Effects of isoxicam and other non-steroidal anti-inflammatory drugs on arachidonic acid metabolism by rat peritoneal leucocytes

Inhibition of prostaglandin formation from [14C]arachidonic acid by rat peritoneal leucocytes occurred with nonsteroidal anti-inflammatory drugs, their order of potency being indomethacin greater than piroxicam greater than naproxen greater than ibuprofen greater than isoxicam. At the lowest concentration tested (1 microgram ml-1), indomethacin markedly increased the accumulation of lipoxygenase products in the cell incubates. Naproxen, ibuprofen or piroxicam 1 or 10 micrograms ml-1 resulted in smaller increases of lipoxygenase products, and there was only a small rise with these concentrations of isoxicam.     

炎息康药效学的研究

应用角叉菜诱导大鼠踝关肿节胀、二甲苯诱导小鼠耳水肿、大鼠佐剂性关节炎、酵母诱导大鼠发热、冰醋酸诱导小鼠扭体反应和小鼠“热板”法等实验模型,研究了炎息康的药理作用,并对其急性和亚急性毒性进行了系统观察。结果表明,炎息康有明显而较持久的抗炎、解熟和镇痛效应,其急性抗炎和镇痛作用(ED50分别为4和5.01mg/kg)类似于炎痛喜康和消炎痛。该药几乎无急性毒性。     

In vitro biosynthesis of cyclooxygenase metabolites in ovalbumin-sensitized and control lungs of guinea pigs

Cyclooxygenase metabolism may regulate mediator release in anaphylaxis. The in vitro biosynthesis of cyclooxygenase metabolites was examined, using isolated microsomal membranes from ovalbumin-sensitized and control guinea pig lungs, under conditions in which the substrate concentration ([³H]arachidonic acid) was varied (5–168 μM). With microsomes from sensitized lungs, there was stimulation of cyclooxygenase activity at substrate concentrations from 20 to 100 μM, with the major increases in activity occurring in the biosynthesis of thromboxane B₂ and prostaglandin D₂. At substrate concentrations greater than 100 μM, the biosynthesis of thromboxane B₂ and prostaglandin D₂ decreased in microsomes of sensitized lungs to the level of production found in control-lung microsomes. In contrast, prostacyclin production was significantly higher in the control-lung microsomes at the higher substrate concentrations. The ratio of prostacyclin to thromboxane production was lower in sensitized-lung microsomes at all substrate concentrations. No changes in the biosynthesis of prostaglandins F_2α or E₂ were detected between the two groups. Kinetic analysis of the data demonstrated that the cyclooxygenases in control and sensitized-lung microsomes exhibited different apparent K_m and V_max values. When the enzymes from both the control and the sensitized-lung microsomes were assayed in the presence of indomethacin (1–10 μM), a cyclooxygenase inhibitor, thromboxane synthesis was preferentially inhibited. The microsomal enzymes from control and sensitized lungs showed similar responses to the drug. At the indomethacin concentrations used, no significant inhibition of prostacyclin or prostaglandin production occurred. The results of these in vitro experiments support the hypothesis that net changes in the biosynthesis of cyclooxygenase metabolites may modulate the anaphylactic response of the lungs in sensitized animals.     

Biological Evaluation of 2‐(4‐Amino‐Phenyl)‐3‐(3,5‐Dihydroxylphenyl) Propenoic Acid

