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PubMed1983

Indomethacin inhibition of glutathione S-transferases.

Indomethacin inhibited rat liver glutathione S-transferases (EC 2.5.1.18). Its inhibition was non-competitive with respect to 3,4-dichloronitrobenzene with an apparent Ki of 5.3 X 10(-5) M and uncompetitive with respect to glutathione with an apparent Ki of 4.0 X 10(-5) M. 4-Chlorobenzoic acid and 5-methoxy-2-methylindole-3-acetic acid, two metabolites of indomethacin, were weak inhibitors of the enzymes. On the other hand, meclofenamic acid was a competitive inhibitor of the enzymes with an apparent Ki of 3.0 X 10(-4) M. Possible significance of these findings in arachidonic acid metabolism is discussed.

Animals↗

PubMed1988

Eicosanoids and control of mesangial cell contraction.

Contraction of glomerular mesangial cells is stimulated in vitro by the vasoconstrictor metabolite of arachidonic acid, thromboxane A2. To establish the role of mesangial prostaglandin (PG) synthesis in the modulation of contractile responses, we studied the effects of the stable thromboxane A2/endoperoxide analogue U-46619 on cultured rat mesangial cells preincubated with 1) four structurally unrelated, nonsteroidal anti-inflammatory drugs, indomethacin, acetylsalicylic acid, meclofenamate, and piroxicam, to inhibit the synthesis of PGE2, the major mesangial metabolite of arachidonic acid; 2) exogenous PGE2 and the stable analogue of PGI2, iloprost; and 3) indomethacin in the presence of exogenous PGE2. Computer-assisted image analysis microscopy demonstrated enhancement of spontaneous and agonist-induced contraction by nonsteroidal anti-inflammatory drugs in individual cells grown on a glass substrate, from 37.2 +/- 7.3% to a maximum of 75.5 +/- 6.4% of the cells with piroxicam, at 1 microM U-46619. PGE2 and iloprost dose-dependently inhibited U-46619-induced contraction, to 5.0 +/- 2.8% and 12.5 +/- 4.7% of the cells, respectively, at 1 microM U-46619. PGE2 also completely reversed the effects of indomethacin. Both PGE2 and iloprost dose-dependently stimulated intracellular cyclic AMP (cAMP) accumulation during 3-minute incubations, an effect that was blocked by the inhibitor of adenylate cyclase, 2',5'-dideoxyadenosine. The latter reversed the inhibitory action of PGE2, enhancing spontaneous and agonist-induced contractility, thus indicating a modulatory role of cAMP. We conclude that endogenous arachidonate metabolism regulates mesangial cell contraction through elevation of intracellular cAMP.

Animals↗

PubMed1976

Comparison of ocular prostaglandin synthesis inhibitors.

A comparative study was carried out of the inhibitory effect of 14 nonsteroidal anti-inflammatory compounds, administered topically, on the intraocular pressure and aqueous humor protein elevation induced by arachidonic acid in rabbits. The most effective agents were flurbiprofen solution and suspensions of indoxole (polysorbate-dispersed), meclofenamic acid, indomethacin, and clonixin.

Animals↗

PubMed1995

Distinct systems mediate the unidirectional efflux of methotrexate and cholate in human CCRF-CEM cells.

Human CCRF-CEM cells were shown to contain energy-dependent and unidirectional efflux systems for the extrusion of methotrexate and cholate. Efflux activity was sensitive to temperature and to energy deprivation by treatment with antimycin A and to various other compounds which do not affect energy metabolism. A comparison of inhibitor sensitivities revealed that methotrexate and cholate efflux exhibit substantial differences in half-maximal inhibition (IC50) by indomethacin, reserpine, ethacrynic acid, ketoprofen, probenecid, and bromosulfophthalein, although these systems could not be distinguished by their responses to prostaglandin A1, meclofenamic acid, indoprofen, and biphenylacetic acid. Comparisons between cell lines showed that methotrexate efflux in CCRF-CEM cells exhibits an inhibitor response comparable to a secondary efflux system for methotrexate in L1210 cells (system II), whereas the inhibitor response of cholate efflux in CCRF-CEM cells resembles efflux system I in L1210 cells, the primary efflux route for both methotrexate and cholate. These results indicate that CCRF-CEM cells contain similar but separate systems for the efflux of methotrexate and cholate. CCRF-CEM cells thus differ from L1210 cells in that the latter mediate the efflux of methotrexate and cholate primarily via a single system.

