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PubMed1993

Effect of prostaglandin synthesis inhibition on macula densa-stimulated renin secretion.

The purpose of the present studies was to evaluate directly the role of prostaglandins in macula densa-mediated renin release. Individual juxtaglomerular apparatus specimens were microdissected from rabbit kidney and perfused with a solution containing either high NaCl (Na+ = 141 meq/l; Cl- = 122 meq/l) or low NaCl (Na+ = 26 meq/l; Cl- = 7 meq/l) concentration. With a step decrease in perfusate NaCl (high to low), renin secretion rate was markedly stimulated (from 15.06 to 63.1 nGU/min, P < 0.01), and the response was almost fully reversible. When specimens were bathed with cyclooxygenase inhibitors flurbiprofen (10(-5) M) or flufenamic acid (10(-4) M), this macula densa-activated increase in renin release was largely or completely abolished (flurbiprofen, 3.5-10.5 nGU/min, not significant; flufenamic acid, 9.0-12.3 nGU/min, not significant). Exposing the macula densa to a step increase in perfusate NaCl concentration (low to high) resulted in a significant and reversible suppression of renin secretion in control specimens, but no significant suppression was seen in specimens treated with flufenamic acid. These data provide direct evidence to support the hypothesis that locally produced prostaglandins may act as a primary mediator of the renin response to macula densa activation.

Animals↗
PubMed1982

[Anti-inflammatory, analgesic and anti-pyretic activities of a non-steroidal anti-inflammatory drug, etofenamate, in experimental animals].

Anti-inflammatory, analgesic, and anti-pyretic activities of orally administered etofenamate, the diethylene glycol ester of flufenamic acid, were investigated in experimental animals. Against acetic acid-induced vascular permeability in mice and ultra-violet light-induced erythema in guinea pigs, etofenamate produced a dose related inhibition at doses of 40--320 mg/kg and 5--20 mg/kg, respectively. In rats, felt-pellet-induced granuloma formation and adjuvant-induced arthritis were significantly inhibited by repeated administration of etofenamate at doses of 20 mg/kg/day for 5 days and 40 mg/kg/day for 21 days, respectively. Etofenamate showed an inhibitory activity on the squeak response caused by flexing and extending the silver nitrate-induced arthritic joint in rats; and it produced a dose related anti-writhing activity at doses of 50--300 mg/kg and 10--80 mg/kg in mice and rats, respectively, in the acetic acid-induced writhing test. Etofenamate showed a significant anti-pyretic activity at doses of 0.2 mg/kg or more. These potencies of etofenamate were 0.5 to 1.6 times those of flufenamic acid. In particular, the anti-erythema, anti-arthritis, and anti-pyretic activities of etofenamate were approximately equivalent to or superior to those of flufenamic acid. From these results, it was suggested that etofenamate given orally, like other non-steroidal anti-inflammatory drugs, showed anti-inflammatory, analgesic, and anti-pyretic activities in experimental animals.

Analgesics↗
PubMed2005

Effects of inhibitors of nonselective cation channels on the acetylcholine-induced depolarization of circular smooth muscle from the guinea-pig stomach antrum.

