terutroban and Atherosclerosis

Conventional antiplatelet agents such as aspirin, ticlopidine, and clopidogrel are currently used in the prevention of cardiovascular and cerebrovascular events. However, side effects such as bleeding complications and gastrointestinal disorders and, in some patients, resistance have made the development of new agents desirable. Recently, thromboxane receptors (thromboxane and prostaglandin endoperoxide PGG2-PGH2 receptors) called TP receptors have received increasing attention. These receptors are membrane-bound G-coupled receptors found not only on platelets but also on macrophages, monocytes, vascular endothelial cells, and smooth muscle cells. Antagonists of TP receptors have advantages over aspirin as they not only block the effect of thromboxane A2 on platelets, but also inhibit other ligands such as prostaglandin endoperoxides and isoprostanes. Given the distribution of TP receptors in platelets, in circulating inflammatory cells, in the vascular wall and in atherosclerotic plaques, they also inhibit the effects of thromboxane A2 over TP receptors on vascular cells or in the plaque. Terutroban (Triplion or S18886), a new oral specific TP receptor antagonist, has, aside from being an antithrombotic agent, important vascular properties. It improves endothelial function and has an antiatherosclerotic effect. The potential therapeutic applications of terutroban in the prevention of atherothrombosis, particularly in the cerebrovascular and cardiovascular fields including stroke and coronary artery disease, are based on a number of convincing experimental animal and clinical studies. A large trial is currently comparing the efficacy and safety of terutroban versus aspirin in secondary prevention of cardiovascular events in patients who have suffered a stroke or transient ischemic attack (PERFORM Study).

Topics: Atherosclerosis; Humans; Naphthalenes; Propionates; Receptors, Thromboxane; Stroke; Thrombosis

Treatment of thrombotic diseases implicates the use of anti-platelet agents, anti-coagulants and pro-fibrinolytic substances. Amongst the anti-platelet drugs, aspirin occupies a unique position. As soon as it became evident that the major action of aspirin is indirect blockade, through inhibition of cyclooxygenase (COX), of the production of thromboxane A2 (TXA2), a powerful vasoconstrictor and platelet activator, research for new anti-thrombotics that interact more specifically with the production and/or the action of TXA2 was started. Terutroban (S 18886) is a selective antagonist of TP receptors, the receptors for TXA2, that are present on platelets and on vascular smooth muscle cells, but also on endothelial cells. The role played by the platelet and smooth muscle cell TP receptors in thrombotic disease is well known, and preclinical and clinical studies with terutroban have illustrated the powerful antithrombotic effects of this agent. The implication of endothelial TP receptors in the development of atherosclerotic disease has only been examined during the past five years and studies with terutroban have been crucial for understanding the role of these endothelial receptors in cardiovascular physiopathology. The goal of the present review is to discuss the arguments in favour of the hypothesis suggesting that activation of endothelial TP receptors, by causing expression of adhesion molecules, favours adhesion and infiltration of monocytes/macrophages in the arterial wall, thereby stimulating the development of atherosclerosis. The review will also highlight the important contribution of the studies performed with terutroban in this research area. The triple activity (anti-thrombotic, anti-vasoconstrictor, anti-atherosclerotic) observed with terutroban in preclinical studies, stressed by the first results in clinical development, places terutroban as an innovative drug with a unique potential for treatment of cardiovascular disorders.

Topics: Animals; Apolipoproteins E; Aspirin; Atherosclerosis; Cell Adhesion; Cell Adhesion Molecules; Cholesterol; Clinical Trials as Topic; Dogs; Drug Evaluation, Preclinical; Endothelium, Vascular; Fibrinolytic Agents; Foam Cells; Guinea Pigs; Humans; Macrophages; Mice; Mice, Knockout; Models, Biological; Monocytes; Naphthalenes; Platelet Aggregation Inhibitors; Propionates; Receptors, Thromboxane A2, Prostaglandin H2; Swine; Thromboxane A2

