[The new anti-inflammatory acids. Niflumic acid in rheumatology].
Explore the source record for details and available documents.
Anti-Inflammatory Agents↗
SEARCH · Search PubMed
Results for “Niflumic Acid”
Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.
Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.
Direct block of the cystic fibrosis transmembrane conductance regulator Cl(-) channel by niflumic acid.
Niflumic acid is widely used to inhibit Ca(2+) -activated Cl(-) channels. However, the chemical structure of niflumic acid resembles that of diphenylamine-2-carboxylate, a drug that inhibits the cystic fibrosis transmembrane conductance regulator (CFTR) Cl(-) channel. To investigate how niflumic acid inhibits CFTR Cl(-) channel, we studied recombinant wild-type human CFTR in excised inside-out membrane patches. When added to the intracellular solution, niflumic acid caused a concentration- and voltage-dependent decrease of CFTR Cl(-) current with half-maximal inhibitory concentration (K(i)) of 253 microM and Hill co-efficient of approximately 1, at -50 mV. Niflumic acid inhibition of single CFTR Cl(-) channels was characterized by a very fast, flickery block that decreased dramatically current amplitude without altering open-probability. Consistent with these data, spectral analysis of CFTR Cl(-) currents suggested that channel block by niflumic acid was described by the closed <--> open <--> blocked kinetic scheme with blocker on rate (k(on)) = 13.9 x 10(6) M(-1)s(-1), off rate (k(off))=3348 s(-1) and dissociation constant (K(d)) = 241 microM, at -50 mV. Based on these data, we tested the effects of niflumic acid on transepithelial Cl(-) secretion and cyst growth using type I MDCK epithelial cells. Niflumic acid (200 microM) inhibited cAMP-stimulated, bumetanide-sensitive short-circuit current by 55%. Moreover, the drug potently retarded cyst growth. We conclude that niflumic acid is an open-channel blocker of CFTR that inhibits Cl(-) permeation by plugging the channel pore. It or related agents might be of value in the development of new therapies for autosomal dominant polycystic kidney disease.
Animals↗
Flufenamic acid, mefenamic acid and niflumic acid inhibit single nonselective cation channels in the rat exocrine pancreas.
The non-steroidal anti-inflammatory drugs, flufenamic acid, mefenamic acid and niflumic acid, block Ca2(+)-activated non-selective cation channels in inside-out patches from the basolateral membrane of rat exocrine pancreatic cells. Half-maximal inhibition was about 10 microM for flufenamic acid and mefenamic acid, whereas niflumic acid was less potent (IC50 about 50 microM). Indomethacin, aspirin, diltiazem and ibuprofen (100 microM) had not effect. It is concluded that the inhibitory effect of flufenamate, mefenamate and niflumate is dependent on the specific structure, consisting of two phenyl rings linked by an amino bridge.
Animals↗
Differential modulation of alpha 3 beta 2 and alpha 3 beta 4 neuronal nicotinic receptors expressed in Xenopus oocytes by flufenamic acid and niflumic acid.