In circular smooth muscle bundles isolated from the guinea-pig stomach antrum, the effects of quinidine, Ni2+, flufenamic acid, niflumic acid, La3+, SKF-96365 and 4'-diisothiocyanatostilbene-2,2'-disulphonic acid (DIDS) on acetylcholine (ACh)-induced depolarization were investigated. Recording membrane potentials from smooth muscle cells with intracellular microelectrodes revealed that ACh (1 microM) depolarized the membrane by 5-8 mV and increased the amplitude and frequency of slow potentials. These effects were inhibited by atropine. Quinidine (10 microM) increased the amplitude of ACh-induced depolarization, with no alteration to the properties of slow potentials. Ni2+ (50 microM) transiently (5-10 min) depolarized the membrane by about 5 mV, with an associated increase in frequency and amplitude of slow potentials. In the stabilized condition with Ni2+, the amplitude of ACh-induced depolarization remained unchanged. Flufenamic acid (10 microM) inhibited the generation of slow potentials, with no change in either the amplitude of ACh-induced depolarization or of the amplitude and frequency of slow potentials generated during ACh stimulation. A high concentration of flufenamic acid (100 microM) depolarized the membrane and increased the amplitude of ACh-induced depolarization. Niflumic acid (10 microM) hyperpolarized the membrane and increased the amplitude and frequency of slow potentials and also the amplitude of ACh-induced depolarization. DIDS (100 microM) hyperpolarized the membrane and inhibited the amplitude and frequency of slow potentials, with no alteration to the amplitude of ACh-induced depolarization. SKF-96365 (3-50 microM) depolarized the membrane in a concentration-dependent manner, but did not change the level of ACh-induced depolarization. La3+ (50 microM) did not alter the properties of the slow potentials or the ACh-induced responses. These results provide evidence that ACh-induced depolarization is not inhibited by chemicals known to inhibit non-selective cation channels. We suggest that muscarinic receptor-mediated signal transduction may be different in smooth muscle and interstitial cells.

4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid↗
PubMed1985

Anti-inflammatory drugs in experimental atherosclerosis. Part 6. Combination therapy with steroid and non-steroid agents.

The pathological changes which accompany enhanced cholesterol deposition in atherosclerosis include inflammatory responses mediated by the prostaglandin cyclooxygenase and lipoxygenase-leukotriene metabolite of the arachidonic acid cascade. Cortisone suppresses arachidonic acid release, whereas non-steroid anti-inflammatory drugs inhibit principally the cyclooxygenase enzyme. Groups of New Zealand white rabbits were fed a 1% cholesterol diet for 12 weeks. Diets of selected groups were further supplemented daily with the non-steroid anti-inflammatory drugs phenylbutazone (100 mg), oxyphenylbutazone (240 mg), flufenamic acid (100 mg), either singly or in combination with cortisone acetate (10 mg or 5 mg), or 9-alpha-fluorohydrocortisone (30 micrograms or 200 micrograms). Serum lipid levels were measured at 0, 4, 8 and 12 weeks, and atherosclerotic plaque intensity in thoracic aorta was measured at 12 weeks using a planimetric technique: serum cholesterol levels in control groups increased from 38 +/- 5 to 1190 +/- 139 mg/100 ml. Neither the rate of increase nor the final lipid values attained were significantly changed by the non-steroid drugs. The non-steroid drugs reduced plaque coverage by about one third (phenylbutazone 34 +/- 10%, flufenamic acid 36 +/- 11%) compared to controls. In combination therapy, addition of cortisone acetate resulted in further plaque suppression. Cortisone 10 mg + phenylbutazone gave 100% suppression; cortisone 5 mg + phenylbutazone gave 82 +/- 18%, and cortisone 5 mg + flufenamic acid gave 84 +/- 3%.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1977

Anti-inflammatory properties of griseofulvin.

Anti-inflammatory activity of griseofulvin has been investigated in comparison with indomethacin and flufenamic acid. In vitro, griseofulvin has been proved the most effective of these agents in suppressing the contractions of smooth muscle preparations induced by a variety of proposed mediators of inflammation, i.e. histamine, 5-hydroxy-tryptamine, bradykinin and prostaglandin E2. In vivo, griseofulvin was unable to modify dextran oedema but suppressed carrageenin oedema, although its activity was poor when compared to that exhibited by indomethacin and flufenamic acid. When tested in rat pleurisy induced by dextran or homologous serum griseofulvin was able to prevent polymorph migration into the pleural space while mononuclears remained virtually unaffected. In contrast indomethacin and flufenamic acid mainly suppressed mononuclear migration while polymorphs resulted only slightly affected. Similar results have been exhibited by the drugs when tested on mononuclear turnover in pleural cavities from normal rats. Results are discussed in the light of the clinically established ability of griseofulvin to prevent cutaneous inflammatory reactions as well as of its effectiveness in the treatment of several polyarthritic syndromes.