Abstract: 2‐(4‐Aminophenyl)‐3‐(3,5‐dihydroxylphenyl) propenoic acid (CSN‐07001) is a new compound based on the combination of resveratrol and propenoic acid derivatives. In vitro cyclooxygenase (COX)/5‐lipoxygenase (5‐LOX) inhibition assays showed that the test compound exhibited a dual inhibitory activity against the COX (COX‐1 IC₅₀ = 2.20 μM, COX‐2 IC₅₀ = 1.76 μM) and 5‐LOX (IC₅₀ = 0.28 μM) enzymes. Further, the enhanced COX‐1/COX‐2/5‐LOX expression in lipopolysaccaride‐induced lung inflammation in mice was also suppressed by CSN‐07001 in a concentration‐dependent manner. In vivo studies showed that CSN‐07001 exhibited potent anti‐inflammatory and antinociceptive effects in different experimental models. We further examined the risk of gastric damage induced by CSN‐07001. The test compound was gastric‐sparing in that it elicited markedly fewer stomach lesions than indomethacin in rats. Taken together, our data indicate that CSN‐07001 exhibits a novel class of dual inhibitors of COX and 5‐LOX having therapeutic potential as non‐steroidal anti‐inflammatory agents with an enhanced gastric safety profile.     

Effects of eicosanoids and nitric oxide on the noradrenaline‐induced contractions in the rat mesenteric bed

1 The effects of the inhibition of the metabolism of arachidonic acid (AA) on the constrictor responses to noradrenaline (NA) were studied in the rat perfused mesenteric bed. The inhibitor of all the pathways of AA metabolism, 10 μm eicosatetraynoic acid (ETYA), reduced the constrictor responses to all the concentrations of NA assayed.
2 The constrictor responses to NA were also reduced by the cyclooxygenase (COX) inhibitor, indomethacin (10 μm) , as well as by the lipoxygenase inhibitor, nordihidroguaiaretic acid (1 μm; NDGA), whereas they were unmodified by the cytochrome P450 monooxigenase inhibitors, clotrimazole (10 μm ), metyrapone (10 μm ) and proadifen (10 μm ).
3 The reduction in NA contractility induced by indomethacin was reverted with a decreasing order of potency by the thromboxane A₂ analogue, U‐46619>prostaglandin (PG) E₂>PGF₂α. The exposure of the mesenteric bed to NA increased the production of PGF₂α, whereas it did not modify the production of the remaining AA metabolites.
4 The increase in the NA‐induced contractions caused by endothelium removal, as well as by the inhibition of nitric oxide synthase (NOs) with N^G‐nitro‐l ‐arginine methyl ester (400 μm; L‐NAME), was suppressed by indomethacin but not by NDGA. These observations suggest that the lipoxygenase‐derived metabolites are formed in the endothelium, whereas the COX‐derived metabolites are formed in the vascular smooth muscle.
5 The TP receptor antagonist, SQ29548, did not modify the NA‐induced contractions, either in the presence or in the absence of the endothelium.
6 Contractions elicited by KCl (60–100 mm ) were unmodified by the AA metabolism inhibitors, ETYA, NDGA and indomethacin.
7 In summary, these results show that metabolites of AA, through both the COX and the lipoxygenase pathways, are involved in the NA‐induced contractions in the rat mesenteric bed. The lipoxygenase metabolites are likely to be formed in the vascular endothelium, whereas the COX metabolite, which could be PGF₂α, is apparently formed within the vascular smooth muscle.     

Non-steroidal antiinflammatory drug therapy: advantages and disadvantages of long half-life drugs versus slow-release formulations

A single daily administration of non-steroidal antiinflammatory drugs is widely recognized as the best dose regimen in chronic diseases such as degenerative osteoarthropathy, in inflammatory affections of the skeletal muscles, etc. Biomedical research has therefore developed drugs characterized either by a long half-life or available in a slow-release formulation. Isoxicam, piroxicam and benoxaprofen, which possess long half-lives, were compared with diclofenac sodium, indomethacin and ketoprofen, in their slow-release formulations, in terms of pharmacodynamics, pharmacokinetics and toxicity. Isoxicam, piroxicam and diclofenac showed excellent long lasting antiinflammatory properties: however the evidence showed that in cases of mild or severe renal pathology, drugs in their slow-release formulations are to be preferred.     

