Page last updated: 2024-11-07

tezosentan

Description Research Excerpts Clinical Trials Roles Classes Pathways Study Profile Bioassays Related Drugs Related Conditions Protein Interactions Research Growth Market Indicators

Description

tezosentan: structure in first source [Medical Subject Headings (MeSH), National Library of Medicine, extracted Dec-2023]

Cross-References

ID SourceID
PubMed CID151174
CHEMBL ID61780
SCHEMBL ID4524
MeSH IDM0331838

Synonyms (38)

Synonym
act-050089
tezosentan
n-(6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)-2-(2-(1h-tetrazol-5-yl)-4-pyridinyl)-4-pyrimidinyl)-5-(1-methylethyl)-2-pyridinesulfonamide
tezosentan [inn]
n-(6-(2-hydroxyethoxy)-5-(o-methoxyphenoxy)-2-(2-(1h-tetrazol-5-yl)-4-pyridyl)-4-pyrimidinyl)-5-isopropyl-2-pyridinesulfonamide
2-pyridinesulfonamide, n-(6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)-2-(2-(1h-tetrazol-5-yl)-4-pyridinyl)-4-pyrimidinyl)-5-(1-methylethyl)-
ro 61-0612
ro 610612
5-isopropyl-pyridine-2-sulfonic acid {6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2-[2-(1h-tetrazol-5-yl)-pyridin-4-yl]-pyrimidin-4-yl}-amide
bdbm50143800
CHEMBL61780 ,
ro-610612
L001546
n-[6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)-2-[2-(2h-tetrazol-5-yl)pyridin-4-yl]pyrimidin-4-yl]-5-propan-2-ylpyridine-2-sulfonamide
180384-57-0
unii-64j9j55263
tezosentan [inn:ban]
64j9j55263 ,
AKOS015967353
FT-0675128
tezosentan [vandf]
tezosentan [mi]
tezosentan [mart.]
5-isopropyl-pyridine-2-sulfonic acid [6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2-[2-(1h-tetrazole-5-yl)-pyridine-4-yl]-pyrimidine-4-yl]-amide
TUYWTLTWNJOZNY-UHFFFAOYSA-N
SCHEMBL4524
n-(2-(2-(2h-tetrazol-5-yl)pyridin-4-yl)-6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)pyrimidin-4-yl)-5-isopropylpyridine-2-sulfonamide
DTXSID20170956
5-isopropyl-pyridine-2-sulfonic acid 6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2-(2-1h-tetrazol-5-yl-pyridin-4-yl)-pyrimidin-4-ylamide
CS-0006249
HY-17351
Q426203
DB06558
MS-30667
ro610612
2-pyridinesulfonamide, n-[6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)-2-[2-(2h-tetrazol-5-yl)-4-pyridinyl]-4-pyrimidinyl]-5-(1-methylethyl)-
GLXC-25611
AKOS040742723

Research Excerpts

Overview

Tezosentan is an IV nonselective endothelin (ET)-1 antagonist. It has improved cardiac output and reduced pulmonary and systemic vascular resistance in experimental animal models and in initial human acute decompensated heart failure studies.

ExcerptReferenceRelevance
"Tezosentan is a novel dual endothelin receptor antagonist. "( Endothelin receptor antagonism by tezosentan attenuates lung injury induced by aortic ischemia-reperfusion.
Gülmen, S; Kapucuoğlu, N; Kiriş, I; Narin, C; Sütçü, R; Yilmaz, N,
)
1.85
"Tezosentan is a dual endothelin receptor antagonist, and it has improved cardiac output and reduced pulmonary and systemic vascular resistance in experimental animal models and in initial human acute decompensated heart failure studies."( Tezosentan in patients with acute heart failure and acute coronary syndromes: design of the Randomized Intravenous Tezosentan study (RITZ-4).
Adams, KF; Frey, A; Gattis, WA; Gheorghiade, M; Kobrin, I; O'Connor, CM; Shah, MR, 2002
)
2.48
"Tezosentan is an IV nonselective endothelin (ET)-1 antagonist that yields favorable hemodynamic effects in patients with acute congestive heart failure (CHF)."( RITZ-5: randomized intravenous TeZosentan (an endothelin-A/B antagonist) for the treatment of pulmonary edema: a prospective, multicenter, double-blind, placebo-controlled study.
Caspi, A; Cotter, G; Frey, A; Kaluski, E; Kaplan, S; Kobrin, I; Krakov, O; Krakover, R; Marmor, A; Milo, O; Vered, Z; Zimlichman, R, 2003
)
2.05
"Tezosentan is an endothelin receptor antagonist in development by Actelion Ltd and Genentech Inc for the potential treatment of cardiovascular disorders, including acute heart failure (AHF) and congestive heart failure. "( Tezosentan. Actelion/Genentech.
De Servi, S; Rossetti, E, 2003
)
3.2
"Tezosentan is a dual endothelin receptor antagonist that has been shown to improve cardiac output, decrease pulmonary capillary wedge pressure, and reduce pulmonary and systemic vascular resistance in initial clinical studies in acute decompensated HF."( Tezosentan in patients with acute heart failure and acute coronary syndromes: results of the Randomized Intravenous TeZosentan Study (RITZ-4).
Adams, KF; Chandler, B; Frey, A; Gattis, WA; Gheorghiade, M; Hasselblad, V; Kobrin, I; O'Connor, CM; Rainisio, M; Shah, MR; Teerlink, J, 2003
)
3.2
"Tezosentan is a dual ET-1 receptor antagonist that has demonstrated efficacy in improving cardiac index and reducing pulmonary capillary wedge pressure in patients with acute, decompensated heart failure. "( Tezosentan in the treatment of acute heart failure.
Gums, JG; Tovar, JM, 2003
)
3.2
"Tezosentan is an antagonist of endothelin-1 receptors A and B."( Pharmacology of new agents for acute heart failure syndromes.
Gheorghiade, M; Mebazaa, A; Teerlink, JR, 2005
)
1.05
"Tezosentan is an intravenous short-acting endothelin receptor antagonist that has favorable hemodynamic actions in heart failure."( Effects of tezosentan on symptoms and clinical outcomes in patients with acute heart failure: the VERITAS randomized controlled trials.
Bourge, RC; Cleland, JG; Cotter, G; Frey, A; Jondeau, G; Kobrin, I; Krum, H; Lewsey, J; McMurray, JJ; Metra, M; O'Connor, CM; Parker, JD; Rainisio, M; Teerlink, JR; Torre-Amione, G; van Veldhuisen, DJ, 2007
)
1.45
"Tezosentan is a new dual ET(A)/ET(B) receptor antagonist."( Short-term endothelin receptor blockade with tezosentan has both immediate and long-term beneficial effects in rats with myocardial infarction.
Clozel, JP; Clozel, M; Hess, P; Qiu, C; Qiu, CS, 2002
)
1.3

Effects

Tezosentan has the potential for effective pharmacological treatment of pulmonary arterial hypertension following acute lung injury.

ExcerptReferenceRelevance
"Tezosentan has been previously shown to improve hemodynamics in patients with stable chronic HF."( Hemodynamic and clinical effects of tezosentan, an intravenous dual endothelin receptor antagonist, in patients hospitalized for acute decompensated heart failure.
Colucci, WS; Cotter, G; Elkayam, U; Frey, A; Kobrin, I; Lewis, BS; Pratt, C; Rainisio, M; Stangl, K; Teerlink, JR; Torre-Amione, G; Young, JB, 2003
)
2.04
"Tezosentan has the potential for effective pharmacological treatment of pulmonary arterial hypertension following acute lung injury."( Tezosentan decreases pulmonary artery pressure and improves survival rate in an animal model of meconium aspiration.
Fischer, V; Fratz, S; Geiger, R; Kleinsasser, A; Loeckinger, A; Maier, S; Navarro-Psiha, S; Neu, N; Pajk, W; Treml, B, 2006
)
2.5

Actions

ExcerptReferenceRelevance
"Tezosentan was able to inhibit the negative impact of TNF-alpha on AR and dP/dt but not on P(mcf)."( Haemodynamic effects of endothelin receptor antagonist, tezosentan, in tumour necrosis factor-alpha treated anaesthetized rats.
Ford, CA; Tabrizchi, R, 2003
)
1.29

Treatment

Tezosentan-treatment markedly attenuated plasma HBP and extravascular lung water, and these parameters correlated significantly in all 3 models. In tezosenten-treated lambs, PBF continued to increase and LPVR to decrease over the 4 h study period.

ExcerptReferenceRelevance
"Tezosentan-treatment markedly attenuated plasma HBP and extravascular lung water, and these parameters correlated significantly."( Heparin-binding protein (HBP/CAP37) - a link to endothelin-1 in endotoxemia-induced pulmonary oedema?
Halldorsdottir, H; Herwald, H; Lindbom, L; Oldner, A; Persson, BP; Rossi, P; Weitzberg, E, 2014
)
1.12
"Tezosentan treatment significantly improved serum transaminase and histology after IRI in all 3 models."( Tezosentan, a novel endothelin receptor antagonist, markedly reduces rat hepatic ischemia and reperfusion injury in three different models.
Anselmo, D; Busuttil, RW; Clozel, M; Farmer, DG; Kaldas, F; Kaldas, M; Katori, M; Kupiec-Weglinski, J; Lassman, C; Shen, XD, 2008
)
2.51
"In tezosentan-treated lambs, PBF continued to increase and LPVR to decrease over the 4 h study period."( Tezosentan increases nitric oxide signaling via enhanced hydrogen peroxide generation in lambs with surgically induced acute increases in pulmonary blood flow.
Aggarwal, S; Azakie, A; Black, SM; Datar, SA; Fineman, JR; Hou, Y; Kumar, S; Oishi, PE; Rafikov, R; Sharma, S, 2013
)
2.35
"Tezosentan pre-treatment resulted in a histologically normal gallbladder, but the WBCC and gallbladder endothelin levels were elevated."( Endogenous endothelin increases gallbladder tone and leads to acute cholecystitis in the Australian possum.
Al-Jiffry, BO; Menadue, M; Oliver, J; Saccone, GT; Shaffer, EA; Thomas, AC; Toouli, J; Woods, CM; Young, F, 2004
)
1.04
"Tezosentan treatment markedly attenuated the pulmonary hypertension, with a 32% decrease in MPAP (from 23 +/- 2 mm Hg to 15 +/- 2 mm Hg; P<.01) and a 22% decrease in PVR (from 860 +/- 105 dyn.s.cm(-5) to 670 +/- 96 dyn.s.cm(-5); P<.01) at the end of study."( Acute cardiopulmonary effects of a dual-endothelin receptor antagonist on oleic acid-induced pulmonary arterial hypertension in dogs.
Bai, CX; Matthay, MA; Su, X; Wang, L; Ware, LB; Zhu, DM,
)
0.85
"Tezosentan treatment was ineffective in protecting against acute lung injury in this model."( Effects of a dual endothelin-1 receptor antagonist on airway obstruction and acute lung injury in sheep following smoke inhalation and burn injury.
Burke, AS; Chandra, A; Cox, RA; Enkhabaatar, P; Hawkins, HK; Herndon, DN; Katahira, J; Shimoda, K; Traber, DL; Traber, LD, 2005
)
1.05
"The tezosentan pretreatment group received the dual endothelin receptor antagonist tezosentan 20 mins before and hyperoxic gas (Fio2 0.6) after chlorine gas exposure."( Effects of endothelin receptor antagonism on acute lung injury induced by chlorine gas.
Edston, E; Oldner, A; Walther, SM; Wang, J; Winskog, C, 2006
)
0.81
"Tezosentan postinjury treatment also decreased pulmonary vascular resistance to levels significantly lower than in the air and oxygen groups (p<.001)."( Effects of endothelin receptor antagonism on acute lung injury induced by chlorine gas.
Edston, E; Oldner, A; Walther, SM; Wang, J; Winskog, C, 2006
)
1.06
"Tezosentan treatment significantly reduced both the number of CC3-immunoreactive cells and GFAP levels, suggesting that inhibition of endothelinergic receptors could play a role in photoreceptor survival."( Endothelin receptors in light-induced retinal degeneration.
Iribarne, M; Suburo, AM; Torbidoni, V, 2006
)
1.06
"Tezosentan treatment attenuated the increase in LVEDP and in lung weight and slightly reduced MAP without affecting dP/dt(max)."( Short-term endothelin receptor blockade with tezosentan has both immediate and long-term beneficial effects in rats with myocardial infarction.
Clozel, JP; Clozel, M; Hess, P; Qiu, C; Qiu, CS, 2002
)
1.3
"Treatment with tezosentan did not significantly affect the plasma cytokine, angiotensin II, or aldosterone response to endotoxemia."( The endothelin receptor antagonist tezosentan improves renal microcirculation in a porcine model of endotoxemic shock.
Andersson, A; Fenhammar, J; Forestier, J; Frithiof, R; Hjelmqvist, H; Sollevi, A; Weitzberg, E, 2008
)
0.96
"Pre-treatment with tezosentan before hypoxia, additionally attenuates the initial hypoxia-induced mean pulmonary artery pressure rise by approx."( Dual endothelin receptor blockade with tezosentan markedly attenuates hypoxia-induced pulmonary vasoconstriction in a porcine model.
Hedelin, P; Kylhammar, D; Rådegran, G, 2012
)
0.97
"Treatment with tezosentan caused a dose-dependent increase in cardiac index ranging from 24.4% to 49.9% versus 3.0% with placebo."( Hemodynamic effects of tezosentan, an intravenous dual endothelin receptor antagonist, in patients with class III to IV congestive heart failure.
Bozkurt, B; Durand, J; Kobrin, I; Mann, DL; Pratt, CM; Torre-Amione, G; Young, JB, 2001
)
0.96

