Bibliographie sur le tepoxalin

 

(Bibliographie tablie par une consultation de bases de donnes bibliographiques internationales. Les donnes sont ici issues de base de donnes de mdecine humaine lexception de la dernire rfrence n 27 qui est issue dune base de donnes spcifiquement vtrinaire).

 

 

1) Bertolini A, Ottani A, Sandrini M.

Dual acting anti-inflammatory drugs: a reappraisal.

Pharmacol Res. 2001 Dec;44(6):437-50. Review.

 

Abstract

Department of Biomedical Sciences, Section of Pharmacology, University of Modena and Reggio Emilia, Via G. Campi 287, 41100 Modena, Italy. Bertolini.Alfio@unimo.it

Rheumatic diseases are the most prevalent causes of disability in western countries, and non-steroidal anti-inflammatory drugs (NSAIDs) are still the most commonly used remedies. However, NSAIDs cause several serious adverse effects, the most important being from gastric injury to gastric ulceration and renal damage. Attempts to develop non-steroidal anti-inflammatory remedies devoid of these shortcomings-especially gastrointestinal toxicity-have followed several strategies. Non-steroidal anti-inflammatory drugs have, therefore, been associated with gastroprotective agents that counteract the damaging effects of prostaglandin synthesis suppression; however, a combination therapy introduces other problems of pharmacokinetics, toxicity, and patient's compliance. More recently, incorporation of a nitric oxide (NO)-generating moiety into the molecule of several NSAIDs was shown to greatly attenuate their ulcerogenic activity; however, several findings suggest a possible involvement of NO in the pathogenesis of arthritis and subsequent tissue destruction. A most promising approach seemed to be the preparation of novel NSAIDs, targeted at the inducible isoform of prostaglandin synthase (COX-2); they appear to be devoid of gastrointestinal toxicity, in that they spare mucosal prostaglandin synthesis. However, a number of recent studies have raised serious questions about the two central tenets that support this approach, namely that the prostaglandins that mediate inflammation and pain are produced solely via COX-2 and that the prostaglandins that are important in gastrointestinal and renal function are produced solely via COX-1. So, a growing body of evidence shows that COX-2 (not only COX-1) also plays a physiological role in several body functions and that, conversely, COX-1 (not only COX-2) may also be induced at sites of inflammation. More recent and puzzling data shows that COX-2 is induced during the resolution of an inflammatory response, and at this point it produces anti-inflammatory (PGD2 and PGF2alpha), but not proinflammatory (PGE2) prostaglandins; inhibition of COX-2 at this point thus results in persistence of the inflammation. Moreover, COX-2 selective NSAIDs have lost the cardiovascular protective effects of non-selective NSAIDs, effects which are mediated through COX-1 inhibition (in addition, COX-2 has a role in sustaining vascular prostacyclin production). The generation of other very important products of the arachidonic acid cascade (besides cyclooxygenase-produced metabolites) is inhibited neither by non-selective nor by COX-2 selective NSAIDs. The products generated by the 5-lipoxygenase pathway (leukotrienes) are particularly important in inflammation; indeed, leukotrienes increase microvascular permeability and are potent chemotactic agents. Moreover, inhibition of 5-lipoxygenase indirectly reduces the expression of TNF-alpha (a cytokine that plays a key role in inflammation). These data and considerations explain the efforts to obtain drugs able to inhibit both 5-lipoxygenase and cyclooxygenases, the so-called dual acting anti-inflammatory drugs. Such compounds retain the activity of classical NSAIDs, while avoiding their main drawbacks, in that curtailed production of gastroprotective prostaglandins is associated with a concurrent curtailed production of the gastro-damaging and bronchoconstrictive leukotrienes. Moreover, thanks to their mechanism of action, dual acting anti-inflammatory drugs could not merely alleviate symptoms of rheumatic diseases, but might also satisfy, at least in part, the criteria of a more definitive treatment. Indeed, leukotrienes are pro-inflammatory, increase microvascular permeability, are potent chemotactic agents and attract eosinophils, neutrophils and monocytes into the synovium. Copyright 2001 Academic Press.

 

 

2) Panes J, Molla M, Casadevall M, Salas A, Sans M, Conill C, Anderson DC, Rosello-Catafau J, Granger DN, Pique JM.

Tepoxalin inhibits inflammation and microvascular dysfunction induced by abdominal irradiation in rats.

Aliment Pharmacol Ther. 2000 Jun;14(6):841-50.