Effects of flufenamic acid (FFA) and niflumic acid (NFA), which are often used to block Ca(2+)-activated Cl- current, have been investigated in voltage-clamped Xenopus oocytes expressing alpha 3 beta 2 and alpha 3 beta 4 nicotinic ACh receptors (nAChRs). NFA and FFA inhibit alpha 3 beta 2 nAChR-mediated inward currents and potentiate alpha 3 beta 4 nAChR-mediated inward currents in normal, Cl(-)-free and Ca(2+)-free solutions to a similar extent. The concentration-dependence of the inhibition of alpha 3 beta 2 nAChR-mediated ion current yields IC50 values of 90 microM for FFA and of 260 microM for NFA. The potentiation of alpha 3 beta 4 nAChR-mediated ion current by NFA yields an EC50 value of 30 microM, whereas the effect of FFA does not saturate for concentrations of up to 1 mM. At 100 microM, FFA reduces the maximum of the concentration-effect curve of ACh for alpha 3 beta 2 nAChRs, but leaves the EC50 of ACh unaffected. The same concentration of FFA potentiates alpha 3 beta 4 nAChR-mediated ion currents for all ACh concentrations and causes a small shift of the concentration-effect curve of ACh to lower agonist concentrations. The potentiation, like the inhibition, is most likely due to a noncompetitive effect of FFA. Increasing ACh-induced inward current either by raising the agonist concentration from 10 microM to 200 microM or by coapplication of 10 microM ACh and 200 microM FFA causes a similar enhancement of block of the alpha 3 beta 4 nAChR-mediated ion current by Mg2+. This suggests that the effects of FFA and of an increased agonist concentration result in a similar functional modification of the alpha 3 beta 4 nAChR-operated ion channel. It is concluded that alpha 3 beta 4 and alpha 3 beta 2 nAChRs are oppositely modulated by FFA and NFA through a direct beta-subunit-dependent effect.
Animals↗
Comparative inhibitory effects of niflumic acid and novel synthetic derivatives on the rat isolated stomach fundus.
Novel derivatives of 2-[3-(trifluoromethyl)-analino]nicotinic acid (niflumic acid) were synthesized. The compounds were compared for their inhibitory effects on 5-hydroxytryptamine (5-HT)- and KCI-induced contraction of the rat fundus. The aim was to assess structure-activity relationships regarding the selectivity and potency of these compounds. Niflumic acid (1-100 microM) concentration-dependently inhibited 5-HT-induced tonic contractions with an IC50 value (concentration reducing the control contractile response by 50%, calculated from semi-log graphs) of 0.24 x 10(4) M (n = 9). In contrast, it was significantly less potent at inhibiting KCl-induced responses (IC50 = 1.49 x 10(4) M, n = 9). The methyl ester (NFAme) and amido (NFAm) analogues showed no selectivity between 5-HT- and KCl-induced contractions with IC50 values of 1.64 x 10(-4) M (n = 8) and 1.87 x 10(-4) M (n = 9) for 5-HT responses, and 2.61 x 10(-4) M (n = 8) and 2.55 x 10(-4) M (n = 7) for KCl-induced responses, respectively. Our results suggest that alteration of the carboxylic acid moiety of niflumic acid reduces the selectivity and potency of its inhibitory action on 5-HT-induced contractile responses of the rat fundus, possibly via a reduced interaction with calcium-activated chloride channels.
Animals↗
[Experiences with niflumic acid in inflammatory glomerulopathies].
Thirty patients with histologically ascertained blomerulonephritis and proteinuria were treated over an average period of 4 months with 750 mg/die 2-m-trigluoromethylanilino-nicotinic acid (niflumic acid, Actol). The following was shown: 1. In 73% of the cases the proteinuria diminished. 2. Kidney function remained unchanged, that is, it worsened only in such cases in which there was already limited functioning. 3. In case of initially increased values the secretion of fibrinogen degradation products diminished in 70% of the cases. 4. When the medication was stopped, its effects vanished. Niflumic acid shows to be an effective drug in the treatment of the nephrotic syndrome and the number of complications is smaller due to the improved condition of protein metabolism. Therefore, this form of treatment, in certain ways, influences the prognosis of the disease.
Depression, Chemical↗
Stability studies of some glycolamide ester prodrugs of niflumic acid in aqueous buffers and human plasma by HPLC with UV detection.
