-
European Journal of Medicinal Chemistry Nov 2023A series of diclofenac hybrid molecules were synthesized and evaluated for their NO-inhibitory ability in LPS-induced RAW 264.7 macrophage cells. Among them, compound 1...
A series of diclofenac hybrid molecules were synthesized and evaluated for their NO-inhibitory ability in LPS-induced RAW 264.7 macrophage cells. Among them, compound 1 showed the highest NO-inhibitory ability (approximately 66%) and no significant cytotoxicity. Compound 1 exhibited superior NF-κB-inhibitory ability compared to diclofenac through the activation of Nrf2/HO-1 signaling pathway in RAW 264.7. 20 mg/kg compound 1 resulted in remarkable colitis improvement in dextran sulfate sodium (DSS)-induced mice model by up-regulating HO-1 and down-regulating phosphorylation level of NF-κB p65. Moreover, 50 mg/kg dose of compound 1 showed a lower ulcerogenic potential compared to diclofenac in rats. The diclofenac-eugenol hybrid (compound 1) may serve as a novel anti-inflammatory agent based on its role in inhibiting the NF-κB signaling pathway and activating HO-1 expression with no toxicity in vitro and in vivo.
Topics: Animals; Mice; Rats; Anti-Inflammatory Agents; Diclofenac; Eugenol; Heme Oxygenase-1; Lipopolysaccharides; NF-E2-Related Factor 2; NF-kappa B; RAW 264.7 Cells
PubMed: 37517204
DOI: 10.1016/j.ejmech.2023.115669 -
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 -
Journal of Drugs in Dermatology : JDD Oct 2023Porokeratosis is a rare group of acquired or hereditary dermatoses characterized by linear or annular plaques with a keratotic border. DSAP is the most common... (Review)
Review
Porokeratosis is a rare group of acquired or hereditary dermatoses characterized by linear or annular plaques with a keratotic border. DSAP is the most common porokeratosis, and lesions range from asymptomatic to pruritic circular pink to brown macules, papules, or plaques surrounded by a raised border. DSAP carries about 7.5-10% risk of malignant transformation to SCC or BCC. While in the past DSAP has been widely treated with topical diclofenac, ingenol mebutate, topical vitamin D analog, 5-fluorouracil, imiquimod, photodynamic therapy, retinoids, cryotherapy, and laser therapy, these therapies have shown limited efficacy and have caused adverse effects including inflammatory reactions, hyperpigmentation, pain, and erythema. Recently, a formulation of topical statin and cholesterol has surfaced as a new and promising treatment for DSAP which has shown clinical improvement with a tolerable adverse effect profile when compared to the current therapies. Of the 8 case studies with a total of 20 patients with DSAP, 90% (18/20) reported clinical improvement with various forms of topical statin therapy. While promising, larger randomized controlled trials are needed to evaluate the long-term use of topical statins for DSAP. J Drugs Dermatol. 2023;22(10): doi:10.36849/JDD.7540.
Topics: Humans; Porokeratosis; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Photochemotherapy; Imiquimod; Retinoids
PubMed: 37801522
DOI: 10.36849/JDD.7540 -
Photodiagnosis and Photodynamic Therapy Sep 2023Photodynamic therapy (PDT) is approved for treatment of actinic keratoses (AKs) and field-cancerisation. Pretreatment with pharmacological compounds holds potential to... (Review)
Review
BACKGROUND
Photodynamic therapy (PDT) is approved for treatment of actinic keratoses (AKs) and field-cancerisation. Pretreatment with pharmacological compounds holds potential to improve PDT efficacy, through direct interaction with PpIX formation or through an independent response, both of which may improve PDT treatment.
OBJECTIVE
To present the currently available clinical evidence of pharmacological pretreatments prior to PDT and to associate potential clinical benefits with the pharmacological mechanisms of action of the individual compounds.
METHODS
A comprehensive search on the Embase, MEDLINE, and Web of Science databases was performed.
RESULTS
In total, 16 studies investigated 6 pretreatment compounds: 5-fluorouracil (5-FU), diclofenac, retinoids, salicylic acid, urea, and vitamin D. Two of these, 5-FU and vitamin D, robustly increased the efficacy of PDT across multiple studies, illustrated by mean increases in clearance rates of 21.88% and 12.4%, respectively. Regarding their mechanisms, 5-FU and vitamin D both increased PpIX accumulation, while 5-FU also induced a separate anticarcinogenic response. Pretreatment with diclofenac for four weeks improved the clearance rate in one study (24.9%), administration of retinoids had a significant effect in one of two studies (16.25%), while salicylic acid and urea did not lead to improved PDT efficacy. Diclofenac and retinoids demonstrated independent cytotoxic responses, whereas salicylic acid and urea acted as penetration enhancers to increase PpIX formation.