Contribution of cAMP to the inhibitory effect of non-steroidal anti-inflammatory drugs in rat uterine smooth muscle

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Activation of arachidonoyl phospholipase A2 in prostaglandin-mediated action of sucralfate

1. The mechanism of sucralfate-induced gastric mucosal prostaglandin generation was investigated using mucosal cells labeled with [¹⁴C]choline and [³H]arachidonic acid.2. In comparison to the controls, the cells maintained in the presence of sucralfate showed a concentration dependent increase in lysophosphatidylcholine (LPC) synthesis and PGE₂ generation. The maximal effect was attained at 25 μM sucralfate giving a 45.7% increase in LPC and 70% increase in PGE₂.3. Pretreatment with indomethacin prior to sucralfate, while causing inhibition in PGE₂ generation, had no effect on LPC production and led to accumulation of free arachidonic acid. In the case of pretreatment with NDGA, the sucralfate caused increased LPC synthesis accompanied by enhanced PGE₂ generation without free arachidonic acid accumulation.4. The stimulatory effect of sucralfate on LPC synthesis and PGE₂ generation was inhibited by phospholipase A₂ inhibitors, mepacrine and BPB. The inhibitory effect was concentration dependent and attained maximum at 40 μM for BPB and 80 μM for mepacrine.5. The results for the first time demonstrate that the enhancement in gastric mucosal prostaglandin generation by sucralfate results from the stimulation of mucosal phospholipase A₂ for arachidonic acid release.     

Discovery of cyclooxygenase inhibitors from medicinal plants used to treat inflammation

Eleven authenticated botanicals used in the traditional Chinese medicine Huo-Luo-Xiao-Ling Dan were screened for ligands to cyclooxygenase (COX) using pulsed ultrafiltration liquid chromatography–mass spectrometry, and a mass spectrometry-based enzyme assay was used to determine the concentration of each of 17 ligands that inhibited COX-1 or COX-2 by 50% (IC₅₀). Acetyl-11-keto-β-boswellic acid, β-boswellic acid, acetyl-α-boswellic acid, acetyl-β-boswellic acid, and betulinic acid were COX-1 selective inhibitors with IC₅₀ values of approximately 10 μM. Senkyunolide O and cryptotanshinone were COX-2 selective inhibitors with IC₅₀ values of 5 μM and 22 μM, respectively. Roburic acid and phenethyl-trans-ferulate inhibited COX-1 and COX-2 equally. COX inhibition and the IC₅₀ values of most of these natural product ligands have not been reported previously.     

Neurokinin A-induced guinea pig gallbladder contraction: Potential mechanism of action

The present study was performed to examine the mechanism of action of neurokinin A (NKA) on guinea pig gallbaldder smooth muscle. Muscle strips were prepared and mounted in 10 mL tissue bath containing Krebs' solution under 1 g tension. NKA induced a concentration-dependent increase in gallbladder muscle tension and reached a maximal response at 1 μM. The EC₅₀ value was approximately 30nM. Preincubation of the muscle strips with neurotoxins, tetrodotoxin (1 μM), or omega-conotoxin (0.1 μM) had no effect on the NKA contractile response. NKA-induced gallbladder contractions were insensitive to cyclooxygenase inhibitors (5 μM) piroxicam and indomethacin. In contrast, the calcium channel blockers verapamil and diltiazem (0.1–1 μM) significantly blocked the contractile response to NKA. The intracellular calcium chelator BAPTA/AM had no significant effect on NKA activity. The removal of extracellular calcium, however, completely abolished the contractile response of NKA. These data suggest that NKA has a direct contractile effect on guinea pig gallbladder smooth muscle, which is independent of prostaglandin release. The primary source of calcium involved in mediating the NKA contractile response is the extracellular pool, suggesting that NKA might act via activation of L-type voltage-operated calcium channels to mediate its action. © 1992 Wiley-Liss, Inc.     