Biological Transport↗

PubMed1995

Arginine 120 of prostaglandin G/H synthase-1 is required for the inhibition by nonsteroidal anti-inflammatory drugs containing a carboxylic acid moiety.

The therapeutic action of nonsteroidal anti-inflammatory drugs (NSAIDs) is exerted through the inhibition of prostaglandin G/H synthase (PGHS), which is expressed as two isoenzymes, termed PGHS-1 and PGHS-2. From the crystal structure of sheep PGHS-1, it has been proposed that the carboxylic acid group of flurbiprofen is located in a favorable position for interacting with the arginine 120 residue of PGHS-1 (Picot, D., Loll, P. J., and Garavito, R. M. (1994) Nature 367, 243-249). Mutation of this Arg120 residue to Glu was performed and expressed in COS-7 cells using a vaccinia virus expression system. Comparison of microsomal enzyme preparations show that the mutation results in a 20-fold reduction in the specific activity of PGHS-1 and in a 100-fold increase in the apparent Km for arachidonic acid. Indomethacin, flurbiprofen, and ketoprofen, inhibitors of PGHS activity containing a free carboxylic acid group, do not exhibit any inhibitory effects against the activity of PGHS-1(Arg120-->Glu). Diclofenac and meclofenamic acid, other NSAIDs containing a free carboxylic acid group, were 50-100-fold less potent inhibitors of the activity of the mutant as compared with the wild type PGHS. In contrast, the nonacid PGHS inhibitors, 5-bromo-2-(4-fluorophenyl)-3-(4-methylsulfonyl)thiophene (DuP697) and a desbromo-sulfonamide analogue of DuP697 (L-746,483), were both more potent inhibitors of PGHS-1(Arg120-->Glu) than of the wild tyupe PGHS-1. Inhibition of PGHS-1(Arg120-->Glu) was time-dependent for diclofenac and time-independent for DuP697, as observed for the wild type enzyme, indicating that the mutation does not alter the basic mechanism of inhibition. Aspirin is an acid NSAID that inhibits PGHS-1 through a unique covalent acetylation of the enzyme and also showed a reduced rate of inactivation of the mutated enzyme. These data provide biochemical evidence of the importance of the Arg120 residue in PGHS-1 for interaction with arachidonic acid and NSAIDs containing a free carboxylic acid moiety.

Animals↗

PubMed1993

Indomethacin/ibuprofen-like anti-inflammatory agents selectively potentiate the gamma-aminobutyric acid-antagonistic effects of several norfloxacin-like quinolone antibacterial agents on [35S]t-butylbicyclophosphorothionate binding.

Four piperazinoquinolone antibacterial drugs (norfloxacin, ciprofloxacin, enoxacin, and pipemidic acid), known to be gamma-aminobutyric acid (GABA) antagonists, fully reversed the inhibitory effect of GABA on [35S]t-butylbicyclophosphorothionate ([35S] TBPS) binding to rat brain membranes in vitro. Twelve indomethacin/ibuprofen-like arylalkanoic acid (AAA) anti-inflammatory drugs alone had no effect on [35S]TBPS binding, or on its inhibition by GABA, but potentiated the GABA-antagonistic effects of the four quinolones. Felbinac (4-biphenylacetic acid) was most potent in this respect (EC50 = 110 nM, together with 5 microM norfloxacin), followed by flurbiprofen > anirolac > metiazinic acid > tolmetin = ketoprofen = fenbufen = indomethacin > fenoprofen > ibuprofen = (+)-naproxen = sulindac. Other anti-inflammatory analgesic drugs, including aspirin, diclofenac, diflunisal, meclofenamic acid, mefenamic acid, nambumetone, phenacetin, piroxicam, and phenylbutazone, failed to potentiate the GABA-antagonistic effect of norfloxacin. Felbinac (1 microM) increased the GABA-antagonistic potencies of norfloxacin and enoxacin about 26-fold, while increasing those of ciprofloxacin and pipemidic acid 7-fold and 2.3-fold, respectively. Using subsaturating concentrations of the four quinolones, concentration-response curves for felbinac yielded EC50 values ranging from 110 nM with 5 microM norfloxacin to 1.3 microM with 100 microM pipemidic acid. Three other piperazinoquinolone antibacterial agents (amifloxacin, difloxacin, and fleroxacin) and four nonpiperazinoquinolone anti-bacterial agents (oxolinic acid, cinoxacin, nalidixic acid, and piromidic acid) were much weaker GABA antagonists and were not significantly potentiated by felbinac. All other known GABAA receptor blockers tested, including R 5135, pitrazepin, bicuculline, SR 95531, strychnine, D-tubocurarine, thebaine, securinine, theophylline, and caffeine, were not potentiated by felbinac. Our results suggest that norfloxacin and related piperazinoquinolones, acting at GABAA receptors, may induce a high affinity binding site for indomethacin/ibuprofen-like anti-inflammatory agents (the AAA site) that, when occupied, reciprocally increases the affinities of the quinolones for GABAA receptors. The AAA binding site may be a new site in the GABAA receptor complex.