CONCLUSION
5-FU and vitamin D are well-tested, promising candidates for pharmacological pretreatment prior to PDT. Both compounds affect the haem biosynthesis, providing a target for potential pretreatment candidates.
KEY WORDS
Photodynamic Therapy, Actinic Keratosis,Pre-tretment,Review,enhancement.
Topics: Humans; Keratosis, Actinic; Photosensitizing Agents; Aminolevulinic Acid; Photochemotherapy; Diclofenac; Salicylic Acid; Fluorouracil; Retinoids; Vitamin D; Urea; Treatment Outcome
PubMed: 37429460
DOI: 10.1016/j.pdpdt.2023.103703 -
European Heart Journal. Cardiovascular... Jul 2023To examine the dose dependency of diclofenac's cardiovascular risks.
AIMS
To examine the dose dependency of diclofenac's cardiovascular risks.
METHODS AND RESULTS
Using Danish health registries and the target trial emulation design, we conducted a series of 300 nationwide cohort studies during 1996-2020, each mimicking the strict design criteria of a clinical trial. Adults eligible for inclusion had no recent non-steroidal anti-inflammatory drug prescriptions, contraindications (gastrointestinal diseases, thrombocytopenia, or heart failure), or conditions with low adherence (dementia or psychiatric disease). Diclofenac initiators were compared to healthcare-seeking non-initiators and head-to-head using an approximated high dose of ≥150 mg/day vs. low dose of <150 mg/day. Cox regression was used to compute the incidence rate ratio (IRR) of major adverse cardiovascular events (MACE) within 30 days following initiation. We adjusted for age, sex, calendar period, comorbidity, comedication, and socioeconomic position. Compared with non-initiators (n = 3 789 617), diclofenac initiators (n = 1 894 834) had an approximately 50% increased rate of MACE (IRR 1.53, 95% confidence interval [CI]: 1.43-1.63), reflecting IRRs of 1.54 (95% CI: 1.40-1.69) for myocardial infarction, 1.29 (1.14-1.45) for ischaemic stroke, and 1.92 (1.71-2.16) for cardiac death. The risk increase was observed for most conditions with chronic pain, in particular headache (IRR 5.10, 95% CI: 1.46-17.85). The risk increase was similar for initiators of high- (IRR 1.55, 95% CI: 1.40-1.71) and low-dose diclofenac (IRR 1.52, 1.41-1.63), which was confirmed in a head-to-head analysis (IRR 1.01, 95% CI: 0.90-1.12).
CONCLUSIONS
Initiators of high- and low-dose diclofenac had comparably increased cardiovascular risks. This finding provides evidence against the assumption that low-dose diclofenac is risk-neutral.
Topics: Adult; Humans; Diclofenac; Brain Ischemia; Stroke; Anti-Inflammatory Agents, Non-Steroidal; Cardiovascular System
PubMed: 36921986
DOI: 10.1093/ehjcvp/pvad018 -
Veterinary World Sep 2023Ruiz and Pav. (also known as "Pájaro bobo") is known for its medicinal properties, including antiulcer, antiasthmatic, leishmanicidal, antipyretic, antispasmodic,...
BACKGROUND AND AIM
Ruiz and Pav. (also known as "Pájaro bobo") is known for its medicinal properties, including antiulcer, antiasthmatic, leishmanicidal, antipyretic, antispasmodic, diuretic, anti-inflammatory, analgesic, and hepatoprotective effects. Therefore, we aimed to evaluate its hepatoprotective and nephroprotective effects using a rat model of diclofenac-induced toxicity.
MATERIALS AND METHODS
We administered three different doses of the methanolic extract of (100, 200, and 400 mg/kg/day orally) and compared them with the commercial medicine silymarin (100 mg/kg orally). The rats received the extracts for 5 days, and on days 3 and 4, 1 h after receiving the extracts, diclofenac was administered intraperitoneally at a dose of 50 mg/kg. The animals were euthanized 48 h after the last diclofenac injection, and blood samples were obtained to measure biochemical parameters related to liver and kidney function, such as alanine aminotransferase (ALT), aspartate aminotransferase (AST), bilirubin, cholesterol, triglycerides, creatinine, and urea. Kidney and liver tissues were preserved in 10% formaldehyde and sent for histopathological analysis.