The antiinflammatory action of guanabenz is mediated through 5-lipoxygenase and cyclooxygenase inhibition

Guanabenz (2,6-dichlorobenzylidene amino guanidine acetate), an α₂-agonist, possesses antiinflammatory substances, the effect of guanabenz on LT and Since leukotrienes (LT) and prostaglandins(PG) are proinflammatory substances, the effect of guanabenz on LT and PG synthesis by inflammatory cells was investigated. Guanabenz, but not clonidine, B-HT 920 or B-HT 933 inhibited zymosan-induced LTC₄ (IC₅₀=13 μM) and PGE₂ (IC₅₀=10.9 μM) synthesis with no concomitant reduction in zymosan phagocytosis or cell viability. Similarlyguanabenz reduced LTB₄ (IC₅₀=37.4 μM) and PGE₂ (IC₅₀=13.8 μM) synthesis by A23187-stimulated rat glycogen elicited neutrophils. Furthermore, guanabenz did not inhibit platelet 12-lipoxygenase or phospholipase A₂. In vivo, guanabenz was orally active against rat carrageenan paw edema and adjuvant arthritis (ED_50^s=9 and 10 mg/kg, respectively). Topically applied guanabenz reduced arachidonic acid (AA)- or tetradecanoyl phorbol acetate (TPA)-induced ear inflammation (ED_50^s:AAA-induced ear edema, 1.4 mg/ear; PMA-induced ear edema, 0.013 mg/ear). Therefore, the antiinflammatory activity of guanabenz may be due to its ability to inhibit the formation of 5-lipoxygenase and cyclooxygenase products.     

Identification of 5-lipoxygenase and microsomal prostaglandin E2 synthase-1 as functional targets of the anti-inflammatory and anti-carcinogenic garcinol

Garcinol (camboginol) from the fruit rind of Guttiferae species shows anti-carcinogenic and anti-inflammatory properties, but the underlying molecular mechanisms are unclear. Here we show that garcinol potently interferes with 5-lipoxygenase (EC 7.13.11.34) and microsomal prostaglandin (PG)E₂ synthase (mPGES)-1 (EC 5.3.99.3), enzymes that play pivotal roles in inflammation and tumorigenesis. In cell-free assays, garcinol inhibited the activity of purified 5-lipoxygenase and blocked the mPGES-1-mediated conversion of PGH₂ to PGE₂ with IC₅₀ values of 0.1 and 0.3 μM, respectively. Garcinol suppressed 5-lipoxygenase product formation also in intact human neutrophils and reduced PGE₂ formation in interleukin-1β-stimulated A549 human lung carcinoma cells as well as in human whole blood stimulated by lipopolysaccharide. Moreover, garcinol interfered with isolated cyclooxygenase (COX)-1 (EC 1.14.99.1, IC₅₀ = 12 μM) and with the formation of COX-1-derived 12(S)-hydroxy-5-cis-8,10-trans-heptadecatrienoic acid and thromboxane B₂ in human platelets. In contrast, neither Ca²⁺-ionophore (A23187)-induced arachidonic acid release in neutrophils nor COX-2 activity in A549 cells or whole blood, measured as formation of 6-keto PGF_1α, or isolated human recombinant COX-2 were significantly affected by garcinol (≤30 μM). Together, the high potency of garcinol to selectively suppress PGE₂ synthesis and 5-lipoxygenase product formation provides a molecular basis for the anti-inflammatory and anti-carcinogenic effects of garcinol and rationalizes its therapeutic use.     

Fluvoxamine is a More Potent Inhibitor of Lidocaine Metabolism than Ketoconazole and Erythromycin in vitro

