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At least 19 recordsLinked to original sources
PubMed1994

Testing of lipoxygenase inhibitors, cyclooxygenase inhibitors, drugs with immunomodulating properties and some reference antipsoriatic drugs in the modified mouse tail test, an animal model of psoriasis.

Topical administration of lipoxygenase and cyclooxygenase inhibitors, antipsoriatic drugs and some immunomodulating drugs on adult mouse tail scales showed variable induction of of orthokeratosis. Dithranol and retinoic acid showed ED50 concentrations of 0.5% and 0.23%, respectively. The lipoxygenase inhibitors catechol and octyl gallate showed ED50 of 2.5 and 13.4%. 10% lonapalene showed 20% activity, curcumin, linoleic acid, primrose oil and AA673 10-15% activity, methyl and ethyl gallate 5% activity, nordihydroguaiaretic acid, diethylcarbamazine, ebselen, esculetin, quercetin, AA861, gallic acid, dodecyl gallate and 15-hydroxyeicosatetraenoic acid no activity. The cyclooxygenase inhibitors indomethacin, acetylsalicylic acid and bufexamac were inactive, benoxaprofen showed 14% activity. The immunomodulating drugs fluorouracil and triamcinolone showed > 10% activity, cyclosporin A and thalidomide no activity. Fumaric acid showed 5% activity. The results show that this model could be proposed for screening antipsoriatic drugs.

Animals↗
PubMed1992

Blunted hypoxic vasoconstriction in oleic acid lung injury: effect of cyclooxygenase inhibitors.

Cyclooxygenase inhibitors have been reported to accentuate pulmonary hypertension and to improve gas exchange in oleic acid (OA) lung injury (Leeman et al. J. Appl. Physiol. 65: 662-668, 1988), suggesting inhibition of hypoxic pulmonary vasoconstriction by a vasodilating prostaglandin. To test this hypothesis, the hypoxic pulmonary vasoreactivity was examined at constant flow (Q; with an arteriovenous femoral bypass or a balloon catheter placed in the inferior vena cava) before and after OA in three groups of anesthetized and ventilated [inspired O2 fraction (FIO2) 0.4] dogs. Intrapulmonary shunt was measured using a SF6 infusion. A time control group (n = 7) had two consecutive hypoxic challenges after OA and received no drug. A treatment group (n = 6) received indomethacin (2 mg/kg iv) before the second hypoxic challenge after OA. A pretreatment group received indomethacin (2 mg/kg iv, n = 7) or aspirin (30 mg/kg iv, n = 6) before OA. In control and treated dogs, the hypoxic pulmonary vasopressor response was attenuated after OA. It was restored after indomethacin but also during the second hypoxic stimulus in the control dogs. After OA, gas exchange at FIO2 0.4 improved with indomethacin but not in controls. In pretreated dogs the hypoxic vasopressor response to hypoxia was preserved after OA, and gas exchange at FIO2 0.4 was less deteriorated compared with nonpretreated dogs (arterial O2 pressure 139 +/- 7 vs. 76 +/- 6 Torr, P less than 0.01, and intrapulmonary shunt 14 +/- 2 vs. 41 +/- 5%, P less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed2003

Role of 3-hydroxy-3-methylglutaryl coenzyme a reductase inhibitors, angiotensin-converting enzyme inhibitors, cyclooxygenase-2 inhibitors, and aspirin in anti-inflammatory and immunomodulatory treatment of cardiovascular diseases.

The immunologic response in atherosclerosis involves not only intrinsic cells of the artery wall, but also circulating leukocytes, lymphocytes, and macrophages. Interaction of various arms of the immune response modulates plaque development and stability, and it is conceivable that immunologic effects of some cardiovascular therapies may contribute to their mechanism of benefit. The preponderance of data has accrued with the 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins). Statin effects, such as inhibition of T cell activation, tissue factor expression, or reduction of platelet hyperreactivity, may elicit beneficial effects in vitro and in vivo in patients with coronary artery disease. Moreover, aspirin may limit oxidation of lipoproteins and fibrinogen, and it may inhibit cytokine-induced nitric oxide synthase II expression. The hypothesis that selective inhibition of cyclooxygenase-2 (COX-2) may increase risk of myocardial infarction is controversial and may also be of questionable clinical significance. Finally, angiotensin-converting enzyme (ACE) inhibitors not only reduce proinflammatory mediators, such as interleukin-6, but also enhance the concentration of anti-inflammatory cytokines, such as interleukin-10. Because ACE is expressed at the shoulder region of atherosclerotic plaques, and ACE activity is enhanced in unstable plaques, ACE inhibition may also contribute to plaque stability. This article reviews the potential immunomodulatory potencies of aspirin, COX-2 inhibitors, statins, and ACE inhibitors as established pharmacotherapy in patients with coronary artery disease.