Animals↗
PubMed2000

Orientation-dependent (19)F dipolar couplings within a trifluoromethyl group are revealed by static multipulse NMR in the solid state.

The homonuclear dipolar coupling between the three equivalent (19)F-spins of a trifluoromethyl group, rotating about its threefold symmetry axis, was studied by multipulse solid-state NMR. A modified CPMG sequence was used first to resolve the dipolar splitting of a powder sample, and then to follow its orientation-dependence in uniaxially aligned samples. Our aim is to employ the CF(3)-group as a highly sensitive reporter to describe the mobility and spacial alignment of (19)F-labeled molecules in biomembranes. As an example, the fluorinated anti-inflammatory drug, flufenamic acid, was embedded as a guest compound in lipid bilayers. Undistorted (19)F dipolar spectra of its CF(3)-group were obtained without (1)H-decoupling, revealing a sharp triplet lineshape. When an oriented membrane sample was tilted in the magnetic field, the change in dipolar splittings confirmed that the guest molecule is motionally averaged about the membrane normal, as expected. A different behavior of flufenamic acid, however, was observed under conditions of low bilayer hydration. From this set of orientation-dependent lineshapes we conclude that the axis of motional averaging becomes aligned perpendicular to the sample normal. It thus appears that flufenamic acid induces a hexagonal phase in the membrane at low hydration. Finally, the dipolar (19)F NMR experiments were extended to frozen samples, where no molecular diffusion occurs besides the fast rotation about the CF(3)-axis. Also under these conditions, the CPMG experiment with composite pulses could successfully resolve the dipolar coupling between the three (19)F-nuclei.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1999

Influence of inhibitors on increase in intracellular free calcium and proliferation induced by platelet-activating factor in bovine oviductal cells.

Oviductal endosalpingeal cells were isolated mechanically from heifers and cultured until there was 100% confluency. The cells were loaded with the Ca(2+)-sensitive fluorochrome, fura-2/acetoxymethylester, and cytosolic free calcium ([Ca2+]i) was monitored by spectrofluorimetry. Platelet-activating factor, at a concentration of 30 nmol l-1, induced an intracellular Ca2+ increase in cultured bovine oviductal cells, mainly via influx from the extracellular space. In fura-2-loaded oviductal cells, different Ca2+ channel blockers were investigated to characterize the pathways responsible for the Ca2+ influx. The negative effects of Ni(2+)-, La(3+)-activated K+ channel blockers, such as apamin and charybdotoxin, and Ca2+ channel blockers, such as dotarizine, on the platelet-activating factor-induced [Ca2+]i increase indicate the minor participation of the voltage-gated Ca2+ channels. TMB-8 and flufenamic acid blocked the platelet-activating factor-induced Ca2+ increase directly on non-selective cationic channels or acted via a Ca2+ release-triggered Ca2+ influx. Platelet-activating factor, at concentrations of 1.25 mumol l-1 and 2.5 mumol l-1, significantly stimulated the proliferation and depolarization of oviductal cells, but 10 mumol l-1 significantly decreased both parameters and exerted a cytotoxic effect on cells. After incubation with TMB-8 or flufenamic acid, the cell proliferation was inhibited in a concentration-dependent manner, with IC50 values of 26.57 mumol l-1 and 95.29 mumol l-1, respectively. The depolarization was significantly inhibited at 50 mumol l-1 for both TMB-8 and flufenamic acid. The results of the present study may contribute to further understanding of the mechanism behind the actions of platelet-activating factor on oviductal cells.

Analysis of Variance↗
PubMed1981

Inactivation of purified human alpha 2-antiplasmin and purified human C1 inhibitor by synthetic fibrinolytic agents.

