Pulmonary hypertension: diagnostic approach and optimal management

Hambly, Nathan; Alawfi, Fahad; Mehta, Sanjay

doi:10.1503/cmaj.151075

Cited by 19 publications

(9 citation statements)

References 56 publications

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“…While treatment with NTP42 at this dose had no significant effect on RV vascularization per se (Supplemental Figure 5D), considering both RV hypertrophy and vascularisation together within a "Metabolic Index" parameter, treatment with NTP42 led to a significant increase in this indicative parameter of cardiac adaptation (Supplemental Figure 5E). Finally, the progress observed in the clinical management of PAH has been largely attributed to the development of combination therapy strategies, and on the staggered escalation of those dual-or even triplecombination therapies based on close monitoring and assessment of clinical outcomes in line with established treatment algorithms [55][56][57]. Consistent with these clinical guidelines, it will be important to assess the efficacy of NTP42 alongside other therapies such as PDE5 inhibitors (e.g.…”

Section: Limitations Of Studymentioning

confidence: 99%

NTP42, a novel antagonist of the thromboxane receptor, attenuates experimentally induced pulmonary arterial hypertension

et al. 2020

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Background: 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 2 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 F 2α , 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. Methods: 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. Results: 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 standardof-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.

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Section: Limitations Of Studymentioning

confidence: 99%

NTP42, a novel antagonist of the thromboxane receptor, attenuates experimentally induced pulmonary arterial hypertension

et al. 2020

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“…Finally, the progress observed in the clinical management of PAH has been largely attributed to the development of combination therapy strategies, and on the staggered escalation of those dual-or even triple-combination therapies based on close monitoring and assessment of clinical outcomes in line with established treatment algorithms. (55)(56)(57) Consistent with these clinical guidelines, it will be important to assess the efficacy of NTP42 alongside other therapies such as PDE5 inhibitors (e.g. Sildenafil), prostacyclin analogues (e.g.…”

Section: Limitations Of Studymentioning

confidence: 99%

NTP42, a novel antagonist of the thromboxane receptor, attenuates experimentally induced pulmonary arterial hypertension

Mulvaney¹,

Reid²,

Bialešová³

et al. 2020

Preprint

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Background 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 2 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 F 2α , 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. Methods 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. Results 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. Conclusions 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.

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“…Pulmonary arterial hypertension (PAH) is an uncommon and lifethreatening disease with limited literature regarding its prevalence and aetiology in South Africa (SA). [1 , 2] Pulmonary hypertension (PH) was initially classified as a mean pulmonary artery pressure (mPAP) ≥25 mmHg at rest; however, this was changed at the 6th World Symposium on Pulmonary Hypertension in 2018 to be mPAP >20 mmHg at rest. [3] It is broadly classified into 5 groups by the World Health Organization (WHO) based on similar clinical and pathophysiological characteristics.…”

Section: Introductionmentioning

confidence: 99%

Pulmonary hypertension: Spectrum of disease, clinical presentation and treatment outcomes at the main respiratory pulmonary hypertension clinic in KwaZulu‑Natal Province, South Africa

Dahim

Mitha²,

Connolly

et al. 2021

Afr J Thorac Crit Care Med

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Background. There are many causes of pulmonary hypertension (PH). However, the aetiology, management and treatment outcomes in South Africa (SA), which has a high burden of HIV, are lacking in the literature. Objectives. To characterise patient demographics, aetiology, clinical presentation and management of patients presenting to the only government-funded PH clinic in Durban, SA. Methods. We retrospectively reviewed electronic charts of patients with confirmed PH who attended the respiratory PH clinic between 2011 and 2018. Demographic and clinical data, symptoms, pulmonary function testing, pulmonary artery pressure on echocardiography and treatment were analysed. Patients with group 2 PH were excluded from the present study as they were managed by cardiologists. Results. We identified 93 patients with confirmed PH and the majority were female (82.8%; n=77). The majority of the patients were between the ages of 30 and 39 years at the time of diagnosis. Most patients were black African (64.5%; n=60), followed by Indians (26.9%; n=25) and whites (8.6%; n=8). The most common cause of PH was group 1 (75%; n=70), followed by group 4 (13%; n=12) and then group 3 (12%; n=11). HIV-associated PH accounted for 27% of all patients and was the main cause of PH in those classified in group 1 (38%; n=29). Two-thirds (66%) of patients were treated with sildenafil, the only treatment that was available. Patients on treatment showed significant improvement indicated by the World Health Organization functional class, mean 6-minute walk test and reduction in mean pulmonary artery pressure on echocardiography. Conclusion. HIV-associated PH is the most common cause of PH in SA. Sildenafil, the only drug available in our setting, is beneficial to most patients with PH.

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Pulmonary hypertension: diagnostic approach and optimal management

Cited by 19 publications

References 56 publications

NTP42, a novel antagonist of the thromboxane receptor, attenuates experimentally induced pulmonary arterial hypertension

NTP42, a novel antagonist of the thromboxane receptor, attenuates experimentally induced pulmonary arterial hypertension

NTP42, a novel antagonist of the thromboxane receptor, attenuates experimentally induced pulmonary arterial hypertension

Pulmonary hypertension: Spectrum of disease, clinical presentation and treatment outcomes at the main respiratory pulmonary hypertension clinic in KwaZulu‑Natal Province, South Africa

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