytic effect, mediated via increased surface area and pore size of mineral surface in the low pH. Conversely, anatase, a crystal phase of titanium dioxide (TiO), diminished the diclofenac degradation compared to treatments without TiO. Hematite, on the other hand, showed no effect on diclofenac degradation. Photo-degradation products also varied with the mineral surface. We further assessed in vitro toxicological effects of photo-degraded products on two human cell lines, HEK293T and HepG2. Biological assays confirmed that photo-degraded compound 6 (1-(2,6-dichlorophenyl)indolin-2-one) decreased HEK293T cell survival significantly (p < 0.05) when compared to diclofenac in all concentrations. At lower concentrations, inhibition of HEK293T cells caused by compounds 4 (2-(8-chloro-9H-carbazol-1-yl)acetic acid), and 5 (2-(9H-carbazol-1-yl)acetic acid) was greater than diclofenac. Compound 7 (1-phenylindolin-2-one) was toxic only at 250 µM. Additionally, compound 6 decreased HepG2 cell viability significantly when compared to diclofenac. Overall, our data highlighted that mineralogy plays a vital role in environmental diclofenac transformation and its photo-degraded products. Some photo-degraded compounds can be more cytotoxic than the parent compound, diclofenac.
Topics: Humans; Diclofenac; Kaolin; HEK293 Cells; Titanium; Water Pollutants, Chemical
PubMed: 36201921
DOI: 10.1016/j.ecoenv.2022.114138 -
Physiological Reports Sep 2023The aim of our study is to investigate the electrophysiological and anti-inflammatory effects of diclofenac potassium on epileptiform activity, which is the liquid form...
The aim of our study is to investigate the electrophysiological and anti-inflammatory effects of diclofenac potassium on epileptiform activity, which is the liquid form of diclofenac, and frequently used clinically for inflammatory process by inhibiting cyclooxygenase enzyme (COX). Wistar rats aged 2-4 months were divided into Epilepsy, Diazepam, Diclofenac potassium, and Diazepam+diclofenac potassium groups. Diazepam and diclofenac potassium were administered intraperitoneally 30 min after the epileptiform activity was created with penicillin injected intracortically under anesthesia. After the electrophysiological recording was taken in the cortex for 125 min, interleukin-1β (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) were evaluated by the ELISA in the serums. No change was observed between the groups in serum IL-1β, IL-6, and TNF-α values. It was observed that the co-administration of diclofenac potassium and diazepam at 51-55, 56-60, 61-65, 111-115, and 116-120 min was more effective in reducing spike amplitude than diclofenac potassium alone (p < 0.05). Single-dose diclofenac potassium did not have an anti-inflammatory effect in epileptiform activity but both diazepam and diclofenac potassium reduced the epileptiform activity.
Topics: Rats; Animals; Rats, Wistar; Diclofenac; Interleukin-6; Tumor Necrosis Factor-alpha; Cyclooxygenase 2; Diazepam; Anti-Inflammatory Agents
PubMed: 37688418
DOI: 10.14814/phy2.15800 -
Medicina (Kaunas, Lithuania) May 2024: Stem cell-based regeneration strategies have shown therapeutic efficacy in various fields of regenerative medicine. These include bone healing after bone augmentation,...
: Stem cell-based regeneration strategies have shown therapeutic efficacy in various fields of regenerative medicine. These include bone healing after bone augmentation, often complicated by pain, which is managed by using nonsteroidal anti-inflammatory drugs (NSAIDs). However, information is limited about how NSAIDs affect the therapeutic potential of stem cells. : We investigated the effects of ibuprofen and diclofenac on the characteristics, morphology, and immunophenotype of human mesenchymal stromal cells isolated from the dental pulp () and cultured in vitro, as well as their effects on the expression of angiogenic growth factors ( and ) and selected genes in apoptosis signalling pathways (, , , , and 2). : Ibuprofen and diclofenac significantly reduced the viability of DPSCs, while the expression of mesenchymal stem cell surface markers was unaffected. Both ibuprofen and diclofenac treatment significantly upregulated the expression of , while the expression of remained unchanged. Ibuprofen significantly altered the expression of several apoptosis-related genes, including the upregulation of and , with decreased expression. BAK, CASP3, CASP9, and BCL2 expressions were significantly increased in the diclofenac-treated DPSCs, while no difference was demonstrated in BAX expression. : Our results suggest that concomitant use of the NSAIDs ibuprofen or diclofenac with stem cell therapy may negatively impact cell viability and alter the expression of apoptosis-related genes, affecting the efficacy of stem cell therapy.
