Engineered Hydrophobin as a Crystallization Inhibitor for Flufenamic Acid

2021 ◽  
Author(s):  
Nathanael Sallada ◽  
Yongjun Li ◽  
Bryan Berger ◽  
Matthew S. Lamm
Keyword(s):  
Flufenamic Acid ◽  
Crystallization Inhibitor

Inhibition of the Activities of α2-Plasmin inhibitor (PI) and CI inhibitor (CI-Inh) by the Synthetic Fibrinolytic Agent, 3-Hydroxypropyl Flufenamide (Flu-HPA)

1979 ◽  
Author(s):  
L Miles ◽  
J Burnier ◽  
M Verlander ◽  
M Goodman ◽  
A Kleiss ◽  
...  
Keyword(s):  
Plasminogen Activators ◽  
Inhibitory Effect ◽  
Mechanisms Of Action ◽  
Flufenamic Acid ◽  
Clot Lysis ◽  
Factor Xiia ◽  
Dependent Inhibition ◽  
Normal Human ◽  
Plasmin Inhibitor

Flu-HPA is one of a series of flufenamic acid derivations that enhances plasminogen-dependent clot lysis in vitro. Studies of possible mechanisms of action of Flu-HPA were undertaken. The influence of Flu-HPA on the inhibition of purified plasmin by purified PI was studied. PI activity was assessed by its inhibition of the clevage of the tripeptide S-2251 (H-D-Val-Leu-Lys-pNA) by plasmin. Flu-HPA was dissolved in DMF or in methonol and preincubated with PI before addition of plasmin. At Flu-HPA concentrations greater than 1mM and up to 60mM, the inhibitory activity of PI was totally lost. The inhibitory effect of normal human plasma on plasmin was also completely abolished at concentrations of Flu-HPA between 2.5 and 40mM. The effect of Flu-HPA on the inhibition of purified plasma kallikrein by purified CI-Inh was also studied. CI-Inh activity was measured by its inhibition of cleavage of the tripeptide Bz-Pro-Phe-Arg-pNA by kallikrein. When Flu-HPA, dissolved in DMF or in methonol, was preincubated with CI-Inh, a concentration dependent inhibition of CI-Inh activity was observed. CI-Inh activity was abolished by concentrations of Flu-HPA greater than 1mM. Flu-HPA also inhibited the activity of CI-Inh on purified Factor XIIa. These observations suggest that this flufenamic acid derivative may enhance fibrinolysis not only by inhibiting PI activity but also by decreasing the inactivation of plasminogen activators by CI-Inh.

ROS Inhibitory Activity and Cytotoxicity Evaluation of Benzoyl, Acetyl, Alkyl Ester, and Sulfonate Ester Substituted Coumarin Derivatives

2020 ◽  
Vol 16 (8) ◽  
pp. 1099-1111
Author(s):  
Uzma Salar ◽  
Khalid M. Khan ◽  
Almas Jabeen ◽  
Aisha Faheem ◽  
Farwa Naqvi ◽  
...  
Keyword(s):  
Inhibitory Activity ◽  
Antiinflammatory Drug ◽  
Vital Role ◽  
Alkyl Ester ◽  
Flufenamic Acid ◽  
Coumarin Derivatives ◽  
Inflammatory Disorders ◽  
Enhanced Chemiluminescence ◽  
Anti Inflammatory ◽  
Sulfonate Ester

Background: A number of non-steroidal anti-inflammatory drugs (NSAIDs) including aspirin, indomethacin, ibuprofen, flufenamic acid, and phenylbutazone are being clinically used to treat inflammatory disorders. These NSAIDs are associated with serious side effects such as gastric ulceration, nephrotoxicity, and bleeding. Therefore, the identification of potent and safe therapy for inflammatory disorders is still of great interest to the medicinal chemist. Methods: A series of varyingly substituted benzoyl, acetyl, alkyl ester, and sulfonate ester substituted coumarins 1-64 were screened for the inhibition of ROS, generated from zymosan activated whole blood phagocytes, using luminol-enhanced chemiluminescence technique. Results: Among all tested compounds, 8 (IC50 = 65.0 ± 3.1 μM), 24 (IC50 = 41.8 ± 1.5 μM), 26 (IC50 = 10.6 ± 2.8 μM), 28 (IC50 = 20.9 ± 1.5 μM), and 41 (IC50 = 4.6 ± 0.3 μM) showed good anti- inflammatory potential as compared to standard antiinflammatory drug ibuprofen (IC50 = 54.3 ± 1.9 μM). Specifically, compounds 24, 26, 28, and 41 showed superior activity than standard antiinflammatory drug. Furthermore, compounds 12 (IC50 = 219.0 ± 1.4 μM), 14 (IC50 = 216.5 ± 6.2 μM), 16 (IC50 = 187.4 ± 2.2 μM), and 20 (IC50 = 196.2 ± 2.0 μM) showed moderate ROS inhibitory activity. Limited SAR study revealed that the hydroxy-substituted compound showed better ROS inhibition potential in case of 3-benzoyl and 3-ethylester coumarin derivatives. Whereas, chloro substitution was found to be important in case of 3-acetyl coumarin derivatives. Similarly, in case of sulfonate ester, chloro, and nitro groups especially at positions -4 and -3 of ring “R” played vital role in ROS inhibition. Furthermore, cytotoxicity of all active compounds was also checked on NIH-3T3 cell line. Compounds 12, 14, and 20 were found to be non-cytotoxic. Whereas, 8, 16, 24, 26, 28, and 41 were found to be very weak cytotoxic as compared to standard cycloheximide (IC50 = 0.13 ± 0.02 μM). Conclusion: Identified ROS inhibitors offer the possibility of additional modifications that could give rise to lead structures for further research in order to obtain more potent, and safer antiinflammatory agent.