RESULTS
The results show that has hepatoprotective and nephroprotective effects. These effects are verified by the lower blood levels of ALT, AST, urea, and creatinine compared to the diclofenac group, which exhibited elevated biochemical parameters. In addition, histopathological analysis showed that the groups that received did not display necrosis or infiltration, which were observed in the diclofenac group.
CONCLUSION
The methanolic extract of has hepatoprotective and nephroprotective effects, with the highest protective activity observed at a dose of 400 mg/kg/day.
PubMed: 37859960
DOI: 10.14202/vetworld.2023.1933-1939 -
International Journal of Pharmaceutics Aug 2023We have synthesized new lipidic prodrugs of diclofenac by grafting aliphatic chains (C10, C12, C16 and C18) to diclofenac through an ester bond. Their molecular formulas...
We have synthesized new lipidic prodrugs of diclofenac by grafting aliphatic chains (C10, C12, C16 and C18) to diclofenac through an ester bond. Their molecular formulas were confirmed through HR-MS and the formation of ester bond by FTIR and NMR spectroscopy. Nanoparticles of the different prodrugs were successfully formulated using emulsion evaporation method and DSPE-PEG as the only excipient. All nanoparticles were spherical and had a size between 110 and 150 nm, PdI ≤ 0.2 and negative Zeta potential values from -30 to -50 mV. In addition, they were stable upon storage at 4 °C up to 30-35 days. The encapsulation efficiency of the prodrug was above 90 % independently of the aliphatic chain length grafted. Nanoparticles did not induce any toxicity on LPS-activated THP-1 cells up to a concentration of 100 μg/mL (equivalent diclofenac) whereas diclofenac sodium salt IC was around 20 μg/mL. Following incubation of nanoparticles with LPS-activated THP-1 cells, a dose dependent inhibition of TNF-α was observed comparable to standard diclofenac sodium. Based on in vitro studies representative nanoparticles, Prodrug 3 NPs (C16 aliphatic chain) were selected for further in vitro and in vivo studies. Upon incubation in murine plasma, Prodrug 3 NPs underwent an enzymatic cleavage and almost 70 % of diclofenac was released from nanoparticles in 8 h. In vivo studies on a collagen induced arthritis murine model showed contrasted results: on one hand Prodrug 3 NPs led to a significant decrease of arthritis score and of paw volume compared to PBS after the second injection, on the other hand the third injection induced an important hepatic toxicity with the death of half of the mice from the NP group. To promote the reduction of inflammation while avoiding hepatic toxicity using NPs would require to precisely study the No Observable Adverse Effect Level and the schedule of administration in the future.
Topics: Mice; Animals; Diclofenac; Prodrugs; Lipopolysaccharides; Arthritis, Rheumatoid; Nanoparticles; Esters
PubMed: 37453671
DOI: 10.1016/j.ijpharm.2023.123227 -
Current Molecular Medicine Jun 2024Pregabalin and diclofenac diethylamine are anti-inflammatory molecules that are effective in relieving inflammation and pain associated with musculoskeletal disorders,...
Pregabalin and diclofenac diethylamine are anti-inflammatory molecules that are effective in relieving inflammation and pain associated with musculoskeletal disorders, arthritis, and post-traumatic pain, among others. Intravenous and oral delivery of these two molecules has their limitations. However, the transdermal route is believed to be an alternate viable option for the delivery of therapeutic molecules with desired physicochemical properties. To this end, it is vital to understand the physicochemical properties of these drugs, dosage, and strategies to enhance permeation, thereby surmounting the associated constraints and concurrently attaining a sustained release of these therapeutic molecules when administered in combination. The present work hypothesizes the enhanced permeation and sustained release of Pregabalin and diclofenac diethylamine across the skin, entrapped in the adhesive nano-organogel formulation, including permeation enhancers. The solubility studies of Pregabalin and diclofenac diethylamine in combination were performed in different permeation enhancers. Oleic acid was optimized as the best permeation enhancer based on in vitro studies. Pluronic organogel containing Pregabalin and diclofenac diethylamine with oleic acid was fabricated. Duro-Tak® (87-2196) was added to the organogel formulation as a pressure-sensitive adhesive to sustain the release profile of these two therapeutic molecules. The adhesive organogel was characterized for particle size, scanning electron microscopy, and contact angle measurement. The HPLC method developed for the quantification of the dual drug showed a retention time of 3.84 minutes and 9.69 minutes for pregabalin and diclofenac, respectively. The fabricated nanogel adhesive formulation showed the desired results with particle size and contact angle of 282 ± 57 nm and ≥120⁰, respectively. In vitro studies showed the percentage cumulative release of 24.90 ± 4.65% and 33.29 ± 4.81% for pregabalin and diclofenac, respectively. In order to accomplish transdermal permeation, the suggested hypothesis of fabricating PG and DEE nano-organogel in combination with permeation enhancers will be a viable drug delivery method. In comparison to a traditional gel formulation, oleic acid as a permeation enhancer increased the penetration of both PG and DEE from the organogel formulation. Notably, the studies showed that the use of pressure-sensitive adhesives enabled the sustained release of both PG and DEE.Therefore, the results anticipated the hypothesis that the transdermal delivery of adhesive PG and DEE-based nanogel across the human skin can be achieved to inhibit inflammation and pain.