 

 

3) Fiebich BL, Hofer TJ, Lieb K, Huell M, Butcher RD, Schumann G, Schulze-Osthoff K, Bauer J.

The non-steroidal anti-inflammatory drug tepoxalin inhibits interleukin-6 and alpha1-anti-chymotrypsin synthesis in astrocytes by preventing degradation of IkappaB-alpha.

Neuropharmacology. 1999 Sep;38(9):1325-33.

 

 

4) Lee DH, Macintyre JP, Taylor GR, Wang E, Plante RK, Tam SS, Pope BL, Lau CY.

Tepoxalin enhances the activity of an antioxidant, pyrrolidine dithiocarbamate, in attenuating tumor necrosis factor alpha-induced apoptosis in WEHI 164 cells.

J Pharmacol Exp Ther. 1999 Jun;289(3):1465-71.

 

Abstract

The R.W. Johnson Pharmaceutical Research Institute, Toronto, Canada. dlee@prius.jnj.com

The nuclear transcription factor-kappaB (NF-kappaB) and free radicals are known to be involved in apoptosis. We studied the effects of a series of di-aryl-substituted pyrazole NF-kappaB inhibitors including tepoxalin on tumor necrosis factor alpha (TNFalpha)-induced apoptosis in murine fibrosarcoma WEHI 164 cells. We found that potent inhibitors of NF-kappaB were also effective in attenuating apoptosis. WEHI 164 cells that had been dually treated with tepoxalin and the antioxidant pyrrolidine dithiocarbamate (PDTC) were significantly protected from TNFalpha-induced killing. To study the role of free radicals in mediating TNFalpha-induced apoptosis, stable WEHI 164 cells overexpressing Bcl-2, an antioxidant protein, were generated. These cells were protected from TNFalpha-induced apoptosis and neither tepoxalin nor PDTC provided further significant protection. These results suggest that Bcl-2, PDTC, and tepoxalin may attenuate apoptosis in this system by affecting the same signaling pathway or converging pathways. Because tepoxalin suppresses the release of free radicals, PDTC scavenges free radicals and Bcl-2 is an antioxidant protein, free radicals are among the key mediators of this TNF-induced killing event. Tepoxalin and antioxidants may be useful in developing new therapeutics for treating neurodegenerative diseases, autoimmune deficiency syndrome, and ischemia-reperfusion injuries.

 

 

5) Connolly PJ, Wetter SK, Beers KN, Hamel SC, Chen RH, Wachter MP, Ansell J, Singer MM, Steber M, Ritchie DM, Argentieri DC.

N-hydroxyurea and hydroxamic acid inhibitors of cyclooxygenase and 5-lipoxygenase.

Bioorg Med Chem Lett. 1999 Apr 5;9(7):979-84.

 

 

6) Lee JI, Burckart GJ.

Nuclear factor kappa B: important transcription factor and therapeutic target.

J Clin Pharmacol. 1998 Nov;38(11):981-93. Review.

 

 

7) Willburger RE, Wittenberg RH, Schmidt K, Kleemeyer KS, Peskar BA.

Antiinflammatory effect of tepoxalin: blood and synovial tissue studied in patients with knee arthrosis.

Acta Orthop Scand. 1998 Jun;69(3):295-300.

 

Abstract

Department of Orthopedics, Ruhr University, St. Josef-Hospital, Bochum, Germany.

Our aim was to determine the amounts of eicosanoids in blood and synovial tissue of patients with knee arthrosis and to examine the effects of 2 doses of tepoxalin (50 mg twice, 200 mg twice), administered p.o. for 3.5 days. Concentrations of leukotriene B4 (LTB4, LTC4, and thromboxane B2 (TXB2) were measured in blood before and after oral administration of tepoxalin and release of prostaglandin E2 (PGE2), 6-keto-PGF1alpha, and LTC4 was measured in incubation media of synovial tissue, taken at surgery from patients treated with tepoxalin. Radioimmunoassay (RIA) was used to determine the levels of the eicosanoids. LT and TXB2 release was reduced by tepoxalin in both doses used. Under these conditions, PGE2, 6-keto-PGF1alpha, and LTC4 release from synovial tissue was detectable only after stimulation with calcium ionophore A23187. Washed synovial tissue, in which tepoxalin concentrations should be reduced, released higher amounts of all eicosanoids measured than directly incubated synovial tissue did. Pain after tepoxalin administration was significantly reduced. Relevant drug concentrations were detected in plasma and synovial fluid. Tepoxalin was well tolerated and had no marked adverse effects. At 400 mg, tepoxalin is a dual inhibitor of cyclooxygenase (CO) and 5-lipoxygenase (5-LO) in blood and synovial tissue.