4-Quinolones↗

PubMed1990

Arachidonic acid metabolite production following focal cerebral ischemia: time course and effect of meclofenamate.

Arachidonic acid metabolites have been implicated in the development of cerebral edema following ischemia. To define the time course of metabolite production, subtemporal craniectomies were performed on 60 male Sprague-Dawley rats (350-400 g). Thirty rats underwent middle cerebral artery occlusion while 30 rats underwent craniectomy alone. Five rats in each of two groups (middle cerebral artery occlusion and sham) were sacrificed at 15 minutes, 1 hour, 4 hours, 1 day, 3 days, and 6 days. The cerebral hemispheres were removed and divided in the midsagittal plane. Each hemisphere was immediately frozen in isopentane cooled in dry ice and stored at -70 degrees C. Tissue prostaglandins E2 and 6-keto F1 alpha, and leukotrienes (LT) B4 and C4 were measured by radioimmunoassay. Prostaglandin E2 and 6-keto prostaglandin F1 alpha were significantly elevated at 15 minutes in the middle cerebral artery occlusion hemispheres (p less than 0.05). Prostaglandins were not significantly elevated after 15 minutes. LT B4 and C4 were never significantly elevated. Meclofenamate, a nonsteroidal anti-inflammatory agent, was administered to 21 additional rats. Seven controls underwent middle cerebral artery occlusion alone, 7 were given intraperitoneal meclofenamate (20 mg/kg) 30 minutes prior to middle cerebral artery occlusion, and 7 underwent middle cerebral artery occlusion followed immediately by intraperitoneal meclofenamate (20 mg/kg). The animals were sacrificed at 15 minutes and similarly studied. There was a significant reduction of prostaglandin E2 and 6-keto prostaglandin F1 alpha following pretreatment with meclofenamate (p less than 0.01 and p less than 0.05). In pretreated rats, leukotrienes were not affected by meclofenamate. Similarly, prostaglandins and leukotrienes did not change when meclofenamate was administered after middle cerebral artery occlusion. We conclude that cyclo-oxygenase metabolite production begins within 15 minutes of middle cerebral artery occlusion. Treatment with meclofenamate prior to middle cerebral artery occlusion significantly reduced cyclooxygenase metabolite production, suggesting a protective effect of meclofenamate against ischemia-induced elevations of vasoactive prostaglandins implicated in the development of cerebral edema. Lipoxygenase metabolite production was not affected by middle cerebral artery occlusion or pharmacological intervention.

6-Ketoprostaglandin F1 alpha↗

PubMed1999

Characterization of homogeneous recombinant rat ovarian 20alpha-hydroxysteroid dehydrogenase: fluorescent properties and inhibition profile.

