Dual Inhibitor Of Cyclooxygenase Research Articles

Synthesis and biological evaluation of 1,3-diphenylprop-2-yn-1-ones as dual inhibitors of cyclooxygenases and lipoxygenases

A new class of 1,3-diphenylprop-2-yn-1-ones possessing a p-MeSO 2 COX-2 phamacophore on the C-3 phenyl ring was designed for evaluation as dual inhibitors of cyclooxygenase (COX) and lipoxygenase (LOX). Among the group of compounds evaluated, 1-(4-fluorophenyl)-3-(4-methanesulfonylphenyl)prop-2-yn-1-one ( 11j) exhibited excellent COX-2 inhibitory potency (COX-2 IC 50 = 0.1 μM) and selectivity (SI = 300), whereas 1-(4-cyanophenyl)-3-(4-methanesulfonylphenyl)prop-2-yn-1-one ( 11d) exhibited an optimal combination of COX and LOX inhibition (COX-2 IC 50 = 1.0 μM; COX-2 SI = 31.5; 5-LOX IC 50 = 1.0 μM; 15-LOX IC 50 = 3.2 μM).

Ginger--an herbal medicinal product with broad anti-inflammatory actions.

The anti-inflammatory properties of ginger have been known and valued for centuries. During the past 25 years, many laboratories have provided scientific support for the long-held belief that ginger contains constituents with antiinflammatory properties. The original discovery of ginger's inhibitory effects on prostaglandin biosynthesis in the early 1970s has been repeatedly confirmed. This discovery identified ginger as an herbal medicinal product that shares pharmacological properties with non-steroidal anti-inflammatory drugs. Ginger suppresses prostaglandin synthesis through inhibition of cyclooxygenase-1 and cyclooxygenase-2. An important extension of this early work was the observation that ginger also suppresses leukotriene biosynthesis by inhibiting 5-lipoxygenase. This pharmacological property distinguishes ginger from nonsteroidal anti-inflammatory drugs. This discovery preceded the observation that dual inhibitors of cyclooxygenase and 5-lipoxygenase may have a better therapeutic profile and have fewer side effects than non-steroidal anti-inflammatory drugs. The characterization of the pharmacological properties of ginger entered a new phase with the discovery that a ginger extract (EV.EXT.77) derived from Zingiber officinale (family Zingiberaceae) and Alpina galanga (family Zingiberaceae) inhibits the induction of several genes involved in the inflammatory response. These include genes encoding cytokines, chemokines, and the inducible enzyme cyclooxygenase-2. This discovery provided the first evidence that ginger modulates biochemical pathways activated in chronic inflammation. Identification of the molecular targets of individual ginger constituents provides an opportunity to optimize and standardize ginger products with respect to their effects on specific biomarkers of inflammation. Such preparations will be useful for studies in experimental animals and humans.

Stimulation of protease‐activated receptor‐2 inhibits airway eosinophilia, hyperresponsiveness and bronchoconstriction in a murine model of allergic inflammation

