terutroban (S-18886) / Servier - LARVOL DELTA

Effect of some prostanoid receptor modulators on cholinergic and purinergic pathways in rat model of hemorrhagic cystitis: potential beneficial action of selexipag and alprostadil. (PubMed, Naunyn Schmiedebergs Arch Pharmacol) - "Cystitis was induced in rats by cyclophosphamide single injection (300 mg/kg) and confirmed histopathologically...S18886 inhibited purinergic contractions in normal bladder...TP receptor is involved in purinergic signaling in normal physiology. Selexipag and alprostadil may have a potential beneficial action in cystitis and merit further investigation."

Journal • Preclinical • Hematological Disorders

Platelet aggregation response to cyclooxygenase inhibition and thromboxane receptor antagonism using impedance aggregometry: A pilot study. (PubMed, Physiol Rep) - "We hypothesized (1) impedance aggregometry would produce repeatable results, (2) inhibition of cyclooxygenase with aspirin would attenuate aggregation responses to collagen and abolish the aggregation response to arachidonic acid (AA), and (3) thromboxane receptor antagonism (terutroban) would attenuate the aggregation response to AA. [col 1] shows sufficient repeatability for longitudinal investigations of platelet function. [col 5] and AA may be used to investigate mechanisms of platelet function and metabolism at a single time point."

Journal

Endothelial Extracellular Signal-Regulated Kinase/Thromboxane A2/Prostanoid Receptor Pathway Aggravates Endothelial Dysfunction and Insulin Resistance in a Mouse Model of Metabolic Syndrome. (PubMed, J Am Heart Assoc) - "In vivo, S18886 improved endothelial dysfunction, systolic blood pressure, fasting serum glucose and insulin levels, and suppressed nonalcoholic fatty liver disease scores only in HFHSD-fed controls. Conclusions Endothelial ERK2 increased superoxide level and decreased NO bioactivity, resulting in the deterioration of endothelial function, insulin resistance, and steatohepatitis, which were improved by a TP receptor antagonist, in a mouse model of metabolic syndrome."

Journal • Preclinical • Cardiovascular • Hepatology • Hypertension • Metabolic Disorders • Non-alcoholic Fatty Liver Disease • MAPK1

Increased thromboxane/prostaglandin receptors contribute to high glucose-induced podocyte injury and mitochondrial fission through ROCK1-Drp1 signaling. (PubMed, Int J Biochem Cell Biol) - "S18886 attenuated podocyte mitochondrial fission, glomerular injury and renal dysfunction in diabetic mice...Finally, pharmacological inhibition of Drp1 alleviated excessive mitochondrial fragmentation and podocyte damage in TP receptor overexpressing podocytes. Our data suggests that increased expression of the TP receptor can occur in a human cultured podocyte cell line and in podocytes derived from streptozotocin (STZ)-induced diabetic mice, which contributes to mitochondrial excessive fission and podocyte injury via ROCK1-Drp1 signaling."

Journal • Diabetes • Diabetic Nephropathy • Nephrology • Renal Disease

Modulation by antenatal therapies of cardiovascular and renal programming in male and female offspring of preeclamptic rats. (PubMed, Naunyn Schmiedebergs Arch Pharmacol) - "Histopathologically, antenatal terutroban or atrasentan was more effective than α-MD in rectifying cardiac structural damage, myofiber separation, and cytoplasmic alterations, in PE offspring. The repair by antenatal terutroban or atrasentan of cardiovascular and renal anomalies in PE offspring is mostly sex-independent and surpasses the protection offered by α-MD, the conventional PE therapy."

Journal • Preclinical • Cardiovascular • Gynecology • Hypertension • Immunology • Inflammation • Oncology • Renal Disease • TNFA

Prenatal endothelin or thromboxane receptor antagonism surpasses sympathoinhibition in improving cardiorenal malfunctions in preeclamptic rats. (PubMed, Toxicol Appl Pharmacol) - "The effects of co-exposure to atrasentan (ETA receptor blocker, 10 mg/kg/day) or terutroban (TXA2 receptor blocker, 10 mg/kg/day) on cardiovascular and renal anomalies induced by PE were assessed on gestational day 20 (GD20) and at weaning time and compared with those evoked by the sympatholytic drug α-methyldopa (α-MD, 100 mg/kg/day), a prototypic therapy for PE management. Signs of histopathological damage in cardiac and renal tissues of PE rats were mostly improved by all therapies. Together, pharmacologic elimination of ETA or TXA2 receptors offers a relatively better prospect than α-MD in controlling perinatal cardiorenal irregularities sparked by PE."