 

 

8) Kirchner T, Aparicio B, Argentieri DC, Lau CY, Ritchie DM.

Effects of tepoxalin, a dual inhibitor of cyclooxygenase/5-lipoxygenase, on events associated with NSAID-induced gastrointestinal inflammation.

Prostaglandins Leukot Essent Fatty Acids. 1997 Jun;56(6):417-23.

 

Abstract

Department of Immunopharmacology, The R.W. Johnson Pharmaceutical Research Institute, Raritan, NJ 08869, USA. tkirchne@prius.jnj.com

Prostaglandins and thromboxanes are products of arachidonic acid metabolism via the cyclooxygenase (CO) enzyme and are responsible for the pain and swelling common to sites of inflammation. Non-steroidal anti-inflammatory drugs (NSAIDs) inhibit the production of these substances and are used in the treatment of inflammatory diseases such as arthritis. However, one of the major side-effects of NSAID therapy is gastric ulceration. It is possible that inhibition of prostaglandin production and a related increase in the formation of leukotrienes via the 5-lipoxygenase (5-LO) enzymatic pathway are responsible for attracting inflammatory cells, causing local sites of inflammation and producing ulceration. To determine the effects of 5-LO inhibition on this hypothesis, studies were performed in rats to evaluate the effects of tepoxalin, a dual CO/LO inhibitor on leukotriene B4 levels in gastric mucosa and neutrophil adhesion in mesenteric venules. In rats, chronic oral administration of an NSAID, indomethacin (2 mg/kg daily over 4 days), resulted in 40% mortality, accompanied by intestinal adhesions and perforations when evaluated 24 h after the fourth dose of drug. Additionally, neutrophil adhesion was increased in the mesenteric venules and cell infiltration was evident in the mesenteric interstitium. These gastrointestinal side-effects were inhibited in a separate group of rats administered tepoxalin (20 mg/kg, p. o) 30 min prior to each daily indomethacin treatment. Further studies were performed to determine tepoxalin's effects on early events associated with NSAID-induced gastrointestinal inflammation, including neutrophil adhesion, lipid peroxide generation and LTB4 production. Indomethacin (100 mg/kg, p.o.) produced elevated levels of LTB4 in rat gastric mucosa 90 min after administration. Additionally, neutrophil adhesion in mesenteric venules was increased at this dose and with the administration of another NSAID, naproxen. No generation of lipid peroxides was evident in the gastric mucosa at this timepoint. Tepoxalin (up to 400 mg/kg, p.o.) did not have an effects on gastric mucosal LTB4 generation and lipid peroxide levels. A decrease in neutrophil adhesion was observed at the highest dose. In another study, pretreatment with tepoxalin (ED50=7.5 mg/kg, p.o.) or the selective 5-LO inhibitor zileuton (100 mg/kg, p.o.) prevented the increases in gastric mucosal LTB4 levels and neutrophil adhesion induced by indomethacin (100 mg/kg, p.o.). These data suggest that LO inhibition may play a vital role in the prevention of NSAID-induced gastric inflammation, providing insight into the lack of ulcerogenicity with tepoxalin and new approaches to anti-inflammatory therapy which may prevent gastric side effects.

 

 

9) Lee DH, Tam SS, Wang E, Taylor GR, Plante RK, Lau CY.

The NF-kappa B inhibitor, tepoxalin, suppresses surface expression of the cell adhesion molecules CD62E, CD11b/CD18 and CD106.

Immunol Lett. 1996 Nov;53(2-3):109-13.

 

 

10) Willburger RE, Wittenberg RH, Kleemeyer KS, Hoos R, Brunner-Ferber FL, Peskar BA.

Inhibition of eicosanoid release from synovial organ culture by incubation with tepoxalin and its acid metabolite.

Prostaglandins. 1996 Oct;52(4):327-38.

 

Abstract

Dept. of Orthopaedic Surgery, St. Josef-Hospital, Ruhr University, Bochum, Germany.