In rat ovary, 20alpha-hydroxysteroid dehydrogenase (20alpha-HSD), a member of the aldo-keto reductase (AKR) superfamily, converts progesterone into the inactive progestin 20alpha-hydroxyprogesterone and has been implicated in the termination of pregnancy. Here we report a convenient overexpression system that permits the purification of milligram quantities of homogeneous recombinant 20alpha-HSD with wild-type enzyme activity. The availability of this enzyme has permitted detailed kinetic, inhibition and fluorescence analyses. The enzyme exhibited narrow steroid specificity, catalysing reactions only at C-20; it reduced progesterone and 17alpha-hydroxyprogesterone and oxidized 20alpha-hydroxypregnanes. It also turned over common AKR substrates, such as 9, 10-phenanthrenequinone and 4-nitrobenzaldehyde. The intrinsic fluorescence spectrum of 20alpha-HSD was characterized and was quenched on the binding of NADP(H), yielding a KNADPd of 0.36 microM and a KNADPHd of 0.64 microM. NADP(H) binding generated an energy transfer band that could not be quenched by steroids. Inhibition studies conducted with non-steroidal and steroidal anti-inflammatory drugs and synthetic oestrogens indicated that even though rat ovarian 20alpha-HSD and rat liver 3alpha-hydroxysteroid dehydrogenase (3alpha-HSD) share more than 67% amino acid identity, their inhibition profiles are markedly different. Unlike 3alpha-HSD, most of these compounds did not inhibit 20alpha-HSD. Only meclofenamic acid and hexoestrol were potent competitive inhibitors for 20alpha-HSD, yielding K(i) values of 18.9 and 14.3 microM respectively. These studies suggest that selective non-steroidal AKR inhibitors could be developed for 20alpha-HSD that might be useful in maintaining pregnancy and that specific inhibitors might be developed from either N-phenylanthranilates or biphenols.

20-Hydroxysteroid Dehydrogenases↗

PubMed1983

Soybean lipoxygenase inhibition by nonsteroidal antiinflammatory drugs.

Eighteen known nonsteroidal antiinflammatory drugs (NSAID) were tested for their action against soybean lipoxygenase (E.C.1.13.11.12) using linoleic acid as substrate. It was found that the best inhibitors of lipoxygenase were naproxen, BW 755C, indomethacin and isoxicam. Drugs with intermediate potency were meclofenamic acid, phenylbutazone and benoxaprofen. Other drugs such as ibuprofen and zomepirac were only weakly active in the test.

4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyraz↗

PubMed1976

Prostaglandins, nonsteroidal anti-inflammatory agents and eye disease.

The prostaglandins produce elevation of intraocular pressure and breakdown of the blood-aqueous barrier. They act via the secondary messenger system, cyclic AMP. Although the pathogenesis of many forms of ocular inflammation, both external and internal, is unclear, it is evident that some forms of ocular inflammation are prostaglandin-mediated, at least in part. Others may be totally mediated by prostaglandin synthesis. At present the corticosteroids are the mainstay of therapy of these conditions. However, the corticosteroids are poor inhibitors of prostaglandin synthesis and have many deleterious side effects such as induction of ocular hypertension, cataract, and infection. The search for new agents that will obviate these side effects and be more specific for the disease process is crucial. The discovery that the mode of action of many nonsteroidal anti-inflammatory agents is via inhibition of prostaglandin synthesis places a premium on elucidating which of these agents is most effective and least toxic in the eye and by which route of administration. The arachidonic acid screening model is ideal for initially choosing which agent has the greatest potential clinically. Arachidonic acid, a PGE2 precursor, when given topically also elevates intraocular pressure and aqueous humor protein, and these effects are blocked by the nonsteroidal anti-inflammatory drugs. This occurs if the arachidonic acid is injected into the vitreous humor, too, providing evidence that this in vivo model involves intraocular mechanisms. Utilizing the arachidonic acid system, a comparative study of nonsteroidal inhibitors of prostaglandin synthesis shows that the most effective of 14 agents were flurbiprofen solution and suspensions of polysorbate-dispersed indoxole, meclofenamic acid, indomethacin, and clonixin. Animal uveitis is not an ideal model for the human condition. Nevertheless, proving the superior efficacy of a screened drug in this system will identify those drugs to be tested in the human disease states. Only after the very few best drugs of this nature are identified should the ultimate steps of human testing be initiated.

Animals↗

PubMed1980

Prostacyclin and thromboxane A2 synthesis by rabbit pulmonary artery.

