Efficacy and safety of riociguat in combination therapy for patients with pulmonary arterial hypertension (PATENT studies)

Ghofrani, Hossein‐Ardeschir; Grünig, Ekkehard; Jansa, Pavel; Langleben, David; Rosenkranz, Stephan; Preston, Ioana R.; Rahaghi, Franck; Sood, Namita; Busse, Dennis; Meier, Christian; Humbert, Marc

doi:10.1177/2045894020942121

Cited by 4 publications

(5 citation statements)

References 19 publications

(65 reference statements)

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“…In this study, patients who were treated with riociguat had improvement in 6-minute walk distance (6MWD), pulmonary vascular resistance (PVR), N-terminal prohormone of brain natriuretic peptide (NT-proBNP), World Health Organization functional class (WHO-FC), time to clinical worsening, and Borg dyspnea scale rating (7). These improvements were sustained in the long term extension study PATENT-2 (12,13). Similar findings were observed in the RESPITE study (9).…”

Section: Discussionmentioning

confidence: 90%

“…Overall, riociguat has been well tolerated in adult clinical studies. The most commonly reported drug-related adverse events in ∼40–50% of the patients include hypotension, syncope, dyspepsia, nausea, vomiting, dizziness, headache, cough and upper respiratory infections ( 7 , 9 , 10 , 12 , 13 ). Adverse events leading to discontinuation of riociguat were reported in 3%–9% of patients ( 7 , 9 , 10 , 53 ).…”

Section: Discussionmentioning

confidence: 99%

“…Unlike phosphodiesterase-5 (PDE5) inhibitors that block the degradation of cGMP, riociguat acts as a direct stimulator of sGC to increase cGMP production in a manner similar to the mechanism for inhaled nitric oxide (iNO). Recent literature supports the efficacy and tolerability of riociguat as an alternative agent for adults with PAH who have insufficient response to treatment with PDE5 inhibitors (7,(9)(10)(11)(12)(13). The use of riociguat in pediatric PAH, however, has not been approved because of limited data on its therapeutic use in children (14).…”

Section: Introductionmentioning

confidence: 99%

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Novel use of riociguat in infants with severe pulmonary arterial hypertension unable to wean from inhaled nitric oxide

et al. 2022

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IntroductionRiociguat, an oral soluble guanylate cyclase stimulator, has been approved for use in adults with pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension. However, there is limited data on its therapeutic use in children.Case PresentationWe report the case of two infants with severe suprasystemic pulmonary hypertension who were successfully treated with riociguat after failure to wean off inhaled nitric oxide (iNO) despite combination PAH therapy. Case 1 is a 6-month-old term male with TBX4 deletion who presented with severe hypoxemic respiratory failure and severe PAH immediately after birth. Initial cardiac catheterization showed PVRi 15.5 WU*m2. Marked hypoxemia and PAH persisted despite aggressive therapy with sildenafil, bosentan, intravenous treprostinil, and milrinone. The infant required high doses of inhaled nitric oxide (60 ppm) and manifested significant post-ductal hypoxemia and hemodynamic instability with any attempt at weaning. After discontinuation of sildenafil, initiation, and very slow uptitration of riociguat, the patient was able to maintain hemodynamic stability and wean from nitric oxide over 6 weeks with persistently severe but not worsened pulmonary hypertension. Case 2 is a 4-month-old term male with compound heterozygous SLC25A26 mutation and severe pulmonary hypertension. Initial cardiac catheterization showed PVRi 28.2 WU*m2. After uptitration of sildenafil, bosentan, and IV treprostinil, serial echocardiograms continued to demonstrate near-systemic pulmonary hypertension. He failed multiple attempts to wean off typical doses of iNO (10–20 ppm) over the following weeks with tachypnea, hypoxemia, and worsening pulmonary hypertension on echocardiogram despite continued aggressive combination targeted therapy. After a 24-h sildenafil washout, he was initiated and uptitrated on riociguat with concomitant, successful wean of nitric oxide over one week that was well tolerated. No serious adverse effects in the titration period were observed.ConclusionRiociguat may be considered as an adjuvant therapeutic agent in selected children with severe PAH who are poorly responsive to sildenafil therapy and unable to wean from iNO.