1. An emerging body of evidence indicates that PGE(2) has a privileged anti-inflammatory role within the airways. Stimulants of protease-activated receptor-2 (PAR(2)) inhibit airway smooth muscle tone in vitro and in vivo predominantly via cyclooxygenase (COX)-dependent generation of prostaglandin E(2) (PGE(2)). Thus, the current study tested the hypothesis that PAR(2)-induced generation of PGE(2) inhibits the development of allergic airways inflammation and hyperresponsiveness. 2. Bronchoalveolar lavage (BAL) fluid recovered from ovalbumin (OVA)-sensitised and -challenged (allergic) mice contained elevated numbers of eosinophils, which peaked at 48 h postchallenge. Intranasal (i.n.) administration of a PAR(2)-activating peptide (PAR(2)-AP) SLIGRL (25 mg kg(-1), at the time of OVA challenge) caused a 70% reduction in the numbers of BAL eosinophils (compared to the scrambled peptide LSIGRL, 25 mg kg(-1)). 3. Pretreatment of allergic mice with either indomethacin (1 mg kg(-1), dual COX inhibitor) or nimesulide (3 mg kg(-1), COX-2-selective inhibitor) blocked SLIGRL-induced reductions in BAL eosinophils. 4. I.n. SLIGRL, but not LSIGRL, inhibited the development of antigen-induced airways hyperresponsiveness. The inhibitory effect of SLIGRL was blocked by indomethacin. 5. Exposure of isolated tracheal preparations from allergic mice to 100 microM SLIGRL was associated with a 5.0-fold increase in PGE(2) levels (P<0.05, compared to 100 microM LSIGRL). SLIGRL induced similar increases in PGE(2) levels in control mice (OVA-sensitised, saline-challenged). 6. I.n. administration of PGE(2) (0.15 mg kg(-1)) to allergic mice significantly inhibited eosinophilia and airways hyperresponsiveness to methacholine. 7. In anaesthetised, ventilated allergic mice, SLIGRL (5 mg kg(-1), i.v.) inhibited methacholine-induced increases in airways resistance. Consistent with this bronchodilator effect, SLIGRL induced pronounced relaxation responses in isolated tracheal preparations obtained from allergic mice. LSIGRL did not inhibit bronchomotor tone in either of these in vivo or in vitro experiments. 8. In summary, a PAR(2)-AP SLIGRL inhibited the development of airway eosinophilia and hyperresponsiveness in allergic mice through a COX-dependent pathway involving COX-2-mediated generation of the anti-inflammatory mediator PGE(2). SLIGRL also displayed bronchodilator activity in allergic mice. These studies support the concept that PAR(2) exerts predominantly bronchoprotective actions within allergic murine airways.

Phenidone, a dual inhibitor of cyclooxygenases and lipoxygenases, ameliorates rat paralysis in experimental autoimmune encephalomyelitis by suppressing its target enzymes

This study examined whether phenidone, a dual inhibitor of cyclooxygenase (COX) and lipoxygenase (LOX), affects the clinical symptoms of experimental autoimmune encephalomyelitis (EAE) in the rat, and the expression of both COX-1/-2 and 5-LOX in EAE spinal cords. Oral phenidone (200 mg/kg) significantly suppressed the incidence and clinical severity of EAE paralysis. Western blot analysis showed that phenidone significantly inhibited the increases in COX-1/-2 and 5-LOX in the spinal cords of rats with EAE. This finding was paralleled by immunohistochemical observations. Overall, these findings suggest that COX-1/-2 and 5-LOX are important inflammatory mediators in the pathogenesis of EAE, and that the inhibition of both COX and LOX ameliorates the autoimmune disorder of the central nervous system.

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 B(2) (TXB(2)) and leukotriene B(4) (LTB(4)) formation in calcium ionophore (A23187)- and formyl-methionyl-leucyl-phenylalanine (fMLP)-stimulated rat neutrophils. Norathyriol was 3-4 times more active against LTB(4) formation than against TXB(2) formation (IC(50) about 2.8 vs. 10 microM, respectively). Norathyriol also inhibited prostaglandin D(2) (PGD(2)) formation in A23187-stimulated rat mast cells (IC(50) 3.0+/-1.2 microM) 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 TXB(2) and LTB(4) formation in A23187-stimulated neutrophils. Moreover, norathyriol inhibited COX-2 and 12-LO with IC(50) values (19.6+/-1.5 and 1.2+/-0.1 microM, respectively) similar to those required for the inhibition of COX-1 and 5-LO (16.2+/-1.5 and 1.8+/-0.4 microM, 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 A(2) (PLA(2)) 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.

Synthesis of the Butanamide Derivative S 19812 (XIII), a New Dual Inhibitor of Cyclooxygenase and Lipoxygenase Pathways.

