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At least 595 records · Page 33Linked to original sources
PubMed2004

Development of nonsteroidal anti-inflammatory drug analogs and steroid carboxylates selective for human aldo-keto reductase isoforms: potential antineoplastic agents that work independently of cyclooxygenase isozymes.

Human aldo-keto reductases (AKRs) regulate nuclear receptors by controlling ligand availability. Enzymes implicated in regulating ligand occupancy and trans-activation of the nuclear receptors belong to the AKR1C family (AKR1C1-AKR1C3). Nuclear receptors regulated by AKR1C members include the steroid hormone receptors (androgen, estrogen, and progesterone receptors) and the orphan peroxisome proliferator-activated receptor (PPARgamma). In human myeloid leukemia (HL-60) cells, ligand access to PPARgamma is regulated by AKR1C3, which diverts PGD(2) metabolism away from J-series prostanoids (Desmond et al., 2003). Inhibition of AKR1C3 by indomethacin, a nonsteroidal anti-inflammatory drug (NSAID), caused PPARgamma-mediated terminal differentiation of the HL-60 cells. To discriminate between antineoplastic effects of NSAIDs that are mediated by either AKR1C or cyclooxygenase (COX) isozymes, selective inhibitors are required. We report a structural series of N-phenylanthranilic acid derivatives and steroid carboxylates that selectively inhibit recombinant AKR1C isoforms but do not inhibit recombinant COX-1 or COX-2. The inhibition constants, IC(50), K(I) values, and inhibition patterns were determined for the NSAID analogs and steroid carboxylates against AKR1C and COX isozymes. Lead compounds, 4-chloro-N-phenylanthranilic acid and 4-benzoyl-benzoic acid for the N-phenylanthranilic acid analogs and most steroid carboxylates, exhibited IC(50) values that had greater than 500-fold selectivity for AKR1C isozymes compared with COX-1 and COX-2. Crystallographic and molecular modeling studies showed that the carboxylic acid of the inhibitor ligand was tethered by the catalytic Tyr55-OH(2)(+) and explained why A-ring substituted N-phenylanthranilates inhibited only AKR1C enzymes. These compounds can be used to dissect the role of the AKR1C isozymes in neoplastic diseases and may have cancer chemopreventive roles independent of COX inhibition.

Alcohol Oxidoreductases↗
PubMed1993

Potassium current in circular smooth muscle of human jejunum activated by fenamates.

Thirty-eight cells, freshly isolated from circular smooth muscle of normal human jejunum obtained from nine patients undergoing weight-reduction surgery for morbid obesity, were patch clamped using a perforated patch-clamp technique. A highly potassium-selective voltage-dependent outward current was present in all cells. The current was carried by a 220-pS channel that activated near -75 mV and reached unit open probability at about +10 mV. Blockade of the current by quinidine (50 microM) and tetraethylammonium (25 mM) was accompanied by membrane depolarization to 0 to -3 mV, suggesting that this current was the major determinant of the membrane potential. Flufenamic and mefenamic acid at concentrations comparable with blood levels reached when these drugs are used in clinical therapy as nonsteroidal anti-inflammatory agents, activated the potassium outward current and hyperpolarized the membrane potential. The shift in the membrane potential for 250 microM flufenamic acid was -36 +/- 24 (SD) mV. Activation was rapid (seconds) and reversible. It was concluded that normal human jejunal circular smooth muscle cells have a highly potassium-selective outward current, which is the major determinant of the membrane potential and which is activated by fenamates.

4-Aminopyridine↗
PubMed2000

Capillary isotachophoretic determination of flufenamic, mefenamic, niflumic and tolfenamic acid in pharmaceuticals.

Anionic capillary isotachophoresis (ITP) with conductimetric detection has been used for determining selected non-steroid anti-inflammatory and analgesic drugs of the phenamate group, namely tolfenamic (I), flufenamic (II), mefenamic (III) and niflumic (IV) acid. Initially the pKa values (proton lost) of I-IV were determined as 5.11, 4.91, 5.39 and 4.31, respectively, by the UV spectrophotometry in aqueous 50% (w/w) methanol. The optimised ITP electrolyte system consisted of 10 mM HCl + 20 mM imidazole (pH 7.1) as the leading electrolyte and 10 mM 5,5'-diethylbarbituric acid (pH 7.5) as the terminating electrolyte. The driving and detection currents were 100 microA (for 450 s) and 30 microA, respectively (a single analysis took about 20 min). Under such conditions the effective mobilities of I-IV varied between 23.6 and 24.6 m2 V(-1) s(-1) (evaluated with orotic acid as the mobility standard). The calibration graphs relating the ITP zone length to the concentration of the analytes were rectilinear (r = 0.9987-0.9999) in the range 10-100 mg l(-1) of the drug standard. The R.S.D.s were 0.96-1.55% (n = 6) when determining 50 mg l(-1) of the analytes in pure test solutions. The method has been applied to the assay of the phenamates in six commercial mass-produced pharmaceutical preparations (Mobilisin gel and ointment, Lysalgo capsules, Nifluril cream, Niflugel gel, and Clotam capsules). According to the validation procedure based on the standard addition technique the recoveries were 98.4-104.3% of the drug and the R.S.D. values were 1.25-3.32% (n = 6).

