- 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 Aug 20; :1-28
- 1. 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 ac...
1. 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. 2. 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 6 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. 3. 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 6 new highly lipophilic acid drug candidates (protein binding >99.97%) and diflunisal, montelukast, and cerivastatin predicted based on hepatocytes suspended in serum were within 3-fold differences of their total clearance in vivo in rats, guinea pigs, or monkeys, except for montelukast in monkeys (5.8-fold). 4. 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 Bio-inspired Suzuki-Miyaura Couplings using Aryltrifluoroborates as Effective Partners in Deep Eutectic Solvents. [Journal Article]
- CChemSusChem 2018 Aug 03
- Pd-catalysed Suzuki-Miyaura cross-couplings between (hetero)aryl halides (Cl, Br, I) and versatile, moisture-stable mono- and bifunctional potassium aryltrifluoroborates proceed efficiently and chemo...
Pd-catalysed Suzuki-Miyaura cross-couplings between (hetero)aryl halides (Cl, Br, I) and versatile, moisture-stable mono- and bifunctional potassium aryltrifluoroborates proceed efficiently and chemoselectively in air and under generally mild conditions, with a catalyst loading as low as 1 mol%, in the absence of additional ligands, and employing Na2CO3 as base, and the deep eutectic solvent (DES) choline chloride/glycerol (1:2) as a sustainable and environmentally responsible medium. Catalyst, base and DES have been 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 and above 98%; over 50 cases have been compared and discussed. The methodology was also applied to the synthesis of the non-steroidal 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.
- Unusual duplication mutation in a surface loop of human transthyretin leads to an aggressive drug-resistant amyloid disease. [Journal Article]
- PNProc Natl Acad Sci U S A 2018 Jul 10; 115(28):E6428-E6436
- Transthyretin (TTR) is a globular tetrameric transport protein in plasma. Nearly 140 single amino acid substitutions in TTR cause life-threatening amyloid disease. We report a one-of-a-kind pathologi...
Transthyretin (TTR) is a globular tetrameric transport protein in plasma. Nearly 140 single amino acid substitutions in TTR cause life-threatening amyloid disease. We report a one-of-a-kind pathological variant featuring a Glu51, Ser52 duplication mutation (Glu51_Ser52dup). The proband, heterozygous for the mutation, exhibited an unusually aggressive amyloidosis that was refractory to treatment with the small-molecule drug diflunisal. To understand the poor treatment response and expand therapeutic options, we explored the structure and stability of recombinant Glu51_Ser52dup. The duplication did not alter the protein secondary or tertiary structure but decreased the stability of the TTR monomer and tetramer. Diflunisal, which bound with near-micromolar affinity, partially restored tetramer stability. The duplication had no significant effect on the free energy and enthalpy of diflunisal binding, and hence on the drug-protein interactions. However, the duplication induced tryptic digestion of TTR at near-physiological conditions, releasing a C-terminal fragment 49-129 that formed amyloid fibrils under conditions in which the full-length protein did not. Such C-terminal fragments, along with the full-length TTR, comprise amyloid deposits in vivo. Bioinformatics and structural analyses suggested that increased disorder in the surface loop, which contains the Glu51_Ser52dup duplication, not only helped generate amyloid-forming fragments but also decreased structural protection in the amyloidogenic residue segment 25-34, promoting misfolding of the full-length protein. Our studies of a unique duplication mutation explain its diflunisal-resistant nature, identify misfolding pathways for amyloidogenic TTR variants, and provide therapeutic targets to inhibit amyloid fibril formation by variant TTR.
- Effect of freeze-thawing conditions for preparation of chitosan-poly (vinyl alcohol) hydrogels and drug release studies. [Journal Article]
- CPCarbohydr Polym 2018 Sep 01; 195:476-485
- The freezing-thawing is an advantageous method to produce hydrogels without crosslinking agents. In this study chitosan-poly(vinyl alcohol) (CS-PVA) hydrogels were prepared by varying the freezing co...
The freezing-thawing is an advantageous method to produce hydrogels without crosslinking agents. In this study chitosan-poly(vinyl alcohol) (CS-PVA) hydrogels were prepared by varying the freezing conditions and composition, which affect the final characteristics of the products. The swelling degree, morphology, porosity, and diflunisal drug loading, as well as the drug release profiles were evaluated. The hydrogel swelling ratio was found to be mainly affected by the CS content, the number of freezing cycles and the temperature. SEM micrographs and porosity data confirm that pore size increases with the chitosan content. However, the use of either lower temperatures or longer freezing times, results in higher porosity and smaller pores. The drug release times of the CS-PVA hydrogels were as long as 30 h, and according to the mathematical fitting, a simple diffusion mechanism dominates the process. Moreover, a mathematical model predicting the hydrogels physical and structural behavior is proposed.
- Comparison table: some oral/topical opioid analgesics. [Journal Article]
- MLMed Lett Drugs Ther 2018 Apr 09; 60(1544):e64-e67
- The AMPK-v-ATPase-pH axis: A key regulator of the pro-fibrogenic phenotype of human hepatic stellate cells. [Journal Article]
- HepHepatology 2018 Apr 17
- CONCLUSIONS: The down-regulation of v-ATPase might represent a new promising target for the development of anti-fibrotic strategies. This article is protected by copyright. All rights reserved.
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- Benefits and harms associated with analgesic medications used in the management of acute dental pain: An overview of systematic reviews. [Journal Article]
- JAJ Am Dent Assoc 2018; 149(4):256-265.e3
- CONCLUSIONS: The best available data suggested that the use of nonsteroidal medications, with or without acetaminophen, offered the most favorable balance between benefits and harms, optimizing efficacy while minimizing acute adverse events.