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The Biochemical Journal Jul 2004In familial amyloidotic polyneuropathy, TTR (transthyretin) variants are deposited as amyloid fibrils. It is thought that this process involves TTR tetramer... (Comparative Study)
Comparative Study
In familial amyloidotic polyneuropathy, TTR (transthyretin) variants are deposited as amyloid fibrils. It is thought that this process involves TTR tetramer dissociation, which leads to partially unfolded monomers that aggregate and polymerize into amyloid fibrils. This process can be counteracted by stabilization of the tetramer. Several small compounds, such as diclofenac, diflunisal and flufenamic acid, have been reported to bind to TTR in vitro, in the T4 (thyroxine) binding channel that runs through the TTR tetramer, and consequently are considered to stabilize TTR. However, if these agents bind plasma proteins other than TTR, decreased drug availability will occur, compromising their use as therapeutic agents for TTR amyloidosis. In the present work, we compared the action of these compounds and of new derivatives designed to increase both selectivity of binding to TTR and inhibitory potency in relation to TTR amyloid fibril formation. We found two diflunisal derivatives that, in contrast with diclofenac, flufenamic acid and diflunisal, displaced T4 from TTR in plasma preferentially over binding to albumin and thyroxine binding globulin. The same diflunisal derivatives also had a stabilizing effect on TTR tetramers in plasma, as studied by isoelectric focusing of whole plasma under semi-denaturing conditions. In addition, by transmission electron microscopy, we demonstrated that, in contrast with other proposed TTR stabilizers (namely diclofenac, flufenamic acid and diflunisal), one of the diflunisal derivatives tested efficiently inhibited TTR aggregation. Taken together, our ex vivo and in vitro studies present evidence for the selectivity and efficiency of novel diflunisal derivates as TTR stabilizers and as inhibitors of fibril formation.
Topics: Amyloid Neuropathies; Diclofenac; Diflunisal; Flufenamic Acid; Humans; Iodine; Iodobenzoates; Molecular Structure; Prealbumin; Protein Binding; Thyroxine
PubMed: 15080795
DOI: 10.1042/BJ20040011 -
Polymers Jul 2020The effects of three hydrophilic polymers, namely, carboxymethyl cellulose sodium (CMC-Na), polyvinyl alcohol (PVA) and poloxamer-188 (PXM-188) on the solubility and...
The effects of three hydrophilic polymers, namely, carboxymethyl cellulose sodium (CMC-Na), polyvinyl alcohol (PVA) and poloxamer-188 (PXM-188) on the solubility and dissolution of diflunisal (DIF) in complexation with β-cyclodextrin (βCD) or hydroxypropyl β-cyclodextrin (HPβCD), were investigated. The kneading method was used at different drug to cyclodextrin weight ratios. Increases in solubility and drug release were observed with the DIF/βCD and DIF/HPβCD complexes. The addition of hydrophilic polymers at 2.5, 5.0 and 10.0% w/w markedly improved the complexation and solubilizing efficiency of βCD and HPβCD. Fourier-transform infrared (FTIR) showed that DIF was successfully included into the cyclodextrin cavity. Differential scanning calorimetry (DSC) and X-ray diffractometry (XRD) confirmed stronger drug amorphization and entrapment in the molecular cage of cyclodextrins. The addition of PVA, CMC-Na or PXM-188 reduced further the intensity of the DIF endothermic peak. Most of the sharp and intense peaks of DIF disappeared with the addition of hydrophilic polymers. In conclusion, PXM-188 at a weight ratio of 10.0% w/w was the best candidate in enhancing the solubility, stability and release of DIF.
PubMed: 32679660
DOI: 10.3390/polym12071564 -
Scientia Pharmaceutica 2013A simple, rapid, and highly selective HPLC-DAD method was developed for the simultaneous determination of diclofenac sodium (DIC) and diflunisal (DIF) in pure form and...
A simple, rapid, and highly selective HPLC-DAD method was developed for the simultaneous determination of diclofenac sodium (DIC) and diflunisal (DIF) in pure form and in their combined formulation. Effective chromatographic separation was achieved using a Zorbax SB-C8 (4.6×250 mm, 5 μm particle size) column with a mobile phase composed of 0.05 M phosphoric acid, acetonitrile, and methanol in the ratio of 40:48:12 (by volume). The mobile phase was pumped isocratically at a flow rate of 1 mL/min, and quantification of the analytes was based on measuring their peak areas at 228 nm. The retention times for diflunisal and diclofenac were about 7.9 and 9.5 min, respectively. The reliability and analytical performance of the proposed HPLC procedure were statistically validated with respect to system suitability, linearity, ranges, precision, accuracy, specificity, robustness, detection, and quantification limits. Calibration curves were linear in the ranges of 5-100 μg/mL for both drugs with correlation coefficients >0.9998. The proposed method proved to be selective and stability-indicating by the resolution of the two analytes from four of their related substances and potential impurities as well as from forced-degradation (hydrolysis, oxidation, photolysis, and dry heat) products. The validated HPLC method was successfully applied to the analysis of DIC and DIF in their combined dosage form (suppositories). The proposed method made use of the diode array detector (DAD) as a tool for peak identity and purity confirmation.