Glycolamide esters (compounds 1-17) of 2-(3-trifluoromethyl-phenylamino)nicotinic acid (niflumic acid, CAS 4394-00-7) have been synthesized and evaluated as possible prodrugs. In-vitro hydrolysis studies were conducted at selected pH values (1.2, 3.5, 4.8, 7.4 and 7.8) and in human plasma at 37 +/- 0.5 degree C using HPLC with UV detection. The aqueous (pH 7.4 and 7.8) and enzymatic rates of hydrolysis were substantially affected by the nature of promoieties in this series. The compounds showed good chemical stability in the buffers of low pH values (1.2, 3.5 and 4.8) and appreciable hydrolysis under alkaline conditions and in human plasma. They exhibited long hydrolytic half-lives of 7-46 h in aqueous buffer solutions (pH 7.4 and 7.8) and 14-21 min in human plasma, respectively. It was observed that N,N-disubstituted and cyclic glycolamide derivatives showed 2 fold more hydrolysis in the alkaline pH than monosubstituted derivatives, whereas the piperidino and thiomorpholino derivatives did not undergo chemical hydrolysis. The compounds contain two possible sites for hydrolysis with an increased hydrolytic susceptibility at the terminal aliphatic carbonyl site in aqueous buffers and human plasma solutions. They were found to be cleaved at two hydrolytic carbonyls, namely the nicotinyl (2-5 % in enzymatic hydrolysis) and the aliphatic site (7-55 % and 70-85 % in buffer and plasma hydrolysis, respectively) as revealed by HPLC analysis. The glycolamide ester prodrugs of niflumic acid underwent chemical and enzymatic hydrolysis to release mainly the metabolite 2-(3-trifluoromethyl-phenylamino) nicotinic acid carboxymethyl ester (III) and not the parent drug 2-(3-trifluoromethyl-phenylamino)nicotinic acid. The structure of the metabolite was confirmed by liquid chromatography-mass spectroscopy (LCMS).
Anti-Inflammatory Agents, Non-Steroidal↗
[Drug cytopenia with active antibodies in the presence of acetyl-salicylic acid and niflumic acid].
Explore the source record for details and available documents.
Adenine↗
Inhibition of mycophenolic acid glucuronidation by niflumic acid in human liver microsomes.
OBJECTIVES: The first aim of this investigation was to study the variability of mycophenolic acid (MPA) glucuronidation rate in human liver. The second aim was to study the inhibition type of niflumic acid (NA) for MPA glucuronidation in human liver. The third aim was to study the variability of the IC(50) value of NA for MPA glucuronidation in human liver. METHODS: The rate of MPA glucuronidation was measured by employing an assay based on uridine 5'-diphosphate-[U-(14)C]-glucuronic acid (UDPGA), and MPA glucuronide was isolated by means of thin-layer chromatography. The necessary concentration for UDPGA and MPA was 1 mM. The rate of MPA glucuronidation was measured in 50 human liver samples. The inhibition type of NA for MPA glucuronidation was studied in 5 human liver samples. The NA IC(50) value was measured in 27 human liver samples using six concentrations of NA ranging from 1.05 microM to 34 microM. RESULTS: MPA glucuronidation rate was positively skewed, was not gender regulated and did not correlate with the liver donor's age. The rate of MPA glucuronidation varied 4.8-fold within the 5th and 95th percentiles, with a mean+/-SD and a median of 2.8+/-1.0 nmol/min/mg and 2.5 nmol/min/mg, respectively. The inhibition type of NA for MPA glucuronidation was mixed non-competitive. The Ki value of NA (mean+/-SD) was 15+/-10 microM and, in non-inhibited samples, the K(m) value for MPA was 0.41+/-0.06 mM. The distribution of NA IC(50) value varied 3.3-fold within the 5th and 95th percentiles with a mean+/-SD and a median of 5.6+/-2.1 microM and 5.2 microM, respectively. The distribution of NA IC(50) value did not deviate significantly from normality. CONCLUSION: The range of hepatic rate of MPA glucuronidation is narrow relative to those of ethinyloestradiol, testosterone and zidovudine glucuronidation obtained from literature. The Ki value of NA is one order of magnitude lower than the K(m) for MPA in non-inhibited samples. This indicates that the inhibitor affinity for glucuronosyl transferase is greater than that of the substrate. The range of variation of NA IC(50) values is narrow.