Flufenamic Acid in Rheumatoid Arthritis: The Second Six Months of Treatment

Rheumatology ◽  
1966 ◽  
Vol VIII (suppl 1) ◽  
pp. 111-113
Author(s):  
M. R. Simpson ◽  
N. R. W. Simpson ◽  
H. C. Masheter ◽  
S. M. Hardy
Keyword(s):  
Rheumatoid Arthritis ◽  
Flufenamic Acid

scholarly journals Activation of Slo2.1 channels by niflumic acid

2010 ◽  
Vol 135 (3) ◽  
pp. 275-295 ◽  
Author(s):  
Li Dai ◽  
Vivek Garg ◽  
Michael C. Sanguinetti
Keyword(s):  
Voltage Dependence ◽  
Reversal Potential ◽  
Niflumic Acid ◽  
Flufenamic Acid ◽  
Channel Activation ◽  
Outward Currents ◽  
Transmembrane Voltage ◽  
High K ◽  
Charged Residues ◽  
K Current

Slo2.1 channels conduct an outwardly rectifying K+ current when activated by high [Na+]i. Here, we show that gating of these channels can also be activated by fenamates such as niflumic acid (NFA), even in the absence of intracellular Na+. In Xenopus oocytes injected with <10 ng cRNA, heterologously expressed human Slo2.1 current was negligible, but rapidly activated by extracellular application of NFA (EC50 = 2.1 mM) or flufenamic acid (EC50 = 1.4 mM). Slo2.1 channels activated by 1 mM NFA exhibited weak voltage dependence. In high [K+]e, the conductance–voltage (G-V) relationship had a V1/2 of +95 mV and an effective valence, z, of 0.48 e. Higher concentrations of NFA shifted V1/2 to more negative potentials (EC50 = 2.1 mM) and increased the minimum value of G/Gmax (EC50 = 2.4 mM); at 6 mM NFA, Slo2.1 channel activation was voltage independent. In contrast, V1/2 of the G-V relationship was shifted to more positive potentials when [K+]e was elevated from 1 to 300 mM (EC50 = 21.2 mM). The slope conductance measured at the reversal potential exhibited the same [K+]e dependency (EC50 = 23.5 mM). Conductance was also [Na+]e dependent. Outward currents were reduced when Na+ was replaced with choline or mannitol, but unaffected by substitution with Rb+ or Li+. Neutralization of charged residues in the S1–S4 domains did not appreciably alter the voltage dependence of Slo2.1 activation. Thus, the weak voltage dependence of Slo2.1 channel activation is independent of charged residues in the S1–S4 segments. In contrast, mutation of R190 located in the adjacent S4–S5 linker to a neutral (Ala or Gln) or acidic (Glu) residue induced constitutive channel activity that was reduced by high [K+]e. Collectively, these findings indicate that Slo2.1 channel gating is modulated by [K+]e and [Na+]e, and that NFA uncouples channel activation from its modulation by transmembrane voltage and intracellular Na+.

Androgen receptors in prostate cancer.

2002 ◽  
pp. 155-170 ◽  
Author(s):  
Z Culig ◽  
H Klocker ◽  
G Bartsch ◽  
A Hobisch
Keyword(s):  
Prostate Cancer ◽  
Cell Cycle ◽  
Point Mutations ◽  
Growth Factor Receptor ◽  
Clinical Situation ◽  
Activation Function ◽  
Flufenamic Acid ◽  
Cell Cycle Regulators ◽  
Industrialized Countries ◽  
Chemopreventive Agents