Abstract CYP3A4 is generally believed to be the major CYP enzyme involved in the biotransformation of lidocaine in man; however, recent in vivo studies suggest that this may not be the case. We have examined the effects of the CYP3A4 inhibitors erythromycin and ketoconazole and the CYP1A2 inhibitor fluvoxamine on the N-deethylation, i.e. formation of monoethylglycinexylidide (MEGX), and 3-hydroxylation of lidocaine by human liver microsomes. The experiments were carried out at lidocaine concentrations of 5 μM (clinically relevant concentration) and 800 μM. The formation of both MEGX and 3-hydroxylidocaine was best described by a two-enzyme model. At 5 μM of lidocaine, fluvoxamine was a potent inhibitor of the formation of MEGX (IC₅₀ 1.2 μM). Ketoconazole and erythromycin also showed an inhibitory effect on MEGX formation, but ketoconazole (IC₅₀ 8.5 μM) was a much more potent inhibitor than erythromycin (IC₅₀ 200 μM). At 800 μM of lidocaine, fluvoxamine (IC₅₀ 20.7 μM) and ketoconazole (IC₅₀ 20.4 μM) displayed a modest inhibitory effect on MEGX formation, whereas erythromycin was a weak inhibitor (IC₅₀>250 μM). The 3-hydroxylation of lidocaine was potently inhibited by fluvoxamine at both lidocaine concentrations (IC₅₀ 0.16 μM at 5 μM and 1.8 μM at 800 μM). Erythromycin and ketoconazole showed a clear inhibitory effect on the 3-hydroxylation of lidocaine at 5 μM of lidocaine (IC₅₀ 9.9 μM and 13.9 μM, respectively), but did not show a consistent effect at 800 μM of lidocaine (IC₅₀>250 μM and 75.0 μM, respectively). Although further studies are needed to elucidate the role of distinct CYP enzymes in the biotransformation of lidocaine in humans, the findings of this study suggest that while both CYP1A2 and CYP3A4 are involved in the metabolism of lidocaine by human liver microsomes, CYP1A2 is the more important isoform at clinically relevant lidocaine concentrations.     

The effects of aminosalicylic acid derivatives on nitric oxide in a cell-free system

Aims and Methods: To determine the effect of aminosalicylic acid derivatives on the concentration of nitric oxide produced in a cell-free system, by the use of a sensitive and specific polarographic meter. Results: The aminosalicylic acid derivatives 3-ASA (IC₅₀ 100 μm ), 4-ASA (IC₅₀ 350 μm ) and 5-ASA (IC₅₀ 5 μm ) all decreased the nitric oxide signal. These drugs had a similar inhibitory effect on the formation in vitro of nitrite from sodium nitroprusside (IC₅₀ 200 μm , 500 μm and 100 μm , respectively). Sulphasalazine (31.1 ± 5% decrease in signal at 1 mm ) was less effective than 5-ASA, but sulphapyridine, N-acetyl 5-ASA, indomethacin and hydrocortisone produced no decrease in nitric oxide signal at all. Conclusions: Nitric oxide binding may be part of the mechanism by which ASA derivatives exert their therapeutic effect, and this work suggests that it may be an important factor in the pathogenesis of ulcerative colitis.     

<Emphasis Type="Italic">In vitro</Emphasis> anti-inflammatory activity of carvacrol: Inhibitory effect on COX-2 catalyzed prostaglandin E<Subscript>2</Subscript> biosynthesisb

Possible anti-inflammatory effect of carvacrol was evaluated by in vitro cyclooxygenase-2 (COX-2) assay. Carvacrol inhibited production of prostaglandin E₂ catalysed by COX-2 with an IC₅₀ value of 0.8 μM what is practically the same concentration as the IC₅₀ obtained for the standard inhibitors indomethacin and NS-398 with values of 0.7 μM and 0.8 μM, respectively. The COX-1 was inhibited approximately at the same rate (IC₅₀ of 0.7 μM for carvacrol), which suggests non-selective inhibition of both enzyme isoforms. The results of the study demonstrate possible anti-inflammatory potential of this compound due to the inhibition of inducible COX-2 isoform.     