PubMed: 24106669
DOI: 10.3797/scipharm.1301-24 -
British Medical Journal Aug 1978
Topics: Analgesics; Ephedrine; Female; Humans; Middle Aged; Salicylates
PubMed: 698637
DOI: 10.1136/bmj.2.6137.640-a -
Revista Espanola de Cardiologia... May 2024
Topics: Humans; Amyloid Neuropathies, Familial; Diflunisal; Male; Cardiomyopathies; Female; Aged; Treatment Outcome; Middle Aged
PubMed: 38325700
DOI: 10.1016/j.rec.2023.10.016 -
British Journal of Clinical Pharmacology Feb 1977The effect of diflunisal on platelet function and blood coagulation in volunteers was studied. The drug was double-blind tested in 20 healthy males randomly assigned to... (Clinical Trial)
Clinical Trial Randomized Controlled Trial
The effect of diflunisal on platelet function and blood coagulation in volunteers was studied. The drug was double-blind tested in 20 healthy males randomly assigned to diflunisal and placebo groups. The effect of high dosage was tested in an open design in six healthy males. Test systems were haemoglobin, mH, blood glucose, platelet counts, bleeding time, ADP- and collagen-induced platelet aggregation, PT, PTT, thrombin time, fibrinogen, antithrombin III, clot lysis, serum FDP and diflunisal blood levels. Paired and covariance tests were computed. The study design in both the double-blind and the open study was as follows: Acute single dose trial — diflunisal or placebo orally on day 1. Tests were monitored before and at regular intervals after administration on day 1 and further in the fasting state on days, 2, 4, 8, 10 and 12. Chronic multiple dose trial — diflunisal or placebo twice daily orally from day 15 to day 21. The same tests were monitored before and at regular intervals after administration on day 15, and in the fasting state on days 16, 18, 21, 25, 29, 31 and 33. Diflunisal at the dosages studied did not cause significant changes in any parameter measured at any time. Blood levels of diflunisal were comparable to those obtained during analgesic therapy. In the high dosage open study there were slight effects on platelet aggregation. Bleeding times were not influenced.
Topics: Adult; Anti-Inflammatory Agents, Non-Steroidal; Blood Coagulation; Blood Glucose; Double-Blind Method; Fluorobenzenes; Humans; Male; Platelet Aggregation; Salicylates; Time Factors
PubMed: 301745
DOI: 10.1111/j.1365-2125.1977.tb04512.x -
Science Translational Medicine Aug 2011A valine-to-isoleucine mutation at position 122 of the serum protein transthyretin (TTR), found in 3 to 4% of African Americans, alters its stability, leading to...
A valine-to-isoleucine mutation at position 122 of the serum protein transthyretin (TTR), found in 3 to 4% of African Americans, alters its stability, leading to amyloidogenesis and cardiomyopathy. In addition, 10 to 15% of individuals older than 65 years develop senile systemic amyloidosis and cardiac TTR deposits because of wild-type TTR amyloidogenesis. Although several drugs are in development, no approved therapies for TTR amyloid cardiomyopathy are yet available, so the identification of additional compounds that prevent amyloid-mediated cardiotoxicity is needed. To this aim, we developed a fluorescence polarization-based high-throughput screen and used it to identify several new chemical scaffolds that target TTR. These compounds were potent kinetic stabilizers of TTR and prevented TTR tetramer dissociation, partial unfolding, and aggregation of both wild type and the most common cardiomyopathy-associated TTR mutant, V122I-TTR. High-resolution co-crystal structures and characterization of the binding energetics revealed how these diverse structures bound to tetrameric TTR. These compounds effectively inhibited the proteotoxicity of V122I-TTR toward human cardiomyocytes. Several of these ligands stabilized TTR in human serum more effectively than diflunisal, which is a well-studied inhibitor of TTR aggregation, and may be promising leads for the treatment or prevention of TTR-mediated cardiomyopathy.