Toxicity

ExcerptReferenceRelevance
" The most common side effect during the infusion was headache (9 of 12 tezosentan-treated patients and both dobutamine-treated patients)."( A pilot safety trial of prolonged (48 h) infusion of the dual endothelin-receptor antagonist tezosentan in patients with advanced heart failure.
Durand, JB; Kobrin, I; Nagueh, S; Pratt, C; Torre-Amione, G; Vooletich, MT, 2001
)
0.76

Pharmacokinetics

ExcerptReferenceRelevance
" Blood samples were collected frequently for pharmacokinetic determinations and measurement of plasma endothelin-1 concentrations."( Pharmacokinetics and pharmacodynamics of tezosentan, an intravenous dual endothelin receptor antagonist, following chronic infusion in healthy subjects.
Clozel, M; Dingemanse, J; van Giersbergen, PL, 2002
)
0.58
" A two-compartment model could describe its pharmacokinetic profile."( Pharmacokinetics and pharmacodynamics of tezosentan, an intravenous dual endothelin receptor antagonist, following chronic infusion in healthy subjects.
Clozel, M; Dingemanse, J; van Giersbergen, PL, 2002
)
0.58
" Blood and urine samples were collected for pharmacokinetic determinations."( Effect of severe renal impairment on the pharmacokinetics and tolerability of the parenteral endothelin antagonist tezosentan.
Dingemanse, J; van Giersbergen, PL, 2003
)
0.53
" pharmacokinetic data on 670 drugs representing, to our knowledge, the largest publicly available set of human clinical pharmacokinetic data."( Trend analysis of a database of intravenous pharmacokinetic parameters in humans for 670 drug compounds.
Lombardo, F; Obach, RS; Waters, NJ, 2008
)
0.35
" Patients are more sensitive than healthy subjects to the pharmacodynamic effects of tezosentan, as reflected in increases in endothelin-1 concentrations."( Influence of liver cirrhosis on the pharmacokinetics, pharmacodynamics, and safety of tezosentan.
Dingemanse, J; Halabi, A; van Giersbergen, PL, 2009
)
0.8
" A target-mediated drug disposition (TMDD) pharmacokinetic (PK) model described the non-linearity in the PK of bosentan caused by its high receptor binding affinity with time-dependent varying receptor expression or reappearance."( Target-Mediated Population Pharmacokinetic Modeling of Endothelin Receptor Antagonists.
Dingemanse, J; Krause, A; Lehr, T; Volz, AK, 2019
)
0.51

Compound-Compound Interactions

ExcerptReferenceRelevance
"Stimulation of soluble guanylate cyclase (sGC) with BAY 41-8543 was hypothesized to attenuate acute hypoxic pulmonary vasoconstriction alone and combined with dual endothelin (ET)-receptor antagonist tezosentan."( sGC stimulation totally reverses hypoxia-induced pulmonary vasoconstriction alone and combined with dual endothelin-receptor blockade in a porcine model.
Hedelin, P; Kylhammar, D; Lundgren, J; Rådegran, G, 2012
)
0.57
" Thus, sGC stimulation, alone or combined with dual ET-receptor blockade, could offer a means to treat pulmonary hypertension related to hypoxia and potentially other causes."( sGC stimulation totally reverses hypoxia-induced pulmonary vasoconstriction alone and combined with dual endothelin-receptor blockade in a porcine model.
Hedelin, P; Kylhammar, D; Lundgren, J; Rådegran, G, 2012
)
0.38

Bioavailability

ExcerptReferenceRelevance
" Here we report an expansion of this work by substituting a variety of electron-withdrawing groups at the ortho position and evaluating their effects on oral bioavailability as well as structure-activity relationships."( Discovery, modeling, and human pharmacokinetics of N-(2-acetyl-4,6-dimethylphenyl)-3-(3,4-dimethylisoxazol-5-ylsulfamoyl)thiophene-2-carboxamide (TBC3711), a second generation, ETA selective, and orally bioavailable endothelin antagonist.
Berens, KL; Blok, N; Bourgoyne, AR; Brock, TA; Bui, H; Decker, ER; Dixon, RA; Holland, GW; Knowles, V; Wang, J; Wu, C; You, TJ, 2004
)
0.32

Dosage Studied

The data in healthy subjects suggest that caucasian and Japanese patients can be treated with a similar dosing regimen. Tezosentan in the current dosage counteracted the deterioration of lung function caused by endotoxin.

ExcerptRelevanceReference
" This study was designed to determine the effective dosage range, hemodynamic effects, and tolerability of tezosentan, an intravenous dual endothelin receptor antagonist, in patients with advanced heart failure."( The dual endothelin receptor antagonist tezosentan acutely improves hemodynamic parameters in patients with advanced heart failure.
Bertel, O; Cotter, G; Guyene, TT; Kiowski, W; Kobrin, I; Reisin, L; Schalcher, C, 2001
)
0.79
" The similar beneficial effects of the two dosages and the increased dose-related adverse events with the higher dosage suggest that the optimal dosing regimen is <50 mg/h."( Hemodynamic and clinical effects of tezosentan, an intravenous dual endothelin receptor antagonist, in patients hospitalized for acute decompensated heart failure.
Colucci, WS; Cotter, G; Elkayam, U; Frey, A; Kobrin, I; Lewis, BS; Pratt, C; Rainisio, M; Stangl, K; Teerlink, JR; Torre-Amione, G; Young, JB, 2003
)
0.59
" Tezosentan in the current dosage counteracted the deterioration of lung function caused by endotoxin, as measured by dead space, venous admixture, and compliance."( Tezosentan counteracts endotoxin-induced pulmonary edema and improves gas exchange.
Konrad, D; Oldner, A; Rossi, P; Wanecek, M, 2004
)
2.68
" To investigate whether factors released by cardiac myocytes contributed to decreased vascular responsiveness to ET, we performed ET-1 dose-response curves in isolated coronary arterioles (70-200 microm)."( Contribution of endothelin to coronary vasomotor tone is abolished after myocardial infarction.
Boomsma, F; Duncker, DJ; Houweling, B; Merkus, D; van den Meiracker, AH, 2005
)
0.33
"The data in healthy subjects suggest that caucasian and Japanese patients can be treated with a similar dosing regimen of tezosentan."( Comparison of the pharmacokinetics, pharmacodynamics and tolerability of tezosentan between caucasian and Japanese subjects.
Dingemanse, J; Gunawardena, KA; van Giersbergen, PL, 2006
)
0.77
" At 25-30 days, 48 h after interrupting bosentan, rats randomly underwent either a dose-response evaluation (0."( Haemodynamic and neuroendocrine effects of tezosentan in chronic experimental pulmonary hypertension.
Fontoura, D; Leite-Moreira, AF; Lourenço, AP; Oliveira-Pinto, J; Roncon-Albuquerque, R; Vasques-Nóvoa, F, 2012
)
0.64
[information is derived through text-mining from research data collected from National Library of Medicine (NLM), extracted Dec-2023]

Protein Targets (2)

Inhibition Measurements

ProteinTaxonomyMeasurementAverageMin (ref.)Avg (ref.)Max (ref.)Bioassay(s)
Endothelin receptor type BHomo sapiens (human)IC50 (µMol)0.02100.00010.65659.8000AID1626368
Endothelin-1 receptorHomo sapiens (human)IC50 (µMol)0.02050.00000.76479.9000AID1626371; AID66198
[prepared from compound, protein, and bioassay information from National Library of Medicine (NLM), extracted Dec-2023]

Biological Processes (109)