Blood-vessel wall arachidonate metabolism and its pharmacological modification in a new in vitro assay system

Summary Prostacyclin and thromboxane production was measured in human umbilical cord arteries bathed in clotting human blood and compared with arteries bathed in Krebs buffer or clotting blood without vessels. In comparison with the combined system, vessels in buffer generated only minute amounts of immunoreactive thromboxane B₂ while blood alone generated only minute amounts of immunoreactive 6-oxo-PGF₁. Incubation of vessels in blood was associated with an enhanced 6-oxo-PGF₁ formation at 1–2 h of incubation, demonstrating an active prostacyclin synthetase and a transfer of the platelet endoperoxide precursor to this enzyme.This new combined system was used to reevaluate the selectivity of cyclooxygenase inhibitors for vascular and platelet derived eicosanoid formation. With respect to 6-oxo-PGF₁ accumulation, the IC₅₀ value [moles/l] for tiaprofenic acid (8.5 ± 3.0) was significantly higher than that for diclofenac (0.14 ± 0.03) (P < 0.05) while acetylsalicylic acid (18.0 ± 7.0) was less potent than diclofenac and indomethacin (2.4 ± 1.0) (P < 0.05). With respect to thromboxane B₂ formation, the IC₅₀ values for diclofenac (0.26 ± 0.04), indomethacin (IC₅₀ 0.30 ± 0.05) and tiaprofenic acid (IC₅₀ 0.71 ± 0.08) were not significantly different from each other. Acetylsalicylic acid (7.7 ± 1.8) was less potent than either of the other compounds (P < 0.01). While these IC₅₀ values might suggest different potencies for inhibition of vascular and platelet cyclooxygenases by tiaprofenic acid and, possibly, indomethacin, statistical analysis was not possible because of different slopes of the dose-response curves. Moreover, a nearly complete inhibition of both enzymes might be expected at therapeutic antiinflammatory plasma levels of the compounds in vivo.It is concluded that this in vitro system using solely human tissues might be a useful tool to analyse time-dependent alterations in endogenous arachidonate metabolism during blood-vessel wall interactions and its modification by drugs and that this system might be superior to either blood or vessel preparations alone.     

Anti-Elastase and Anti-Hyaluronidase Activities of Saponins and Sapogenins from Hedera helix,Aesculus hippocastanum,and Ruscus aculeatus: Factors Contributing to their Efficacy in the Treatment of Venous Insufficiency

Triterpene and steroid saponins and sapogenins of medicinal plants (Aesculus hippocastanum L., Hedera helix L., Ruscus aculeatus L.) are claimed to be effective for the treatment/prevention of venous insufficiency. In this work we evaluated the inhibitory effects of these plant constituents on the activity of elastase and hyaluronidase, the enzyme systems involved in the turnover of the main components of the perivascular amorphous substance. The results evidence that for Hedera helix L., the sapogenins only non-competitively inhibit hyaluronidase activity in a dose-dependent fashion, showing comparable IC₅₀ values (hederagenin IC₅₀ = 280.4 μM; oleanolic acid IC₅₀ = 300.2 μM); both the saponins hederacoside C and α-hederin are very weak inhibitors. The same behaviour is observed for serine protease porcine pancreatic elastase: the glycosides are devoid of inhibitory action, while genins are potent competitive inhibitors (oleanolic acid IC₅₀ = 5.1 μM; hederagenin IC₅₀ = 40.6 μM). Constituents from Aesculus hippocastanum L. show inhibitory effects only on hyaluronidase, and this activity is mainly linked to the saponin escin (IC₅₀ = 149.9 μM), less to its genin escinol (IC₅₀ = 1.65 μM). By contrast, ruscogenins from Ruscus aculeatus L., ineffective on hyaluronidase activity, exhibit remarkable anti-elastase activity (IC₅₀ = 119.9 μM; competitive inhibition). The mechanism of elastase inhibition by triterpene and steroid aglycones, with a nitroanilide derivative as substrate, is discussed.     