Superfused spiral strips of rabbit intrapulmonary artery (i.p.a.) were contracted by arachidonic acid (AA) and by the following substances in order of potency: prostaglandin (PG) endoperoxide analog (U46619) > PGH2 > PGF2 alpha. Intrapulmonary artery strips were consistently relaxed by PGE2 and by the enzyme inhibitors, indomethacin, aspirin, meclofenamic acid and 1-pentylimidazole. These latter inhibitors of cyclooxygenase and thromboxane (TX) synthetase also blocked the AA-induced contraction of rabbit i.p.a. Prostacyclin had no effect on the i.p.a. or produced either a small contraction or relaxation. TXA2, formed by incubating horse platelet microsomes with PHG2, always contracted the tissue and was more potent than the parent endoperoxide. Incubations of [14C]AA with i.p.a. produced mainly [14C]-6-keto-PGF1 alpha (he breakdonw product of prostacyclin ) and [14C]TXB2 (the breakdown product of TXA2); the identities of these products were confirmed by radioimmunoassay and by gas chromatography-mass spectrometry. The synthesis of TXB2 by i.p.a. cannot be attributed to adhering lung tissue or platelets and appears to be produced by the vascular tissue itself. It is concluded that, although both prostacyclin and thromboxane may contribute to the resting tone of the rabbit i.p.a., the response to AA is mainly due to production of TXA2.

Animals↗

PubMed1980

Pre- and postjunctional effects of prostaglandin E2, prostaglandin synthetase inhibitors and atropine on cholinergic neurotransmission in guinea pig ileum and bovine iris.

The effects of prostaglandin E2, arachidonic acid, prostaglandin synthetase inhibitors and atropine on cholinergic neuromuscular transmission were examined in isolated guinea pig ileum longitudinal muscle and bovine iris sphincter muscle. Prostaglandin E2 and arachidonic acid markedly enhanced contraction responses induced by nerve stimulation. In addition, prostaglandin E2, enhanced contraction responses to acetylcholine and direct muscle stimulation, approximately to the same extent as those to nerve stimulation. Prostaglandin synthetase inhibitors (indomethacin, meclofenamic acid and eicosatetraynoic acid) very effectively reduced contraction responses to nerve stimulation or acetylcholine, and they annulled the stimulant effect of arachidonic acid. Basal and nerve-induced efflux of acetylcholine from the eserinized tissues, as measured by mass fragmentography, was unaltered by prostaglandin E2, but diminished slowly during indomethacin. Subsequent prostaglandin administration caused a slight increase of nerve-induced release of acetylcholine. Atropine markedly increased overflow of acetylcholine form stimulated preparations of both types. This indicates that muscarinic receptors, causing diminished acetylcholine release in eserinized tissue, may be present also at postganglionic terminals. During atropine, an effect of prostaglandin E2 on acetylcholine release could still not be seen. Thus, using physicochemical determination of acetylcholine, we could not verify earlier reports, employing bioassay, claiming enhanced release of transmitter during prostaglandin E2 treatment. However, it seems likely that prostaglandin E2 takes part in the regulation of contractility and tone of the smooth muscle cells.

Acetylcholine↗

PubMed1996

Cytokine-induced inhibition of bone matrix proteins is not mediated by prostaglandins.

Interleukin-1 (IL-1) and tumor necrosis factor (TNF), two pleiotropic cytokines produced in inflammatory processes, inhibit bone matrix biosynthesis and stimulate prostanoid formation in osteoblasts. In the present study, the importance of prostaglandin formation in IL-1 and TNF-induced inhibition of osteocalcin and type I collagen formation has been examined. In the human osteoblastic cell line MG-63, IL-1 alpha (10-1000 pg/ml), IL-1 beta (3-300 pg/ml) and TNF-alpha (1-30 ng/ml) stimulated prostaglandin E2 (PGE2) formation and inhibited 1,25(OH)2-vitamin D3-induced osteocalcin biosynthesis as well as basal production of type I collagen. Addition of PGE2 or increasing the endogenous formation of PGE2 by treating the cells with arachidonic acid, bradykinin, Lys-bradykinin or des-Arg9-bradykinin, did not affect osteocalcin and type I collagen formation in unstimulated or 1,25(OH)2-vitamin D3-stimulated osteoblasts. Four non-steroidal antiinflammatory drugs, indomethacin, flurbiprofen, naproxen and meclofenamic acid, inhibited basal, IL-1 beta- and TNF-alpha-stimulated PGE2 formation in the MG-63 cells without affecting IL-1 beta- or TNF-alpha-induced inhibition of osteocalcin and type I collagen formation. In isolated, non-transformed, human osteoblast-like cells, IL-1 beta and TNF-alpha stimulated PGE2 formation and concomitantly inhibited 1,25(OH)2-vitamin D3-stimulated osteocalcin biosynthesis, without affecting type I collagen formation. In these cells, indomethacin and flurbiprofen abolished the effects of IL-1 beta and TNF-alpha on prostaglandin formation without affecting the inhibitory effects of the cytokines on osteocalcin biosynthesis. These data show that IL-1 and TNF inhibit osteocalcin and type I collagen formation in osteoblasts independently of prostaglandin biosynthesis and that non-steroidal antiinflammatory drugs do not affect the effects of IL-1 and TNF on bone matrix biosynthesis.