Thromboxane prostaglandin receptors have been implicated to be involved in the atherosclerotic process. We assessed whether Terutroban, a thromboxane prostaglandin receptor antagonist, affects the progression of atherosclerosis, as measured by common carotid intima-media thickness and carotid plaques.. A substudy was performed among 1141 participants of the aspirin-controlled Prevention of Cerebrovascular and Cardiovascular Events of Ischemic Origin with Terutroban in Patients with a History of Ischemic Stroke or Transient Ischemic Attack (PERFORM) trial. Common carotid intima-media thickness and carotid plaque occurrence was measured during a 3-year period.. Baseline characteristics did not differ between Terutroban (n=592) and aspirin (n=549) treated patients and were similar as in the main study. Mean study and treatment duration were similar (28 and 25 months, respectively). In the Terutroban group, the annualized rate of change in common carotid intima-media thickness was 0.006 mm per year (95% confidence interval, -0.004 to 0.016) and -0.005 mm per year (95% confidence interval, -0.015 to 0.005) in the aspirin group. There was no statistically significant difference between the groups in the annualized rate of change of common carotid intima-media thickness (0.011 mm per year; 95% confidence interval, -0.003 to 0.025). At 12 months of follow-up, 66% of Terutroban patients had no emergent plaques, 31% had 1 to 2 emergent plaques, and 3% had ≥3 emergent plaques. In the aspirin group, the corresponding percentages were 64%, 32%, and 4%. Over time, there was no statistically significant difference in the number of emergent carotid plaques between treatment modalities (rate ratio, 0.91; 95% confidence interval, 0.77-1.07).. Compared with aspirin, Terutroban did not beneficially affect progression of carotid atherosclerosis among well-treated patients with a history of ischemic stroke or transient ischemic attacks with an internal carotid stenosis <70%.. http://www.controlled-trials.com. Unique identifier: ISRCTN66157730.

Topics: Aged; Aged, 80 and over; Atherosclerosis; Brain Ischemia; Carotid Artery Diseases; Carotid Artery, Common; Carotid Intima-Media Thickness; Disease Progression; Female; Humans; Male; Middle Aged; Naphthalenes; Propionates; Receptors, Thromboxane; Treatment Outcome

• Terutroban is a selective TP receptor antagonist, i.e. a specific antagonist of the thromboxane A(2) and prostaglandin endoperoxide receptors, shown to improve endothelial function after a single administration in patients with coronary artery disease.. • This randomized, double-blind, placebo-controlled trial demonstrates that repeated-dose terutroban for 15 days improves endothelial function and inhibits thromboxane A(2) -induced platelet aggregation in high-cardiovascular-risk patients taking 300 mg of aspirin per day. Terutroban may prove useful for preventing cardiovascular events in such patients.. The specific TP receptor antagonist terutroban improves endothelial function after a single dose in patients with coronary artery disease. Our aim was to evaluate the effects and dose dependency of repeated-dose terutroban on endothelial function and platelet aggregation in high-cardiovascular-risk patients with carotid atherosclerosis.. We randomly allocated 48 patients taking 300 mg aspirin per day to placebo or to one of three terutroban dosages (2.5, 5 or 10 mg) for 15 days in a double-blind study. Flow-mediated vasodilatation was evaluated before and 2 h after the first oral dose on day 0 and 2 h after the last oral dose on day 14.. On day 0 and day 14, all three terutroban dosages improved flow-mediated vasodilatation and abolished platelet aggregation induced by the TP receptor agonist U46619, without changing the aggregation response to ADP or collagen.. Terutroban, by chronically improving endothelium-dependent vasodilatation and inhibiting platelet aggregation, may prove useful for preventing cardiovascular events in high-risk patients.