Adult↗
Niflumic acid in osteoarthrosis. A comparative study of niflumic acid and indomethacin in osteoarthrosis of the knee.
Explore the source record for details and available documents.
Administration, Oral↗
Determination of protonation macro- and microconstants and octanol/water partition coefficient of the antiinflammatory drug niflumic acid.
The drug niflumic acid is an amphoteric substance with overlapping pKa values. The acid-base chemistry of the molecule has been characterized in terms of protonation macroconstants (with reference to stoichiometric ionizations) and microconstants (with reference to ionizations of individual species). The proton-binding sites were assigned using 1H and 13C NMR spectroscopy. Due to the very poor water solubility of niflumic acid, the aqueous pKa values were determined from the apparent ionization constants in methanol-water solutions of various proportions by extrapolation to zero co-solvent using the Yasuda-Shedlovsky procedure. The kz tautomerization microconstant of the equilibrium unionized form<-->zwitterionic form was determined from mixtures of organic solvent (dioxane or methanol) with aqueous buffer (at the pH of isoelectric point) by UV spectroscopy, and used for calculation of the other protonation microconstants. The zwitterionic form of the molecule predominates over the uncharged form, the concentration being maximal at the isoelectric pH. The apparent partition coefficients (Papp) of niflumic acid were measured in octanol/water solution by the shake-flask method over a wide pH range. The lipophilicity profile (logPapp vs pH) shows a parabolic shape near its maximum at the isoelectric point. A relationship derived between Papp, PXH0(micropartition coefficient of the uncharged microspecies) and PX-(partition coefficient of the anion) is valid for amphoteric drugs, in cases where the partition of the unionized form and the ion-pair partition of anion can be confirmed. The logP values of microspecies indicate the high lipophilicity of niflumic acid, which is consistent with its good skin penetration and absorption.
1-Octanol↗
Proteoglycan metabolism in isolated chondrocytes from human cartilage. Influence of niflumic acid.
The effect of niflumic acid on hyaluronic acid and proteoglycan metabolism of human cartilage cells was investigated in vitro. Cartilage cells were obtained from five different donors. Niflumic acid levels used in the test systems ranged from 0 to 22 microgramsr/ml and were comparable to serum concentrations in humans after oral intake. Niflumic acid increased the synthesis rates of proteoglycan in some batches of isolated and monolayer-cultured chondrocytes. The effect on hyaluronate synthesis was less pronounced. The fact that this increase in the synthesis of proteoglycan was restricted to some of the donors whereas isolated cells or tissue samples from other individuals remained unaffected illustrates the heterogeneity of different human donors. Depression of proteoglycan synthesis in the presence of the drug was never observed.
Carbon Radioisotopes↗
In vitro inhibitory effects of non-steroidal anti-inflammatory drugs on 4-methylumbelliferone glucuronidation in recombinant human UDP-glucuronosyltransferase 1A9--potent inhibition by niflumic acid.
The inhibitory potencies of non-steroidal anti-inflammatory drugs (NSAIDs) on UDP-glucuronosyltransferase (UGT) 1A9 activity were investigated in recombinant human UGT1A9 using 4-methylumbelliferone (4-MU) as a substrate for glucuronidation. 4-MU glucuronidation (4-MUG) showed Michaelis-Menten kinetics with a Km value of 6.7 microM. The inhibitory effects of the following seven NSAIDs were investigated: acetaminophen, diclofenac, diflunisal, indomethacin, ketoprofen, naproxen and niflumic acid. Niflumic acid had the most potent inhibitory effect on 4-MUG with an IC50 value of 0.0341 microM. The IC50 values of diflunisal, diclofenac and indomethacin were 1.31, 24.2, and 34.1 microM, respectively, while acetaminophen, ketoprofen and naproxen showed less potent inhibition. Niflumic acid, diflunisal, diclofenac and indomethacin inhibited 4-MUG competitively with Ki values of 0.0275, 0.710, 53.3 and 69.9 microM, respectively, being similar to each IC50 value. In conclusion, of the seven NSAIDs investigated, niflumic acid was the most potent inhibitor of recombinant UGT1A9 via 4-MUG in a competitive manner.