Adjuvants, Immunologic↗
PubMed1987

The induction of ornithine decarboxylase caused by 12-O-tetradecanoylphorbol-13-acetate in isolated epidermal cells is inhibited by lipoxygenase inhibitors but not by cyclooxygenase inhibitors.

The effects of lipoxygenase and cyclooxygenase inhibitors on ornithine decarboxylase (ODC) induction by a potent tumor promoter, 12-O-tetradecanoylphorbol-13-acetate (TPA) were examined in vitro in isolated mouse epidermal cells. Lipoxygenase inhibitors such as quercetin, nordihydroguaiaretic acid (NDGA), 3,4,2',4'-tetrahydroxychalcone, 3-amino-1-(3-trifluoromethylphenyl)-2-pyrazoline (BW755C) inhibited the TPA-caused ODC induction. Indomethacin, a selective cyclooxygenase inhibitor, failed to inhibit it. These results suggest that the lipoxygenase inhibitors inhibit TPA-caused epidermal ODC induction in mouse skin at least in part by acting directly on epidermal cells while cyclooxygenase inhibitor inhibits it indirectly by acting on cells other than epidermal cells, e.g. cells which are involved in the prostaglandin-dependent inflammatory process.

4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyraz↗
PubMed1982

Effect of cyclooxygenase inhibitors and protease inhibitors on phorbol-induced stimulation of oxygen consumption and superoxide production by rat pulmonary macrophages.

Oxygen consumption and superoxide anion production by pulmonary macrophages are both increased by phorbol myristate acetate (PMA) but the two processes have been separated using protease inhibitors and cyclooxygenase inhibitors. Pretreatment with the protease inhibitors (L-1-tosylamido-2-phenylethylchloromethyl ketone (TPCK) and N-alpha-p-tosyl-L-lysine chloromethyl ketone (TLCK), as well as with the cyclooxygenase inhibitors acetylsalicylic acid (ASA) and ibuprofen (IBU), inhibited the stimulation of superoxide production and oxygen consumption by phorbol myristate acetate. However, whereas the order of potency for inhibition of stimulation of superoxide production was TPCK greater than TLCK greater than IBU greater than ASA, the order of potency for inhibition of stimulation of oxygen consumption was ASA greater than IBU greater than TPCK = TLCK. Although all four agents were effective inhibitors of PMA-stimulated superoxide production and oxygen consumption when added before PMA, in contrast to the cyclooxygenase inhibitors. TPCK was unable to inhibit oxygen consumption by more than 70-80% regardless of the concentration used, although superoxide generation could be inhibited completely. When added after PMA, ASA did not suppress either oxygen consumption or superoxide production and ibuprofen was only one-half as effective as an inhibitor. TPCK and TLCK, when added after PMA, accelerated the return to basal rates of both oxygen consumption and superoxide production. None of the four agents had any effect on basal superoxide production or oxygen consumption at the concentrations used. The data support the interpretation that both prostaglandin biosynthesis and protease activity may be associated with the activation of the superoxide-generating system of pulmonary macrophages. The consumption of molecular oxygen following stimulation of the cells with phorbol myristate acetate is not due solely to the generation of superoxide, however, since each process is inhibited with different potency by the same group of inhibitors. There appears to be a component of oxygen consumption which results from the activation of cyclooxygenase and, unlike superoxide production, cannot be completely inhibited by treatment with protease inhibitors.

Animals↗
PubMed2001

Increased expression of cyclooxygenase-2 in human pancreatic neoplasms and potential for chemoprevention by cyclooxygenase inhibitors.

BACKGROUND: Cyclooxygenase-2 (COX-2) is thought to be linked to carcinogenesis; however, very little is known about its expression in pancreatic neoplasms. The authors studied the expression of COX-2 in human pancreatic neoplasms and investigated the effect of COX inhibitors on the growth of human pancreatic carcinoma cells. METHODS: Expression of COX-2 protein was immunohistochemically examined in 42 human pancreatic duct cell carcinomas (PDCs) and in 29 intraductal papillary mucinous tumors (IPMTs [adenomas, 19; carcinomas, 10]) of the pancreas that were resected surgically at the National Cancer Center Hospital in Tokyo. The growth of four human pancreatic carcinoma cell lines also was evaluated in the presence of COX inhibitors. RESULTS: Marked COX-2 expression was observed in 57% (24 of 42) of PDCs, in 58% (11 of 19) of adenomas, and in 70% (7 of 10) of adenocarcinomas of IPMTs. However, there was no correlation between COX-2 expression and clinicopathologic indices of the patients. All four pancreatic cancer cell lines expressed COX-2 protein weakly or strongly, and the inhibitory effect of aspirin on cell growth was correlated with the expression of COX-2. CONCLUSIONS: COX-2 was expressed in adenomas of IPMTs as well as in carcinomas and might have played a role in the development of pancreatic tumors. In this study, COX inhibitors, as nonsteroidal anti-inflammatory drugs, were shown to be possible preventive agents against pancreatic neoplasms.