Topics: Humans; Dental Pulp; Diclofenac; Apoptosis; Ibuprofen; Cell Survival; Anti-Inflammatory Agents, Non-Steroidal; Stem Cells; Mesenchymal Stem Cells; Cells, Cultured
PubMed: 38792973
DOI: 10.3390/medicina60050787 -
The Cochrane Database of Systematic... Dec 2022Cataract surgery is the most common ambulatory incisional surgery performed in the USA. Cystoid macular edema (CME), the accumulation of fluid in the central retina due... (Review)
Review
BACKGROUND
Cataract surgery is the most common ambulatory incisional surgery performed in the USA. Cystoid macular edema (CME), the accumulation of fluid in the central retina due to leakage from dilated capillaries, is the most common cause of vision impairment following cataract surgery. Acute CME, defined as CME of less than four months' duration, often resolves spontaneously. CME that persists for four months or longer is termed chronic CME. Non-steroidal anti-inflammatory drugs (NSAIDs) have been used to treat CME. This update adds new evidence and analyses to the previously published review.
OBJECTIVES
To examine the effectiveness of NSAIDs in the treatment of CME following cataract surgery.
SEARCH METHODS
We searched the CENTRAL (2022, Issue 3); Ovid MEDLINE; Embase; PubMed; LILACS; mRCT (discontinued in 2014, last searched August 2011), ClinicalTrials.gov, and WHO ICTRP databases. We did not use any date or language restrictions in the electronic search for trials. We last searched the electronic databases on 20 March 2022. SELECTION CRITERIA: We included randomized controlled trials evaluating the effects of NSAIDs for CME following cataract surgery.
DATA COLLECTION AND ANALYSIS
Two review authors independently screened all titles and abstracts, reviewed full-text publications against eligibility criteria, independently extracted data from newly included trials and assessed risk of bias for each included trial. We contacted trial authors for clarification or to request missing information. We provided a narrative synthesis of all included trials and their results. For continuous and dichotomous outcomes, we separately performed pooled analysis and reported mean difference (MD) and risk ratio (RR) as well as the associated 95% confidence interval (CI) whenever feasible. Two review authors independently graded the overall certainty of the evidence for each outcome using the GRADE approach.
MAIN RESULTS
We included nine trials with a total of 390 participants (393 eyes). Study participants' mean age was 72.2 years (interquartile range [IQR] 68.8 to 73.6) and 72% were women (IQR 69% to 74%). Three trials included participants with acute CME, and four included participants with chronic CME; the remaining two trials enrolled both participants with acute and chronic CME or participants with unknown CME duration. We assessed trials as having unclear (33%) or high risk of bias (67%). Visual improvement of two or more lines at the end of treatment Data from one trial in participants with acute CME show no treatment effect of topical ketorolac compared to placebo (RR 2.00, 95% CI 0.46 to 8.76; 22 participants). Data from a three-arm trial in participants with acute CME demonstrate that, when compared with topical prednisolone, topical ketorolac (RR 1.33, 95% CI 0.58 to 3.07; 17 participants) or topical ketorolac and prednisolone combination therapy (RR 1.78, 95% CI 0.86 to 3.69; 17 participants) may have little or no effect on visual improvement. Results of subgroup analysis from two studies in participants with chronic CME suggest that, after treatment for 90 days or longer, NSAIDs may increase participants' likelihood of visual improvement by 1.87 fold (RR 2.87, 95% CI 1.58 to 5.22; I = 33%; 2 trials, 121 participants) relative to placebo. However, there was no evidence of treatment effects in the subgroup with two months of treatment or less (RR 0.72, 95% CI 0.30 to 1.73; P = 0.19, I = 41%; 2 trials, 34 participants). Overall, this evidence is very low certainty. A single-study estimate in patients with mixed CME indicates that topical diclofenac may increase the likelihood of visual improvement by 40% when compared to topical ketorolac (RR 1.40, 95% CI 1.02 to 1.94; 68 participants). However, the same trial reported no difference between the groups in mean final visual acuity in Snellen lines (MD 0.40, 95% CI -0.93 to 1.73). A three-arm trial in patients with mixed CME reporting visual changes in ETDRS letters in comparisons between ketorolac and diclofenac (34 participants) or