ChemInformVolume 35, Issue 9 Heterocyclic Compounds Synthesis of the Butanamide Derivative S 19812 (XIII), a New Dual Inhibitor of Cyclooxygenase and Lipoxygenase Pathways. Charles Tordjman, Charles Tordjman Dep. Med. Chem., Inst. Rech. Servier, F-92150 Suresnes, Fr.Search for more papers by this authorFrederic Sauveur, Frederic Sauveur Dep. Med. Chem., Inst. Rech. Servier, F-92150 Suresnes, Fr.Search for more papers by this authorMonique Droual, Monique Droual Dep. Med. Chem., Inst. Rech. Servier, F-92150 Suresnes, Fr.Search for more papers by this authorSylvie Briss, Sylvie Briss Dep. Med. Chem., Inst. Rech. Servier, F-92150 Suresnes, Fr.Search for more papers by this authorNathalie Andre, Nathalie Andre Dep. Med. Chem., Inst. Rech. Servier, F-92150 Suresnes, Fr.Search for more papers by this authorIsabelle Bellot, Isabelle Bellot Dep. Med. Chem., Inst. Rech. Servier, F-92150 Suresnes, Fr.Search for more papers by this authorChristine Deschamps, Christine Deschamps Dep. Med. Chem., Inst. Rech. Servier, F-92150 Suresnes, Fr.Search for more papers by this authorMichel Wierzbicki, Michel Wierzbicki Dep. Med. Chem., Inst. Rech. Servier, F-92150 Suresnes, Fr.Search for more papers by this author Charles Tordjman, Charles Tordjman Dep. Med. Chem., Inst. Rech. Servier, F-92150 Suresnes, Fr.Search for more papers by this authorFrederic Sauveur, Frederic Sauveur Dep. Med. Chem., Inst. Rech. Servier, F-92150 Suresnes, Fr.Search for more papers by this authorMonique Droual, Monique Droual Dep. Med. Chem., Inst. Rech. Servier, F-92150 Suresnes, Fr.Search for more papers by this authorSylvie Briss, Sylvie Briss Dep. Med. Chem., Inst. Rech. Servier, F-92150 Suresnes, Fr.Search for more papers by this authorNathalie Andre, Nathalie Andre Dep. Med. Chem., Inst. Rech. Servier, F-92150 Suresnes, Fr.Search for more papers by this authorIsabelle Bellot, Isabelle Bellot Dep. Med. Chem., Inst. Rech. Servier, F-92150 Suresnes, Fr.Search for more papers by this authorChristine Deschamps, Christine Deschamps Dep. Med. Chem., Inst. Rech. Servier, F-92150 Suresnes, Fr.Search for more papers by this authorMichel Wierzbicki, Michel Wierzbicki Dep. Med. Chem., Inst. Rech. Servier, F-92150 Suresnes, Fr.Search for more papers by this author First published: 03 February 2004 https://doi.org/10.1002/chin.200409088Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat No abstract is available for this article. Volume35, Issue9March 2, 2004 RelatedInformation

Is licofelone, a dual inhibitor of cyclo-oxygenase and 5-lipoxygenase, a promising alternative in anti-inflammatory therapy?

As prostaglandins and leukotrienes are critical in inflammation, dual cyclo-oxygenase and 5-lipoxygenase enzymes inhibitors, especially licofelone, are being developed by pharmaceutical companies. Experimental data indicate that licofelone shares the antipyretic, analgesic, anti-inflammatory and anti-platelet activities of conventional nonsteroidal anti-inflammatory drugs (NSAIDs), and exhibits anti-allergic properties. Although licofelone may lead to similar adverse effects on the kidney than available NSAIDs, it appeared to induce less gastrointestinal damaging effects than nonselective NSAIDs in animals. Unfortunately, preliminary clinical studies provided less impressive data with respect to efficacy. Finally, the experimental promise of licofelone as a safe and potent anti-inflammatory and analgesic agent remains to be proved in humans.

The pharmacological profile of ovalbumin-induced paw oedema in rats.