Inhibition of prostaglandin biosynthesis in rat small intestine by SL-573

The 20,000g supernatant of rat small intestine homogenates converted [1-¹⁴C]arachidonic acid into several compounds, including prostaglandin F_2α (20.0 per cent), E₂ (16.1 per cent), D₂ (45.2 per cent), and other unknown products (18.7 per cent). The identity of each prostaglandin, which was isolated by Sephadex LH-20 column chromatography and subsequent preparative thin-layer chromatography (t.l.c.), was performed by t.l.c., bioassay (contraction of rat stomach fundus strip), sodium borohydride reduction and mass spectrometry. The predominant prostaglandin biosynthesized by rat small intestine was prostaglandin D₂. 1-Cyclopropylmethyl-4-phenyl-6-methoxy-2-(1H)-quinazolinone (SL-573) and indomethacin inhibited the prostaglandin biosynthesis by the rat small intestinal enzymes. The ic₅₀ values (concentration of inhibitor resulting in 50 per cent inhibition) were 9.1 μg/ml for SL-573 and 5.6 μg/ml for indomethacin. The inhibition of prostaglandin biosynthesis by either drug was reversible. The reversible inhibition of indomethacin in this case may be due to the presence of endogeneous arachidonic acid in the enzyme preparation, since arachidonic acid protected against the irreversible and time-dependent inhibition of the bovine seminal vesicle enzymes by indomethacin.     

Effect of impairment of renal function on the accumulation and disposition of isoxicam

Summary The accumulation and disposition of the non-steroidal antiinflammatory drug isoxicam were investigated following its oral administration to 6 subjects with normal renal function and 13 patients with diminished renal function. Isoxicam was given daily as a single oral dose for 14–15 consecutive days. Steady-state plasma levels were achieved after 13 days. The effect of differences in renal function on the kinetics of isoxicam appeared to be minimal. Accumulation of isoxicam was similar in both groups of subjects and there was no significant difference between the groups in the plasma clearance or terminal half-life of isoxicam. There were substantial differences between individuals in the apparent plasma clearance and half-life of the drug, and this is reflected in the 7-fold range of steady-state plasma isoxicam concentrations encountered in the subjects.     

Inhibition of the arachidonic acid cascade by norathyriol via blockade of cyclooxygenase and lipoxygenase activity in neutrophils

Recent studies have suggested that dual inhibitors of cyclooxygenase (COX) and lipoxygenase (LO) may be more beneficial in the treatment of inflammatory diseases in which platelet-leukocyte interaction dominates the underlying inflammatory process, than inhibitors of COX or LO alone. In this study, we examined oxygenated xanthones, shown previously to inhibit platelet and neutrophil activation, with respect to the potency of COX inhibition. 1,3,6,7-Tetrahydroxyxanthone (norathyriol) was the most potent. Norathyriol suppressed thromboxane B₂ (TXB₂) and leukotriene B₄ (LTB₄) formation in calcium ionophore (A23187)- and formyl-methionyl-leucyl-phenylalanine (fMLP)-stimulated rat neutrophils. Norathyriol was 3–4 times more active against LTB₄ formation than against TXB₂ formation (IC₅₀ about 2.8 vs. 10 µM, respectively). Norathyriol also inhibited prostaglandin D₂ (PGD₂) formation in A23187-stimulated rat mast cells (IC₅₀ 3.0±1.2 µM) and in arachidonic acid (AA)-activated mast cell lysate. Norathyriol was a more effective inhibitor of 5-LO activity than of COX, as shown also by analyses of enzyme activities in a cell-free system, of COX and 5-LO metabolic capacity in neutrophils and of ex vivo TXB₂ and LTB₄ formation in A23187-stimulated neutrophils. Moreover, norathyriol inhibited COX-2 and 12-LO with IC₅₀ values (19.6±1.5 and 1.2±0.1 µM, respectively) similar to those required for the inhibition of COX-1 and 5-LO (16.2±1.5 and 1.8±0.4 µM, respectively). Inhibition of 15-LO by norathyriol was slightly less active. Norathyriol had no effect on A23187-induced AA release from neutrophils and did not affect phospholipase A₂ (PLA₂) activity in a cell-free system. These results indicate that norathyriol inhibits the formation of PGs and LTs in neutrophils probably through direct blockade of COX and 5-LO activities. Norathyriol, a single molecule with multiple targets, might provide a potential therapeutic benefit in the treatment of inflammatory diseases.