The pharmacological profile of a novel dual inhibitor, tepoxalin and of its carboxylic acid metabolite on cyclooxygenase and lipoxygenase pathways was evaluated by in vitro incubation with synovial tissue. Tissue specimens obtained at surgery in rheumatoid arthritis (RA, n = 10) or osteoarthritis (OA, n = 11) patients were incubated. Tepoxalin (10(-7), 10(-6), 10(-5) M) decreased eicosanoid release calculated in % of tyrode control for OA: LTC4 to 71-33%, 6-keto-PGF1a to 37-20%, PGE2 to 29-6%. For RA: LTC4 to 56-22%, 6-keto-PGF1a to 43-22%, PGE2 to 57-32%. Similarly, its metabolite (10(-7), 10(-5)M) decreased release in OA: LTC4 to 99 and 60%, PGE2 to 42 and 20%, 6-keto-PGF1a to 54 and 25%. In RA:LTC4 to 81 and 45%, PGE2 to 61 and 30%, 6-keto-PGF1a to 46 and 18%. Significance (P < 0.05) was achieved for all but 1 group (LTC4 metabolite at 10(-7)M vs tyrode). In summary a marked and dose dependent decrease of LT and PG release was obtained when incubating the dual inhibitor tepoxalin and its active carboxylic acid metabolite with synovial tissue at doses expected to be reached in the joint during therapy.

 

 

11) Knight EV, Kimball JP, Keenan CM, Smith IL, Wong FA, Barrett DS, Dempster AM, Lieuallen WG, Panigrahi D, Powers WJ, Szot RJ.

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

Fundam Appl Toxicol. 1996 Sep;33(1):38-48.

 

Abstract

Department of Drug Safety Evaluation, The R. W. Johnson Pharmaceutical Research Institute, Raritan, New Jersey, 08869-0602, USA.

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.

DOGS 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.

 

 

12) Pahl HL, Baeuerle PA.

Activation of NF-kappa B by ER stress requires both Ca2+ and reactive oxygen intermediates as messengers.

FEBS Lett. 1996 Aug 26;392(2):129-36.

 

 

13) Waldman SA, Vitow C, Osborne B, Gillen L, Argentieri DC, Wong FA, Smith IL, Chow AT, Misiti J, Bjornsson TD.

Pharmacokinetics and pharmacodynamics of tepoxalin after single oral dose administration to healthy volunteers.

J Clin Pharmacol. 1996 May;36(5):462-8.

 

Abstract

Department of Medicine, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA.

This study was conducted to examine the pharmacokinetics and pharmacodynamics of tepoxalin in healthy volunteers, an antiinflammatory compound that inhibits cyclooxygenase and lipoxygenase. Tepoxalin was absorbed after oral administration of single doses from 35 to 300 mg, after which it was rapidly converted to an acidic metabolite, RWJ 20142, which inhibits cyclooxygenase but not lipoxygenase. The areas under the concentration-time curve (AUC) of tepoxalin and RWJ 20142 in plasma increased in a dose-dependent fashion. Administration of the lowest dose of tepoxalin completely inhibited whole blood cyclooxygenase for the entire period of observation. This inhibition correlated closely with that of secretion and aggregation induced by collagen of platelets obtained from these subjects. Similarly, administration of tepoxalin was associated with significant inhibition of lipoxygenase in whole blood. Lipoxygenase was inhibited a maximum of 60% in a time-dependent fashion, and the duration of inhibition was dose-dependent. These studies demonstrate that tepoxalin inhibits whole blood cyclooxygenase, lipoxygenase, and platelet function after oral administration in humans.

 

 

14) Burinsky DJ, Armstrong BL, Oyler AR, Dunphy R.

Characterization of tepoxalin and its related compounds by high-performance liquid chromatography/mass spectrometry.

J Pharm Sci. 1996 Feb;85(2):159-64.

 

 

15) Depre M, Van Hecken A, Verbesselt R, Verpooten GA, Arnout J, Brunner F, Jurgens A, Pousset V, Chow A, Baldauf C, Vermylen J, De Broe M, De Schepper PJ.

Biochemical activity, pharmacokinetics and tolerability of tepoxalin, a cyclooxygenase/5-lipoxygenase inhibitor, in man.

Int J Clin Pharmacol Res. 1996;16(1):1-8.

 

Abstract

Centre for Clinical Pharmacology, Katholieke Universiteit Leuven, Belgium.