bromfenac (34 participants) suggests no evidence of effects. Overall, NSAIDs may slightly improve visual acuity in participants with mixed CME but the evidence is very uncertain. Persistence of improvement of vision one month after discontinuation of treatment One trial of participants with chronic CME tested oral indomethacin (RR 0.40, 95% CI 0.10 to 1.60; 20 participants) and the other compared topical ketorolac to placebo (RR 4.00, 95% CI 0.51 to 31.1; 26 participants). While there is no evidence of treatment effects, evidence suggests substantial between-group heterogeneity (P = 0.07, I = 69.9%; very low-certainty evidence). None of the trials in patients with acute or mixed CME reported this outcome. Proportion of participants with improvement in leakage on fundus fluorescein angiography One three-arm trial in participants with acute CME shows that, when compared with topical prednisolone, there is no treatment benefit of topical ketorolac (RR 1.11, 95% CI 0.45 to 2.75; 17 participants) or topical ketorolac and topical prednisolone combination therapy (RR 1.56, 95% CI 0.72 to 3.38; 17 participants). This evidence is very low certainty. The combined estimate from two trials in participants with chronic CME indicates NSAIDs have little to no effect over placebo on improving leakage (RR 1.93, 95% CI 0.62 to 6.02; 40 participants; very low-certainty evidence). Neither of the trials in patients with mixed CME reported this outcome. Proportion of participants with improved contrast sensitivity Very low-certainty evidence from one trial in participants with acute CME shows no treatment benefit of ketorolac (RR 1.11, 95% CI 0.45 to 2.75; 17 participants) or ketorolac and prednisolone combination therapy (RR 1.78, 95% CI 0.86 to 3.69; 17 participants) compared with topical prednisolone. None of the trials in patients with chronic or mixed CME reported this outcome. Proportion of participants with improved central macular thickness on optical coherence tomography; measures of quality of life No included trial reported these outcomes. Adverse effects Most trials observed no differences in ocular adverse events, such as corneal toxicity or elevated intraocular pressure, between comparison groups.
AUTHORS' CONCLUSIONS
Evidence on effects of NSAIDs in patients with CME is very uncertain and further investigation is warranted. Our findings are limited by small sample sizes, and heterogeneity in interventions, assessments, and reporting of clinically important outcomes.
Topics: Humans; Female; Aged; Male; Macular Edema; Anti-Inflammatory Agents, Non-Steroidal; Ketorolac; Diclofenac; Quality of Life; Cataract; Prednisolone
PubMed: 36520144
DOI: 10.1002/14651858.CD004239.pub4 -
Texas Heart Institute Journal Jan 2023Diclofenac is a widely used analgesic, anti-inflammatory, antipyretic drug. In several case reports, its use was associated with the occurrence of Kounis syndrome. The... (Review)
Review
BACKGROUND
Diclofenac is a widely used analgesic, anti-inflammatory, antipyretic drug. In several case reports, its use was associated with the occurrence of Kounis syndrome. The aim of this review was to investigate and summarize published cases of Kounis syndrome suspected to be associated with the use of diclofenac.
METHODS
Electronic searches were conducted in PubMed/MEDLINE, Scopus, Web of Science, Google Scholar, and the Serbian Citation Index.
RESULTS
Twenty publications describing the 20 patients who met inclusion criteria were included in the systematic review. Specified patient ages ranged from 34 to 81 years. Eighteen (90.0%) patients were male. Five patients (25.0%) reported a previous reaction to diclofenac. Reported time from the used dose of diclofenac to onset of the first reaction symptoms ranged from immediately to 5 hours. Diclofenac caused both type I and type II Kounis syndrome, with the presence of various cardiovascular, gastrointestinal, dermatologic, and respiratory signs and symptoms. Most patients experienced hypotension (n = 15 [75.0%]) and chest pain (n = 12 [60.0%]). The most frequently reported finding on electrocardiogram was ST-segment elevations (n = 17 [85.0%]). Coronary angiogram showed normal coronary vessels in 9 patients (45.0%), with some pathologic findings in 8 patients (40.0%).
CONCLUSION
Clinicians should be aware that Kounis syndrome may be an adverse effect of diclofenac. Prompt recognition and withdrawal of the drug, with treatment of both allergic and cardiac symptoms simultaneously, is important.