PubMed: 38847251
DOI: 10.2174/0115665240291343240306054318 -
Environmental Toxicology and Chemistry Mar 2024The vast majority of knowledge related to the question "To what extent do pharmaceuticals in the environment pose a risk to wildlife?" stems from the Asian vulture...
The vast majority of knowledge related to the question "To what extent do pharmaceuticals in the environment pose a risk to wildlife?" stems from the Asian vulture crisis (>99% decline of some species of Old World vultures on the Indian subcontinent related to the veterinary use of the nonsteroidal anti-inflammatory drug [NSAID] diclofenac). The hazard of diclofenac and other NSAIDs (carprofen, flunixin, ketoprofen, nimesulide, phenylbutazone) to vultures and other avian species has since been demonstrated; indeed, only meloxicam and tolfenamic acid have been found to be vulture-safe. Since diclofenac was approved for veterinary use in Spain and Italy in 2013 (home to ~95% of vultures in Europe), the risk of NSAIDs to vultures in these countries has become one of the principal concerns related to pharmaceuticals and wildlife. Many of the other bodies of work on pharmaceutical exposure, hazard and risk to wildlife also relate to adverse effects in birds (e.g., poisoning of scavenging birds in North America and Europe from animal carcasses containing pentobarbital, secondary and even tertiary poisoning of birds exposed to pesticides used in veterinary medicine as cattle dips, migratory birds as a vector for the transfer of antimicrobial and antifungal resistance). Although there is some research related to endocrine disruption in reptiles and potential exposure of aerial insectivores, there remain numerous knowledge gaps for risk posed by pharmaceuticals to amphibians, reptiles, and mammals. Developing noninvasive sampling techniques and new approach methodologies (e.g., genomic, in vitro, in silico, in ovo) is important if we are to bridge the current knowledge gaps without extensive vertebrate testing. Environ Toxicol Chem 2024;43:595-610. © 2022 The Authors. Environmental Toxicology and Chemistry published by Wiley Periodicals LLC on behalf of SETAC. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.
Topics: Humans; Animals; Animals, Wild; Diclofenac; Anti-Inflammatory Agents, Non-Steroidal; Meloxicam; Falconiformes; Birds; Pharmaceutical Preparations; Mammals
PubMed: 36398854
DOI: 10.1002/etc.5528 -
Exploration of Targeted Anti-tumor... 2024Cells are separated from the environment by a lipid bilayer membrane that is relatively impermeable to solutes. The transport of ions and small molecules across this... (Review)
Review
Cells are separated from the environment by a lipid bilayer membrane that is relatively impermeable to solutes. The transport of ions and small molecules across this membrane is an essential process in cell biology and metabolism. Monocarboxylate transporters (MCTs) belong to a vast family of solute carriers (SLCs) that facilitate the transport of certain hydrophylic small compounds through the bilipid cell membrane. The existence of 446 genes that code for SLCs is the best evidence of their importance. In-depth research on MCTs is quite recent and probably promoted by their role in cancer development and progression. Importantly, it has recently been realized that these transporters represent an interesting target for cancer treatment. The search for clinically useful monocarboxylate inhibitors is an even more recent field. There is limited pre-clinical and clinical experience with new inhibitors and their precise mechanism of action is still under investigation. What is common to all of them is the inhibition of lactate transport. This review discusses the structure and function of MCTs, their participation in cancer, and old and newly developed inhibitors. Some suggestions on how to improve their anticancer effects are also discussed.
PubMed: 38464385
DOI: 10.37349/etat.2024.00210