Tepoxalin, a novel inhibitor of cyclooxygenase (CO) and 5-lipoxygenase (5-LO), was investigated for biochemical activity and pharmacokinetics in two studies. Study I was a 4-period, double-blind, randomized, single rising dose using 2 alternating panels (A, B) with interspersed placebo design (A: 25, 100, 400 mg, B: 50, 200, 800 mg p.o.). Study II was a 3-panel, randomized, placebo-controlled, double-blind, multiple dose study (A: 100 mg, B: 200 mg, C: 400 mg). In both studies, CO inhibition was assessed by generation of serum thromboxane (TxB2), 5-LO activity by LTB4 production ex vivo in Caionophore-stimulated blood. Plasma drug concentrations were assayed by HPLC for tepoxalin and its identified acid metabolite. It was found in both studies that at all dose levels the TxB2 generation was markedly suppressed (> 95% 2 h postdose). In study I, at 2 h postdose, % inhibition of LTB4 biosynthesis was marginal for the 3 lower doses but significant at 200 (14%), 400 (25%) and 800 mg (43%). In study II, the only significant inhibition occurred at the 400 mg dose at 6 h postdose on day 1 (17%) and on day 8 at 4, 6 and 8 h postdose (32, 42 and 32% respectively). In both studies and at all doses, plasma concentrations of tepoxalin varied widely between subjects. Linearity between plasma concentrations and dose could not be ascertained, and correlation between drug plasma levels and effect on LTB4 synthesis was poor. Single doses up to 800 mg and multiple doses up to 400 mg of tepoxalin were generally well tolerated.

 

 

16) Rainsford KD, Ying C, Smith F.

Effects of 5-lipoxygenase inhibitors on interleukin production by human synovial tissues in organ culture: comparison with interleukin-1-synthesis inhibitors.

J Pharm Pharmacol. 1996 Jan;48(1):46-52.

 

 

17) Zhou L, Pope BL, Chourmouzis E, Fung-Leung WP, Lau CY.

Tepoxalin blocks neutrophil migration into cutaneous inflammatory sites by inhibiting Mac-1 and E-selectin expression.

Eur J Immunol. 1996 Jan;26(1):120-9.

 

Abstract

Discovery Research, R. W. Johnson Pharmaceutical Research Institute, Ontario, Canada.

Inflammation is characterized by the migration of polymorphonuclear leukocytes from the vasculature into the tissue causing profound injury. Adhesion and migration of neutrophils across the vascular bed are governed by a series of complex events including cytokine/chemokine production which in turn orchestrates the temporal expression of a cohort of adhesion molecules mediating the migration. Many of these adhesion molecules and their inducers are under the control of inflammatory response transcriptional factors such as NF kappa B and AP-1. Recently we showed tepoxalin, previously known as a dual cyclooxygenase/lipoxygenase (CO/LO) inhibitor, to be a potent inhibitor of NF kappa B-induced transcription in vitro. In this study, we demonstrated that when administered in vivo, tepoxalin but not naproxen (a nonsteroidal anti-inflammatory drug, NSAID) or zileuton (an LO inhibitor), effectively inhibits neutrophil migration into inflammatory sites in murine skin stimulated by either lipopolysaccharide (LPS) or tumor necrosis factor-alpha. Immunohistochemical analysis indicates that 10-50 mg/kg of tepoxalin inhibits neutrophil migration. It also effectively blocks the upregulation of Mac-1 (CD11b/CD18) on neutrophils. Quantitative polymerase chain reaction Mac-1 analysis shows that LPS-induced transcription of E-selectin mRNA was dramatically suppressed by both 25 and 50 mg/kg of tepoxalin, whereas the level of ICAM-1 was only affected by 50 mg/kg of tepoxalin. Since it has been documented that the expression of E-selectin and Mac-1 is regulated either directly or indirectly by the transcription factor NF kappa B, our studies provide in vivo evidence that tepoxalin is a potent inhibitor of NF kappa B-mediated events in animal models and this novel molecular mechanism clearly defines it as a new class of anti-inflammatory compounds.

 

 

18) Ritchie DM, Argentieri DC, Aparicio BL, Plante RK, Lau CY, Barbone AG.

Cytokine-modulating activity of tepoxalin, a new potential antirheumatic.

Int J Immunopharmacol. 1995 Oct;17(10):805-12.

 

 

19) Fung-Leung WP, Pope BL, Chourmouzis E, Panakos JA, Lau CY.

Tepoxalin, a novel immunomodulatory compound, synergizes with CsA in suppression of graft-versus-host reaction and allogeneic skin graft rejection.

Transplantation. 1995 Aug 27;60(4):362-8.

 

Abstract

R.W. Johnson Pharmaceutical Research Institute, Don Mills, Ontario, Canada.

