- Diflunisal tolerability in transthyretin cardiac amyloidosis: a single center's experience. [Journal Article]
- AAmyloid 2018 Nov 02; :1-6
- CONCLUSIONS: Diflunisal was well-tolerated in both the ATTRm- and ATTRwt-CA populations. Withdrawal due to side effects was related to gastrointestinal complaints, but most patients had no adverse events. Diflunisal can be safely used in a selected group of ATTR-CA patients with appropriate clinical, renal and hematologic monitoring.
- Hereditary transthyretin-related amyloidosis. [Journal Article]
- ANActa Neurol Scand 2018 Oct 08
- Hereditary transthyretin(TTR)-related amyloidosis (ATTRm amyloidosis) is an endemic/non-endemic, autosomal-dominant, early- and late-onset, rare, progressive disorder, predominantly manifesting as le...
Hereditary transthyretin(TTR)-related amyloidosis (ATTRm amyloidosis) is an endemic/non-endemic, autosomal-dominant, early- and late-onset, rare, progressive disorder, predominantly manifesting as length-dependent, small fiber dominant, axonal polyneuropathy and frequently associated with cardiac disorders and other multisystem diseases. ATTRm amyloidosis is due to variants in the TTR gene, with the substitution Val30Met as the most frequent mutation. TTR mutations lead to destabilization and dissociation of TTR tetramers into variant TTR monomers, and formation of amyloid fibrils, which are consecutively deposited extracellularly in various tissues, such as nerves, heart, brain, eyes, intestines, kidneys, or the skin. Neuropathy may not only include large nerve fibers but also small fibers, and not only sensory and motor fibers but also autonomic fibers. Types of TTR variants, age at onset, penetrance, and clinical presentation vary between geographical areas. Suggestive of a ATTRm amyloidosis are a sensorimotor polyneuropathy, positive family history, autonomic dysfunction, cardiomyopathy, carpal tunnel syndrome, unexplained weight loss, and resistance to immunotherapy. If only sensory A-delta or C fibers are affected, small fiber neuropathy ensues. Diagnostic tests for small fiber neuropathy include determination of intraepidermal nerve fiber density, laser-evoked potentials, heat- and cold-detection thresholds, and measurement of the electrochemical skin conductance. Therapy currently relies on liver transplantation and TTR-stabilizers (tafamidis, diflunisal).
- Diflunisal-adjoined cobalt(iii)-polypyridyl complexes as anti-cancer stem cell agents. [Journal Article]
- DTDalton Trans 2018 Oct 09; 47(39):13761-13765
- We report a novel series of cobalt(iii)-polypridyl complexes, 4-6, that can selectively release diflunisal, a nonsteroidal anti-inflammatory drug, under reducing conditions. Remarkably, the 1,10-phen...
We report a novel series of cobalt(iii)-polypridyl complexes, 4-6, that can selectively release diflunisal, a nonsteroidal anti-inflammatory drug, under reducing conditions. Remarkably, the 1,10-phenanthroline-bearing complex 5 displays selective potency towards hard-to-kill cancer stem cells (CSCs) (IC50 = 2.1 ± 0.1 μM) over bulk cancer (IC50 = 3.9 ± 0.2 μM) and normal cells (IC50 = 21.2 ± 1.3 μM). This complex induces CSC apoptosis by DNA damage and cyclooxygenase-2 inhibition.
- Binding Interaction of Organofluorine-Serum Albumin: A Comparative Ligand-Detected 19F NMR Analysis. [Journal Article]
- JPJ Phys Chem B 2018 Oct 11; 122(40):9409-9418
- In the present study, we attempt to characterize fluorinated ligand-serum albumin interaction in solution by a set of one-dimensional 19F ligand-based experiments. In this regard, a model system difl...
