terutroban and Cardiovascular-Diseases

S-18886, the active isomer of S-18204, is a thromboxane A2 receptor antagonist with a long duration of action. The compound is under development by Servier for the potential treatment of cardiovascular diseases [269611]. By 2000, a clinical trial had been carried out in patients with coronary artery disease [389458]; advanced clinical trials were ongoing in August 2001 [420310].

Topics: Animals; Cardiovascular Diseases; Clinical Trials as Topic; Drug Industry; Humans; Naphthalenes; Propionates; Tetrahydronaphthalenes

Ischemic stroke is the leading cause of mortality worldwide and a major contributor to neurological disability and dementia. Terutroban is a specific TP receptor antagonist with antithrombotic, antivasoconstrictive, and antiatherosclerotic properties, which may be of interest for the secondary prevention of ischemic stroke. This article describes the rationale and design of the Prevention of cerebrovascular and cardiovascular Events of ischemic origin with teRutroban in patients with a history oF ischemic strOke or tRansient ischeMic Attack (PERFORM) Study, which aims to demonstrate the superiority of the efficacy of terutroban versus aspirin in secondary prevention of cerebrovascular and cardiovascular events.. The PERFORM Study is a multicenter, randomized, double-blind, parallel-group study being carried out in 802 centers in 46 countries. The study population includes patients aged > or =55 years, having suffered an ischemic stroke (< or =3 months) or a transient ischemic attack (< or =8 days). Participants are randomly allocated to terutroban (30 mg/day) or aspirin (100 mg/day). The primary efficacy endpoint is a composite of ischemic stroke (fatal or nonfatal), myocardial infarction (fatal or nonfatal), or other vascular death (excluding hemorrhagic death of any origin). Safety is being evaluated by assessing hemorrhagic events. Follow-up is expected to last for 2-4 years. Assuming a relative risk reduction of 13%, the expected number of primary events is 2,340. To obtain statistical power of 90%, this requires inclusion of at least 18,000 patients in this event-driven trial. The first patient was randomized in February 2006.. The PERFORM Study will explore the benefits and safety of terutroban in secondary cardiovascular prevention after a cerebral ischemic event.

Topics: Aged; Aged, 80 and over; Aspirin; Cardiovascular Diseases; Dose-Response Relationship, Drug; Double-Blind Method; Endpoint Determination; Female; Humans; International Cooperation; Ischemic Attack, Transient; Male; Middle Aged; Naphthalenes; Platelet Aggregation Inhibitors; Propionates; Receptors, Thromboxane; Stroke; Treatment Outcome

Topics: Animals; Atrasentan; Cardiovascular Diseases; Disease Models, Animal; Endothelin A Receptor Antagonists; Female; Kidney Diseases; Male; Methyldopa; Naphthalenes; NG-Nitroarginine Methyl Ester; Pre-Eclampsia; Pregnancy; Prenatal Care; Propionates; Rats; Receptors, Thromboxane A2, Prostaglandin H2; Sex Factors; Sympatholytics

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