(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.