In the present study, we attempt to characterize fluorinated ligand-serum albumin interaction in solution by a set of one-dimensional 19F ligand-based experiments. In this regard, a model system diflunisal (DFL)-human serum albumin (HSA) has been chosen to benchmark the utility of 19F relaxation and diffusion-based experiments in deciphering ligand-protein interactions. Further, we extend the application of a similar set of 19F experiments to unravel the molecular interaction in an unexplored system of 2,6-difluorobenzoic acid (DFBA)-bovine serum albumin (BSA). Interaction analysis of DFBA-SA is of particular interest because DFBA is not only a stable metabolite of a number of pesticides but also used as the starting reagent of many fluorinated drugs. Observation of 19F-1H & 1H-1H saturation transfer difference effects confirmed binding of the ligands to SA. Further, these ligand-protein complexes were probed in terms of the dissociation constant ( KD), number of binding sites ( n), bound fraction of the ligand ( Pb), the complex lifetime (τres), and exchange rate ( Kex). Although Carr-Purcell-Meiboom-Gill (CPMG)-based transverse relaxation and diffusion analysis quantified the former three quantities, the latter two were determined by the constant time fast pulsing CPMG method. Additionally, 19F competition binding experiments performed with well-characterized BSA site markers and DFBA indicated nonspecific binding of DFBA to BSA, whereas similar measurements in the case of HSA with DFL and DFBA revealed superior binding interaction of DFL with SA.
- In vivo hepatic clearance of lipophilic drugs predicted by in vitro uptake data into cryopreserved hepatocytes suspended in sera of rats, guinea pigs, monkeys and humans. [Journal Article]
- XXenobiotica 2018 Sep 21; :1-8
- Evaluation of uptake of lipophilic acid compounds into hepatocytes was an unresolved drug development issue because of their adsorption to cells and materials and low analytical sensitivity and accur...
Evaluation of uptake of lipophilic acid compounds into hepatocytes was an unresolved drug development issue because of their adsorption to cells and materials and low analytical sensitivity and accuracy in assessment of protein bindings. Uptake assays of compounds using hepatocytes suspended in serum were expected to solve these problems for prediction of in vivo hepatic clearance. Here, for compounds with high protein binding (>99%), diflunisal, montelukast, cerivastatin, telmisartan, fluvastatin and six new drug candidates, in vivo hepatic clearance predicted based on hepatic depletion and uptake (CLh, uptake, predicted) data using hepatocytes in the absence and presence of sera was investigated. In vitro hepatic uptake results with hepatocytes suspended in serum improved prediction of human hepatic clearance values for highly lipophilic montelukast and telmisartan. In vivo CLh, uptake, predicted values of six new highly lipophilic acid drug candidates (protein binding >99.97%) and diflunisal, montelukast and cerivastatin predicted based on hepatocytes suspended in serum were within threefold differences of their total clearance in vivo in rats, guinea pigs or monkeys, except for montelukast in monkeys (5.8-fold). These results suggest that the human hepatic uptake in hepatocytes suspended in serum is useful for prediction of CLh, uptake, predicted, especially for highly lipophilic/protein binding acid compounds.
- Synthesis and preliminary anti-inflammatory and anti-bacterial evaluation of some diflunisal aza-analogs. [Journal Article]
- MMedchemcomm 2018 Jun 01; 9(6):1017-1032
- Our aim was to identify new multi-target compounds endowed with both anti-inflammatory and anti-bacterial activities for treatment of human infections. Diflunisal, a nonsteroidal anti-inflammatory ag...
Our aim was to identify new multi-target compounds endowed with both anti-inflammatory and anti-bacterial activities for treatment of human infections. Diflunisal, a nonsteroidal anti-inflammatory agent, has recently been repurposed for its anti-virulence properties against methicillin-resistant Staphylococcus aureus. Effective synthesis of some aza-analogs of the anti-inflammatory drug diflunisal was carried out following the route involving key oxazole intermediates to obtain o- and m-hydroxypyridinecarboxylic acid derivatives. The newly synthesized diflunisal aza-analogs did not exhibit cytotoxic activity up to 80 μM and some of them exhibited anti-inflammatory activities, decreasing the levels of pro-inflammatory cytokines and prostaglandins induced by bacterial lipopolysaccharide in human primary macrophages. Ten of the diflunisal aza-analogs were found to have interesting antibacterial activity, sensitizing S. aureus, Streptococcus pyogenes, Enterococcus faecium, and Pseudomonas aeruginosa to the antibacterial effects of beta-lactam antibiotics and protein synthesis inhibitors.
- Synthesis, Molecular Docking and Anticancer Activity of Diflunisal Derivatives as Cyclooxygenase Enzyme Inhibitors. [Journal Article]
- MMolecules 2018 Aug 06; 23(8)
- Cyclooxygenase enzymes play a vital role in inflammatory pathways in the human body. Apart from their relation with inflammation, the additional involvement of COX-2 enzyme with cancer activity was r...