Anti-Inflammatory Agents, Non-Steroidal↗
Modulation of membrane currents and mechanical activity by niflumic acid in rat vascular smooth muscle.
The effects of niflumic acid on whole-cell membrane currents and mechanical activity were examined in the rat portal vein. In freshly dispersed portal vein cells clamped at -60 mV in caesium (Cs+)-containing solutions, niflumic acid (1-100 microM) inhibited calcium (Ca2+)-activated chloride currents (IC1(Ca)) induced by caffeine (10 mM) and by noradrenaline (10 microM). In a potassium (K+)-containing solution and at a holding potential of - 10 mV, niflumic acid (10-100 microM) induced an outward K+ current (IK(ATP)) which was sensitive to glibenclamide (10-30 microM). At concentrations < 30 microM and at a holding potential of -2 mV, niflumic acid had no effect on the magnitude of the caffeine- or noradrenaline-stimulated current (IBK(Ca)) carried by the large conductance, Ca(2+)-sensitive K+ channel (BKCa). However, at a concentration of 100 microM, niflumic acid significantly inhibited IBK(Ca)) evoked by caffeine (10 mM) but not by NS1619 (1-(2'-hydroxy-5'-trifluoromethylphenyl)-5-trifluoromethyl-2(3 H) benzimidazolone; 20 microM). In Cs(+)-containing solutions, niflumic acid (10-100 microM) did not inhibit voltage-sensitive Ca2+ currents. In intact portal veins, niflumic acid (1-300 microM) inhibited spontaneous mechanical activity, an action which was partially antagonised by glibenclamide (1-10 microM), and contractions produced by noradrenaline (10 microM), an effect which was glibenclamide-insensitive. It is concluded that inhibition of ICl(Ca) and stimulation of IK(ATP) both contribute to the mechano-inhibitory actions of niflumic acid in the rat portal vein.
Adrenergic alpha-Agonists↗
Effect of niflumic acid on noradrenaline-induced contractions of the rat aorta.
1. The effects of niflumic acid, an inhibitor of calcium-activated chloride channels, were compared with the actions of the calcium channel antagonist nifedipine on noradrenaline-evoked contractions in isolated preparations of the rat aorta. 2. The cumulative concentration-effect curve to noradrenaline (NA) was depressed by both nifedipine and niflumic acid in a reversible and concentration-dependent manner. The degree of inhibition of the maximal contractile response to NA (1 microM) produced by 10 microM niflumic acid (38%) was similar to the effect of 1 microM nifedipine (39%). 3. Contractions to brief applications (30 s) of 1 microM NA were inhibited by 55% and 62% respectively by 10 microM niflumic acid and 1 microM nifedipine. 4. In the presence of 0.1 microM nifedipine, niflumic acid (10 microM) produced no further inhibition of the NA-evoked contractions. Thus, the actions of niflumic acid and nifedipine were not additive. 5. In Ca-free conditions the transient contraction induced by 1 microM NA was not inhibited by niflumic acid (10 microM) and therefore this agent does not reduce the amount of calcium released from the intracellular store or reduce the sensitivity of the contractile apparatus to calcium. 6. Niflumic acid 10 microM did not inhibit the contractions produced by KCl (up to 120 mM) which were totally blocked by nifedipine. Contractions induced by 25 mM KCl were completely inhibited by 1 microM levcromakalim but were unaffected by niflumic acid. 7. It was concluded that niflumic acid produces selective inhibition of a component of NA-evoked contraction which is probably mediated by voltage-gated calcium channels. These data are consistent with a model in which NA stimulates a calcium-activated chloride conductance which leads to the opening of voltage-gated calcium channels to produce contraction.
Animals↗
A double blind, placebo controlled study of niflumic acid gel in the treatment of acute tendinitis.