Topics: Amyloidosis; Benzophenones; Cardiomyopathies; Cell Line; Cell Line, Tumor; Fluorescence Polarization; Humans; Molecular Structure; Prealbumin; Protein Binding; Protein Multimerization
PubMed: 21865539
DOI: 10.1126/scitranslmed.3002473 -
Annals of the Rheumatic Diseases Apr 1979Diflunisal (750 mg per day) has been compared with acetylsalicylic acid (ASA) (3000 mg per day) in the treatment of osteoarthrosis of the hip and knee in a double-blind,... (Clinical Trial)
Clinical Trial Comparative Study Randomized Controlled Trial
Diflunisal (750 mg per day) has been compared with acetylsalicylic acid (ASA) (3000 mg per day) in the treatment of osteoarthrosis of the hip and knee in a double-blind, randomised, multicentre, outpatient study. Thirty-one patients entered the diflunisal group and 29 the ASA group. The response of the 2 groups was comparable, but the incidence of side effects was higher in the ASA group. At the end of the 12-week period more patients in the diflunisal group chose to remain in a further, open study.
Topics: Adult; Aged; Anti-Inflammatory Agents, Non-Steroidal; Aspirin; Bone Diseases; Clinical Trials as Topic; Double-Blind Method; Female; Hip Joint; Humans; Joint Diseases; Knee Joint; Male; Middle Aged; Random Allocation
PubMed: 375849
DOI: 10.1136/ard.38.2.148 -
Antimicrobial Agents and Chemotherapy Jun 2020osteomyelitis is a debilitating infection of bone. Treatment of osteomyelitis is impaired by the propensity of invading bacteria to induce pathological bone remodeling...
osteomyelitis is a debilitating infection of bone. Treatment of osteomyelitis is impaired by the propensity of invading bacteria to induce pathological bone remodeling that may limit antibiotic penetration to the infectious focus. The nonsteroidal anti-inflammatory drug diflunisal was previously identified as an osteoprotective adjunctive therapy for osteomyelitis, based on the ability of this compound to inhibit quorum sensing and subsequent quorum-dependent toxin production. When delivered locally during experimental osteomyelitis, diflunisal significantly limits bone destruction without affecting bacterial burdens. However, because diflunisal's "quorum-quenching" activity could theoretically increase antibiotic recalcitrance, it is critically important to evaluate this adjunctive therapy in the context of standard-of-care antibiotics. The objective of this study is to evaluate the efficacy of vancomycin to treat osteomyelitis during local diflunisal treatment. We first determined that systemic vancomycin effectively reduces bacterial burdens in a murine model of osteomyelitis and identified a dosing regimen that decreases bacterial burdens without eradicating infection. Using this dosing scheme, we found that vancomycin activity is unaffected by the presence of diflunisal and Similarly, locally delivered diflunisal still potently inhibits osteoblast cytotoxicity and bone destruction in the presence of subtherapeutic vancomycin. However, we also found that the resorbable polyester urethane (PUR) foams used to deliver diflunisal serve as a nidus for infection. Taken together, these data demonstrate that diflunisal does not significantly impact standard-of-care antibiotic therapy for osteomyelitis, but they also highlight potential pitfalls encountered with local drug delivery.
Topics: Animals; Anti-Bacterial Agents; Diflunisal; Mice; Osteomyelitis; Staphylococcal Infections; Staphylococcus aureus; Vancomycin
PubMed: 32340992
DOI: 10.1128/AAC.00182-20 -
The Journal of Organic Chemistry May 2023Starting with highly fluorinated benzoates, we develop the directed photocatalytic hydrodefluorination (HDF) of fluorinated aryl benzoates and demonstrate its...
Starting with highly fluorinated benzoates, we develop the directed photocatalytic hydrodefluorination (HDF) of fluorinated aryl benzoates and demonstrate its synergistic use with other HDF strategies, along with C-H arylation, decarboxylative coupling, and decarboxylative protonation, to access most fluorination patterns found in benzoate derivatives and by extension benzene derivatives via a molecular sculpting approach. Mild reaction conditions and excellent regioselectivity make the approach ideal for synthesis. This approach provides access to 16 benzoate derivatives with different fluorination patterns from just a couple of highly fluorinated, commercially available benzoic acids. We synthesize key intermediates or the active pharmaceutical ingredient for sitagliptin, diflunisal, and other pharmaceutically important molecules. Importantly, we provide key insights into relative rates of defluorination and strategies to alter these rates. We provide demonstrations of the synergistic use of HDF and related technologies to rapidly enhance the synthetic complexity of these simple commercially available perfluoroarenes to form complex partially fluorinated molecules.
PubMed: 36656262
DOI: 10.1021/acs.joc.2c02332