Topics: Humans; Male; Adult; Middle Aged; Aged; Aged, 80 and over; Female; Diclofenac; Kounis Syndrome; Electrocardiography; Coronary Angiography
PubMed: 36735919
DOI: 10.14503/THIJ-21-7802 -
Environmental Science and Pollution... Mar 2023Diclofenac, ibuprofen, and carbamazepine are three of the most widely detected and most concerning pharmaceutical residues in aquatic ecosystems. The aim of this study...
Diclofenac, ibuprofen, and carbamazepine are three of the most widely detected and most concerning pharmaceutical residues in aquatic ecosystems. The aim of this study was to identify bacteria that may be involved in their degradation from a bacterial biofilm. Selective enrichment cultures in mineral salt solution containing pharmaceutical compounds as sole source of carbon and energy were set up, and population dynamics were monitored using shotgun metagenome sequencing. Bacterial genomes were reconstructed using genome-resolved metagenomics. Thirty bacterial isolates were obtained, identified at species level, and tested regarding pharmaceutical biodegradation at an initial concentration of 1.5 mg l. The results indicated that most probably diclofenac biodegrading cultures consisted of members of genera Ferrovibrio, Hydrocarboniphaga, Zavarzinia, and Sphingopyxis, while in ibuprofen biodegradation Nocardioides and Starkeya, and in carbamazepine biodegradation Nocardioides, Pseudonocardia, and Sphingopyxis might be involved. During the enrichments, compared to the initial state the percentage relative abundance of these genera increased up to three orders of magnitude. Except Starkeya, the genomes of these bacteria were reconstructed and annotated. Metabolic analyses of the annotated genomes indicated that these bacteria harbored genes associated with pharmaceutical biodegradation. Stenotrophomonas humi DIC_5 and Rhizobium daejeonense IBU_18 isolates eliminated diclofenac and ibuprofen during the tests in the presence of either glucose (3 g l) or in R2A broth. Higher than 90% concentration reduction was observed in the case of both compounds.
Topics: Ibuprofen; Diclofenac; Ecosystem; Carbamazepine; Bacteria; Biodegradation, Environmental; Groundwater; Biofilms; Pharmaceutical Preparations
PubMed: 36690856
DOI: 10.1007/s11356-022-24975-6 -
British Journal of Cancer Aug 2023B-raf inhibitors (BRAFi) are effective for BRAF-mutated papillary (PTC) and anaplastic (ATC) thyroid carcinomas, although acquired resistance impairs tumour cells'...
BACKGROUND
B-raf inhibitors (BRAFi) are effective for BRAF-mutated papillary (PTC) and anaplastic (ATC) thyroid carcinomas, although acquired resistance impairs tumour cells' sensitivity and/or limits drug efficacy. Targeting metabolic vulnerabilities is emerging as powerful approach in cancer.
METHODS
In silico analyses identified metabolic gene signatures and Hif-1α as glycolysis regulator in PTC. BRAF-mutated PTC, ATC and control thyroid cell lines were exposed to HIF1A siRNAs or chemical/drug treatments (CoCl, EGF, HGF, BRAFi, MEKi and diclofenac). Genes/proteins expression, glucose uptake, lactate quantification and viability assays were used to investigate the metabolic vulnerability of BRAF-mutated cells.
RESULTS
A specific metabolic gene signature was identified as a hallmark of BRAF-mutated tumours, which display a glycolytic phenotype, characterised by enhanced glucose uptake, lactate efflux and increased expression of Hif-1α-modulated glycolytic genes. Indeed, Hif-1α stabilisation counteracts the inhibitory effects of BRAFi on these genes and on cell viability. Interestingly, targeting metabolic routes with BRAFi and diclofenac combination we could restrain the glycolytic phenotype and synergistically reduce tumour cells' viability.
CONCLUSION
The identification of a metabolic vulnerability of BRAF-mutated carcinomas and the capacity BRAFi and diclofenac combination to target metabolism open new therapeutic perspectives in maximising drug efficacy and reducing the onset of secondary resistance and drug-related toxicity.
Topics: Humans; Diclofenac; Proto-Oncogene Proteins B-raf; Mutation; Protein Kinase Inhibitors; Thyroid Neoplasms; Glycolysis; Phenotype; Glucose; Cell Line, Tumor
PubMed: 37198319
DOI: 10.1038/s41416-023-02282-2