Adenocarcinoma, Mucinous↗
PubMed1998

Pharmacokinetic and pharmacodynamic interaction between the lipoxygenase inhibitor MK-0591 and the cyclooxygenase inhibitor ibuprofen in man.

Twelve healthy male subjects participated in a double-blind, placebo-controlled, randomized, three-period, crossover study to investigate the safety, tolerability, biochemical activity and pharmacokinetics of ibuprofen, a cyclooxygenase inhibitor and MK-0591, a 5-lipoxygenase inhibitor, given as single entities and in combination. Each subject received for three consecutive 8-day periods, separated by 1 week washout, each of the following treatments: ibuprofen 600 mg three times a day with 125 mg MK-0591 twice a day, ibuprofen 600 mg three times a day with placebo for MK-0591 and MK-0591 125 mg twice a day with placebo for ibuprofen. Cyclooxygenase inhibition was measured by platelet thromboxane (TxB2) generation test, and 5-lipoxygenase inhibition was measured by urinary leukotriene E4 excretion and ex vivo LTB4 generation in calcium-ionophore-stimulated blood. TxB2 suppression on day 8 by ibuprofen was not affected by concomitant treatment with MK-0591. MK-0591 alone had no effect on TxB2 generation. Leukotriene biosynthesis was inhibited by more than 90% by MK-0591 alone and by combined treatment, while ibuprofen alone had no effect. Coadministration appears to affect the pharmacokinetics of MK-0591 (decrease of area under the plasma concentration-vs-time curve [AUC] and maximum plasma concentrations [Cmax]) and of ibuprofen (increase of AUC and half-lives of elimination (t1/2) of the (S)-enantiomer, increase of t1/2 the (R)-enantiomer). Combined treatment had no effect on creatinine clearance nor on the number and intensity of the reported adverse experiences.

Adult↗
PubMed1992

Potentiation by cyclooxygenase inhibitors of the release of catecholamines from the rabbit carotid body and its reversal by prostaglandin E2.

Salicylates, at the high therapeutic doses used in the treatment of rheumatoid arthritis, produce an increase in ventilation and augment the carotid body reactivity to hypoxic stimulus, leading to an exaggerated hyperventilation during hypoxia. These effects had been related to the action of salicylates as uncouplers of oxidative phosphorylation. In the present study, carried out in an in vitro preparation of the rabbit carotid body, we show that acetylsalicylic acid and indomethacin, two anti-inflammatory drugs that are also powerful inhibitors of cyclooxygenase, the prostaglandin-synthetizing enzyme, produce an increase in the [3H]catecholamine release evoked by low oxygen stimulation. The drugs did not affect basal normoxic release, a finding that suggests that at the concentration used these anti-inflammatory agents do not have uncoupling actions, and that their effects on hypoxic-induced release of [3H]catecholamines is mediated by their specific action as cyclooxygenase inhibitors. In agreement with this suggestion we found that prostaglandin E2 completely prevented the effects of both anti-inflammatory agents. In addition, our data indicate that endogenously synthetized prostaglandins are powerful modulators of chemoreceptor cell function.

Animals↗
PubMed1990

Cardiorenal actions of endothelin, Part II: Effects of cyclooxygenase inhibitors.

