sildenafil-citrate and selexipag

NTP42 is a novel antagonist of the thromboxane prostanoid receptor (TP), currently in development for the treatment of pulmonary arterial hypertension (PAH). PAH is a devastating disease with multiple pathophysiological hallmarks including excessive pulmonary vasoconstriction, vascular remodelling, inflammation, fibrosis, in situ thrombosis and right ventricular hypertrophy. Signalling through the TP, thromboxane (TX) A. PAH was induced by subcutaneous injection of 60 mg/kg MCT in male Wistar-Kyoto rats. Animals were assigned into groups: 1. 'No MCT'; 2. 'MCT Only'; 3. MCT + NTP42 (0.25 mg/kg BID); 4. MCT + Sildenafil (50 mg/kg BID), and 5. MCT + Selexipag (1 mg/kg BID), where 28-day drug treatment was initiated within 24 h post-MCT.. From haemodynamic assessments, NTP42 reduced the MCT-induced PAH, including mean pulmonary arterial pressure (mPAP) and right systolic ventricular pressure (RSVP), being at least comparable to the standard-of-care drugs Sildenafil or Selexipag in bringing about these effects. Moreover, NTP42 was superior to Sildenafil and Selexipag in significantly reducing pulmonary vascular remodelling, inflammatory mast cell infiltration and fibrosis in MCT-treated animals.. These findings suggest that NTP42 and antagonism of the TP signalling pathway have a relevant role in alleviating the pathophysiology of PAH, representing a novel therapeutic target with marked benefits over existing standard-of-care therapies.

Topics: Acetamides; Animals; Antihypertensive Agents; Disease Models, Animal; Heart Ventricles; Hemodynamics; Humans; Hypertrophy, Right Ventricular; Male; Monocrotaline; Pulmonary Arterial Hypertension; Pulmonary Artery; Pyrazines; Rats; Rats, Inbred WKY; Receptors, Thromboxane; Sildenafil Citrate; Vascular Remodeling

Topics: Acetamides; Adolescent; Antihypertensive Agents; Asymptomatic Diseases; Bone Morphogenetic Protein Receptors, Type II; Cardiac Catheterization; Disease Progression; Dyspnea; Echocardiography; Exercise Tolerance; Female; Genetic Testing; Heterozygote; Humans; Male; Phenylpropionates; Pulmonary Arterial Hypertension; Pyrazines; Pyridazines; Sildenafil Citrate; Syncope; Vasodilator Agents

Topics: Acetamides; Antihypertensive Agents; Drug Substitution; Drug Therapy, Combination; Epoprostenol; Female; Humans; Infusion Pumps; Middle Aged; Phenylpropionates; Pulmonary Arterial Hypertension; Pyrazines; Pyridazines; Sildenafil Citrate; Tadalafil; Vasodilator Agents

Patients with congenital diaphragmatic hernia (CDH) often suffer from severe pulmonary hypertension, and the choice of current vasodilator therapy is mostly based on trial and error. Because pulmonary vascular abnormalities are already present early during development, we performed a study to modulate these pulmonary vascular changes at an early stage during gestation. Pregnant Sprague-Dawley rats were treated with nitrofen at day 9.5 of gestation (E9.5) to induce CDH in the offspring, and subsequently, the phosphodiesterase-5 inhibitor sildenafil and/or the novel prostaglandin-I receptor agonist selexipag (active compound NS-304) were administered from E17.5 until E20.5. The clinical relevant start of the treatment corresponds to week 20 of gestation in humans, when CDH is usually detected by ultrasound. CDH pups showed increased density of air saccules that was reverted after the use of only sildenafil. The pulmonary vascular wall was thickened, and right ventricular hypertrophy was present in the CDH group and improved both after single treatment with sildenafil or selexipag, whereas the combination therapy with both compounds did not have additive value. In conclusion, antenatal treatment with sildenafil improved airway morphogenesis and pulmonary vascular development, whereas selexipag only acted positively on pulmonary vascular development. The combination of both compounds did not act synergistically, probably because of a decreased efficiency of both compounds caused by cytochrome- P450 3A4 interaction and induction. These new insights create important possibilities for future treatment of pulmonary vascular abnormalities in CDH patients already in the antenatal period of life.

Topics: Acetamides; Animals; Drug Therapy, Combination; Hernias, Diaphragmatic, Congenital; Humans; Lung; Pyrazines; Rats; Rats, Sprague-Dawley; Sildenafil Citrate