Tepoxalin, a dual 5-lipoxygenase and cyclooxygenase inhibitor with nonsteroidal antiinflammatory effects, has recently been shown to suppress NF kappa B transactivation and inhibit T cell proliferation via a mechanism very different from cyclosporine (CsA). In this report, we demonstrate that this novel immunosuppressive effect of tepoxalin is manifested in in vivo transplantation models. Tepoxalin suppressed murine spleen cell proliferation in a mixed lymphocyte reaction (MLR) with an IC50 of 1.3 microM. Coadministration of tepoxalin and CsA in MLR cultures showed an additive inhibitory effect. Oral administration of tepoxalin at 12 mg/kg/day to mice suppressed local graft-versus-host (GVH) responses by about 40% (n = 10). Combination of tepoxalin and CsA at suboptimal doses synergized their immunosuppressive effects on GVH responses (n = 20). In skin transplantation, the median survival time of allogeneic BALB/cByJ (H-2d) mouse skin grafted onto C3H/HeJ (H-2 kappa) mice was 10.5 days (n = 8), and was prolonged to 15.0 days (n = 9) for recipient mice administered tepoxalin at 50 mg/kg/day. Coadministration of suboptimal doses of tepoxalin (12.5 mg/kg/day) and CsA (50 mg/kg/day) prolonged skin graft rejections dramatically (55% of the grafts survived for more than 40 days, n = 9). Taken together, these results demonstrate that tepoxalin is a potent immunomodulatory compound that, when combined with CsA, provides synergistic immunosuppressive activity. The fact that tepoxalin and CsA act on different transcription factors, NF kappa B and NFAT respectively, might explain the synergistic suppressive effects when both compounds were used. Tepoxalin could be an important addition to the cohort of immunosuppressive therapies currently used in solid organ and bone marrow transplantations.

 

 

20) Tam SS, Lee DH, Wang EY, Munroe DG, Lau CY.

Tepoxalin, a novel dual inhibitor of the prostaglandin-H synthase cyclooxygenase and peroxidase activities.

J Biol Chem. 1995 Jun 9;270(23):13948-55.

 

Abstract

R. W. Johnson Pharmaceutical Research Institute, Don Mills, Ontario, Canada.

Prostaglandin-H synthase-1, the rate-limiting enzyme in prostaglandin synthesis, has both cyclooxygenase (CO) and peroxidase (PO) activities. While most nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit only the CO activity, we describe an inhibitor, tepoxalin, that inhibits both the CO (IC50 = 0.1 microM) and the PO (IC50 = 4 microM) activities. Unlike many NSAIDs which are competitive inhibitors of CO, tepoxalin is a noncompetitive inhibitor of CO and its inhibitory effect on PO but not CO is reversed by excess heme. Moreover, inhibition of the PO activity by tepoxalin is not dependent on the enzymatic turnover of the CO activity. The hydroxamic acid of tepoxalin is responsible for the PO inhibition since a carboxylic acid derivative of tepoxalin retains full CO but not PO inhibition. We postulated that the hydroxamic group might confer the ability to inhibit PO on conventional CO inhibitors. This idea was supported by the observation that naproxen hydroxamic acid, but not naproxen showed PO inhibition. Furthermore, tepoxalin's carboxylic acid analogue and naproxen each competitively relieved PO inhibition by their respective hydroxamic acids. The intracellular activity of PO as monitored by the release of reactive oxygen species was also inhibited by both tepoxalin and naproxen hydroxamic acid. These observations suggest a strategy for design of novel compounds to inhibit prostaglandin synthase PO. The therapeutic implications of these novel PO inhibitors are discussed.

 

 

21) Kazmi SM, Plante RK, Visconti V, Taylor GR, Zhou L, Lau CY.

Suppression of NF kappa B activation and NF kappa B-dependent gene expression by tepoxalin, a dual inhibitor of cyclooxygenase and 5-lipoxygenase.

J Cell Biochem. 1995 Feb;57(2):299-310.

 

 

22) Argentieri DC, Ritchie DM, Ferro MP, Kirchner T, Wachter MP, Anderson DW, Rosenthale ME, Capetola RJ.

Tepoxalin: a dual cyclooxygenase/5-lipoxygenase inhibitor of arachidonic acid metabolism with potent anti-inflammatory activity and a favorable gastrointestinal profile.

J Pharmacol Exp Ther. 1994 Dec;271(3):1399-408.

 

Abstract

Research Laboratories, R. W. Johnson Pharmaceutical Research Institute, Raritan, New Jersey.