Topics: Adult; Aged; Aged, 80 and over; Atherosclerosis; Coronary Artery Disease; Dose-Response Relationship, Drug; Double-Blind Method; Endothelium, Vascular; Female; Humans; Male; Middle Aged; Naphthalenes; Platelet Aggregation; Propionates; Receptors, Thromboxane; Treatment Outcome

PERFORM is exploring the efficacy of terutroban versus aspirin for secondary prevention in patients with a history of ischemic stroke or transient ischemic attacks (TIAs). The PERFORM Vascular Project will evaluate the effect of terutroban on progression of atherosclerosis, as assessed by change in carotid intima-media thickness (CIMT) in a subgroup of patients.. The Vascular Project includes structural (CIMT, carotid plaques) and functional (carotid stiffness) vascular studies in all patients showing at least one carotid plaque at entry. Expected mean follow-up is 36 months. Primary endpoint is rate of change of CIMT. Secondary endpoints include emergent plaques and assessment of carotid stiffness. 1,100 patients are required for 90% statistical power to detect treatment-related CIMT difference of 0.025 mm. The first patient was randomized in April 2006.. The PERFORM Vascular Project will investigate terutroban's effect on vascular structure and function in patients with a history of ischemic stroke or TIAs.

Topics: Aged; Aged, 80 and over; Aspirin; Atherosclerosis; Carotid Arteries; Carotid Stenosis; Data Interpretation, Statistical; Double-Blind Method; Endpoint Determination; Epidemiologic Research Design; Female; Humans; Male; Middle Aged; Naphthalenes; Platelet Aggregation Inhibitors; Propionates; Quality Control; Reproducibility of Results; Sample Size; Stroke; Tunica Intima; Ultrasonography, Doppler, Duplex

Thromboxane A(2) and other eicosanoids such as isoprostanes contribute to vascular proliferation and atherosclerosis by binding to the thromboxane/prostaglandin endoperoxide receptors. The effects of terutroban, a thromboxane/prostaglandin endoperoxide receptor antagonist, on aorta remodeling were evaluated in spontaneously hypertensive stroke-prone rats (SHRSPs), a model of severe hypertension, endothelial dysfunction, vascular inflammation, and cerebrovascular diseases. Male SHRSPs were allocated to three groups receiving a standard diet (n = 5) or a high-sodium permissive diet plus vehicle (n = 6) or plus terutroban (30 mg · kg(-1) · day(-1); n = 6). After 6 wk of dietary treatment, all of the animals were injected with bromodeoxyuridine and simultaneously euthanized for aorta collection. The aortic media thickness-to-lumen ratio significantly (P < 0.0001) increased in the salt-loaded rats compared with the rats fed a standard diet, whereas terutroban treatment completely prevented media thickening (P < 0.001). When compared with vehicle, terutroban was also effective in preventing cell proliferation in the media, as indicated by the reduced number of bromodeoxyuridine-positive (P < 0.0001) and proliferating cell nuclear antigen-positive cells (P < 0.0001). Severe fibrosis characterized by a significant accumulation of collagen and fibronectin in the vascular wall was observed in the vehicle-treated rats (P < 0.01) but was completely prevented by terutroban (P < 0.001). The latter also inhibited heat shock protein-47 (P < 0.01) and TGF-1β expression (P < 0.001), which were significantly increased by the high-salt diet. In conclusion, terutroban prevents the development of aorta hyperplasia and has beneficial effects on fibrotic processes by affecting TGF-β and heat shock protein-47 expression in SHRSPs. These findings provide mechanistic data supporting the beneficial effects of terutroban in preventing or retarding atherogenesis.

Topics: Animals; Aorta; Atherosclerosis; Collagen; Endothelium, Vascular; Fibronectins; Fibrosis; Hyperplasia; Hypertrophy; Male; Naphthalenes; Propionates; Rats; Rats, Inbred SHR; Receptors, Prostaglandin; Sodium Chloride, Dietary; Transforming Growth Factor beta1; Tunica Media