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1977

Effect of indomethacin and related drugs on the calcium ion-dependent secretion of lysosomal and other enzymes by neutrophil polymorphonuclear leucocytes in vitro.

1 Rabbit isolated peritoneal neutrophil polymorphonuclear leucocytes were depleted of calcium by exposure for 1 h to calcium-free bathing fluid at 4 degrees C. 2 Addition of calcium ions to the previously calcium-depleted calls during incubation at 37 degrees C stimulated the release of beta-glucuronidase and of lysozyme but not of lactate dehydrogenase. 3 Low concentrations of indomethacin, flufenamate or salicylate, such as those which occur in the blood plasma after therapeutic doses of these drugs, selectively inhibited the calcium-induced release of beta-glucuronidase. The slight release of this enzyme which occurred in the absence of added calcium ions was not altered by these drugs, neither was the release of lactate dehydrogenase. 4 Release of lysozyme was inhibited by low concentrations of salicylate, amidopyrine or oxyphenbutazone, independent of the presence or absence of calcium ions. 5 Chloroquine, hydrocortisone or colchicine did not alter the release of leucocyte enzymes.

Animals↗
PubMedDate not supplied

Reaction of 1-O-acyl glucuronides with 4-(p-nitrobenzyl)pyridine.

In this investigation, 31 1-O-acyl glucuronides were synthesized and 25 of these were shown to react with 4-(p-nitrobenzyl)pyridine (NBP), a standard chemical nucleophil, on thin layer chromatography plates. A quantitative NBP assay was developed based on existing methods, and the rates of reaction of three acyl glucuronides, clofibric 1-O-acyl glucuronide, indomethacin 1-O-acyl glucuronide, and flufenamic 1-O-acyl glucuronide, were determined. These rates ranged from 0.436 min-1 to 1.08 min-1. Chlorambucil, a powerful alkylating agent, reacted with NBP 127 times faster than the most reactive of the three glucuronides assayed. The half-lives of these three 1-O-acyl glucuronides, determined at pH 2.0, 4.0, 6.0, 7.4, and 10.0 in aqueous phosphate solution, ranged from greater than 1000 hr at pH 2 to less than 1 min at pH 10.0. Determination of the rates of reaction of 1-O-acyl glucuronides with NBP and the rates of hydrolysis as a function of pH further characterize these compounds as activated phase II metabolites.

Alkylation↗
PubMed1975

[New esters of N-arylanthranilic acids].

A series of acyloxy- and alkyloxymethyl esters of meclofenamic, flufenamic and mefenamic acids has been synthesized and its antiinflammatory, analgesic and antipyretic activities have been compared with those of the corresponding acids and the methyl, beta,gamma-isopropylidene-dioxypropyl, N,N-diethylaminoethyl esters. The acyloxy- and alkyloxymethyl esters are the most interesting compounds, because they possess pharmacological activity of the same order as that of the corresponding acids and a lower toxicity. The ethoxymethyl ester of the N-(2,6-dichloro-m-tolyl)anthranilic acid is presently under clinical investigation.

Analgesics↗
PubMed2000

Vacuolar chloride transport in Mesembryanthemum crystallinum L. measured using the fluorescent dye lucigenin.

To study vacuolar chloride (Cl(-)) transport in the halophilic plant Mesembryanthemum crystallinum L., Cl(-) uptake into isolated tonoplast vesicles was measured using the Cl(-)-sensitive fluorescent dye lucigenin (N,N'-dimethyl-9,9'-bisacridinium dinitrate). Lucigenin was used at excitation and emission wavelengths of 433 nm and 506 nm, respectively, and showed a high sensitivity towards Cl(-), with a Stern-Volmer constant of 173 m(-1) in standard assay buffer. While lucigenin fluorescence was strongly quenched by all halides, it was only weakly quenched, if at all, by other anions. However, the fluorescence intensity and Cl(-)-sensitivity of lucigenin was shown to be strongly affected by alkaline pH and was dependent on the conjugate base used as the buffering ion. Chloride transport into tonoplast vesicles of M. crystallinum loaded with 10 mm lucigenin showed saturation-type kinetics with an apparent K(m) of 17.2 mm and a V(max) of 4.8 mm min(-1). Vacuolar Cl(-) transport was not affected by sulfate, malate, or nitrate. In the presence of 250 microm p-chloromercuribenzene sulfonate, a known anion-transport inhibitor, vacuolar Cl(-) transport was actually significantly increased by 24%. To determine absolute fluxes of Cl(-) using this method, the average surface to volume ratio of the tonoplast vesicles was measured by electron microscopy to be 1.13 x 10(7) m(-1). After correcting for a 4.4-fold lower apparent Stern-Volmer constant for intravesicular lucigenin, a maximum rate of Cl(-) transport of 31 nmol m(-2) sec(-1) was calculated, in good agreement with values obtained for the plant vacuolar membrane using other techniques.