3-Hydroxypropyl flufenamide (Flu-HPA) is one of a series of flufenamic acid derivatives that enhances blood clot lysis in vitro. Studies of possible mechanisms of action of Flu-HPA were undertaken. The profibrinolytic activity of Flu-HPA in clot lysis assays was found to be dependent on plasminogen. The influence of Flu-HPA on the ability of purified alpha 2-antiplasmin to inhibit purified plasmin was studied. Plasmin activity was determined using 125I-fibrin plates or the spectrophotometric tripeptide substrate, Val-Leu-Lys-paranitroanilide. At Flu-HPA concentrations greater than 1 mM, the inhibitory activity of alpha 2-antiplasmin was abolished in a time-dependent and concentration-dependent manner. The influence of Flu-HPA on the ability of purified Cl inhibitor to inhibit purified plasma kallikrein and beta-Factor XIIa was also studied. Cl inhibitor activity was abolished by Flu-HPA at concentrations greater than 2 mM. Notably, Flu-HPA up to 60 mM did not affect the amidolytic activities of plasmin, kallikrein, or beta-Factor XIIa. Flu-HPA did not release enzyme activity from preformed complexes of either alpha 2-antiplasmin and plasmin of Cl inhibitor and kallikrein. A water-soluble derivative of flufenamic acid, N-flufenamyl-glutamic acid, also inactivated alpha 2-antiplasm and Cl inhibitor. This inactivation was shown to be reversible. These results indicate that synthetic fibrinolytic compounds such as flufenamic acid derivatives may promote fibrinolysis by directly inactivating alpha 2-antiplasmin and Cl inhibitor.

Blood Coagulation↗
PubMed1994

Drug binding properties of glycosylated bovine serum albumin as measured by circular dichroism.

The binding properties of Sudlow's site-specific drugs to glycosylated bovine serum albumin (G-BSA) (1.25 mol glucose per mol of albumin) have been investigated using the circular dichroism (CD) method. Site I-specific drugs, phenylbutazone and warfarin, and site II-specific drugs, flufenamic acid and ibuprofen, were used. The induced ellipticities of phenylbutazone, flufenamic acid and ibuprofen-G-BSA complexes diminished and those of warfarin complex were enhanced in comparison with those for the intact bovine serum albumin (BSA) complexes. These CD change suggests that the glycosylation of BSA at the primary modification site influences the binding properties of the site-specific drugs to serum albumin.

Binding Sites↗
PubMed2004

Selective binding to transthyretin and tetramer stabilization in serum from patients with familial amyloidotic polyneuropathy by an iodinated diflunisal derivative.

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.

Amyloid Neuropathies↗
PubMed2000

Nonselective cation and BK channels in apical membrane of outer sulcus epithelial cells.

The outer sulcus epithelium was recently shown to absorb cations from the lumen of the gerbil cochlea. Patch clamp recordings of excised apical membrane were made to investigate ion channels that participate in this reabsorptive flux. Three types of channel were observed: (i) a nonselective cation (NSC) channel, (ii) a BK (large conductance, maxi K or K(Ca)) channel and (iii) a small K(+) channel which could not be fully characterized. The NSC channel found in excised insideout patch recordings displayed a linear current-voltage (I-V) relationship (27 pS) and was equally conductive for Na(+) and K(+), but not permeable to Cl(-) or N-methyl-d-glucamine. Channel activity required the presence of Ca(2+) at the cytosolic face, but was detected at Ca(2+) concentrations as low as 10(-7) m (open probability (P(o)) = 0.11 +/- 0.03, n = 8). Gadolinium decreased P(o) of the NSC channel from both the external and cytosolic side (IC(50) approximately 0.6 microm). NSC currents were decreased by amiloride (10 microm - 1 mm) and flufenamic acid (0.1 mm). The BK channel was also frequently (38%) observed in excised patches. In symmetrical 150 mm KCl conditions, the I-V relationship was linear with a conductance of 268 pS. The Goldman-Hodgkin-Katz equation for current carried solely by K(+) could be fitted to the I-V relationship in asymmetrical K(+) and Na(+) solutions. The channel was impermeable to Cl(-) and N-methyl-d-glucamine. P(o) of the BK channel increased with depolarization of the membrane potential and with increasing cytosolic Ca(2+). TEA (20 mm), charybdotoxin (100 nm) and Ba(2+) (1 mm) but not amiloride (1 mm) reduced P(o) from the extracellular side. In contrast, external flufenamic acid (100 microm) increased P(o) and this effect was inhibited by charybdotoxin (100 nm). Flufenamic acid inhibited the inward short-circuit current measured by the vibrating probe and caused a transient outward current. We conclude that the NSC channel is Ca(2+) activated, voltage-insensitive and involved in both constitutive K(+) and Na(+) reabsorption from endolymph while the BK channel might participate in the K(+) pathway under stimulated conditions that produce an elevated intracellular Ca(2+) or depolarized membrane potential.