Rats are commonly used in anaphylaxis models, mainly in intestinal anaphylaxis. Hypersensitivity mechanisms are complex and they are not clearly defined. Ovalbumin (OVA) is commonly used for studies on the hypersensitivity mechanism. However, the potential pro-inflammatory mediators induced by this antigen in the model of paw oedema in immunized rats are still not completely understood. This work examines the pharmacological modulation of several mediators involved in rat hind paw immune oedema induced by OVA. Wistar rats were previously immunized (14-18 days) with OVA (30 microg, intraperitoneally) or sham-sensitized with aluminum hydroxide (control). The paw volumes were measured before the antigenic stimuli and 1, 2, 3 and 4 h after the intraplantar injection of OVA (10 microg/paw). Subcutaneous injection of dexamethasone, diphenhydramine, cyproheptadine, chlorpromazine or methysergide significantly inhibited (p < 0.05) the allergic paw oedema. The dual inhibitor of cyclooxygenase and lipoxygenase (NDGA), the cyclooxygenase inhibitor (indomethacin), the lipoxygenase inhibitor (MK-886), the PAF antagonist (WEB 2086), the mast cell stabilizer (ketotifen), and the anti-histamine (meclizine) did not inhibit the immune oedema. In addition, thalidomide and pentoxifylline (anti-tumour necrosis factor drugs) were ineffective against OVA-induced oedema. The fact that indomethacin, MK-886, NDGA and WEB 2086 are unable to inhibit this allergic oedema indicates that the dexamethasone action seems not to be via phospholipase A2, but possibly due to the synthesis and/or the inhibitory activity of cytokines. The paw oedema inhibition by diphenhydramine, but not by meclizine, may suggest a different mechanism, which is independent of the effect of histamine. These data indicate that allergic oedema is more sensitive to anti-serotonin drugs, mainly anti-5-HT2, suggesting that the principal mediator of this inflammatory response is serotonin.

Dual inhibitors of cyclooxygenase and 5-lipoxygenase. A new avenue in anti-inflammatory therapy?

Nonsteroidal anti-inflammatory drugs (NSAIDs) are a mainstay in the treatment of inflammatory disease and are among the most widely used drugs worldwide. They are anti-inflammatory, antipyretic, and analgesic and are prescribed as first choice for the treatment of rheumatic disorders and, in general, inflammation. The main limitation in using NSAIDs consists in their side-effects, including gastrointestinal ulcerogenic activity and bronchospasm. The mechanism of action of these drugs is attributed to the inhibition of cyclooxygenase (COX), and, consequently, the conversion of arachidonic acid into prostaglandins. It is hypothesized that the undesirable side-effects of NSAIDs are due to the inhibition of COX-1 (constitutive isoform), whereas the beneficial effects are related to the inhibition of COX-2 (inducible isoform). Arachidonic acid can also be converted to leukotrienes (LTs) by the action of 5-lipoxygenase (5-LOX). LTC4, LTD4, and LTE4 are potent bronchoconstrictors, whereas LTB4 is chemotactic for leukocytes and plays an important role in the development of gastrointestinal ulcers by contributing to the inflammatory process. Thus, developing dual inhibitor compounds that will simultaneously inhibit COX and 5-LOX could enhance their individual anti-inflammatory effects and reduce the undesirable side-effects associated with NSAIDs, especially of the gastrointestinal tract. The most promising COX/5-LOX inhibitor is ML3000 ([2,2-dimethyl-6-(4-chlorophenyl)-7-phenyl-2,3-dihydro-1H-pyrrolizine-5-yl]-acetic acid), now in Phase III clinical trials. This new approach will certainly help to unravel the mechanisms at the root of the undesirable effects of NSAIDs and to develop safer NSAIDs.

Discovery and development of ML3000

NSAID management of the inflammatory process has focused on reducing the production of inflammatory prostaglandins by inhibiting the cyclooxygenase (COX) enzyme. However, blocking COX also reduces gastroprotective prostaglandins, causing the well-known gastrointestinal side effects. Furthermore, a shunting of arachidonic acid to the 5-lipoxygenase (5-LOX) pathway may also occur, causing an increase in leukotrienes and further GI damage. Several compounds, designed to block both COX and 5-LOX, have failed in clinical trials due to liver toxicity, related to their redox potential. ML3000 is a new pyrrolizine compound resulting from a systematic approach to design a non-redox substrate analog of arachidonic acid that inhibited both COX and 5-LOX. Pharmacodynamic studies determined that ML3000 is a dual inhibitor of COX and 5-LOX, with analgesic, anti-inflammatory, antipyretic, antiplatelet, and anti-bronchoconstrictive activity, and minimal gastrointestinal side effects. Clinical studies show efficacy in osteoarthritis and excellent gastrointestinal safety. ML3000 is now in phase III development.

Inhibitors of the lipoxygenase pathway block development of Brugia malayi L3 in vitro.