Early manifestations of kidney disease occur in atherosclerosis and activation of TP (thromboxane A(2)) receptors is implicated in atherosclerotic, diabetes, and renal diseases. The purpose of the present study was to analyze, in isolated, perfused mouse kidneys, the participation of TP receptors in renal vasoconstrictions and vasodilatations. In kidneys, taken from wild-type C57BL6, apolipoprotein E-deficient (ApoE-KO) and diabetic ApoE-KO mice, changes in perfusion pressure were recorded. Constrictions to TP receptor ligands U 46619, arachidonic acid, PGH(2), and 8-iso-PGF(2alpha), but not those to angiotensin II, endothelin, or norepinephrine, were inhibited by the selective TP receptor antagonist Triplion (S 18886; 10 nM). Acetylcholine and prostacyclin evoked biphasic responses during methoxamine constrictions; the constrictor part was blocked by Triplion. In ApoE-KO mouse kidneys, compared with C57BL6, a specific decrease in norepinephrine response and no modification in dilator responses were observed. In diabetic ApoE-KO mouse kidneys, constrictions to U 46619 and those to 8-iso-PGF(2alpha) were significantly and selectively augmented, without modification in the expression of the TP receptor, and again without any significant change in vasodilator activity. Thus TP receptors are functional, and their activation is not involved in norepinephrine, endothelin, and angiotensin II vasoconstrictions but is implicated in the unusual vasoconstrictions to acetylcholine and prostacyclin. Increased responsiveness of TP receptors occurs in diabetic ApoE-KO mouse kidneys. Thus early changes in TP receptor-mediated vasoconstrictor activity may participate in the development of kidney disease in atherosclerosis and diabetes.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Acetylcholine; Animals; Apolipoproteins E; Atherosclerosis; Diabetes Mellitus, Experimental; Dinoprost; Disease Models, Animal; Epoprostenol; Kidney; Male; Methoxamine; Mice; Mice, Inbred C57BL; Mice, Knockout; Naphthalenes; Propionates; Receptors, Thromboxane A2, Prostaglandin H2; Streptozocin; Vasoconstriction; Vasoconstrictor Agents; Vasodilation; Vasodilator Agents

It had already showed that several thromboxane A(2) receptor (TP receptor) antagonists might be utilized in the treatment of cardiovascular diseases. In addition, recent reports suggested that TP receptor antagonism may be able to restrict vascular inflammation in atherosclerotic vessels. In particular, S18886 has been developed as a non-prostanoid TP receptor antagonist derived from sulotroban that is characterized by a tetrahydronaphthalene ring as a spacer between the 4-cholophenylsulfonamide group and carboxylic acid. Several reports using experimental animal models of atherosclerosis indicated that S18886 caused a regression of advanced atherosclerosis. More recently, several studies and patents showed that new thromboxane modulators combined with another pharmacological activities have been developed. Ohtake et al. discovered TRA-418 (a benzene-condensed heterocyclic derivative) having a TP receptor antagonistic activity and a prostaglandin I(2) receptor agonistic activity. Cesagrande found that 4-methyl-N- (4-trans-nitrooxycyclohexyl)-N-(3-pyridinylmethyl)-1,3- benzenedicarboxamide is endowed with anti-thromboxane and NO-donor actions. Oketani et al. discovered that E3040, a novel benzothiazole derivative, inhibited TXA(2) synthase and 5-LO activities. EK112, a combined angiotensin II and TP receptor antagonist, was developed. These new compounds may be able to restrict further infiltration of inflammatory cells in atherosclerotic vessels, thus stabilizing vulnerable plaques in the related cardiovascular diseases.