Animals↗
PubMed2002

Inhibition of gap junction hemichannels by chloride channel blockers.

Electrophysiological methods were used to assess the effect of chloride-channel blockers on the macroscopic and microscopic currents of mouse connexin50 (Cx50) and rat connexin46 (Cx46) hemichannels expressed in Xenopus laevis oocytes. Oocytes were voltage-clamped at -50 mV and hemichannel currents (ICx50 or ICx46) were activated by lowering the extracellular Ca2+ concentration ([Ca2+]o) from 5 mM to 10 microM. Ion-replacement experiments suggested that ICx50 is carried primarily (>95%) by monovalent cations (PK : PNa : PCl = 1.0 : 0.74 : 0.05). ICx50 was inhibited by 18beta-glycyrrhetinic acid (apparent Ki, 2 microM), gadolinium (3 microM), flufenamic acid (3 microM), niflumic acid (11 microM), NPPB (15 microM), diphenyl-2-carboxylate (26 microM), and octanol (177 microM). With the exception of octanol, niflumic acid, and diphenyl-2-carboxylate, the above agents also inhibited ICx46. Anthracene-9-carboxylate, furosemide, DIDS, SITS, IAA-94, and tamoxifen had no inhibitory effect on either ICx50 or ICx46. The kinetics of ICx50 inhibition were not altered at widely different [Ca2+]o (10-500 microM), suggesting that drug-hemichannel interaction does not involve the Ca2+ binding site. In excised membrane patches, application of flufenamic acid or octanol to the extracellular surface of Cx50 hemichannels reduced single channel-open probability without altering the single-channel conductance, but application to the cytoplasmic surface had no effect on the channels. We conclude that some chloride-channel blockers inhibit lens-connexin hemichannels by acting on a site accessible only from the extracellular space, and that drug-hemichannel interaction involves a high-affinity site other than the Ca2+ binding site.

Animals↗
PubMed1993

Thyroid hormone uptake by hepatocytes: structure-activity relationships of phenylanthranilic acids with inhibitory activity.

The synthesis of a series of mono- and disubstituted N-phenylanthranilic acids is described. Substituents on the phenyl ring include Cl, CN, OH, CF3, Br, I, CH3, OCH3, and OCF2CF2H. These compounds have been tested for their inhibitory effect on triiodothyronine (T3) uptake by H4 hepatocytes. The nonsteroidal antiinflammatory drugs flufenamic acid, mefenamic acid, and meclofenamic acid and the structurally related compounds 2,3-dimethyldiphenylamine and diclofenac were also tested. The most potent compounds were found to be, in order of decreasing activity, meclofenamic acid (2,6-Cl2,3-CH3), flufenamic acid (3-CF3), mefenamic acid (2,3-(CH3)2), and the compounds with 3,5-Cl2 and 3-OCF2CF2H substituents. The least potent compounds had 3-CN and 3-OH substituents. An analysis of quantitative structure-activity relationships (QSAR) for the series of phenylanthranilic acids showed that the inhibition of T3 uptake is highly dependent on the hydrophobicity of the compound. The relationship between uptake inhibition and the calculated octanol-water partition coefficient (clogP) was found to be parabolic, with optimum inhibitory activity found when the clogP of the phenylanthranilic acid was 5.7. It was also found that the 1-carboxylic acid group of the phenylanthranilic acids was not a prerequisite for uptake inhibition to occur, but its removal or alteration resulted in reduced inhibition.