Brugia malayi L3 molt to the L4 stage in serum-free cultures supplemented with arachidonic, linoleic, or linolenic acids and the basidiomycetous yeast Rhodotorula minuta. These fatty acids are capable of entering the eicosanoid pathway of arachidonate metabolism, the pathway responsible for generating a number of biologically active mediators, including prostaglandins, leukotrienes, and lipoxins. To determine whether this pathway was required for L3 development, we added dual inhibitors of cyclooxygenase and lipoxygenase to in vitro cultures containing B. malayi L3. These compounds significantly inhibited L3 molting. To evaluate whether 1 or both of these pathways of arachidonate metabolism were involved in molting, we tested drugs inhibiting either cyclooxygenase or lipoxygenase. Lipoxygenase inhibitors blocked L3 molting, whereas cyclooxygenase inhibitors did not. To assess whether enzymes operating downstream of lipoxygenase were also involved in L3 molting, we added inhibitors of enzymes involved in leukotriene synthesis and found they were also capable of preventing development. We tested the same inhibitor panel on Dirofilaria immitis L3. A single lipoxygenase inhibitor and inhibitors of 2 different enzymes operating downstream of lipoxygenase disrupted D. immitis development. These results demonstrate that a lipoxygenase pathway product is required for molting of the infective stage larvae of filarial parasites.

Role of Leukotrienes on Coronary Vasoconstriction in Isolated Hearts of Arthritic Rats: Effect of in vivo Treatment with CI-986, a Dual Inhibitor of Cyclooxygenase and Lipoxygenase

In this study, coronary perfusion pressure and force of contraction were investigated in isolated hearts removed from arthritic rats by using the Langendorff method. A strong coronary vasoconstriction was determined in arthritic hearts which was associated with elevated levels of arachidonate 5-lipoxygenase (5-LOX) products, leukotriene B₄ (LTB₄) and LTC₄ in coronary effluents. In vivo treatment with the dual inhibitor of cyclooxygenase (COX) and LOX, CI-986 (2 and 10 mg/kg/day) on days 14– 26 following adjuvant injection, prevented the coronary vasoconstriction and the increased production of LTB₄ and LTC₄. These results suggest that the coronary vasoconstriction in the isolated arthritic hearts is associated with an increased activity of the LOX system and CI-986 could have a preventive effect on constriction of coronary arteries.

Rationalizing cyclooxygenase (COX) inhibition for maximal efficacy and minimal adverse events

New information indicates that cyclooxygenase-2 (COX-2) is constitutively expressed in several tissues, including brain, lung, pancreas, kidney, and ovary, and plays an important role in renal and gastrointestinal function. Selective COX-2 inhibition has been associated in animal studies with impairment of ulcer healing and renal function and inhibition of prostacyclin, an effect that inhibits vasodilation without inhibiting platelet aggregation. The clinical consequences, if any, of these effects remain to be determined in long-term studies in humans. The premise that selective COX-2 inhibitors will cause less gastrointestinal toxicity than nonsteroidal anti-inflammatory drugs that inhibit both COX isoforms needs to take into account the low toxicity of nabumetone. The gastrointestinal safety profile of this nonacidic, dual COX inhibitor that does not undergo enterohepatic circulation has been evaluated in extensive clinical trials. The data submitted to the US Food and Drug Administration in the New Drug Application for nabumetone (Relafen®), the comparative trials subsequently completed, the published databases of the comparative gastrointestinal toxicity of various nonsteroidal anti-inflammatory drugs (NSAIDs), and the meta-analysis published in this issue of The American Journal of Medicine (Schoenfeld, page 48S) indicate that nabumetone has the lowest incidence of gastrointestinal toxicity among the extensively studied NSAIDs. Overall, the incidence is approximately 10-fold less than with comparator drugs. This rate is an appropriate current reference against which the gastrointestinal toxicity of COX-2 inhibitors can be compared.