Processvia Protein(s)Taxonomy
negative regulation of transcription by RNA polymerase IIEndothelin receptor type BHomo sapiens (human)
neural crest cell migrationEndothelin receptor type BHomo sapiens (human)
positive regulation of protein phosphorylationEndothelin receptor type BHomo sapiens (human)
renin secretion into blood streamEndothelin receptor type BHomo sapiens (human)
regulation of heart rateEndothelin receptor type BHomo sapiens (human)
regulation of pHEndothelin receptor type BHomo sapiens (human)
cell surface receptor signaling pathwayEndothelin receptor type BHomo sapiens (human)
negative regulation of adenylate cyclase activityEndothelin receptor type BHomo sapiens (human)
phospholipase C-activating G protein-coupled receptor signaling pathwayEndothelin receptor type BHomo sapiens (human)
positive regulation of cytosolic calcium ion concentrationEndothelin receptor type BHomo sapiens (human)
nervous system developmentEndothelin receptor type BHomo sapiens (human)
peripheral nervous system developmentEndothelin receptor type BHomo sapiens (human)
posterior midgut developmentEndothelin receptor type BHomo sapiens (human)
positive regulation of cell population proliferationEndothelin receptor type BHomo sapiens (human)
gene expressionEndothelin receptor type BHomo sapiens (human)
negative regulation of neuron maturationEndothelin receptor type BHomo sapiens (human)
response to organic cyclic compoundEndothelin receptor type BHomo sapiens (human)
vein smooth muscle contractionEndothelin receptor type BHomo sapiens (human)
calcium-mediated signalingEndothelin receptor type BHomo sapiens (human)
cGMP-mediated signalingEndothelin receptor type BHomo sapiens (human)
heparin metabolic processEndothelin receptor type BHomo sapiens (human)
melanocyte differentiationEndothelin receptor type BHomo sapiens (human)
regulation of fever generationEndothelin receptor type BHomo sapiens (human)
aldosterone metabolic processEndothelin receptor type BHomo sapiens (human)
enteric smooth muscle cell differentiationEndothelin receptor type BHomo sapiens (human)
positive regulation of urine volumeEndothelin receptor type BHomo sapiens (human)
renal sodium excretionEndothelin receptor type BHomo sapiens (human)
epithelial fluid transportEndothelin receptor type BHomo sapiens (human)
vasoconstrictionEndothelin receptor type BHomo sapiens (human)
vasodilationEndothelin receptor type BHomo sapiens (human)
negative regulation of apoptotic processEndothelin receptor type BHomo sapiens (human)
positive regulation of canonical NF-kappaB signal transductionEndothelin receptor type BHomo sapiens (human)
macrophage chemotaxisEndothelin receptor type BHomo sapiens (human)
response to painEndothelin receptor type BHomo sapiens (human)
enteric nervous system developmentEndothelin receptor type BHomo sapiens (human)
regulation of epithelial cell proliferationEndothelin receptor type BHomo sapiens (human)
negative regulation of protein metabolic processEndothelin receptor type BHomo sapiens (human)
canonical Wnt signaling pathwayEndothelin receptor type BHomo sapiens (human)
positive regulation of penile erectionEndothelin receptor type BHomo sapiens (human)
establishment of endothelial barrierEndothelin receptor type BHomo sapiens (human)
renal sodium ion absorptionEndothelin receptor type BHomo sapiens (human)
calcium ion transmembrane transportEndothelin receptor type BHomo sapiens (human)
cellular response to lipopolysaccharideEndothelin receptor type BHomo sapiens (human)
protein transmembrane transportEndothelin receptor type BHomo sapiens (human)
podocyte differentiationEndothelin receptor type BHomo sapiens (human)
endothelin receptor signaling pathwayEndothelin receptor type BHomo sapiens (human)
renal albumin absorptionEndothelin receptor type BHomo sapiens (human)
neuroblast migrationEndothelin receptor type BHomo sapiens (human)
chordate pharynx developmentEndothelin receptor type BHomo sapiens (human)
response to sodium phosphateEndothelin receptor type BHomo sapiens (human)
response to endothelinEndothelin receptor type BHomo sapiens (human)
developmental pigmentationEndothelin receptor type BHomo sapiens (human)
mitotic cell cycleEndothelin-1 receptorHomo sapiens (human)
branching involved in blood vessel morphogenesisEndothelin-1 receptorHomo sapiens (human)
response to hypoxiaEndothelin-1 receptorHomo sapiens (human)
in utero embryonic developmentEndothelin-1 receptorHomo sapiens (human)
blood vessel remodelingEndothelin-1 receptorHomo sapiens (human)
response to amphetamineEndothelin-1 receptorHomo sapiens (human)
regulation of heart rateEndothelin-1 receptorHomo sapiens (human)
glomerular filtrationEndothelin-1 receptorHomo sapiens (human)
cardiac chamber formationEndothelin-1 receptorHomo sapiens (human)
left ventricular cardiac muscle tissue morphogenesisEndothelin-1 receptorHomo sapiens (human)
atrial cardiac muscle tissue developmentEndothelin-1 receptorHomo sapiens (human)
cardiac neural crest cell migration involved in outflow tract morphogenesisEndothelin-1 receptorHomo sapiens (human)
noradrenergic neuron differentiationEndothelin-1 receptorHomo sapiens (human)
intracellular calcium ion homeostasisEndothelin-1 receptorHomo sapiens (human)
smooth muscle contractionEndothelin-1 receptorHomo sapiens (human)
mitochondrion organizationEndothelin-1 receptorHomo sapiens (human)
signal transductionEndothelin-1 receptorHomo sapiens (human)
G protein-coupled receptor signaling pathwayEndothelin-1 receptorHomo sapiens (human)
activation of adenylate cyclase activityEndothelin-1 receptorHomo sapiens (human)
adenylate cyclase-inhibiting G protein-coupled receptor signaling pathwayEndothelin-1 receptorHomo sapiens (human)
phospholipase C-activating G protein-coupled receptor signaling pathwayEndothelin-1 receptorHomo sapiens (human)
positive regulation of cytosolic calcium ion concentrationEndothelin-1 receptorHomo sapiens (human)
respiratory gaseous exchange by respiratory systemEndothelin-1 receptorHomo sapiens (human)
regulation of blood pressureEndothelin-1 receptorHomo sapiens (human)
cell population proliferationEndothelin-1 receptorHomo sapiens (human)
response to woundingEndothelin-1 receptorHomo sapiens (human)
gene expressionEndothelin-1 receptorHomo sapiens (human)
protein kinase A signalingEndothelin-1 receptorHomo sapiens (human)
regulation of glucose transmembrane transportEndothelin-1 receptorHomo sapiens (human)
neural crest cell fate commitmentEndothelin-1 receptorHomo sapiens (human)
artery smooth muscle contractionEndothelin-1 receptorHomo sapiens (human)
neuron remodelingEndothelin-1 receptorHomo sapiens (human)
heparin metabolic processEndothelin-1 receptorHomo sapiens (human)
thyroid gland developmentEndothelin-1 receptorHomo sapiens (human)
cellular response to oxidative stressEndothelin-1 receptorHomo sapiens (human)
embryonic heart tube developmentEndothelin-1 receptorHomo sapiens (human)
aorta developmentEndothelin-1 receptorHomo sapiens (human)
vasoconstrictionEndothelin-1 receptorHomo sapiens (human)
norepinephrine metabolic processEndothelin-1 receptorHomo sapiens (human)
middle ear morphogenesisEndothelin-1 receptorHomo sapiens (human)
positive regulation of canonical NF-kappaB signal transductionEndothelin-1 receptorHomo sapiens (human)
cellular response to human chorionic gonadotropin stimulusEndothelin-1 receptorHomo sapiens (human)
enteric nervous system developmentEndothelin-1 receptorHomo sapiens (human)
sympathetic nervous system developmentEndothelin-1 receptorHomo sapiens (human)
axon extensionEndothelin-1 receptorHomo sapiens (human)
embryonic skeletal system developmentEndothelin-1 receptorHomo sapiens (human)
neuromuscular processEndothelin-1 receptorHomo sapiens (human)
sodium ion homeostasisEndothelin-1 receptorHomo sapiens (human)
canonical Wnt signaling pathwayEndothelin-1 receptorHomo sapiens (human)
face developmentEndothelin-1 receptorHomo sapiens (human)
axonogenesis involved in innervationEndothelin-1 receptorHomo sapiens (human)
establishment of endothelial barrierEndothelin-1 receptorHomo sapiens (human)
pharyngeal arch artery morphogenesisEndothelin-1 receptorHomo sapiens (human)
renal sodium ion absorptionEndothelin-1 receptorHomo sapiens (human)
calcium ion transmembrane transportEndothelin-1 receptorHomo sapiens (human)
cellular response to follicle-stimulating hormone stimulusEndothelin-1 receptorHomo sapiens (human)
cellular response to luteinizing hormone stimulusEndothelin-1 receptorHomo sapiens (human)
protein transmembrane transportEndothelin-1 receptorHomo sapiens (human)
glomerular endothelium developmentEndothelin-1 receptorHomo sapiens (human)
podocyte differentiationEndothelin-1 receptorHomo sapiens (human)
endothelin receptor signaling pathway involved in heart processEndothelin-1 receptorHomo sapiens (human)
renal albumin absorptionEndothelin-1 receptorHomo sapiens (human)
vascular associated smooth muscle cell developmentEndothelin-1 receptorHomo sapiens (human)
mesenchymal cell apoptotic processEndothelin-1 receptorHomo sapiens (human)
sympathetic neuron axon guidanceEndothelin-1 receptorHomo sapiens (human)
semaphorin-plexin signaling pathway involved in axon guidanceEndothelin-1 receptorHomo sapiens (human)
podocyte apoptotic processEndothelin-1 receptorHomo sapiens (human)
meiotic cell cycle process involved in oocyte maturationEndothelin-1 receptorHomo sapiens (human)
cranial skeletal system developmentEndothelin-1 receptorHomo sapiens (human)
response to acetylcholineEndothelin-1 receptorHomo sapiens (human)
regulation of protein localization to cell leading edgeEndothelin-1 receptorHomo sapiens (human)
positive regulation of cation channel activityEndothelin-1 receptorHomo sapiens (human)
endothelin receptor signaling pathwayEndothelin-1 receptorHomo sapiens (human)
developmental pigmentationEndothelin-1 receptorHomo sapiens (human)
[Information is prepared from geneontology information from the June-17-2024 release]

Molecular Functions (5)

Processvia Protein(s)Taxonomy
endothelin receptor activityEndothelin receptor type BHomo sapiens (human)
protein bindingEndothelin receptor type BHomo sapiens (human)
peptide hormone bindingEndothelin receptor type BHomo sapiens (human)
type 1 angiotensin receptor bindingEndothelin receptor type BHomo sapiens (human)
phosphatidylinositol phospholipase C activityEndothelin-1 receptorHomo sapiens (human)
endothelin receptor activityEndothelin-1 receptorHomo sapiens (human)
protein bindingEndothelin-1 receptorHomo sapiens (human)
[Information is prepared from geneontology information from the June-17-2024 release]

Ceullar Components (2)

Processvia Protein(s)Taxonomy
plasma membraneEndothelin receptor type BHomo sapiens (human)
nuclear membraneEndothelin receptor type BHomo sapiens (human)
plasma membraneEndothelin receptor type BHomo sapiens (human)
plasma membraneEndothelin-1 receptorHomo sapiens (human)
plasma membraneEndothelin-1 receptorHomo sapiens (human)
[Information is prepared from geneontology information from the June-17-2024 release]

Bioassays (14)

Assay IDTitleYearJournalArticle
AID540212Mean residence time in human after iv administration2008Drug metabolism and disposition: the biological fate of chemicals, Jul, Volume: 36, Issue:7
Trend analysis of a database of intravenous pharmacokinetic parameters in humans for 670 drug compounds.
AID12105Half life period was evaluated in rat2004Journal of medicinal chemistry, Apr-08, Volume: 47, Issue:8
Discovery, modeling, and human pharmacokinetics of N-(2-acetyl-4,6-dimethylphenyl)-3-(3,4-dimethylisoxazol-5-ylsulfamoyl)thiophene-2-carboxamide (TBC3711), a second generation, ETA selective, and orally bioavailable endothelin antagonist.
AID588212Literature-mined compound from Fourches et al multi-species drug-induced liver injury (DILI) dataset, effect in rodents2010Chemical research in toxicology, Jan, Volume: 23, Issue:1
Cheminformatics analysis of assertions mined from literature that describe drug-induced liver injury in different species.
AID540209Volume of distribution at steady state in human after iv administration2008Drug metabolism and disposition: the biological fate of chemicals, Jul, Volume: 36, Issue:7
Trend analysis of a database of intravenous pharmacokinetic parameters in humans for 670 drug compounds.
AID12754Compound was evaluated for oral bioavailability in rats after iv administration2004Journal of medicinal chemistry, Apr-08, Volume: 47, Issue:8
Discovery, modeling, and human pharmacokinetics of N-(2-acetyl-4,6-dimethylphenyl)-3-(3,4-dimethylisoxazol-5-ylsulfamoyl)thiophene-2-carboxamide (TBC3711), a second generation, ETA selective, and orally bioavailable endothelin antagonist.
AID540213Half life in human after iv administration2008Drug metabolism and disposition: the biological fate of chemicals, Jul, Volume: 36, Issue:7
Trend analysis of a database of intravenous pharmacokinetic parameters in humans for 670 drug compounds.
AID588211Literature-mined compound from Fourches et al multi-species drug-induced liver injury (DILI) dataset, effect in humans2010Chemical research in toxicology, Jan, Volume: 23, Issue:1
Cheminformatics analysis of assertions mined from literature that describe drug-induced liver injury in different species.
AID1626371Displacement of 125I-ET1 from ETA receptor (unknown origin) expressed in CHO cells2016Bioorganic & medicinal chemistry letters, 08-01, Volume: 26, Issue:15
From bosentan (Tracleer®) to macitentan (Opsumit®): The medicinal chemistry perspective.
AID588213Literature-mined compound from Fourches et al multi-species drug-induced liver injury (DILI) dataset, effect in non-rodents2010Chemical research in toxicology, Jan, Volume: 23, Issue:1
Cheminformatics analysis of assertions mined from literature that describe drug-induced liver injury in different species.
AID540211Fraction unbound in human after iv administration2008Drug metabolism and disposition: the biological fate of chemicals, Jul, Volume: 36, Issue:7
Trend analysis of a database of intravenous pharmacokinetic parameters in humans for 670 drug compounds.
AID66198Displacement of [125I]ET-1 from Endothelin A receptor2004Journal of medicinal chemistry, Apr-08, Volume: 47, Issue:8
Discovery, modeling, and human pharmacokinetics of N-(2-acetyl-4,6-dimethylphenyl)-3-(3,4-dimethylisoxazol-5-ylsulfamoyl)thiophene-2-carboxamide (TBC3711), a second generation, ETA selective, and orally bioavailable endothelin antagonist.
AID540210Clearance in human after iv administration2008Drug metabolism and disposition: the biological fate of chemicals, Jul, Volume: 36, Issue:7
Trend analysis of a database of intravenous pharmacokinetic parameters in humans for 670 drug compounds.
AID66214Selectivity for endothelin A receptor over endothelin receptor B2004Journal of medicinal chemistry, Apr-08, Volume: 47, Issue:8
Discovery, modeling, and human pharmacokinetics of N-(2-acetyl-4,6-dimethylphenyl)-3-(3,4-dimethylisoxazol-5-ylsulfamoyl)thiophene-2-carboxamide (TBC3711), a second generation, ETA selective, and orally bioavailable endothelin antagonist.
AID1626368Displacement of radioligand from ETB receptor in human placenta cell membranes2016Bioorganic & medicinal chemistry letters, 08-01, Volume: 26, Issue:15
From bosentan (Tracleer®) to macitentan (Opsumit®): The medicinal chemistry perspective.
[information is prepared from bioassay data collected from National Library of Medicine (NLM), extracted Dec-2023]