Animals↗
PubMed2005

Tibolone metabolism in human liver is catalyzed by 3alpha/3beta-hydroxysteroid dehydrogenase activities of the four isoforms of the aldo-keto reductase (AKR)1C subfamily.

Tibolone [[7alpha,17alpha]-17-hydroxy-7-methyl-19-norpregn-5(10)-en-20-yn-3-one] is used to treat climacteric symptoms and prevent osteoporosis. It exerts tissue-selective effects via site-specific metabolism into 3alpha- and 3beta-hydroxymetabolites and a Delta4-isomer. Recombinant human cytosolic aldo-keto reductases 1C1 and 1C2 (AKR1C1 and AKR1C2) produce 3beta-hydroxytibolone, and the liver-specific AKR1C4 produces predominantly 3alpha-hydroxytibolone. These observations may account for the appearance of 3beta-hydroxytibolone in target tissues and 3alpha-hydroxytibolone in the circulation. Using liver autopsy samples (which express AKR1C1-AKR1C4), tibolone was reduced via 3alpha- and 3beta-hydroxysteroid dehydrogenase (HSD) activity. 3beta-Hydroxytibolone was exclusively formed in the cytosol and was inhibited by the AKR1C2-specific inhibitor 5beta-cholanic acid-3alpha, 7alpha-diol. The cytosolic formation of 3alpha-hydroxytibolone was inhibited by an AKR1C4-selective inhibitor, phenolphthalein. The ratio of these stereoisomers was 4:1 in favor of 3beta-hydroxytibolone. In HepG2 cell cytosol and intact cells (which do not express AKR1C4), tibolone was exclusively reduced to 3beta-hydroxytibolone and was blocked by the AKR1C1-AKR1C3 inhibitor flufenamic acid. In primary hepatocytes (which express AKR1C1-AKR1C4), time-dependent reduction of tibolone into 3beta- and 3alpha-hydroxytibolone was observed again in a 4:1 ratio. 3beta-HSD activity was inhibited by both 5beta-cholanic acid-3alpha,7alpha-diol and flufenamic acid, implicating a role for AKR1C2 and AKR1C1. By contrast, the formation of 3alpha-hydroxytibolone was exclusively inhibited by phenolphthalein implicating AKR1C4 in this reaction. 3beta- and 3alpha-Hydroxytibolone were rapidly metabolized into polar metabolites (>85%). The formation of minor amounts of tibolone was also observed followed by AKR1C-catalyzed epimerization. The low hepatic formation of 3alpha-hydroxytibolone suggests that AKR1C4 is not the primary source of this metabolite and instead it maybe formed by an intestinal or enterobacterial 3alpha-HSD.

17-Hydroxysteroid Dehydrogenases↗
PubMed2004

Detergents profoundly affect inhibitor potencies against both cyclo-oxygenase isoforms.

The sensitivity of Coxs (cyclo-oxygenases) to inhibition is known to be highly dependent on assay conditions. In the present study, the inhibitor sensitivities of purified Cox-1 and -2 were determined in a colorimetric assay using the reducing agent N, N, N ', N '-tetramethyl- p -phenylenediamine. With the detergent genapol X-100 (2 mM) present, the potencies of nimesulide, ibuprofen, flufenamic acid, niflumic acid and naproxen were increased over 100-fold against Cox-2 and titration curve shapes changed, so that maximal inhibition now approached 100%. Indomethacin, diclofenac and flosulide were not changed in potency. Similar effects of genapol were observed with inhibitors of Cox-1. DuP-697 and two analogues became more than 10-fold less potent against Cox-2 with genapol present. Tween-20, Triton X-100 and phosphatidylcholine, but not octylglucoside, gave qualitatively similar effects as genapol. Similar detergent-dependent changes in inhibitor potency were also observed using a [(14)C]arachidonic acid HPLC assay. The increases in potency of ibuprofen, flufenamic acid, isoxicam and niflumic acid towards Cox-2 and ibuprofen towards Cox-1 were accompanied by a change from time-independent to time-dependent inhibition. The interactions of Cox inhibitors has been described in terms of multiple binding step mechanisms. The genapol-dependent increase in inhibitor potency for ketoprofen was associated with an increase in the rate constant for the conversion of the initial enzyme-inhibitor complex to a second, more tightly bound form. The loss of potency for some inhibitors is probably due to inhibitor partitioning into detergent micelles. The present study identifies detergents as another factor that must be considered when determining inhibitor potencies against both Cox isoforms.