The androgen receptor (AR), a transcription factor that mediates the action of androgens in target tissues, is expressed in nearly all prostate cancers. Carcinoma of the prostate is the most frequently diagnosed neoplasm in men in industrialized countries. Palliative treatment for non-organ-confined prostate cancer aims to down-regulate the concentration of circulating androgen or to block the transcription activation function of the AR. AR function during endocrine therapy was studied in tumor cells LNCaP subjected to long-term steroid depletion; newly generated sublines could be stimulated by lower concentrations of androgen than parental cells and showed up-regulation of AR expression and activity as well as resistance to apoptosis. Androgenic hormones regulate the expression of key cell cycle regulators, cyclin-dependent kinase 2 and 4, and that of the cell cycle inhibitor p27. Inhibition of AR expression could be achieved by potential chemopreventive agents flufenamic acid, resveratrol, quercetin, polyunsaturated fatty acids and interleukin-1beta, and by the application of AR antisense oligonucleotides. In the clinical situation, AR gene amplification and point mutations were reported in patients with metastatic disease. These mutations generate receptors which could be activated by other steroid hormones and non-steroidal antiandrogens. In the absence of androgen, the AR could be activated by various growth-promoting (growth factors, epidermal growth factor receptor-related oncogene HER-2/neu) and pleiotropic (protein kinase A activators, interleukin-6) compounds as well as by inducers of differentiation (phenylbutyrate). AR function is modulated by a number of coactivators and corepressors. The three coactivators, TIF-2, SRC-1 and RAC3, are up-regulated in relapsed prostate cancer. New experimental therapies for prostate cancer are aimed to down-regulate AR expression and to overcome difficulties which occur because of the acquisition of agonistic properties of commonly used antiandrogens.

Liquid antisolvent recrystallization and solid dispersion of flufenamic acid with polyvinylpyrrolidone K-30

2021 ◽  
Vol 0 (0) ◽  
Author(s):  
Rahul Kumar ◽  
Sanjay Kumar ◽  
Pranava Chaudhari ◽  
Amit K. Thakur
Keyword(s):  
Particle Size ◽  
Dissolution Rate ◽  
Solid Dispersion ◽  
Fine Particles ◽  
Xrd Analysis ◽  
Solution Concentration ◽  
Injection Rate ◽  
Size Reduction ◽  
Flufenamic Acid ◽  
Particle Size Reduction

Abstract Flufenamic acid (FFA) is a Biopharmaceutical Classification System- II (BCS-II) class drug with poor bioavailability and a lower dissolution rate. Particle size reduction is one of the conventional approaches to increase the dissolution rate and subsequently the bioavailability. The use of the liquid antisolvent method for particle size reduction of FFA was studied in this work. Ethanol and water were used as solvent and antisolvent, respectively. Experimental parameters such as solution concentration (10–40 mg/ml), flow rate (120–480 ml/h), temperature (298–328 K) and stirring speed (200–800 rpm) were investigated. Furthermore, the solid dispersion of FFA was prepared with polyvinylpyrrolidone K-30 (PVP K-30) with different weight ratios (1:1, 1:2, 1:3 and 1:4) and samples were characterized using SEM, FTIR and XRD techniques. The experimental investigation revealed that higher values of concentration, injection rate, stirring speed, along with lower temperature favored the formation of fine particles. SEM analysis revealed that the morphology of raw FFA changed from rock-like to rectangular-like after liquid antisolvent recrystallization. FTIR analysis validated the presence of hydrogen bonding between FFA and PVP in solid dispersion. XRD analysis showed no significant change in the crystallinity of the processed FFA.

Lysophosphatidic acid, serum, and hyposmolarity activate Cl- currents in corneal keratocytes

1995 ◽  
Vol 269 (6) ◽  
pp. C1385-C1393 ◽  
Author(s):  
M. A. Watsky
Keyword(s):  
Lysophosphatidic Acid ◽  
Reversal Potential ◽  
Flufenamic Acid ◽  
Disulfonic Acid ◽  
Hypotonic Stress ◽  
Outward Currents ◽  
Fetal Bovine ◽  
Patch Technique ◽  
Corneal Keratocytes ◽  
In Cells

The influence of serum, lysophosphatidic acid (LPA), and hyposmotic stress on the ion channel activity of normal and cryo-injured rabbit corneal keratocytes was investigated. Whole cell currents were examined using the amphotericin perforated-patch technique. In cells from wounded corneas, fetal bovine serum activated large, holding voltage-insensitive, fast-activating, 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid (DIDS)-, flufenamic acid-, and 5-nitro-2-(3-phenylpropylamino)benzoic acid (NPPB)-blockable outward currents showing inactivation at depolarized voltages. LPA activated identical currents, also only in cells from wounded corneas. Blocker and reversal potential experiments characterized the current as a Cl- currents (Icl). Lysophosphatidylcholine (10 microM) failed to activate the current. An identical current was activated by hyposmotic stimulation in cells from control and wounded corneas. Hyposmotic stimulation also activated Icl in cells from wounded corneas that were unresponsive to LPA. We conclude that serum, LPA, and hypotonic stress activate Icl in keratocytes from wounded corneas. We also conclude that LPA is a serum factor that can activate Icl and that hyposmotic activation may work through a signaling pathway separate from that of LPA.

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