Research

Studies (153)

TimeframeStudies, This Drug (%)All Drugs %
pre-19900 (0.00)18.7374
1990's2 (1.31)18.2507
2000's113 (73.86)29.6817
2010's37 (24.18)24.3611
2020's1 (0.65)2.80
[information is prepared from research data collected from National Library of Medicine (NLM), extracted Dec-2023]

Market Indicators

Research Demand Index: 29.15

According to the monthly volume, diversity, and competition of internet searches for this compound, as well the volume and growth of publications, there is estimated to be moderate demand-to-supply ratio for research on this compound.

MetricThis Compound (vs All)
Research Demand Index29.15 (24.57)
Research Supply Index5.23 (2.92)
Research Growth Index6.02 (4.65)
Search Engine Demand Index36.71 (26.88)
Search Engine Supply Index2.00 (0.95)

This Compound (29.15)

All Compounds (24.57)

Study Types

Publication TypeThis drug (%)All Drugs (%)
Trials29 (18.47%)5.53%
Reviews23 (14.65%)6.00%
Case Studies0 (0.00%)4.05%
Observational1 (0.64%)0.25%
Other104 (66.24%)84.16%
[information is prepared from research data collected from National Library of Medicine (NLM), extracted Dec-2023]

Clinical Trials (30)

Trial Overview

TrialPhaseEnrollmentStudy TypeStart DateStatus
Prostacyclin Treatment in Severe Traumatic Brain Injury: a Microdialysis and Outcome Study [NCT01363583]Phase 148 participants (Actual)Interventional2002-01-31Completed
Multicenter, Open-label, Non-comparative, Proof-of-concept, Phase 2a Study to Evaluate the Effect of a Single Infusion of Tezosentan on Pulmonary Vascular Resistance in Patients With Stable, Chronic Pulmonary Arterial Hypertension, Currently Not Treated W [NCT01077297]Phase 23 participants (Actual)Interventional2010-08-31Terminated(stopped due to Due to slow recruitment, the study was prematurely discontinued)
Double-blind, Placebo Controlled Study to Assess the Efficacy and Safety of VentaProst (Inhaled Epoprostenol Delivered Via Dedicated Delivery System) in Subjects With COVID-19 Requiring Mechanical Ventilation [NCT04452669]Phase 211 participants (Actual)Interventional2020-09-15Completed
Multicenter, Double-blind, Randomized, Placebo-controlled, Parallel-group Study to Assess the Efficacy, Safety and Tolerability of Tezosentan in Patients With Pre-operative Pulmonary Hypertension, Due to Left Heart Disease, Undergoing Cardiac Surgery [NCT00458276]Phase 3274 participants (Actual)Interventional2007-04-30Terminated(stopped due to 6 month vital status report not collected after 28 day follow up analysis indicated no difference between placebo & tezosentan)
Combined Drug Approach to Prevent Ischemia-reperfusion Injury During Transplantation of Livers (CAPITL): a First-in-men Study [NCT02251041]Phase 272 participants (Actual)Interventional2014-09-30Completed
Vasopressin and Inhaled Prostacyclin in Pediatric Pulmonary Hypertension [NCT01370096]Phase 23 participants (Actual)Interventional2012-02-29Terminated(stopped due to Difficulty with patient recruitment)
Effects of Intravenous Epoprostenol Sodium (Flolan®) in Patients With Moderate-to-Severe Pulmonary Thrombo-Embolism [NCT01014156]Phase 414 participants (Actual)Interventional2004-01-31Completed
A Phase IV, Open-label, Randomized, Multicenter Study of the Safety, Tolerability,and Pharmacokinetics of ACT- 385781A Compared to Flolan® in Injectable Prostanoid Treatment-naïve Patients With Pulmonary Arterial Hypertension (PAH) [NCT01105091]Phase 430 participants (Actual)Interventional2010-03-31Completed
Drug Use Investigation for FLOLAN (Epoprostenol) Injection 0.5mg・1.5mg [NCT01387191]748 participants (Actual)Observational1999-08-31Completed
Effects of PGI2 Analogue Use on the Development of Chronic Allograft Nephropathy [NCT01056835]Phase 340 participants (Anticipated)Interventional2009-06-30Completed
Heparin Versus Prostacyclin in Continuous Hemodiafiltration for Acute Renal Failure: Effects on Platelet Responsiveness in the Systemic Circulation and Across the Filter. [NCT00890214]Phase 423 participants (Actual)Interventional2007-09-30Completed
The Effect of Prostaglandin I2 (Beraprost Na), Administered Orally for Eight Weeks, on the Endothelial Cell Functional Disorder in Type II Diabetes Mellitus Patients With Symptoms of a Minute Peripheral Blood Flow Disorder [NCT01061060]Phase 4110 participants (Actual)Interventional2010-01-31Completed
Combined Drug Approach to Prevent Ischemia-reperfusion Injury During Transplantation of Livers (CAPITL): a First-in-men Study [NCT01886443]Phase 110 participants (Actual)Interventional2013-08-31Completed
A Pilot Study of the Effects of Nebulized Epoprostenol (Flolan) and Systemic Phenylephrine on Arterial Oxygenation During One Lung Ventilation [NCT02748265]Phase 48 participants (Actual)Interventional2016-03-31Completed
Migraine Inducing Effects and Changes in Brain Haemodynamics of PGI2 [NCT00510172]12 participants (Anticipated)Interventional2006-12-31Recruiting
Multicenter, Double-blind, Randomized, Placebo-controlled, Parallel Group Study to Assess the Efficacy, Safety, and Tolerability of Tezosentan in Patients With Acute Heart Failure. [NCT00525707]Phase 3735 participants (Actual)Interventional2003-04-30Completed
A Postmarketing Observational Study to Assess Respiratory Tract Adverse Events in Pulmonary Arterial Hypertension Patients Treated With Tyvaso® (Treprostinil) Inhalation Solution [NCT01266265]1,333 participants (Actual)Observational2010-12-31Completed
Multicenter, Double-blind, Randomized, Placebo-controlled, Parallel Group Study to Assess the Efficacy, Safety, and Tolerability of Tezosentan in Patients With Acute Heart Failure. [NCT00524433]Phase 3713 participants (Actual)Interventional2003-04-30Completed
Effect of Prostacyclin Infusion on Cerebral Vessels, Cerebral Bloodflow and Cerebral Metabolism in Patients With Subarachnoid Haemorrhage [NCT01447095]Phase 290 participants (Actual)Interventional2011-10-31Completed
Trial of Inhaled Alprostadil to Improve Hypoxia and Pulmonary Hypertension [NCT00314548]67 participants (Actual)Interventional2006-05-31Completed
The Effect of Prostacyclin on Haemostasis as Evaluated by Thrombelastography and Endothelial Markers in Patients Undergoing Major Abdominal Surgery. A Pilot Study [NCT01528943]Phase 140 participants (Actual)Interventional2012-03-31Completed
Combined Inhaled Nitric Oxide and Inhaled Prostacyclin After Cardiac Surgery for Heart Transplantation and for Left Ventricular Assist Device Placement [NCT01717209]Phase 414 participants (Actual)Interventional2012-10-31Completed
Inhaled Milrinone and Epoprostenol for the Prevention of Difficult Cardiac Pulmonary Bypass Separation: A Randomized, Double-blind, Controlled Trial [NCT05450328]Phase 2141 participants (Anticipated)Interventional2022-09-01Not yet recruiting
Acute Hemodynamic Comparison of Inhaled Nitric Oxide and Inhaled Epoprostenol in Pulmonary Hypertension [NCT04231084]Phase 4108 participants (Anticipated)Interventional2021-01-15Recruiting
An Open-label Extension of Study AC-066A401 Investigating the Safety and Tolerability of ACT-385781A Compared to Flolan® in Injectable Prostanoid Treatment-naïve Patients With Pulmonary Arterial Hypertension (PAH) [NCT01105117]Phase 42 participants (Actual)Interventional2010-05-31Completed
[NCT00004754]Phase 40 participants Interventional1993-08-31Completed
An Open Label, Single-arm Study Evaluating a New Thermostable Formulation of FLOLAN™ in Japanese Subjects With Pulmonary Arterial Hypertension (PAH) [NCT02705807]Phase 410 participants (Actual)Interventional2016-05-31Completed
A Single-arm, Open Label Study Evaluating the Impact on Lifestyle of a New Thermo Stable Formulation of FLOLAN® in Subjects With Pulmonary Arterial Hypertension (PAH). (FLOLAN® is a Registered Trademark of the GlaxoSmithKline Group of Companies.) [NCT01462565]Phase 416 participants (Actual)Interventional2011-11-01Completed
Open-Label, Randomized Study to Evaluate Safety, Tolerability, and Pharmacokinetics of Single and Multiple Doses of Different Formulations of an IP Receptor Agonist [NCT05427162]Phase 1136 participants (Anticipated)Interventional2022-06-21Recruiting
An Open-label Extension of Study AC-066A301 Investigating the Safety and Tolerability of ACT-385781A in Patients With Pulmonary Arterial Hypertension (PAH) [NCT01470144]Phase 341 participants (Actual)Interventional2011-06-01Completed
[information is prepared from clinicaltrials.gov, extracted Sep-2024]