4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid↗
PubMed2004

Infrared studies of the polymorphic states of the fenamates.

Infrared spectroscopy has been used to characterize the polymorphic purity as well as to study the thermal conversion of three of the more common fenamates between their different crystalline forms via measuring changes in the NH stretch region that occur between 3300 and 3350 wavenumbers. Shifts in band frequency for mefenamic acid result from differences in internal hydrogen bonding between the NH group and either the carbonyl or hydroxyl groups of the acid moiety. Due to out-of-plane rotations about the central N-C(ring2) bond additional polymorphic states have been suggested for flufenamic and tolfenamic acids. Rates of conversion are given for flufenamic, mefenamic, and tolfenamic acids at temperatures between 85 and 160 degrees C depending on the polymorphic transition for a particular analyte. Subsequently, these rates are used to calculate the activation energy for the observed polymorphic transition. Values of 71.6, 49.0, and 50.8 kcal/mol are obtained respectively for (1) the polymorph I to II transition of mefenamic acid, (2) the polymorph I to II transition of tolfenamic acid, and (3) the polymorph III to I transition of flufenamic acid.

Spectrophotometry, Infrared↗
PubMed1998

Fenamates inhibit contraction of guinea-pig isolated bronchus in vitro independent of prostanoid synthesis inhibition.

The inhibitory and relaxant effects of flufenamic and tolfenamic acids on guinea-pig isolated bronchus were compared with those of verapamil and indomethacin. Flufenamic and tolfenamic acids (each drug, 20 microM) and verapamil (1 microM) inhibited bronchial contraction induced by Ca2+, KCl or PGF2alpha whereas indomethacin (20 microM) had no inhibitory effect. Only verapamil, but not flufenamic and tolfenamic acids and indomethacin, inhibited methacholine-induced contraction. Flufenamic and tolfenamic acids and verapamil (each drug, 0.1-33 microM) relaxed the bronchus precontracted by KCl or PGF2alpha. In contrast, indomethacin (0.1-33 microM) did not relax KCl- or PGF2alpha-precontracted bronchus. Verapamil, but not flufenamic and tolfenamic acids and indomethacin, relaxed methacholine precontracted bronchus. In conclusion, fenamates inhibit Ca2+-, KCl- and PGF2alpha-induced contractions in guinea-pig isolated bronchus in a manner involving inhibition of Ca2+ influx but not inhibition of prostanoid synthesis.

Administration, Topical↗
PubMed1989

Mechanism of inhibition of prostaglandin H synthase by eugenol and other phenolic peroxidase substrates.

The mechanism of inhibition of prostaglandin H synthase (PHS) by eugenol was investigated using purified apoenzyme reconstituted with either manganese protoporphyrin IX (Mn-PHS) or hematin (Fe-PHS). Eugenol stimulated Fe-PHS activity at low concentrations and inhibited at higher concentrations, an activity typical of many phenolic compounds. Eugenol was also an excellent reducing cosubstrate for the peroxidase, being cooxidized to a reactive quinone methide in the process. Higher concentrations of eugenol were required to inhibit Fe-PHS than Mn-PHS (which retains cyclooxygenase activity but not peroxidase activity). Inhibition by eugenol was highly dependent on arachidonic acid concentration. In experiments using Mn-PHS, eugenol increased the time required for the initiation of O2 consumption after addition of arachidonic acid and also inhibited the rate of O2 uptake. Eugenol did not, however, affect the total amount of O2 consumed. The addition of 10 microM hydroperoxide (prostaglandin G2) to these incubations did not prevent the inhibitory effects of eugenol. Other phenolic compounds, including guaiacol, butylated hydroxyanisole, and acetaminophen inhibited Mn-PHS in a manner similar to eugenol. These results demonstrate that eugenol and other phenolic compounds specifically inhibit the cyclooxygenase component of PHS and that this inhibition occurs in addition to, or independent of, the effect of these compounds on peroxide tone or their peroxidative metabolism. We suggest that this inhibition is due to competition with arachidonic acid for the active site of PHS.

Animals↗