The effects of cyclooxygenase inhibitors (meclofenamate and indomethacin) on endothelin-induced changes in renal function were evaluated in pentobarbital anesthetized female rats. Two groups (n = 5/group) of rats were evaluated: one group received a continuous intravenous infusion of meclofenamate (0.03 mg kg-1 min-1) and the second group received a bolus injection of indomethacin (5 mg/kg). Following surgery, rats were allowed 60 min to stabilize and 3 X 20 min control clearances collected. Endothelin-1 (100 eta kg-1 min-1) was then added into the infusate for 30 min. Neither meclofenamate nor indomethacin caused significant changes on endothelin-induced systemic vasoconstriction; blood pressure increased from 107 +/- 3 to 136 +/- 2 mmHg (p less than 0.01) with endothelin alone, from 103 +/- 6 to 135 +/- 6 mmHg (p less than 0.01) with endothelin plus meclofenamate, and from 105 +/- 6 to 131 +/- 10 mmHg (p less than 0.01) with endothelin plus indomethacin. Similarly, endothelin-induced decreases in glomerular filtration rate (GFR) were not affected by either meclofenamate or indomethacin; GFR decreased from 2.7 +/- 0.2 to 0.8 +/- 0.3 ml/min (p less than 0.01) with endothelin alone, from 2.3 +/- 0.5 to 0.7 +/- 0.4 ml/min (p less than 0.01) with endothelin plus meclofenamate, and from 2.6 +/- 0.4 to 0.6 +/- 0.4 ml/min (p less than 0.01) with endothelin plus indomethacin. Baseline excretion rates of sodium, potassium and urine volume were also not affected by the inhibitors of cyclooxygenase. These data demonstrate that, under the conditions of the current study, endothelin-induced changes in renal and cardiovascular function are not affected by inhibiting prostaglandin production.

Animals↗
PubMed1986

Salicylates inhibit PAF-acether-induced rat paw oedema when cyclooxygenase inhibitors are ineffective.

The cyclooxygenase inhibitors indomethacin, piroxicam, ibuprofen, naproxen and flurbiprofen failed to block rat paw oedema induced by PAF-acether, whereas aspirin and sodium salicylate were effective. Two mixed cyclooxygenase and lipoxygenase inhibitors NDGA, BW 755C and dexamethasone reduced oedema in a dose - dependently. The selective PAF-acether antagonist, BN 52021, was effective against PAF-acether at 5 - 20 mg/kg. The lipoxygenase derivates may be involved in paw oedema induced by PAF-acether in the rat and the inhibition produced by aspirin and by sodium salicylate should involve mechanisms other than the cyclooxygenase pathway.

Animals↗
PubMed1997

Functional stability of hippocampal slices after treatment with cyclooxygenase inhibitors.

The influence of cyclooxygenase inhibitors on functional stability of hippocampal slices, determined by electrophysiological criteria of recovery after slicing and long-term maintainence of population activity, was studied. Transient (3 min) treatment of slices during slicing with indomethacin (45 microM) or aspirin (0.5 mM) allowed registration of the population responses from the second minute. The activity reached 100% after 15 min incubation and could be registrated for 3 days under conditions of overnight hypothermia. The presence of the same drugs for the entire incubation period had the same effect. The present findings suggest that slicing is a crucial point for triggering of pathological events mediated by cyclooxygenase products and that blockade of cyclooxygenase provides for the further high longterm functional stability of brain slices.

Animals↗
PubMed1986

Effects of lipoxygenase and cyclooxygenase inhibitors on the induction of ornithine decarboxylase by 12-O-tetradecanoylphorbol-13-acetate and isoproterenol in mouse tissues in vivo.

I.p. administration of 12-O-tetradecanoylphorbol-13-acetate (TPA) (400 micrograms/kg) caused a remarkable increase in ornithine decarboxylase (ODC) activity in CD-1 mouse liver (8.3-fold), spleen (17.8-fold), kidney (4-fold), lung (7.7-fold) and brain (2.7-fold). TPA induced an increase in ODC activity in liver, spleen and kidney in a dose-dependent manner (100-800 micrograms/kg). The putrescine contents of these tissues were also increased by TPA injection. BW755C, an inhibitor of cyclooxygenase and lipoxygenase, prevented the TPA-induced increase in ODC activity in liver, spleen and kidney in a dose-dependent manner. AA861-a selective lipoxygenase inhibitor, also showed the inhibition of TPA-induced increase in ODC activity in these tissues. Significant inhibition was observed either by BW755C or AA861 at the dose of 30 mg/kg. On the other hand, indomethacin, a selective cyclooxygenase inhibitor, enhanced the TPA-induced increase in ODC activity in these tissues dose-dependently. Significantly enhancement was observed at 3 mg/kg for liver and spleen and 1 mg/kg for kidney. The subcutaneous administration of isoproterenol (1 mg/kg) caused an increase in ODC activity in both liver (11-fold) and spleen (3.4-fold). Both AA861 and BW755C failed to inhibit the isoproterenol-induced increase in ODC activity in these tissues. These results indicate that product(s) of lipoxygenase pathway play an important role in ODC induction caused by TPA in liver, spleen and kidney, while the lipoxygenase pathway does not play an essential role in the isoproterenol-induced increase in ODC activity.

4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyraz↗
PubMed2000

The role of cyclooxygenase inhibitors in repair of ischaemic-injured jejunal mucosa in the horse.