Trial Outcomes

TrialOutcome
NCT01105091 (10) [back to overview]Dose Normalized Pharmacokinetics of 6-keto-Prostacyclin F1alpha at 2 ng/kg/Min
NCT01105091 (10) [back to overview]Dose Normalized Pharmacokinetics of 6-keto-Prostacyclin F1alpha at 4 ng/kg/Min
NCT01105091 (10) [back to overview]Dose Normalized Pharmacokinetics of 6,15-diketo-13,14-dihydro-Prostacyclin F1alpha at 2 ng/kg/Min
NCT01105091 (10) [back to overview]Dose Normalized Pharmacokinetics of 6,15-diketo-13,14-dihydro-Prostacyclin F1alpha at 4 ng/kg/Min
NCT01105091 (10) [back to overview]Blood Pressure - Baseline and Day 28
NCT01105091 (10) [back to overview]Body Weight - Baseline and Day 28
NCT01105091 (10) [back to overview]Heart Rate - Baseline and Day 28
NCT01105091 (10) [back to overview]Patients With New York Heart Association (NYHA) Functional Class Change (Improved or Worsened) From Baseline to Day 28
NCT01105091 (10) [back to overview]Percentage Central Venous Blood Oxygen Saturation (ScVO2) - Baseline and Day 28
NCT01105091 (10) [back to overview]Six-minute Walk Distance (6MWD) - Baseline and Day 28
NCT01105117 (2) [back to overview]Safety and Tolerability of ACT-385781A and Flolan in Injectable Prostanoid Treatment-naïve Patients With PAH - Number of Deaths
NCT01105117 (2) [back to overview]Safety and Tolerability of ACT-385781A and Flolan in Injectable Prostanoid Treatment-naïve Patients With Pulmonary Arterial Hypertension (PAH) - Number of Patients With Adverse Events Leading Discontinuation of Study Treatment
NCT01266265 (1) [back to overview]Prevalence of Respiratory Tract-Related Adverse Events of Interest
NCT01462565 (15) [back to overview]Number of Participants With Any Treatment Emergent Adverse Events (AEs) and Treatment Emergent Serious Adverse Events(SAEs)
NCT01462565 (15) [back to overview]Number of Participants With Infusion Site Reactions During Treatment Period
NCT01462565 (15) [back to overview]World Health Organization [WHO] Functional Class at Baseline and After 4- Weeks of Treatment
NCT01462565 (15) [back to overview]Change From Baseline in Vital Signs at Week 4 : Systolic and Diastolic Blood Pressure
NCT01462565 (15) [back to overview]Breathlessness After 6MWD - Borg Dyspnoea Index (BDI)
NCT01462565 (15) [back to overview]Change From Baseline in Dose of Thermo Stable Epoprostenol Sodium at Week 4
NCT01462565 (15) [back to overview]Change From Baseline in Six Minute Walk Distance Test (6MWD) After 4-weeks of Treatment
NCT01462565 (15) [back to overview]Change From Baseline in Vital Signs at Week 4: Heart Rate
NCT01462565 (15) [back to overview]Number of Participants With Abnormal Clinical Chemistry
NCT01462565 (15) [back to overview]Number of Participants With Abnormal Urinalysis
NCT01462565 (15) [back to overview]Number of Participants With Urine Pregnancy Test Positive
NCT01462565 (15) [back to overview]Change From Baseline in Medical Outcomes Study Short Form 36 (SF-36)
NCT01462565 (15) [back to overview]Change From Baseline in Study Specific Participant Acceptance Survey
NCT01462565 (15) [back to overview]Mean Oxygen Saturation in Blood Over Time
NCT01462565 (15) [back to overview]Number of Participants With Abnormal Hematology
NCT01470144 (2) [back to overview]Treatment-emergent Adverse Events
NCT01470144 (2) [back to overview]Exposure Duration
NCT01717209 (6) [back to overview]Heart Rate
NCT01717209 (6) [back to overview]Mean Arterial Pressure (MAP)
NCT01717209 (6) [back to overview]Pulmonary Hypertension
NCT01717209 (6) [back to overview]Right Heart Dysfunction
NCT01717209 (6) [back to overview]Systemic Vascular Resistance (SVR)
NCT01717209 (6) [back to overview]Central Venous Pressure (CVP)
NCT02705807 (27) [back to overview]Absolute Values of Alanine Aminotransferase, Aspartate Aminotransferase, Alkaline Phosphatase, Gamma Glutamyltransferase, Lactate Dehydrogenase and Creatine Kinase at Baseline and Week 4
NCT02705807 (27) [back to overview]Absolute Values of Albumin and Total Protein at Baseline and Week 4
NCT02705807 (27) [back to overview]Absolute Values of Free Triiodothyronine and Free Thyroxine at Baseline and Week 4
NCT02705807 (27) [back to overview]Absolute Values of Hematocrit at Baseline and Week 4
NCT02705807 (27) [back to overview]Absolute Values of Hemoglobin at Baseline and Week 4
NCT02705807 (27) [back to overview]Absolute Values of Oxygen Saturation
NCT02705807 (27) [back to overview]Absolute Values of Platelet Count and White Blood Cell Count at Baseline and Week 4
NCT02705807 (27) [back to overview]Absolute Values of Red Blood Cell Count at Baseline and Week 4
NCT02705807 (27) [back to overview]Absolute Values of Thyroid Stimulating Hormone at Baseline and Week 4
NCT02705807 (27) [back to overview]Absolute Values of Total and Direct Bilirubin, Creatinine, and Uric Acid at Baseline and Week 4
NCT02705807 (27) [back to overview]Change From Baseline in Heart Rate
NCT02705807 (27) [back to overview]Change From Baseline in Mean Pulmonary Arterial Pressure (mPAP) and Mean Right Atrial Pressure (mRAP)
NCT02705807 (27) [back to overview]Change From Baseline in N-terminal Pro B-type Natriuretic Peptide (NT Pro BNP)
NCT02705807 (27) [back to overview]Change From Baseline in Pulmonary Vascular Resist (PVR)
NCT02705807 (27) [back to overview]Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP)
NCT02705807 (27) [back to overview]Number of Events to Adjust Dose of FLOLAN Based on the Change From Baseline to 3 Hours in Mean Pulmonary Artery Pressure (mPAP)
NCT02705807 (27) [back to overview]Number of Participants in Each World Health Organization (WHO) Functional Class
NCT02705807 (27) [back to overview]Number of Participants With Any Adverse Event (AE) or Serious Adverse Event (SAE)
NCT02705807 (27) [back to overview]Number of Participants With Change of WHO Functional Class From Previous Visit
NCT02705807 (27) [back to overview]Change From Baseline in Cardiac Output (CO)
NCT02705807 (27) [back to overview]Number of Participants With Mild, Moderate or Severe AEs
NCT02705807 (27) [back to overview]Number of Participants With the Indicated Electrocardiogram (ECG) Findings
NCT02705807 (27) [back to overview]Number of Participants With the Indicated Urinalysis Findings
NCT02705807 (27) [back to overview]Number of Participants With the Reason for the Change Dose of the Thermostable Formulation of FLOLAN
NCT02705807 (27) [back to overview]Percentage of Basophils, Eosinophils, Lymphocytes, Monocytes, and Total Neutrophils in Blood at Baseline and Week 4
NCT02705807 (27) [back to overview]Absolute Values of Urea/Blood Urea Nitrogen, Glucose, Chloride, Sodium, Potassium, Magnesium, Phosphorus (Inorganic), and Calcium at Baseline and Week 4
NCT02705807 (27) [back to overview]Change From Baseline in Body Weight

Dose Normalized Pharmacokinetics of 6-keto-Prostacyclin F1alpha at 2 ng/kg/Min

The plasma concentration for the epoprostenol metabolite 6-keto-Prostacyclin F1alpha was measured at 2 ng/kg/min just prior to the next up-titration. Dose-normalized concentrations are used to summarize the results. (NCT01105091)
Timeframe: Day 1

Intervention(pg/ml)/(ng/kg/min) (Median)
ACT-385781A (Epoprostenol for Injection)85.5
Flolan® (Epoprostenol Sodium) for Injection109.2

[back to top]

Dose Normalized Pharmacokinetics of 6-keto-Prostacyclin F1alpha at 4 ng/kg/Min

The plasma concentration for the epoprostenol metabolite 6-keto-Prostacyclin F1alpha was measured at 4 ng/kg/min just prior to the next up-titration. Dose-normalized concentrations are used to summarize the results. (NCT01105091)
Timeframe: Day 1

Intervention(pg/ml)/(ng/kg/min) (Median)
ACT-385781A (Epoprostenol for Injection)93.1
Flolan® (Epoprostenol Sodium) for Injection95.0

[back to top]

Dose Normalized Pharmacokinetics of 6,15-diketo-13,14-dihydro-Prostacyclin F1alpha at 2 ng/kg/Min

The plasma concentration for the epoprostenol metabolite 6,15-diketo-13,14-dihydro-Prostacyclin F1alpha was measured at 2 ng/kg/min just prior to the next up-titration. Dose-normalized concentrations are used to summarize the results. (NCT01105091)
Timeframe: Day 1

Intervention(pg/ml)/(ng/kg/min) (Median)
ACT-385781A (Epoprostenol for Injection)98.0
Flolan® (Epoprostenol Sodium) for Injection83.1

[back to top]

Dose Normalized Pharmacokinetics of 6,15-diketo-13,14-dihydro-Prostacyclin F1alpha at 4 ng/kg/Min

The plasma concentration for the epoprostenol metabolite 6,15-diketo-13,14-dihydro-Prostacyclin F1alpha was measured at 4 ng/kg/min just prior to the next up-titration. Dose-normalized concentrations are used to summarize the results. (NCT01105091)
Timeframe: Day 1

Intervention(pg/ml)/(ng/kg/min) (Median)
ACT-385781A (Epoprostenol for Injection)90.9
Flolan® (Epoprostenol Sodium) for Injection59.6

[back to top]

Blood Pressure - Baseline and Day 28

Blood pressure (systolic and diastolic) were measured indirectly using an automatic oscillometric device, on the same arm for each measurement. The Blood Pressure was assessed at baseline and at Day 28 (End of Study Treatment visit). (NCT01105091)
Timeframe: Baseline and 28 days

,
Interventionmm Hg (Median)
Systolic Blood Pressure (Baseline)Systolic Blood Pressure (Day 28)Diastolic Blood Pressure (Baseline)Diastolic Blood Pressure (Day 28))
ACT-385781A (Epoprostenol for Injection)106.5117.562.071.0
Flolan® (Epoprostenol Sodium) for Injection106.5116.068.073.0

[back to top]

Body Weight - Baseline and Day 28

Body weight was measured both at baseline and day 28. (NCT01105091)
Timeframe: Baseline and 28 days

,
Interventionkg (Median)
BaselineDay 28
ACT-385781A (Epoprostenol for Injection)74.173.6
Flolan® (Epoprostenol Sodium) for Injection74.273.3

[back to top]

Heart Rate - Baseline and Day 28

Heart rate was measured indirectly using an automatic oscillometric device, on the same arm for each measurement. The Heart Rate was assessed at Baseline and at Day 28 (End of Study Treatment visit). (NCT01105091)
Timeframe: Baseline and 28 days

,
InterventionBeats per minute (Median)
BaselineDay 28
ACT-385781A (Epoprostenol for Injection)83.085.0
Flolan® (Epoprostenol Sodium) for Injection77.588.0

[back to top]

Patients With New York Heart Association (NYHA) Functional Class Change (Improved or Worsened) From Baseline to Day 28

Disease severity was assessed by NYHA classification of PAH criteria: Class I: no limitation of physical activity (PA). Ordinary PA: no undue dyspnea/fatigue, chest pain, near syncope. Class II: slight limitation of PA. Comfortable at rest. Ordinary PA: undue dyspnea/fatigue, chest pain, near syncope. Class III: marked limitation of PA. Comfortable at rest. Less than ordinary PA: undue dyspnea/fatigue, chest pain, near syncope. Class IV: inability to carry out PA without symptoms. Right heart failure. Dyspnea/fatigue may even have been present at rest. Discomfort increased by any PA. (NCT01105091)
Timeframe: From baseline to 28 days (+3 days)