Anti-Inflammatory Agents, Non-Steroidal↗

PubMed1986

Regulation of avidin accumulation by prostaglandins in chick oviduct culture.

Regulation of avidin accumulation by prostaglandins (PGs) and their inhibitors was studied in chick oviduct organ culture. Avidin was induced neither by progesterone nor PGF2 alpha in the oviduct of immature chicks. By progesterone and PGs, a high avidin synthesis was induced when the chicks received diethylstilbestrol (DES) for 7 days. Enhanced avidin production was observed by PGF2 alpha, PGE1 and PGE2, whereas PGA2 and PGB2 had a slight inhibitory effect and PGA1 and PGB1 had no effect on avidin production. PGF2 alpha was most effective at a concentration of 10-20 micrograms/ml. The effects of progesterone and PGF2 alpha were not additive. Mefenamic acid, at concentrations of 40 and 60 micrograms/ml, inhibited 50 and 85%, respectively, of the avidin synthesis induced by progesterone, whereas the inhibition of the total protein synthesis was only 20%, and this only by the higher concentration of the drug. Tolfenamic and meclofenamic acid were also inhibitory in the case of progestin-induced avidin synthesis. These studies indicate that the PGs (F2 alpha, E1 and E2) might be involved in the avidin induction in the chick differentiated oviduct. The specific inhibition of the progesterone-dependent avidin synthesis by the PG inhibitors suggests that PGs may be connected with the progesterone action in the oviduct. We propose that the avidin synthesis by the chick oviduct might be considered as a model system for studying PG effects on the synthesis of a specific protein.

Animals↗

PubMed1995

Side-effects of drugs used in the treatment of rheumatoid arthritis.

A number of anti-inflammatory and other drugs used in the treatment of rheumatoid arthritis have been screened for their ability to cause oxidative damage to lipids and proteins in vitro. Although many drugs exhibited an antioxidant profile, a few drugs tested were pro-oxidant, increasing peroxidation of arachidonic acid by mixtures of haem proteins and H2O2. This system may be an appropriate model to use in the inflammatory situation, since microbleeding to release haemoglobin occurs in the inflamed rheumatoid joint, where H2O2 is produced by invading neutrophils. The damaging effects of the pro-oxidant drugs phenylbutazone, meclofenamic acid and flufenamic acid were investigated in some detail using this system. Arachidonic acid peroxidation was accentuated in a dose-dependent manner and in the presence of haem proteins and H2O2, phenylbutazone also causes inactivation of alpha 1-antiproteinase, a major serine proteinase inhibitor in biological fluids. The above drugs may interact with ferryl haemoglobin, produced by the reaction of H2O2 with haemoglobin, to generate drug-derived radicals causing oxidative damage in these systems. If such reactions occur in vivo, they could contribute to the side-effects induced by these drugs on administration to certain rheumatoid arthritis patients.

Adrenal Cortex Hormones↗

PubMed1987

The pharmacology of arachidonic acid-induced rat paw edema.

Arachidonic acid (AA) injected into hindpaws of Lewis rats produces a severe edematous response. Treatment with corticosteroids (dexamethasone, prednisolone), dual inhibitors of arachidonate metabolism (phenidone, SK & F 86002), anti-histamine/serotonin agents (chlorpheniramine, cyproheptadine) and a gold compound (auranofin) inhibited AA-induced edema. In contrast, administration of high doses of cyclooxygenase inhibitors (indomethacin, piroxicam, naproxen, ibuprofen, meclofenamic acid and tiflamizole) did not affect AA-induced hind paw edema. The involvement of lipoxygenase products and mast cell mediators in the edematous response to arachidonic acid render this model potentially useful for studying antiinflammatory agents with a mechanism of action different from that of cyclooxygenase inhibitors.

