Abstract
BackgroundNTP42 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) A2 is a potent vasoconstrictor and mediator of platelet aggregation. It is also a pro-mitogenic, pro-inflammatory and pro-fibrotic agent. Moreover, the TP also mediates the adverse actions of the isoprostane 8-iso-prostaglandin F2α, a free-radical-derived product of arachidonic acid produced in abundance during oxidative injury. Mechanistically, TP antagonists should treat most of the hallmarks of PAH, including inhibiting the excessive vasoconstriction and pulmonary artery remodelling, in situ thrombosis, inflammation and fibrosis. This study aimed to investigate the efficacy of NTP42 in the monocrotaline (MCT)-induced PAH rat model, alongside current standard-of-care drugs.MethodsPAH 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.ResultsFrom 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.ConclusionsThese 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.
Highlights
NTP42 is a novel antagonist of the thromboxane prostanoid receptor (TP), currently in development for the treatment of pulmonary arterial hypertension (PAH)
Mulvaney et al BMC Pulmonary Medicine (2020) 20:85 (Continued from previous page). These findings suggest that NTP42 and antagonism of the T Prostanoid receptor (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
Expression of the TP in human control and PAH lung tissue While signalling through the thromboxane receptor (TP) is implicated in the pathogenesis and progression of PAH, few studies have examined the expression of the TP in human PAH lung tissue
Summary
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. Pulmonary arterial hypertension (PAH) is a chronic progressive disorder of the pulmonary vasculature characterised by abnormal remodelling of small, peripheral resistance vessels in the lung The occlusion of these pulmonary arterioles leads to a persistently elevated pulmonary vascular resistance (PVR), a raised pulmonary arterial pressure (PAP), and death due to right ventricular hypertrophy, decreased cardiac output and heart failure. PAH is primarily treated with drugs from four major drug classes targeting the endothelin, prostacyclin and nitric oxide (NO) signalling pathways These approved therapies mainly treat the excessive pulmonary vasoconstriction/reduced vasodilation but fail to alter the cardiac and pulmonary remodelling associated with the later phases of the disease. There is an urgent unmet medical need for new drugs to new therapeutic targets that offer greater tolerability/compliance and overall efficacy
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