,
Interventionparticipants (Number)
Improved PatientsWorsened Patients
ACT-385781A (Epoprostenol for Injection)60
Flolan® (Epoprostenol Sodium) for Injection30

[back to top]

Percentage Central Venous Blood Oxygen Saturation (ScVO2) - Baseline and Day 28

Central venous blood oxygen saturation assessment was performed only in specific centers. Measurements for ScVO2 were performed during the inpatient hospitalization period on Day 1 (prior to drug initiation) and on Day 28 (EOT). Samples for ScVO2 were obtained by aspirating blood from the indwelling central venous catheter. After the sample had been drawn, the catheter was primed with study drug in order to refill the lumen to avoid interruption in treatment and sudden decompensation. (NCT01105091)
Timeframe: Baseline and 28 days

,
Interventionpercentage oxygen saturation (Median)
BaselineDay 28
ACT-385781A (Epoprostenol for Injection)63.058.0
Flolan® (Epoprostenol Sodium) for Injection61.556.0

[back to top]

Six-minute Walk Distance (6MWD) - Baseline and Day 28

The 6-minute walk test (6MWT) was to be performed prior to initiating study treatment either during the screening visit or on Day 1 prior to drug initiation, and Day 28 (End of treatment (EOT)). This assessment is a non-encouraged test that measures the distance walked for a duration of 6 minutes. The 6MWD was recorded in the Case Report Form (CRF). (NCT01105091)
Timeframe: Baseline and 28 days (+3 days)

,
Interventionmeters (Median)
BaselineDay 28
ACT-385781A (Epoprostenol for Injection)339.0288.0
Flolan (Epoprostenol Sodium) for Injection302.5323.5

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Safety and Tolerability of ACT-385781A and Flolan in Injectable Prostanoid Treatment-naïve Patients With PAH - Number of Deaths

(NCT01105117)
Timeframe: Up to 39 days. Day 1 - until patients transition from study medication to commercially-obtained medication

Interventionparticipants (Number)
ACT-385781A (Epoprostenol for Injection)0
Flolan® (Epoprostenol Sodium) for Injection0

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Safety and Tolerability of ACT-385781A and Flolan in Injectable Prostanoid Treatment-naïve Patients With Pulmonary Arterial Hypertension (PAH) - Number of Patients With Adverse Events Leading Discontinuation of Study Treatment

(NCT01105117)
Timeframe: Up to 39 days. Day 1 - until patients transition from study medication to commercially-obtained medication

Interventionparticipants (Number)
ACT-385781A (Epoprostenol for Injection)0
Flolan® (Epoprostenol Sodium) for Injection0

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Number of Participants With Any Treatment Emergent Adverse Events (AEs) and Treatment Emergent Serious Adverse Events(SAEs)

An AE was defined as any untoward medical occurrence that occurred during the course of the trial after study treatment had started. An adverse event was therefore any unfavourable and unintended sign, symptom, or disease temporally associated with the use of study drug, whether or not considered related to the study drug. An SAE is any untoward medical occurrence that at any dose results in death, are life threatening, requires hospitalization or prolongation of hospitalization or results in disability/incapacity, congenital anomaly/birth defect and medically significant and all events of possible drug-induced liver injury with hyperbilirubinaemia. Only treatment emergent AEs and SAEs were reported in this outcome measure. Specifically, this study reported 2 SAEs, but only 1 was categorized as treatment emergent. (NCT01462565)
Timeframe: Up to visit 3 (Week 4)

InterventionParticipants (Count of Participants)
Any AEsAny SAEs
Epoprostenol Sodium for Injection91

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Number of Participants With Infusion Site Reactions During Treatment Period

Infusion site reactions were reported during the treatment period. Infusion site was inspected for erythema, excoriation, induration, skin necrosis or signs of local sepsis. (NCT01462565)
Timeframe: Baseline visit (Visit 2) to Week 4 (Visit 3)

InterventionParticipants (Count of Participants)
ErythemaSigns of local sepsisOther
Epoprostenol Sodium for Injection111

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World Health Organization [WHO] Functional Class at Baseline and After 4- Weeks of Treatment

World Health Organization functional class was analyzed as class I, class II, class III and class IV. World Health Organization functional class was analyzed at Baseline (Visit 2 i.e. Day-14 [+ or - 7 days]) and Week 4. The classed were defined as Class I: No symptoms of pulmonary arterial hypertension with exercise or at rest, Class II: No symptoms at rest but uncomfortable and short of breath with normal activity, Class III: May not have symptoms at rest but activities greatly limited by shortness of breath, fatigue, or near fainting and Class IV: Symptoms at rest and severe symptoms with any activity. Hence the severity increased from class I (better) to Class IV (worse). (NCT01462565)
Timeframe: Baseline (Visit 2 i.e. Day-14 [+ or - 7 days]) and Week 4

InterventionParticipants (Count of Participants)
Baseline WHO Class IBaseline WHO Class IIBaseline WHO Class IIIBaseline WHO Class IVWeek 4 Class IWeek 4 Class IIWeek 4 Class IIIWeek 4 Class IV
Epoprostenol Sodium for Injection294021040

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Change From Baseline in Vital Signs at Week 4 : Systolic and Diastolic Blood Pressure

Systolic blood pressure is a measure of blood pressure while the heart is beating. Diastolic blood pressure is a measure of blood pressure while the heart is relaxed. Change from Baseline was calculated as the value at the indicated time points minus the value at Baseline. Baseline was Visit 2 i.e. Day-14 (+ or - 7 days). (NCT01462565)
Timeframe: Baseline (Visit 2 i.e. Day-14 [+ or - 7 days]) and Week 4(Visit 3)

InterventionMillimeter of mercury (mmHg) (Mean)
Systolic blood pressureDiastolic blood pressure
Epoprostenol Sodium for Injection-0.40.4

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Breathlessness After 6MWD - Borg Dyspnoea Index (BDI)

The BDI was calculated by using a 10-point scale (0 = None, 10 = Maximum) and indicates the degree of breathlessness after completion of the 6-minute walk test. The BDI scale was assessed by each participant. Change from Baseline = score at observation minus score at Baseline. Baseline visit was Visit 2 i.e. Day-14 (+ or - 7 days). (NCT01462565)
Timeframe: Baseline (Visit 2 i.e. Day-14 [+ or - 7 days]) to Week 4

InterventionScore on a scale (Mean)
Epoprostenol Sodium for Injection0.36

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Change From Baseline in Dose of Thermo Stable Epoprostenol Sodium at Week 4

Dose titration requirement was assessed at the time of discharge. Change from Baseline was calculated as score at observation minus score at Baseline. Units- nanogram per kilogram per minute (ng/kg/min). Baseline was Visit 2 i.e . Day-14 (+ or - 7 days). (NCT01462565)
Timeframe: Baseline (Visit 2 i.e. Day-14 [+ or - 7 days]) and Week 4

Interventionng/kg/min (Mean)
Epoprostenol Sodium for Injection0.22

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Change From Baseline in Six Minute Walk Distance Test (6MWD) After 4-weeks of Treatment

This assessment was a non-encouraged test that measures the distance walked for a duration of 6 minutes. Change from Baseline was calculated as value at observation minus value at Baseline. Baseline visit was Visit 2 i.e. Day-14 (+ or - 7 days). (NCT01462565)
Timeframe: Baseline (Visit 2 i.e. Day-14 [+ or - 7 days]) and Week 4

Interventionmeters (Mean)
Epoprostenol Sodium for Injection-3.55

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Change From Baseline in Vital Signs at Week 4: Heart Rate

Summary mean change in heart rate measured in beats per minute (beats/min or BPM). Change from Baseline was calculated as the value at the indicated time points minus the value at Baseline. Baseline was Visit 2 i.e. Day-14 (+ or - 7 days). (NCT01462565)
Timeframe: Baseline (Visit 2 i.e. Day-14 [+ or - 7 days]) to Week 4

Interventionbeats/min (Mean)
Epoprostenol Sodium for Injection-1.7

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Number of Participants With Abnormal Clinical Chemistry

Abnormal clinical chemistry was analyzed as follows: serum alanine aminotransferase (ALT/SGPT) >= 3 x upper limit of normal (ULN) , aspartate aminotransferase (AST/SGOT) >= 3 x ULN , total bilirubin >= 34.2, creatinine >= 176.8. (NCT01462565)
Timeframe: Up to 1 week after Week 4 (Follow-up)

InterventionParticipants (Count of Participants)
Epoprostenol Sodium for Injection0

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Number of Participants With Abnormal Urinalysis

Dipstick method was used to measure blood, glucose and protein. Data was analyzed up to 1 week after Week 4 (Follow-up visit). (NCT01462565)
Timeframe: Up to 1 week after Week 4 (Follow-up)

InterventionParticipants (Count of Participants)
Epoprostenol Sodium for Injection0

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Number of Participants With Urine Pregnancy Test Positive

Urine samples were collected for urine pregnancy test. Urine samples were collected at up to the treatment follow up (1 week after Visit 3 [Week 4]). Number of participants with urine pregnancy test positive has been reported. (NCT01462565)
Timeframe: up to the treatment follow up (1 week after Visit 3 [Week 4])

InterventionParticipants (Count of Participants)
Epoprostenol Sodium for Injection0

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Change From Baseline in Medical Outcomes Study Short Form 36 (SF-36)

Subject-rated measure of health status comprised of 36 items: 8 subscale scores (physical functioning, role limitations due to physical health problems, bodily pain, general health, vitality, social functioning, role limitations due to emotional problems, and mental health), 2 summary scores (physical component and mental component), and a self-evaluated change in health status. Subscale and summary scores range: 0-100. Higher subscale and summary scores was considered as better health status. Change from Baseline was calculated as score at observation minus score at baseline. Baseline was defined as Visit 2 i.e. Day-14 (+ or - 7 days). (NCT01462565)
Timeframe: Baseline (Visit 2 i.e. Day-14 [+ or - 7 days]) and Week 4 (Visit 3)

InterventionScore on a scale (Mean)
Physical FunctioningRole-PhysicalRole-EmotionalVitalityMental HealthSocial FunctioningBodily PainGeneral HealthPhysical Health ComponentMental Health Component
Epoprostenol Sodium for Injection-1.156-0.7650.0020.7810.8831.7063.065-0.606-0.1231.141

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Change From Baseline in Study Specific Participant Acceptance Survey

Study-specific questionnaire comprised the pre-defined15 questions which included activities of daily living assessment. Participants rated the question on a scale of 1 to 10, where 1 was do not agree and 10 was strongly agree. Change from Baseline was calculated as score at observation minus score at Baseline. Changes from Baseline was assessed for Questions 2 to 12. Baseline was defined as Visit 2 i.e. Day-14 (+ or - 7 days). (NCT01462565)
Timeframe: Baseline (Visit 2 i.e. Day-14 [+ or - 7 days]) and Week 4 (Visit 3).