Journal • Preclinical • Cardiovascular • Gynecology • Immunology • Inflammation

Prostacyclin facilitates vascular smooth muscle cell phenotypic transformation via activating TP receptors when IP receptors are deficient. (PubMed, Acta Physiol (Oxf)) - "PGI induces VSMC phenotypic transformation when IP receptors are impaired. This is attributed to the activation of TP receptor and its downstream signaling cascades, and to the increased membrane distribution of TP receptors. The VSMC detrimental effect of PGI medicated by IP dysfunction and TP activation might probably exacerbate vascular remodelling, accelerating cardiovascular diseases."

Journal • Cardiovascular • MAP2K1 • MAPK8

Puerarin Inhibits Endothelium-Dependent Contractions in Mouse Carotid Arteries. (PubMed, Med Sci Monit) - "RESULTS EDCs induced by ACh only presented in endothelium-intact arteries pretreated by L-NAME and EDCs were prevented by the treatment with cyclooxygenase (COX) inhibitor indomethacin (3 µmol/L) or thromboxane prostanoid receptor (TP receptor) antagonist S18886 (30 nmol/L). However, treatment with puerarin did not inhibit ACh-induced production of prostaglandins (PGs) in endothelium-intact arteries. CONCLUSIONS The present results show that puerarin is able to suppress EDCs in mouse carotid arteries, independent of inhibition of TP receptor or COX2-derived PGs."

Journal • Preclinical

Ageing-related endothelial dysfunction in the femoral vein is mediated by cyclooxygenases: Role of thromboxane prostanoid receptors (ESC 2018) - "...The role of prostanoids was assessed using indomethacin (Indo, cyclooxygenases inhibitor) and S18886 (thromboxane receptor (TP) antagonist), of nitric oxide (NO) using NG-nitro L-arginine (L-NA, NO synthase inhibitor), and of endothelium-derived hyperpolarization (EDH) using TRAM-34 and UCL-1684 (calcium-dependent potassium channel inhibitors)... The present findings indicate a pronounced aged-related endothelial dysfunction in the femoral artery and vein appearing as early as 6 months. The ageing-related endothelial dysfunction in the vein involves predominantly vasoconstrictor prostanoids acting on TP receptors whereas vasoconstrictor prostanoids acting in a TP receptor-independent manner are involved in the femoral artery. They further suggest that an increased activation of TP receptors in the femoral vein might contribute to the increased risk of VTE with increasing age."

Biosimilar • Cardiovascular • Venous Thromboembolism

Thromboxane-prostaglandin receptor antagonist, terutroban, prevents neurovascular events after subarachnoid haemorrhage: a nanoSPECT study in rats. (PubMed, Crit Care) - "Based on in vivo nanoscale imaging, we demonstrated that TBN protected against blood-brain barrier disruption, exerted an anti-apoptotic effect and improved cerebral perfusion. Thus, TP receptor antagonists showed promising results in treating post-haemorrhage neurovascular events."

Journal • Preclinical

endothelial ERK2/thromboxane receptor pathway induces endothelial dysfunction, insulin resistance and steatohepatosis through superoxide with high fat high sucrose diet (ESC 2019) - "...S18886, an antagonist of the thromboxane A2-prostanoid (TP) receptor, decreased superoxide production of aorta in DHE staining resulting in improving endothelial function in the isometric tension measurement of aortic rings... Endothelial ERK2/TP receptor pathway increases superoxide production and decreased NO bioactivity, resulting in deteriorating endothelial function, insulin resistance and steatohepatosis, which were improved by antagonist of the TP receptor in mice model of MetS. The present study indicates that ERK2/TP pathway could be a therapeutic target for complications of MetS."

Non-cardioembolic stroke/transient ischaemic attack in Asians and non-Asians: A post-hoc analysis of the PERFORM study. (PubMed, Eur Stroke J) - "We conducted a post-hoc analysis of data from the PERFORM study, in which 19,100 patients (mean age, 67.2 years; male, 63%; 2178 Asian and 16,922 non-Asian patients) with non-cardioembolic ischaemic stroke/transient ischaemic attack were randomised to aspirin or terutroban and followed for two years. In multivariable analysis, diastolic blood pressure (HR per 5 mm Hg 1.08; 95% CI 1.01-1.16; p = 0.03) and diabetes (HR 1.36; 95% CI 1.22-1.52; p < 0.001) were independent predictors of major adverse cardiovascular events for Asian and non-Asian patients, respectively. Compared with non-Asian patients, Asian patients had significantly higher risk of haemorrhagic events when given antiplatelet monotherapy for secondary prevention after non-cardioembolic stroke/transient ischaemic attack. Lacunar stroke and elevated diastolic blood pressure were more associated with recurrence risk in Asian patients."

Journal • Retrospective data