Effects of compounds extracted from Santolina oblongifolia on TXB2 release in human platelets

A group of compounds isolated from the medicinal plant, Santolina oblongifolia, have been investigated for their effects on the release of platelet cyclo-oxygenase metabolite thromboxane A(2) (measured as thromboxane B(2)) from ionophore-stimulated human platelets. These compounds, which are dual inhibitors of cyclo-oxygenase (prostaglandin E(2)) and lipoxygenase (leukotriene C(4)) activity in vitro, are: apigenin, luteolin, quercetin, herniarin, scopoletin, scopolin and aesculetin. All compounds assayed presented a dose-related response to thromboxane B(2) release, with the percentages of inhibition being slightly lower than the reference drug, ibuprofen. Inhibition was more evident with the flavonoids. Our data support the inhibition of arachidonic acid metabolism as one of the mechanisms for which flavonoids and coumarins from S. oblongifolia exert their anti-inflammatory effect.

Antiphlogistic and antipyretic activity of Peucedanum ostruthium.

Extracts from the roots of Peucedanum ostruthium (L.) Koch were investigated for their antiphlogistic and antipyretic effects as well as for their influence on arachidonic acid metabolism. On carrageenan-induced rat paw edema, oral administration of 10% ethanolic extracts led to a marked inhibition of the edema. By means of bioassay-oriented fractionation of extract, 6-(3-carboxybut-2-enyl)-7-hydroxycoumarin proved to be the most important anti-inflammatory principle of the plant. 30 micrograms/kg of this compound inhibited the formation of edema to an extent of 50%. On the perfused rabbit ear and on polymorphonuclear leukocytes the extract and the active compound have been characterized as dual inhibitors of cyclooxygenase and 5-lipoxygenase activities. Moreover, an antipyretic effect of i.p. administered extract and compound were evaluated in rats with comparable hyperthermia after s.c. injection of brewer's yeast.

Possible mechanisms for the differential effects of high linoleate safflower oil and high α-linolenate perilla oil diets on platelet-activating factor production by rat polymorphonuclear leukocytes

As compared with high dietary linoleate safflower oil, high dietary α-linolenate perilla oil decreased platelet-activating factor (PAF) production by nearly half in calcium ionophore (CaI)-stimulated rat polymorphonuclear leukocytes (PMN). In the CaI-stimulated PMN from the perilla oil group, the accumulated amount of arachidonate (AA) plus eicosapentaenoate (EPA) was 30% less and that of lyso-PAF was 50% less, indicating that the decreased availability of lyso-PAF is a factor contributing to the relatively low PAF production. Consistently, eicosatetraynoic acid (ETYA), a dual inhibitor of cyclooxygenase and lipoxygenase, increased free fatty acids (FFA) and decreased PAF production possibly by decreasing the availability of lyso-PAF. Although, leukotrienes (LTs) have been proposed to stimulate PAF production synergistically, a potent LTB 4 receptor antagonist, ONO-4057, decreased the formation of free fatty acids and LTB 4, but stimulated PAF production somewhat, indicating that LTB 4 may not stimulate PAF production in PMN. Lysophospholipid-induced transacylase (CoA-independent transacylase) activity in PMN homogenates was 25∼30% lower in the perilla oil group but no significant differences were observed in the lyso-PAF acetyltransferase and PAF acetylhydrolase activities between the two dietary groups. Thus, decreased transacylase activity is another factor associated with the relatively low PAF production in the perilla oil group.

Role of prostaglandin H synthase-2-mediated conversion of arachidonic acid in controlling 3T6 fibroblast growth.

The specific role(s) of arachidonic acid (AA) and its metabolites in the signaling pathways that regulated fibroblast growth was studied. A Western blot analysis demonstrated that prostaglandin H synthase-2 (PGHS-2) was expressed by 3T6 fibroblast cultures in RPMI 1640 supplemented with fetal calf serum (10%). Dexamethasone, which inhibits AA release and PGHS-2 expression, significantly reduced cell proliferation. Ketoprofen, a dual cyclooxygenase inhibitor, and CGP-28238, a specific PGHS-2 inhibitor, reduced fibroblast proliferation in a dose-dependent manner. These drugs also reduced [3H]thymidine incorporation into the DNA of fibroblasts. These effects were correlated with a decrease in prostaglandin (PG) E2 levels in the cell medium. However, piroxicam at doses that selectively inhibit PGHS-1 did not have a significant effect on fibroblast proliferation. Finally, we showed that the antiproliferative effect of dexamethasone and PGHS-2 inhibitors was significantly antagonized when PGE2 was added to the culture medium. Our results suggest that PGHS-2 and prostaglandins such as PGE2 might play an important role in the regulation of 3T6 fibroblast growth stimulated by growth factors of serum.