Tepoxalin [5-(4-chlorophenyl)-N-hydroxy-(4-methoxyphenyl)-N-methyl-1H- pyrazole-3-propanamide] is a potent inhibitor of sheep seminal vesicle cyclooxygenase (CO) (IC50 = 4.6 microM), rat basophilic leukemia cell (RBL-1) lysate CO (IC50 = 2.85 microM) and CO from intact RBL-1 cells (IC50 = 4.2 microM). The compound inhibits the production of thromboxane B2 (TxB2) in Ca++ ionophore A-23187-stimulated human peripheral blood leukocytes (HPBL; IC50 = 0.01 microM) and human whole blood (IC50 = 0.08 microM) and is a potent inhibitor of epinephrine-induced human platelet aggregation (IC50 = 0.045 microM). Tepoxalin inhibits lipoxygenase (LO) in RBL-1 lysates (IC50 = 0.15 microM) and intact RBL-1 cells (IC50 = 1.7 microM) and inhibits the generation of leukotriene B4 (LTB4) in calcium ionophore A-23187-stimulated HPBL (IC50 = 0.07 microM) and human whole blood (IC50 = 1.57 microM). Human platelet 12-LO (IC50 = 3.0 microM) is inhibited, but 15-LO is only weakly so (IC50 = 157 microM). In vivo, tepoxalin, administered orally, demonstrated potent anti-inflammatory activity in the established adjuvant arthritic rat (ED50 = 3.5 mg/kg) and potent analgesic activity in the acetic acid abdominal construction assay in mice (ED50 = 0.45 mg/kg). In an ex vivo whole blood eicosanoid production assay, tepoxalin produces a dose-related inhibition of prostaglandin (PG) and LT production in dogs (PGF2 alpha - ED50 = 0.015 mg/kg; LTB4 - ED50 = 2.37 mg/kg) and adjuvant arthritic rats following oral administration. In adjuvant arthritic rats, tepoxalin is devoid of ulcerogenic activity within its anti-inflammatory therapeutic range (1-33 mg/kg p.o.) and does not exhibit ulcerogenic activity in normal rats at doses lower than 100 mg/kg (UD50 = 173 mg/kg p.o.). Tepoxalin represents a new class of anti-inflammatory drugs which may exhibit less gastrointestinal toxicity and may be efficacious in immunoinflammatory disease states where excessive PG and LT production has been implicated and may offer a significant alternative to nonsteroidal and corticosteroidal anti-inflammatory therapy.

 

 

23) Zhou L, Ritchie D, Wang EY, Barbone AG, Argentieri D, Lau CY.

Tepoxalin, a novel immunosuppressive agent with a different mechanism of action from cyclosporin A.

J Immunol. 1994 Dec 1;153(11):5026-37.

 

Abstract

R. W. Johnson Pharmaceutical Research Institute, Ontario, Canada.

Tepoxalin, a compound previously identified as a dual cyclooxygenase/lipoxygenase (CO/LO) inhibitor, is a potent inhibitor of T cell proliferation. Comparing the suppressive effects of tepoxalin and cyclosporin A (CsA) on OKT3-, PMA-, IL-2-, and PMA+ionomycin-induced T cell proliferations revealed marked differences in the mechanism of action between the two compounds. Whereas CsA was most effective in suppressing OKT3-stimulated proliferation, tepoxalin was more potent in inhibiting PMA-, PMA+ionomycin-, and IL-2-induced proliferation. Quantitative PCR (QPCR) assays used to detect cytokine messages showed that tepoxalin blocked IL-2 mRNA transcription in PMA- and PMA+ionomycin-, but not OKT3-stimulated T cells whereas CsA was most potent in inhibiting OKT3-induced IL-2 mRNA induction in these cells. Both tepoxalin and CsA did not inhibit the expression of IL-2R; however, only tepoxalin, but not CsA, inhibited the proliferation of IL-2-dependent blasts and the transcription of IFN-gamma, an IL-2-dependent target gene. Moreover, addition of exogenous IL-2 restored OKT3-induced proliferation to CsA- but not tepoxalin-treated cells. These data suggest that tepoxalin, but not CsA, suppressed T cell proliferation by inhibiting IL-2-induced signal transduction. Consistent with these findings, tepoxalin, unlike CsA, which was most potent when added at the initiation of OKT3 stimulation, was equally active, regardless of whether it was added at the beginning or 48 h after culture initiation. The difference in mechanism of action between tepoxalin and CsA was confirmed further by the synergistic suppressive effects on T cell proliferation upon co-administration of the two compounds.

 

 

24) Wallace JL, McCafferty DM, Carter L, McKnight W, Argentieri D.

Tissue-selective inhibition of prostaglandin synthesis in rat by tepoxalin: anti-inflammatory without gastropathy?

Gastroenterology. 1993 Dec;105(6):1630-6.