Cyclooxygenase enzymes play a vital role in inflammatory pathways in the human body. Apart from their relation with inflammation, the additional involvement of COX-2 enzyme with cancer activity was recently discovered. In some cancer types the level of COX-2 enzyme is increased indicating that this enzyme could be a suitable target for cancer therapy. Based on these findings, we have synthesized some new diflunisal thiosemicarbazides and 1,2,4-triazoles and tested them against androgen-independent prostate adenocarcinoma (PC-3), colon carcinoma (HCT-116), human breast cancer (T47D), breast carcinoma (MCF7) and human embryonic kidney (HEK-293) cell lines. Specifically, the diflunisal and thiosemicarbazide functionality are combined during the synthesis of original compounds anticipating a potency enhancement. Compounds 6, 10, 15 and 16 did not show cytotoxic effects for the HEK293 cell line. Among them, compounds 15 and 16 demonstrated anticancer activity for the breast cancer cell line T47D, whereas compounds 6 and 10 which are thiosemicarbazide derivatives displayed anti-tumourigenic activity against the PC-3 cell line, consistent with the literature. However, no activity was observed for the HCT-116 cancer cell line with the tested thiosemicarbazide derivatives. Only compound 16 displayed activity against the HCT-116 cell line. Therefore, it was speculated that the diflunisal and thiosemicarbazide functionalities potentiate anticancer activity on prostate cancer and the thiosemicarbazide functionality decreases the anticancer activity of diflunisal on colon cancer cell lines. In order to gain insight into the anticancer activity and COX-2 inhibition, molecular docking studies were carried out for COX-1 and COX-2 enzymes utilizing the newly synthesized compounds 15, and 16. Both 15 and 16 showed high selectivity and affinity toward COX-2 isozyme over COX-1, which is in agreement with the experimental results.
- Ligand-Free Bioinspired Suzuki-Miyaura Coupling Reactions using Aryltrifluoroborates as Effective Partners in Deep Eutectic Solvents. [Journal Article]
- CChemSusChem 2018 Oct 11; 11(19):3495-3501
- Pd-catalyzed Suzuki-Miyaura cross-coupling between (hetero)aryl halides (Cl, Br, I) and versatile, moisture-stable mono- and bifunctional potassium aryltrifluoroborates proceeded efficiently and chem...
Pd-catalyzed Suzuki-Miyaura cross-coupling between (hetero)aryl halides (Cl, Br, I) and versatile, moisture-stable mono- and bifunctional potassium aryltrifluoroborates proceeded efficiently and chemoselectively in air and under generally mild conditions; a catalyst loading as low as 1 mol % combined with Na2 CO3 as a base in choline chloride/glycerol (1:2) deep eutectic solvent (DES) was used as a sustainable and environmentally responsible medium. The catalyst, base, and DES were easily and successfully recycled up to six times with an E-factor as low as 8.74. Valuable biaryls and terphenyl derivatives were furnished in yields of up to 98 %; over 50 reactions were compared and discussed. The methodology was applied for the synthesis of the nonsteroidal anti-inflammatory drugs Felbinac and Diflunisal.
- Drugs and Lactation Database (LactMed) [BOOK]
- BOOKNational Library of Medicine (US): Bethesda (MD)
- The small amounts of diflunisal in milk do not appear to pose a serious risk to breastfeeding infants. However, a shorter-acting agents having more published information may be preferred, especially ...
The small amounts of diflunisal in milk do not appear to pose a serious risk to breastfeeding infants. However, a shorter-acting agents having more published information may be preferred, especially while nursing a newborn or preterm infant.
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- Inhibition of the Amyloidogenesis of Transthyretin by Natural Products and Synthetic Compounds. [Review]
- BPBiol Pharm Bull 2018; 41(7):979-984
- Hereditary transthyretin (TTR)-related amyloidosis is caused by mutations in the TTR gene. The mutations destabilize the tetramer and/or monomer of TTR, and thus the stabilization of TTR is a key str...
Hereditary transthyretin (TTR)-related amyloidosis is caused by mutations in the TTR gene. The mutations destabilize the tetramer and/or monomer of TTR, and thus the stabilization of TTR is a key strategy for the treatment of TTR-related amyloidosis. In this review, we summarized the natural products and synthetic compounds that have been shown to inhibit the amyloidogenesis of TTR. The stabilizers and/or the amyloid fibril disrupters isolated from natural sources may become lead compounds for the treatment of TTR-related amyloidosis.