Percutaneously administered niflumic acid gel (Niflugel R, Laboratories UPSA, Rueil Malmaison, France) was compared to placebo in a double blind, placebo controlled, multicentre study in the treatment of acute upper and lower limb tendinitis. Fifty nine subjects were enrolled in three centres and were randomly allocated to receive treatment with 2.5% percutaneous niflumic acid gel or placebo gel applied three times daily for 7 days. Clinical evaluations were carried out on inclusion and after seven days of treatment. The variables measured were pain felt by the patient and the investigators' and patients' overall evaluation of the treatments' efficacy. The patients also kept a daily record of pain scores. Any adverse events that occurred were noted. The results showed that niflumic acid gel was significantly better than placebo in improving patient signs as regards overall efficacy ratings. Global evaluation of efficacy rated by the investigator showed that 25/29 patients (86.2%) were healed or improved in the niflumic acid gel group compared with 11/27 patients (40.7%) on placebo, p = < 0.01. The overall assessment of tolerance showed no difference between groups. Only two minor adverse effects were reported in patients treated with niflumic acid gel, and they did not require patients to stop treatment. The study findings indicate that treatment with topical niflumic acid gel is effective in the treatment of tendinitis and results in improved clinical signs at the end of 7 days.
Acute Disease↗
Transport, distribution space and intracellular concentration of the anti-inflammatory drug niflumic acid in the perfused rat liver.
Transport and distribution space of niflumic acid in the perfused rat liver were investigated employing the multiple-indicator dilution technique with constant infusion of the drug (step input). Niflumic acid permeated the cell membrane in both directions at very high rates and its distribution in the cellular space was flow-limited; at least at 37 degrees, the rates of influx and efflux could not be measured. Dissociation of the niflumic acid-albumin complex also occurred at very high rates. The apparent space of distribution of niflumic acid in the liver depended on the concentration of the drug and varied between 4.37 (1 mM) and 43.5 (10 microM) times the water space; even with 90% extracellular binding to albumin, the apparent space of distribution of niflumic acid was 5.1 times greater than the water space. The high apparent spaces of distribution reflected the high intracellular concentrations. The ratio of intracellular bound plus free concentration to the extracellular bound plus free concentration (Ci/Ce) varied between 6.62 (1 mM portal niflumic acid) and 71.0 (10 microM portal niflumic acid). Metabolic transformation depended on the concentration of the free form. Intracellular binding is probably the major reason for the high concentration of the drug in the hepatic tissue.
Animals↗
Identification of human UDP-glucuronosyltransferase responsible for the glucuronidation of niflumic acid in human liver.
PURPOSE: To assess the uridine diphosphate (UDP)-glucuronosyltransferase (UGT) isozymes involved in the glucuronidation of niflumic acid in human liver. METHODS: The glucuronidation activity of niflumic acid was determined in liver microsomes and recombinant UGT isozymes by incubation of niflumic acid with UDP-glucuronic acid (UDPGA). RESULTS: Incubation of niflumic acid with liver microsomes and UDPGA produced one peak, which was identified as a glucuronide from mass spectrometric analysis. A study involving a panel of recombinant human UGT isozymes showed that glucuronidation activity was highest in UGT1A1 among the isozymes investigated. The glucuronidation in human liver microsomes (HLMs) followed Michaelis-Menten kinetics with a Km value of 16 microM, which is similar to that found with recombinant UGT1A1. The glucuronidation activity of niflumic acid in microsomes from eight human livers significantly correlated with UGT1A1-catalyzed estradiol 3beta-glucuronidation activity (r=0.78, p<0.05). Beta-estradiol inhibited niflumic acid glucuronidation with an IC50 of 25 microM in HLMs, comparable to that for UGT1A1. CONCLUSIONS: These findings indicate that UGT1A1 is the main isozyme involved in the glucuronidation of niflumic acid in the human liver.
Anti-Inflammatory Agents, Non-Steroidal↗