ChemInform Abstract: Non‐Steroidal Antiinflammatory Agents. Part 21. 2‐Aryl‐pyrrolo(2,1‐b) benzothiazoles as Selective or Dual Inhibitors of Cyclooxygenase and 5‐ Lipoxygenase.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

The Effects of ML 3000 on Antigen-induced Responses in Sheep

ML 3000 is a dual inhibitor of cyclooxygenase (COX) and 5-lipoxygenase (5-LO), two enzymes that contribute to the airway inflammation in asthma. When administered as an aerosol at a dose of 100 mg, 0.5 h before antigen challenge in allergic sheep, ML 3000 provided significant inhibition against the early bronchial response (EAR, mean 33% protection,P<0.05), completely blocked the late antigen-induced bronchoconstriction (LAR, mean 81% protection,P<0.05) and the airway hyperresponsiveness (AHR,P<0.05) to aerosolized carbachol that occurs 24 h after antigen challenge in this model. Consistent with this functional protection was a small but significant reduction in the percentage of neutrophils recovered in bronchoalveolar lavage (BAL) at 8 h and 24 h after challenge. These findings are similar to previous data obtained in this animal model with other 5-LO inhibitors (blockade of the LAR and AHR) and COX inhibitors (blockade of AHR). These results suggest that aerosol administration of a dual inhibitor of COX and 5-LO may have beneficial effects in the treatment of allergic airway disease.

Preclinical toxicity evaluation of tepoxalin, a dual inhibitor of cyclooxygenase and 5-lipoxygenase, in Sprague-Dawley rats and beagle dogs.

Tepoxalin [5- (4-chlorophenyl)-N-hydroxy-1-(4-methoxyphenyl)-N-methyl-1H-pyrazole -3-propanamide] is an orally active anti-inflammatory agent, which inhibits both cyclooxygenase and 5-lipoxygenase activities. The oral toxicity of tepoxalin was evaluated in 1- and 6-month rat (up to 50 mg/kg/day) and dog (up to 150 mg/kg bid) studies. In rats, increased liver weight, centrilobular hypertrophy, and hepatic necrosis were observed at dosages >/=20 mg/kg/day. Renal changes indicative of analgesic nephropathy syndrome (i.e., papillary edema or necrosis, cortical tubular dilatation) were seen at >/=15 mg/kg. In rats treated for 1 month, these hepatic and renal effects were largely reversible after a 1-month recovery period. Gastrointestinal erosions and ulcers were seen in female rats given 40 mg/kg/day for 6 months. Changes in clinical pathology parameters included decreases in red blood cell count, hemoglobin, and hematocrit mean values; elevation in platelet counts; and an increase in prothrombin and activated partial thromboplastin times. Mild increases in alanine aminotransferase, aspartate aminotransferase, and cholesterol were also noted in rats. Decreased erythrocyte parameters, increased leukocyte counts, and decreased total protein, albumin, and/or calcium were noted in some dogs in the 300 mg/kg/day group following 6 months of dosing. Small pyloric ulcerations were seen at 100 and 300 mg/kg/day dosages for up to 6 months. In both rats and dogs, no accumulation of tepoxalin or its carboxylic acid metabolite was detected in plasma following multiple dosing over a range of 5 to 50 mg/kg/day for rats and 20 to 300 mg/kg/day for dogs. Plasma concentrations of the carboxylic acid metabolite were severalfold higher than those of the parent compound. The no-effect dosages in rats (5 mg/kg/day) and dogs (20 mg/kg/day) were approximately one and six times the ED50 (3.5 mg/kg), respectively, for inhibition of inflammatory effects in the adjuvant arthritic rat without gastric mucosal damage. In terms of severity, the relative lack of gastrointestinal side effects, within the estimated therapeutic dose range, distinguishes tepoxalin from most marketed anti-inflammatory drugs.