Cyclooxygenase inhibitors are administered to horses to prevent endotoxin-induced elaboration of prostaglandins. However, PGE2 and PGI2 stimulate repair of injured intestine. There are 2 isoforms of cyclooxygenase: COX-1, which constitutively produces prostaglandins and COX-2, which is induced by inflammation. We hypothesised that the nonspecific cyclooxygenase inhibitor flunixin meglumine would retard repair of ischaemic intestinal injury by preventing production of reparative prostaglandins, whereas the selective COX-2 inhibitor, etodolac, would permit repair as a result of continued COX-1 prostaglandin production. Segments of equine jejunum were subjected to ischaemia for 1 h, and recovered for 4 h in Ussing chambers. In ischaemic tissue, treated with the nonspecific cyclooxygenase inhibitor, flunixin meglumine (2.7 x 10(-5) mol/l), production of PGE2 and PGI2 was inhibited, and there was no evidence of recovery based on measurements of transepithelial resistance. Conversely, untreated ischaemic tissues or tissues treated with the specific COX-2 inhibitor etodolac (2.7 x 10(-5) mol/l) had significant elevations in PGE2 and PGI2, and significant recovery of transepithelial resistance. These studies suggest that specific COX-2 inhibitors may provide an advantageous alternative to nonspecific cyclooxygenase inhibitors in horses with colic.

Animals↗
PubMed2002

Cyclooxygenase inhibitor modulation of dopamine-related behaviours.

The sequential action of phospholipase A(2) and cyclooxygenase leads to the production of prostaglandins in the brain, an event hypothesised to cause dopaminergic stimulation. To investigate this further, we examined the effect of the nonselective cyclooxygenase inhibitors indomethacin and piroxicam on several indices of dopaminergic function in adult male rats. Both drugs inhibited catalepsy induced by the dopamine D1-like receptor antagonist R(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine (SCH23390), the dopamine D2-like receptor antagonist raclopride and by haloperidol, findings in agreement with a dopaminergic effect of cyclooxygenase inhibitors. However, neither cyclooxygenase inhibitor had an effect upon disruption of prepulse inhibition of the auditory startle reflex by amphetamine or on the rate of amphetamine self-administration. Both drugs reduced amphetamine-stimulated locomotor activity. Our data indicate that the mechanism by which cyclooxygenase inhibitors alter motor behaviour is unlikely to be due to a simple direct action at the dopaminergic synapse. Their apparent ability to antagonise hypoactivity without generalised dopaminergic stimulation suggests that other, possibly multiple, neurotransmitter systems may be involved.

Amphetamine↗
PubMed2001

Influence of systemic treatment with cyclooxygenase inhibitors on lipopolysaccharide-induced fever and circulating levels of cytokines and cortisol in guinea-pigs.

Peripheral inflammatory stimuli result in the modification of a number of vital brain-controlled functions including the thermoregulatory set-point (induction of fever) and the activity of the hypothalamic-pituitary-adrenal (HPA) axis. We addressed the question of whether both of these components of the acute-phase response are induced by a common signal pathway. For this purpose we recorded body temperature (by remote radio-telemetry), HPA axis activity (circulating concentrations of cortisol by radio-immunoassay) and levels of the pro-inflammatory cytokines tumour necrosis factor and interleukin-6 (TNF, IL-6, using specific bioassays) in six groups of guinea-pigs. The animals received intra-arterial injections of either 10 microg/kg lipopolysaccharide (LPS) plus saline, 10 microg/kg LPS plus 5 mg/kg meloxicam (an inhibitor of the inducible form of cyclooxygenase), 10 microg/kg LPS plus 5 mg/kg diclofenac (a non-selective cyclooxygenase inhibitor), saline plus solvent, saline plus 5 mg/kg meloxicam or saline plus 5 mg/kg diclofenac. Injection of the cyclooxygenase inhibitors per se had no influence on the investigated parameters. Injection of LPS alone resulted in a biphasic fever, a more than fivefold increase in circulating cortisol and pronounced induction of TNF and IL-6. Treatment with the cyclooxygenase inhibitors either attenuated (meloxicam) or abolished (diclofenac) LPS-induced fever, but had no effect on the LPS-induced rise of plasma cortisol or IL-6. Circulating levels of TNF, in response to LPS, were enhanced by meloxicam and diclofenac, reflecting the negative feedback control exerted by prostaglandins on cytokine (specifically TNF) formation. These results provide the first evidence that the prostaglandin-dependent inflammatory pathway for fever induction is distinct from the pathway of HPA axis activation since fever, but not circulating cortisol, was attenuated by an inhibition of prostaglandin formation.

Animals↗