InterventionScore on a scale (Mean)
Q2- ability to perform physical activitiesQ3- ability to perform your basic daily activiesQ4- ability to perform activities with your familyQ5- ability to participate in social activitiesQ6- ability to comply with your Flolan treatmentQ7- ability to perform new activity(Jogging, walk)Q8- overall satisfactionQ9- interested physical activityQ10- feel physically restricted from participatingQ11- confident in my ability to do new activityQ12- treatment regimen constantly weighs on mind
Epoprostenol Sodium for Injection-0.9-1.5-0.8-0.90.30.40.4-0.10.10.6-0.6

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Mean Oxygen Saturation in Blood Over Time

Pulse oximetry (oxygen saturation) was analyzed. Data for Pulse oximetry (oxygen saturation) was analyzed up to the treatment follow up (1 week after Visit 3 [Week 4]). (NCT01462565)
Timeframe: up to the treatment follow up (1 week after Visit 3 [Week 4])

InterventionPercentage of oxygen in blood (Mean)
BaselineWeek 4Follow-up (1 week after Week 4)
Epoprostenol Sodium for Injection94.394.593.0

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Number of Participants With Abnormal Hematology

Values for hemoglobin, hematocrit, and platelet count were analyzed. Participants with abnormal values have been reported. The low and high value concern were as follows: hemoglobin (Males < 98, >180.0) (females <91, >161.0)grams per litre (g/L); hematocrit (Males < 32.0, >54.0) (females <29.0, >50.6) fraction (1); platelet count (< 100, > 500) gram international units per litre (gI/L). (NCT01462565)
Timeframe: Up to 1 week after Week 4 (Follow-up)

InterventionParticipants (Count of Participants)
Hemoglobin (G/L) : Week 4: highHematocrit (1): Screening: LowHematocrit (1): Baseline: LowHematocrit (1): Week 4: LowHematocrit (1): Follow-up: LowPlatelet count (GI/L): Screening: LowPlatelet count (GI/L): Baseline: LowPlatelet count (GI/L): Week 4: LowPlatelet count (GI/L): Follow up: Low
Epoprostenol Sodium for Injection114151515211

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Treatment-emergent Adverse Events

(NCT01470144)
Timeframe: On average 2.72 years

InterventionNumber of patients (Number)
Treatment41

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Exposure Duration

Duration of exposure to EFI (NCT01470144)
Timeframe: On average 2.72 years

Interventionyear (Median)
Treatment2.44

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Heart Rate

Heart Rate was measured as mean of Heart Rate for the initial 8 hours after admission to the Intensive Care Unit (ICU). Normal range for heart rate is generally 60 to 100 beats per minutes in adults, but this can vary. (NCT01717209)
Timeframe: 8 hours (upon arrival at ICU, and after 4 successive 2 hour treatments with 1. iNO only, 2. iNO+iPGI2 (1st), 3. iPGI2 only, and 4. iNO+iPGI2 (2nd))

Interventionbeats/minute (Mean)
At Arrival in ICUFollowing iNOFollowing iNO+iPGI2 (1st)Following iPGI2Following iNO+iPGI2 (2nd)
Combined Nitric Oxide and Prostacyclin111.1112.5108.4106.0104.6

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Mean Arterial Pressure (MAP)

Mean Arterial Pressure (MAP) was measured as mean of MAP for the initial 8 hours after admission to the Intensive Care Unit (ICU). Normal range for MAP is 70-110 mmHg. (NCT01717209)
Timeframe: 8 hours (upon arrival at ICU, and after 4 successive 2 hour treatments with 1. iNO only, 2. iNO+iPGI2 (1st), 3. iPGI2 only, and 4. iNO+iPGI2 (2nd))

InterventionmmHg (Mean)
At Arrival in ICUFollowing iNOFollowing iNO+iPGI2 (1st)Following iPGI2Following iNO+iPGI2 (2nd)
Combined Nitric Oxide and Prostacyclin86.2980.8679.0079.4380.86

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Pulmonary Hypertension

Pulmonary hypertension was measured as mean of Mean Pulmonary Artery Pressure for initial 8 hours after admission to the Intensive Care Unit (ICU). MPAP value ≥25 mmHg (resting) indicates pulmonary hypertension state. (NCT01717209)
Timeframe: 8 hours (upon arrival at ICU, and after 4 successive 2 hour treatments with 1. iNO only, 2. iNO+iPGI2 (1st), 3. iPGI2 only, and 4. iNO+iPGI2 (2nd))

InterventionmmHg (Mean)
At Arrival in ICUFollowing iNOFollowing iNO+iPGI2 (1st)Following iPGI2Following iNO+iPGI2 (2nd)
Combined Nitric Oxide and Prostacyclin31.429.125.925.425.4

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Right Heart Dysfunction

Right Heart Dysfunction was measured as mean of Right Ventricular Stroke Work Index (RVSWI) for the initial 8 hours after admission to the Intensive Care Unit (ICU). RVSWI is measured as the difference in mean pulmonary artery pressure (MPAP) and central venous pressure (CVP), divided by the cardiac index (CI): [(MPAP-CVP) / CI]. Normal range for RVSWI is 5-10 g/m. (NCT01717209)
Timeframe: 8 hours (upon arrival at ICU, and after 4 successive 2 hour treatments with 1. iNO only, 2. iNO+iPGI2 (1st), 3. iPGI2 only, and 4. iNO+iPGI2 (2nd))

Interventiong/m (Mean)
At Arrival in ICUFollowing iNOFollowing iNO+iPGI2 (1st)Following iPGI2Following iNO+iPGI2 (2nd)
Combined Nitric Oxide and Prostacyclin5.25.04.85.44.9

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Systemic Vascular Resistance (SVR)

Systemic Vascular Resistance (SVR) was measured as mean of Systemic Vascular Resistance (SVR) for the initial 8 hours after admission to the Intensive Care Unit (ICU). Normal range for SVR is 800-1200 dynes/sec/cm5. (NCT01717209)
Timeframe: 8 hours (upon arrival at ICU, and after 4 successive 2 hour treatments with 1. iNO only, 2. iNO+iPGI2 (1st), 3. iPGI2 only, and 4. iNO+iPGI2 (2nd))

Interventiondynes/sec/cm^5 (Mean)
At Arrival in ICUFollowing iNOFollowing iNO+iPGI2 (1st)Following iPGI2Following iNO+iPGI2 (2nd)
Combined Nitric Oxide and Prostacyclin1193.91169.71070.61132.41145.9

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Central Venous Pressure (CVP)

Central Venous Pressure (CVP) was measured as mean of CVP for the initial 8 hours after admission to the Intensive Care Unit (ICU). Normal range for CVP is 3-8 mmHg. (NCT01717209)
Timeframe: 8 hours (upon arrival at ICU, and after 4 successive 2 hour treatments with 1. iNO only, 2. iNO+iPGI2 (1st), 3. iPGI2 only, and 4. iNO+iPGI2 (2nd))

InterventionmmHg (Mean)
At Arrival in ICUFollowing iNOFollowing iNO+iPGI2 (1st)Following iPGI2Following iNO+iPGI2 (2nd)
Combined Nitric Oxide and Prostacyclin12.712.611.610.110.6

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Absolute Values of Alanine Aminotransferase, Aspartate Aminotransferase, Alkaline Phosphatase, Gamma Glutamyltransferase, Lactate Dehydrogenase and Creatine Kinase at Baseline and Week 4

Blood samples were collected for measurement of Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST), Alkaline Phosphatase (ALP), Gamma Glutamyltransferase (GGT), Lactate Dehydrogenase (LDH) and Creatine Kinase (CK) at Baseline (BL) and Week 4 (W4). The Baseline values are those collected within 0.5 hr prior to the first dose of the new diluent formulation ('Visit 2 - Baseline') (NCT02705807)
Timeframe: Baseline and Week 4

InterventionInternational units per liter (IU/L) (Mean)
ALT, BLALT, W4AST, BLAST, W4ALP, BLALP, W4GGT, BLGGT, W4LDH, BLLDH, W4CK, BLCK, W4
FLOLAN With New Diluent15.919.614.016.4181.0175.222.722.1165.2160.840.844.7

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Absolute Values of Albumin and Total Protein at Baseline and Week 4

Blood samples were collected for measurement of albumin and total protein at Baseline (BL) and Week 4 (W4). The Baseline values are those collected within 0.5 hr prior to the first dose of the new diluent formulation ('Visit 2 - Baseline') (NCT02705807)
Timeframe: Baseline and Week 4

InterventionG/L (Mean)
Albumin, BLAlbumin, W4Total protein, BLTotal protein, W4
FLOLAN With New Diluent43.841.168.063.9

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Absolute Values of Free Triiodothyronine and Free Thyroxine at Baseline and Week 4

Blood samples were collected for measurement of Free Triiodothyronine (FT3) and Free Thyroxine (FT4) at Baseline (BL) and Week 4 (W4). The Baseline values are those collected within 0.5 hr prior to the first dose of the new diluent formulation ('Visit 2 - Baseline') (NCT02705807)
Timeframe: Baseline and Week 4

Interventionpicomoles per litre (pmol/L) (Mean)
FT3, BLFT3, W4FT4, BLFT4, W4
FLOLAN With New Diluent5.09744.928014.684714.2857

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Absolute Values of Hematocrit at Baseline and Week 4

Blood samples were collected for measurement of hematocrit values at Baseline (BL) and Week 4 (W4). The Baseline values are those collected within 0.5 hr prior to the first dose of the new diluent formulation ('Visit 2 - Baseline') (NCT02705807)
Timeframe: Baseline and Week 4

InterventionLiter (L) (Mean)
BLW4
FLOLAN With New Diluent0.39690.3662

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Absolute Values of Hemoglobin at Baseline and Week 4

Blood samples were collected for measurement of hemoglobin values at Baseline (BL) and Week 4 (W4). The Baseline values are those collected within 0.5 hr prior to the first dose of the new diluent formulation ('Visit 2 - Baseline') (NCT02705807)
Timeframe: Baseline and Week 4

InterventionGram/Liter (G/L) (Mean)
BLW4
FLOLAN With New Diluent135.5124.1

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Absolute Values of Oxygen Saturation

Oxygen saturation was measured by pulse oximetry at Baseline (BL), 1 hr, 3 hr, 24 hr, Week 4 (W4). The Baseline values are those collected within 0.5 hr prior to the first dose of the new diluent formulation ('Visit 2 - Baseline'). (NCT02705807)
Timeframe: Baseline and up to Week 4

InterventionPercentage (Mean)
BL1 hr3 hr24 hrWeek 4
FLOLAN With New Diluent97.698.097.697.797.8

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Absolute Values of Platelet Count and White Blood Cell Count at Baseline and Week 4

Blood samples were collected for measurement of platelets and white blood cells (WBC) at Baseline (BL) and Week 4 (W4). The Baseline values are those collected within 0.5 hr prior to the first dose of the new diluent formulation ('Visit 2 - Baseline') (NCT02705807)
Timeframe: Baseline and Week 4

InterventionGiga/Liter (GI/L) (Mean)
Platelet count, BLPlatelet count, W4WBC count, BLWBC count, W4
FLOLAN With New Diluent181.9153.40.00650.0063

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Absolute Values of Red Blood Cell Count at Baseline and Week 4

Blood samples were collected for measurement of red blood cells at Baseline (BL) and Week 4 (W4). The Baseline values are those collected within 0.5 hr prior to the first dose of the new diluent formulation ('Visit 2 - Baseline') (NCT02705807)
Timeframe: Baseline and Week 4

Interventionterabinary/liter (Ti/L)) (Mean)
BLW4
FLOLAN With New Diluent0.04820.0446

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Absolute Values of Thyroid Stimulating Hormone at Baseline and Week 4

Blood samples were collected for measurement of Thyroid Stimulating Hormone (TSH) at Baseline (BL) and Week 4 (W4). The Baseline values are those collected within 0.5 hr prior to the first dose of the new diluent formulation ('Visit 2 - Baseline') (NCT02705807)
Timeframe: Baseline and Week 4

Interventionmilliunits per litre (mU/L) (Mean)
TSH, BLTSH, W4
FLOLAN With New Diluent2.4261.822

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Absolute Values of Total and Direct Bilirubin, Creatinine, and Uric Acid at Baseline and Week 4