Topics: Animals; Atherosclerosis; Bridged Bicyclo Compounds, Heterocyclic; Cardiovascular Diseases; Fatty Acids, Unsaturated; Humans; Hydrazines; Lipoxygenase Inhibitors; Naphthalenes; Oxidative Stress; Propionates; Receptors, Thromboxane A2, Prostaglandin H2; Signal Transduction

To investigate the effect of S18886, a novel TP (thromboxane A2 and prostaglandin endoperoxide) receptor antagonist, on the development of aortic fatty streaks and advanced lesions in a rabbit model of atherosclerosis and restenosis.. The right iliac artery of 96 rabbits (8 groups, n=12/group) was balloon injured, then the animals were fed a cholesterol-enriched diet for 6 weeks. In Groups 1-4, concomitant oral administration of S18886 at 5 mg/kg/day over the 6-week-period reduced the intima to media ratio of lesions in the uninjured aorta and injured iliac artery, the accumulation of macrophages and the expression of ICAM-1 compared with 1 mg/kg/day S18886, 30 mg/kg/day aspirin and placebo, with no effect on body weight or plasma cholesterol levels. In Groups 5-8, 2 weeks of treatment with 5 mg/kg/day S18886 reduced the intima to media ratio of restenosing lesions when pre-formed iliac artery lesions underwent a second balloon injury at week 6. The smaller lesions resulting from S18886 treatment correlated with a significant decrease in the neointimal area occupied by macrophages, as well as in ICAM-1 expression, with no effect on the smooth muscle component. Aspirin treatment had no significant effect on the neointimal smooth muscle component, but partially inhibited macrophage infiltration, without inhibiting ICAM-1 expression.. Inhibition of the TP receptor using S18886 causes a significant decrease in the recruitment of monocyte/macrophages within fatty streaks in the uninjured aorta and within primary and restenosing atherosclerotic lesions in the iliac artery of rabbits. Since TP receptor agonists, such as thromboxane A2, prostanoid endoperoxides and isoprostanes participate in vessel wall inflammation and are localized and increased in atherosclerotic plaques, treatment with S18886 may enhance atherosclerotic lesion stability by attenuating inflammatory processes that ultimately lead to plaque rupture.

Topics: Animals; Aortic Diseases; Aspirin; Atherosclerosis; Catheterization; Diet, Atherogenic; Drug Evaluation, Preclinical; Drug Synergism; Drug Therapy, Combination; Female; Iliac Artery; Intercellular Adhesion Molecule-1; Macrophages; Male; Naphthalenes; Platelet Aggregation Inhibitors; Propionates; Rabbits; Receptors, Thromboxane; Recurrence; Rupture, Spontaneous; Tunica Intima; Tunica Media; Vasculitis

S18886 is an orally active thromboxane A2 (TXA2) receptor (TP) antagonist in clinical development for use in secondary prevention of thrombotic events in cardiovascular disease. We previously showed that S18886 inhibits atherosclerosis in apolipoprotein E-deficient (apoE(-/-)) mice by a mechanism independent of platelet-derived TXA2. Atherosclerosis is accelerated by diabetes and is associated with increased TXA(2) and other eicosanoids that stimulate TP. The purpose of this study was to determine whether S18886 lessens the enhanced atherogenesis in diabetic apoE(-/-) mice.. Diabetes mellitus was induced in apoE(-/-) mice with streptozotocin and was treated or not with S18886 (5 mg.kg(-1).d(-1)). After 6 weeks, aortic lesion area was increased >4-fold by diabetes in apoE(-/-) mice, associated with similar increases in serum glucose and cholesterol. S18886 largely prevented the diabetes-related increase in lesion area without affecting the hyperglycemia or hypercholesterolemia. S18886 prevented deterioration of endothelial function and endothelial nitric oxide synthase expression, as well as increases in intimal markers of inflammation associated with diabetes. In human aortic endothelial cells in culture, S18886 also prevented the induction of vascular cell adhesion molecule-1 and prevented the decrease in endothelial nitric oxide synthase expression caused by high glucose.. The TP antagonist inhibits inflammation and accelerated atherogenesis caused by diabetes, most likely by counteracting effects on endothelial function and adhesion molecule expression of eicosanoids stimulated by the diabetic milieu.

Topics: Animals; Apolipoproteins E; Atherosclerosis; Crosses, Genetic; Diabetes Mellitus, Experimental; Diabetic Angiopathies; Female; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Naphthalenes; Propionates; Receptors, Thromboxane A2, Prostaglandin H2