 

Abstract

Gastrointestinal Research Group, University of Calgary, Alberta, Canada.

BACKGROUND: Inhibition of prostaglandin synthesis is likely a primary mechanism for both the anti-inflammatory and ulcerogenic effects of nonsteroidal anti-inflammatory drugs (NSAIDs). The present study examined the mechanism underlying the ability of a novel anti-inflammatory drug, tepoxalin, to suppress prostaglandin synthesis without inducing gastric mucosal injury. METHODS: The effects on prostaglandin synthesis by various tissues of tepoxalin, diclofenac, and indomethacin were examined in vivo and in vitro. These compounds were also studied in two inflammation models. The capacity of indomethacin and tepoxalin to induced antral ulceration in the rabbit was compared. RESULTS: In most tissues, tepoxalin was a weaker inhibitor of prostaglandin synthesis than the two NSAIDs. However, at a site of peripheral inflammation, tepoxalin was comparable with the NSAIDs in suppressing prostaglandin synthesis and in exerting anti-inflammatory effects. Indomethacin induced penetrating antral ulcers in rabbits whereas tepoxalin produced no detectable mucosal injury. CONCLUSIONS: The ability of tepoxalin to suppress inflammation without causing gastric mucosal injury appears to be related to its differential suppression of prostaglandin synthesis in various tissues. Compounds that selectively inhibit prostaglandin synthesis at sites of inflammation may represent a class of anti-inflammatory drugs without detrimental effects on the stomach.

 

 

25) Rainsford KD, Ying C, Smith F.

Selective effects of some 5-lipoxygenase inhibitors on synovial interleukin-1 (IL-1) production compared with IL-1 synthesis inhibitors.

Agents Actions. 1993;39 Spec No:C186-8.

PMID: 8273563 [PubMed - indexed for MEDLINE]

 

26) Wallace JL, Cirino G, Cicala C, Anderson DW, Argentieri D, Capetola RJ.

Comparison of the ulcerogenic properties of tepoxalin with those of non-steroidal anti-inflammatory drugs (NSAIDs).

Agents Actions. 1991 Sep;34(1-2):247-50.

 

Abstract

Gastrointestinal Research Group, University of Calgary, Alberta, Canada.

The ability of tepoxalin to render the gastric mucosa susceptible to injury by a topically applied irritant was compared to that of indomethacin, naproxen and diclofenac. While the three NSAIDs significantly increased the extent of mucosal damage at doses in the 1-30 mg/kg range, tepoxalin failed to significantly augment damage at doses of up to 300 mg/kg. Daily treatment with tepoxalin (10-100 mg/kg) for 4 days also did not significantly affect the susceptibility of the gastric mucosa to damage. The absence of ulcerogenic properties of tepoxalin at doses previously shown to be anti-inflammatory may be related to its relative lack of activity as an inhibitor of gastric prostaglandin synthesis, or to its 5-lipoxygenase inhibitory activity.

 

 

27) Goossens, L.; Berthomm, I.

Tepoxalin (Zubrin(R)) - a novel dual cyclooxygenase/5-lipoxygenase-inhibitor for dogs.

Tepoxalin (Zubrin(R)) ein neuer dualer Zyklooxygenase/5-Lipoxygenasehemmer fr Hunde.

Praktische Tierarzt, 2001, Vol.82, No.12, pp.1014-1014...1021, 26 ref.

 

Abstract

Tepoxalin is a new non-steroidal antiinflammatory drug which is approved in the EU under the name Zubrin(R) for the relief of pain associated with musculoskeletal disorders in dogs. Tepoxalin inhibits, in a dual mode of action, both cyclooxygenase and 5-lipoxygenase pathway of the arachidonic acid metabolism. In addition, Tepoxalin inhibits proliferation of lymphocytes and synthesis of several mediators involved in inflammation, such as interleukin-2 (IL2), interleukin-6 (IL6) and tumour necrosis factor (TNF). Moreover, Tepoxalin inhibits migration of neutrophilic granulocytes in inflammatory tissues. In several pharmacological test systems, analgesic and anti-phlogistic properties of Tepoxalin have been confirmed. In controlled clinical studies the efficacy of Tepoxalin in dogs with osteoarthritis was excellent. Tolerance studies with up to 10 and 30 times overdose for 26 and 52 weeks demonstrated a very good safety profile of Tepoxalin. Mild gastrointestinal disturbances only occurred after prolonged administration of the highest dose. It is concluded that Zubrin(R) is highly effective and has excellent properties.

 

 

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