Blood samples were collected for measurement of total and direct bilirubin, creatinine (CRT), and uric acid (UA) at Baseline (BL) and Week 4 (W4). The Baseline values are those collected within 0.5 hr prior to the first dose of the new diluent formulation ('Visit 2 - Baseline') (NCT02705807)
Timeframe: Baseline and Week 4

InterventionMicromoles per liter (Mean)
Total Bilirubin, BLTotal Bilirubin, W4Direct Bilirubin, BLDirect Bilirubin, W4CRT, BLCRT, W4UA, BLUA, W4
FLOLAN With New Diluent9.0638.5500.8551.36858.167250.4764349.1476313.4596

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Change From Baseline in Heart Rate

Heart rate was measured at Baseline, 1 hr, 3 hr, 24 hr, Week 4 (W4). The Baseline values are those collected within 0.5 hr prior to the first dose of the new diluent formulation ('Visit 2 - Baseline'). Change from Baseline is defined as the difference between the post-dose visit value and the Baseline value. (NCT02705807)
Timeframe: Baseline and up to Week 4

InterventionBeats per minute (bpm) (Mean)
1 hr3 hr24 hrWeek 4
FLOLAN With New Diluent1.42.35.14.0

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Change From Baseline in Mean Pulmonary Arterial Pressure (mPAP) and Mean Right Atrial Pressure (mRAP)

mPAP and mRAP are hemodynamic parameters. The Baseline values are those collected within 0.5 hr prior to the first dose of the new diluent formulation ('Visit 2 - Baseline'). Change from Baseline is defined as the difference between the post-dose visit value and the Baseline value. (NCT02705807)
Timeframe: Baseline and up to Week 4

InterventionmmHg (Mean)
mPAP, 1hrmPAP, 3hrmPAP, 24hrmPAP, Week4mRAP, 1hrmRAP, 3hrmRAP, 24hrmRAP, Week4
FLOLAN With New Diluent0.51.5-0.51.9-0.9-0.10.31.5

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Change From Baseline in N-terminal Pro B-type Natriuretic Peptide (NT Pro BNP)

Blood samples were collected at Baseline, 24 hours after the first dose of thermostable formulation of FLOLAN, and Week 4 for measurement of NT pro BNP. The Baseline values are those collected within 0.5 hr prior to the first dose of the new diluent formulation ('Visit 2 - Baseline'). Change from Baseline is defined as the difference between the post-dose visit value and the Baseline value. (NCT02705807)
Timeframe: Baseline and up to Week 4

Interventionnanogram/liter (Mean)
24 hrWeek 4
FLOLAN With New Diluent-1.833.7

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Change From Baseline in Pulmonary Vascular Resist (PVR)

The Baseline values are those collected within 0.5 hr prior to the first dose of the new diluent formulation ('Visit 2 - Baseline'). Change from Baseline is defined as the difference between the post-dose visit value and the Baseline value. (NCT02705807)
Timeframe: Baseline and up to Week 4

Interventionmillimeter mercury/liter/minute (Mean)
1hr3hr24hrWeek 4
FLOLAN With New Diluent0.204-0.0770.1960.368

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Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP)

SBP and DBP were measured at Baseline, 1 hr, 3 hr, 24 hr, Week 4 (W4). The Baseline values are those collected within 0.5 hr prior to the first dose of the new diluent formulation ('Visit 2 - Baseline'). Change from Baseline is defined as the difference between the post-dose visit value and the Baseline value. (NCT02705807)
Timeframe: Baseline, 1 hour, 3 hour, 24 hour and Week 4

InterventionMillimeters of mercury (mmHg) (Mean)
SBP, 1 hrSBP, 3 hrSBP, 24 hrSBP, Week 4DBP, 1 hrDBP, 3 hrDBP, 24 hrDBP, Week 4
FLOLAN With New Diluent4.21.21.12.1-0.60.70.92.5

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Number of Events to Adjust Dose of FLOLAN Based on the Change From Baseline to 3 Hours in Mean Pulmonary Artery Pressure (mPAP)

To assess the frequency of dose adjustment requirements based on the changes from baseline in mPAP up to 3 hours after dosing.The Baseline values are those collected within 0.5 hr prior to the first dose of the new diluent formulation ('Visit 2 - Baseline'). Participants who gave consent to undergo right heart catheterisation (RHC) over 24-hour and at week 4 were assessed. Change from Baseline is defined as the difference between the post-dose visit value and the Baseline value. (NCT02705807)
Timeframe: Up to Week 4

InterventionNumber of events (Number)
YesNo
FLOLAN With New Diluent010

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Number of Participants in Each World Health Organization (WHO) Functional Class

The WHO functional classes of PAH range from Class I (without limitation in physical activity) to Class IV (inability to perform a physical activity without any symptoms). (NCT02705807)
Timeframe: Baseline and Week 4

InterventionParticipants (Number)
WHO Class I, BLWHO Class II, BLWHO Class III, BLWHO Class IV, BLWHO Class I, W4WHO Class II, W4WHO Class III, W4WHO Class IV, W4
FLOLAN With New Diluent190001000

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Number of Participants With Any Adverse Event (AE) or Serious Adverse Event (SAE)

An AE is defined as any untoward medical occurrence in a participant or clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. A SAE is defined as any untoward medical occurrence that, at any dose, results in death, is life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, or is a congenital anomaly/birth defect, important medical events which may require medical or surgical interventions. Intention-to-Treat (ITT) population: comprised of all participants who have received at least one dose of the thermostable formulation of FLOLAN. (NCT02705807)
Timeframe: Up to Week 4

InterventionParticipants (Number)
Any AEAny Drug-Related AEAny SAE
FLOLAN With New Diluent210

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Change From Baseline in Cardiac Output (CO)

Cardiac output is the volume of blood pumped by the heart per minute. The Baseline values are those collected within 0.5 hr prior to the first dose of the new diluent formulation ('Visit 2 - Baseline'). Change from Baseline is defined as the difference between the post-dose visit value and the Baseline value. (NCT02705807)
Timeframe: Baseline and up to Week 4

Interventionliter/minute (Mean)
1hr3hr24hrWeek 4
FLOLAN With New Diluent-0.0700.460-0.0200.408

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Number of Participants With Mild, Moderate or Severe AEs

Intensity for an AE and SAE is categorized as mild if an event is easily tolerated by the participant, causing minimal discomfort and not interfering with everyday activities; moderate if an event is sufficiently discomforting to interfere with normal everyday activities; severe if that prevents normal everyday activities. (NCT02705807)
Timeframe: Up to Week 4

InterventionParticipants (Number)
Mild, NauseaMild, Hepatic function abnormal
FLOLAN With New Diluent11

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Number of Participants With the Indicated Electrocardiogram (ECG) Findings

A safety 12-lead ECG was performed at Baseline (BL), 24 hr after switching to the new Flolan diluent and Week 4 (W4). Any abnormal clinically significant (CS) and not clinically significant (NCS) findings were reported. ECG abnormaility with respect to CS and NCS findings were judged by the investigator. The Baseline values are those collected within 0.5 hr prior to the first dose of the new diluent formulation ('Visit 2 - Baseline') (NCT02705807)
Timeframe: Baseline, 24 hour and Week 4

InterventionParticipants (Number)
BL, NCSBL, CS24 hr, NCS24 hr, CSW4, NCSW4, CS
FLOLAN With New Diluent9191100

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Number of Participants With the Indicated Urinalysis Findings

Urine protein, urine glucose, and occult blood were assessed at Baseline (BL) and Week 4 (W4). Dipstick test was performed for routine urinalysis. Abnormal values such as trace, 1+, 2+, 3+ and positive have been reported. The Baseline values are those collected within 0.5 hr prior to the first dose of the new diluent formulation ('Visit 2 - Baseline'). (NCT02705807)
Timeframe: Baseline and Week 4

InterventionParticipants (Number)
Urine glucose, BL, TraceUrine glucose, BL, 1+Urine glucose, BL, 2+Urine glucose, BL, 3+Urine glucose, BL, PositiveUrine glucose, W4, TraceUrine glucose, W4, 1+Urine glucose, W4, 2+Urine glucose, W4, 3+Urine glucose, W4, PositiveUrine occult blood, BL, TraceUrine occult blood, BL, 1+Urine occult blood, BL, 2+Urine occult blood, BL, 3+Urine occult blood, BL, PositiveUrine occult blood, W4, TraceUrine occult blood, W4, 1+Urine occult blood, W4, 2+Urine occult blood, W4, 3+Urine occult blood, W4, PositiveUrine protein, BL, TraceUrine protein, BL, 1+Urine protein, BL, 2+Urine protein, BL, 3+Urine protein, BL, PositiveUrine protein, W4, TraceUrine protein, W4, 1+Urine protein, W4, 2+Urine protein, W4, 3+Urine protein, W4, Positive
FLOLAN With New Diluent000000000021000010005100020000

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Number of Participants With the Reason for the Change Dose of the Thermostable Formulation of FLOLAN

All reasons for FLOLAN dose adjustments after the switch were listed. (NCT02705807)
Timeframe: Up to Week 4

InterventionParticipants (Number)
Adverse eventOther
FLOLAN With New Diluent02

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Percentage of Basophils, Eosinophils, Lymphocytes, Monocytes, and Total Neutrophils in Blood at Baseline and Week 4

Blood samples were collected for the measurement of percentage of basophils, eosinophils, lymphocytes, monocytes, and total neutrophils in blood at Baseline (BL) and Week 4 (W4). The Baseline values are those collected within 0.5 hour (hr) prior to the first dose of the new diluent formulation ('Visit 2 - Baseline') (NCT02705807)
Timeframe: Baseline and Week 4

InterventionPercentage (Mean)
Basophils BLBasophils W4Eosinophils BLEosinophils W4Lymphocytes BLLymphocytes W4Monocytes BLMonocytes W4Total Neutrophils BLTotal Neutrophils W4
FLOLAN With New Diluent0.610.452.663.2522.8722.375.164.4668.7069.47

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Absolute Values of Urea/Blood Urea Nitrogen, Glucose, Chloride, Sodium, Potassium, Magnesium, Phosphorus (Inorganic), and Calcium at Baseline and Week 4

Blood samples were collected for measurement of urea/Blood Urea Nitrogen (Urea/BUN), glucose, chloride, sodium, potassium, magnesium, phosphorus, inorganic, and calcium at Baseline (BL) and Week 4 (W4). The Baseline values are those collected within 0.5 hr prior to the first dose of the new diluent formulation ('Visit 2 - Baseline') (NCT02705807)
Timeframe: Baseline and Week 4

InterventionMillimoles per litre (mmol/L) (Mean)
Urea/BUN, BLUrea/BUN, W4Glucose, BLGlucose, W4Chloride, BLChloride, W4Sodium, BLSodium, W4Potassium, BLPotassium, W4Magnesium, BLMagnesium, W4Phosphorus, inorganic, BLPhosphorus, inorganic, W4Calcium, BLCalcium, W4
FLOLAN With New Diluent4.67674.46254.99595.7675103.8103.9139.6138.03.613.560.84670.78911.23991.19472.23802.1357

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Change From Baseline in Body Weight

Body weight was measured at Baseline (BL) and Week 4 (W4). The Baseline values are those collected within 0.5 hr prior to the first dose of the new diluent formulation ('Visit 2 - Baseline'). Change from Baseline is defined as the difference between the post-dose visit value and the Baseline value. Participants with body weight outside and within the clinical concern reference range (<50kg) has been presented. (NCT02705807)
Timeframe: Baseline and Week 4

InterventionParticipants (Number)
> clinical concern range, BL< clinical concern range, BL> clinical concern range, W4< clinical concern range, W4
FLOLAN With New Diluent0606

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