Adrenal Cortex Hormones↗

PubMed1983

Possible role of arachidonic acid and of phospholipase A2 in the control of lysosomal enzyme release from human polymorphonuclear leukocytes.

We have studied the role of arachidonic acid (AA) metabolism in the release of lysosomal enzymes (beta-glucuronidase and lysozyme) from human polymorphonuclear leukocytes (PMNs). 5,8,11,14-Eicosatetraenoic acid (ETYA), which inhibits both the cyclo-oxygenase and the lipoxygenase pathways of AA metabolism, was found to cause a dose-dependent inhibition of lysosomal enzyme release from human PMNs induced by immunological (i.e., serum-treated zymosan: Zx) and nonimmunological stimuli (i.e., formyl methionine-containing peptide and the Ca2+ ionophore A23187). In contrast, the non-steroidal anti-inflammatory drugs (indomethacin, meclofenamic acid and aspirin), which only block the cyclo-oxygenase pathway of AA metabolism, had little effect on enzyme release from PMNs induced by the same stimuli. 5,8,11-Eicosatriynoic acid (ETI), a selective inhibitor of the lipoxygenase pathway of AA metabolism, caused a dose-dependent inhibition of lysosomal enzyme release elicited by Zx, f-met peptide, and A23187. p-Bromophenacyl bromide (BPB), which inhibits the phospholipase A2 (PLA2) activity in several tissues, was found to cause a dose-dependent inhibition of lysosomal enzyme release induced by the same immunological and non-immunological stimuli. The inhibitory effect of BPB on enzyme release was irreversible and extremely rapid. It appears that activation of PLA2 and the products of the AA metabolism, generated via a lipoxygenase pathway, play an essential role in the biochemical control of human PMNs activation and secretion.

5,8,11,14-Eicosatetraynoic Acid↗

PubMed1988

Drug and fatty acid effects on serum thyroid hormone binding.

We directly compared the competitor potency for serum T4 binding of 11 nonsteroidal antiinflammatory drugs; the diuretics furosemide, ethacrynic acid, and bumetanide; diphenylhydantoin; the cholecystographic contrast agents iopanoate and ipodate; and six long-chain nonesterified fatty acids (NEFA) using equilibrium dialysis. To avoid artefacts that occur in competitor studies with diluted serum or isolated binding proteins, we used undiluted normal serum, with drugs added at concentrations that achieved high therapeutic total and free serum levels at equilibrium. Drug addition was based on the measured free fraction of each drug in serum. The free T4 fraction in normal serum (Tris buffer, pH 7.4; 37 C) was between 1.40 X 10(-4) and 1.53 X 10(-4). Drug-induced increases in T4 free fraction were: fenclofenac, 90%; aspirin, 62%; meclofenamic acid, 39%; diflunisal, 37%; mefenamic acid, 31%; and furosemide, 31%. Significant increases of 7-15% occurred with diclofenac, flufenamic acid, phenylbutazone, and diphenylhydantoin. Indomethacin, ketoprofen, tolmetin, ethacrynic acid, bumetanide, iopanoate, and ipodate were inactive at the concentrations studied. Addition of 2.0 mmol/L oleic acid had a negligible effect, but 3.5 mmol/L oleic acid inhibited T3 and T4 binding significantly. Other long chain NEFA (addition of 1.5 mmol/L) gave increases in free T4 fraction as follows: arachidonic acid, 26%; linolenic acid, 23%; and linoleic acid, 11%. Stearic and palmitic acids were inactive. The effect of 5 mmol/L oleic acid in serum could be reproduced by addition of 0.5 mmol/L to serum diluted 1:10, indicating that protein binding of NEFA is the major determinant that limits their competitor potency. These findings provide a basis for anticipating which potential inhibitors may cause important changes in serum thyroid hormone binding. The time course of such effects will be influenced by the pharmacokinetics of the inhibitor itself as well as the equilibrium findings described here.

Anti-Inflammatory Agents, Non-Steroidal↗