Cyclooxygenase 1↗
PubMed1975

Action of luteinizing hormone-releasing hormone and synthesis of prostaglandin in the pituitary gland.

The possibility that prostaglandin E2 (PGE2) may play a role in luteinizing hormone (LH) release was examined using an in vitro model. Addition of luteinizing hormone-releasing hormone (LH-RH) to the culture medium stimulated cyclic AMP accumulation and LH-release by incubated hemipituitaries, but did not affect the level of PGE2 or prostaglandin synthetase activity in the gland. Aspirin and indomethacin reduced both prostaglandin synthetase activity and PGE2 or prostaglandin synthetase activity in the gland. Aspirin and indomethacin reduced both prostaglandin synthetase activity and PGE2 content in the pituitary, but did not impair the stimulatory action of LH-RH on either cyclic AMP accumulation or LH-release. Flufenamic acid on its own caused LH-release, but the drug abolished the effect of LH-RH on cyclic AMP accumulation. The mechanism of this action of flufenamic acid is not understood. It is concluded that the stimulatory action of LH-RH on pituitary cyclic AMP production and LH release is not mediated by prostaglandins.

Animals↗
PubMed1977

[Analysis of etofenamate. Particular determination in biological material (author's transl)].

The determination of 2-(2-hydroxyethoxy)-ethyl-N-(a,a,a-trifluoro-m-tolyl)-anthranilate (etofenamate, active principle of Rheumon gel) following its isolation from biological material is reported. Depending on the method of extraction etofenamate, free and alkali-labile conjugated flufenamic acid, total conjugates or the sum of CF3-containing compounds (sum of metabolites) are isolated. Separation is achieved by TLC, quantitative determination is made by degradation to flufenamic acid and fluorimetric measurement in CCl4/trichloracetic acid at 372/445 nm. Etofenamate can be identified by TLC, derivatisation, UV- and fluorescence spectroscopy and differentiated from its metabolites. It is demonstrated that etofenamate is the main component of fenamates in inflamed tissue.

Animals↗
PubMed2002

Effects of anion and cation inhibitors and carbonic anhydrase inhibitors upon the activity of the gypsy moth (Lepidoptera: Lymantriidae) nucleo-polyhedrovirus.

Twenty chemicals that were reported to act as anion transport inhibitors, cation transport inhibitors, and inhibitors of carbonic anhydrase activity were tested at a 1% concentration (wt:wt) for their effects upon the biological activity of the gypsy moth, Lymantria dispar (L.), nucleopolyhedrovirus (LdMNPV). Among the five anion transport inhibitors tested, flufenamic acid acted as a viral enhancer. None of the seven inhibitors of K+ enhanced viral activity and three (4-aminopyridine, diacetyl, and procaine) significantly reduced the activity of LdMNPV. All four Na+ transport inhibitors (abietic acid, amiloride, dicyclohexylcarbodiimide, triamterene) acted as viral enhancers. Triamterene was the most active enhancer, as the LC50 was reduced by approximately 1,750-fold. Five carbonic anhydrase inhibitors were tested and four (acetazolamide, hydrochlorothiazide, methazolamide, sulfanilamide) enhanced the activity of LdMNPV. Acetazolamide (a carbonic anhydrase inhibitor), amiloride (a Na+ transport inhibitor), and flufenamic acid (an anion transport inhibitor) were tested singly and in different combinations. Every combination tested (acetazolamide/amiloride, acetazolamide/flufenamic acid, amiloride/flufenamic acid, acetazolamide/amiloride/flufenamic acid) significantly decreased the LC50 from 7.79 PIB/mm2 to a value as low as 0.008 PIB/mm2 (amiloride/flufenamic acid).

Acetazolamide↗