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Section: Discussionmentioning

confidence: 90%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Novel use of riociguat in infants with severe pulmonary arterial hypertension unable to wean from inhaled nitric oxide

et al. 2022

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“…Drug therapy for patients with PH has a different mechanism of action, e.g., endothelin receptor antagonists (ambrisentan), prostanoids, the prostaglandin I2 (IP) receptor agonist selexipag, phosphodiesterase type 5 inhibitors (tadalafil), and the soluble guanylate cyclase stimulator, riociguat [ 2 ]. Only interventional devices are available to treat PH: pulmonary artery denervation, right ventricular pacing, and mechanical circulatory support with durable ventricular assist devices [ 2 , 3 ].…”

Section: Introductionmentioning

confidence: 99%

Contractions Induced in Human Pulmonary Arteries by a H2S Donor, GYY 4137, Are Inhibited by Low-Frequency (20 kHz) Ultrasound

Tunaitytė,

Abramavičius,

Volkevičiūtė

et al. 2024

Biomolecules

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The present study aimed to investigate the effect of a H2S donor, GYY 4137, on human pulmonary arteries and whether low-frequency ultrasound (20 kHz, 4 W/cm2) inhibits GYY 4137 contractions. Functional studies were conducted on human and rat pulmonary arteries mounted on microvascular myographs. We placed an ultrasonic gadget in the tissue organ bath to insonate the arteries with low-frequency ultrasound. To measure the effect of the low-frequency ultrasound on the entrance of extracellular Ca2+, the preparations were placed in a Ca2+-free solution, and the thromboxane agonist, U46619, and extracellular calcium were added in the presence of insonation. In isolated human pulmonary arteries, GYY 4137 induced contractions, which were most pronounced in the arteries contracted with the thromboxane analogue, U46619. The transient GYY4137 contractions were reversed by low-frequency ultrasound, a blocker of KV7 channels, XE-991 (10 µM), and glibenclamide (1 μM), a blocker of ATP-sensitive channels. Low-frequency ultrasound also inhibited the contractions induced by the smooth muscle entrance of increasing extracellular calcium concentrations. The present findings show that GYY 4137 can cause a transient contraction of pulmonary arteries in human arteries. GYY 4137 alone does not cause significant vascular contraction in rat lung arteries, but it contracts rat lung arteries precontracted with U46619. The transient contractions induced by GYY 4137 can be inhibited by low-frequency ultrasound, probably by counteracting the influx of external Ca2+. The effect of low-frequency ultrasound counteracts contraction in pulmonary arteries; therefore, a possibility could be to develop a larger device allowing treatment of patients with pulmonary hypertension.

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“…There is evidence that specific RVF treatment improves survival and prolongs life expectancy in patients with PAH 6 . Although endothelin receptor antagonists, phosphodiesterase type 5 inhibitors and soluble guanylate cyclase stimulants may be effective in treating PAH, these agents have limited roles in improving RVF 7 . Therefore, there is an urgent need to develop effective pharmacological agents for treating PAH‐induced RVF.…”

Section: Introductionmentioning

confidence: 99%

Preparation of betaine injection and its therapeutic effect in pulmonary arterial hypertension

Che,

Xia,

Liu

et al. 2023

Basic Clin Pharma Tox

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Pulmonary arterial hypertension (PAH) is a life‐threatening disease characterised by elevated pulmonary pressure, right ventricular failure (RVF) and ultimately death. Aggressive treatment of RVF is considered an important therapeutic strategy to treat PAH. Previous studies have indicated that betaine may be may a promising therapeutic approach for PAH‐induced RVF. Therefore, in this study, betaine solution for injection was prepared and characterised using various techniques. The therapeutic efficacy of three different methods of administration (intragastric, nebulised inhalation and intravenous injection) were comprehensively evaluated in terms of pharmacokinetics, tissue distribution and pharmacodynamics. The pharmacokinetic results demonstrated that betaine injection administered via nebulised inhalation significantly prolonged betaine's half‐life and increased its internal circulation time compared to the intragastric and intravenous routes. Biodistribution experiments verified that the betaine formulation accumulated in the lung tissue when administered via inhalation. The results of the pharmacodynamic analysis further confirmed that right ventricular systolic pressure, mean pulmonary artery pressure and right ventricular hypertrophy index increased in the model group and that inhaled betaine suppressed these pathological changes to a level comparable to those observed in the control group. Taken together, these results indicate that betaine administered by inhalation is a promising strategy for the treatment of PAH‐induced RVF.

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Efficacy and safety of riociguat in combination therapy for patients with pulmonary arterial hypertension (PATENT studies)

Cited by 4 publications

References 19 publications

Novel use of riociguat in infants with severe pulmonary arterial hypertension unable to wean from inhaled nitric oxide

Novel use of riociguat in infants with severe pulmonary arterial hypertension unable to wean from inhaled nitric oxide

Contractions Induced in Human Pulmonary Arteries by a H2S Donor, GYY 4137, Are Inhibited by Low-Frequency (20 kHz) Ultrasound

Preparation of betaine injection and its therapeutic effect in pulmonary arterial hypertension

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