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. 2018 Dec 28;8(1):e011343. doi: 10.1161/JAHA.118.011343

Table 2.

Summary of Preclinical Results of Potentially Repurposed Drugs for PAH

Drug Mechanism of Action Downstream Consequence In Vivo Effects Animal Model Used Animal Model Dose Equivalent Human Dosea Maximal Daily Dose in Clinical Practice
Aldosterone antagonist Inhibition of aldosterone signaling 1. Increased nitric oxide levels in the PV
2. Reduced ECM remodeling in the PV
3. Inhibition of mTORC1 signaling leading to reduced PASMC proliferation 		1.Blunted PV remodeling
2. Reduced RVH 		MCT
SU‐5416 hypoxia 		Spironolactone (25 mg/kg/d)
Eplerenone (0.6 mg/g chow) 		Spironolactone: 4.0 mg/kg/d
Eplerenone: 0.1 mg/g food 		Spironolactone: 200 mg
Eplerenone: 100 mg
Allopurinol Xanthine oxidase inhibitor 1. Reduced PCOOH levels
2. Normalization of xanthine oxidase activity
3. Reduction in overall oxidative stress 		1.Blunted PV remodeling
2. Reduced RVH 		Hypoxic adult and neonatal rats 50 mg/kg/d
50 mg/kg every 12 h 		8.1 mg/kg/d
8.1 mg/kg every 12 h 		300 mg
Anakinra Block inflammatory cytokine IL1 1. Reduced IL1 mRNA in lungs
2. Reduced macrophage infiltration into pulmonary vasculature 		1. Blunted PV remodeling in MCT rats
2. Reduced RVH in MCT rats 		MCT
Hypoxia 		Anakinra not used in preclinical study Anakinra not used in preclinical study 100 mg
Anastrozole Inhibitor of estrogen signaling 1. Increased BMPR2 signaling
2. Increased expression of PPAR‐γ
3. Increased expression of CD36
4. Increased insulin sensitivity
5. Reduction in PASMC proliferation 		1. Blunted PV remodeling
2. Reduced RVH 		Hypoxic rats
Hypoxic mice
SU‐5416 hypoxia
BMPR2 R899X mice 		0.03–3 mg/kg/d 0.005–0.5 mg/kg/d 1 mg
Apabetaloneb BRD‐4 inhibitor 1. Reduced levels of oncogenic proteins NFATC2, Bcl‐2, and survivin
2. Increased expression of p21
3. Reduction in PASMC proliferation 		1. Blunted PV remodeling
2. Reduced RVH 		SU‐5416 hypoxia Apabetalone not used in preclinical study Apabetalone not used in preclinical study 300 mg
β‐Adrenergic blockers Counteract excessive sympathetic nervous system activation in right ventricle and pulmonary vasculature 1. Normalization of β‐adrenergic signaling in the right ventricle
2. Increased SERCA2a mRNA levels 		1. Blunted PV remodeling
2. Decreased RV fibrosis
3. Improved RV function
4. Augmented exercise capacity
5. Improved survival 		MCT,
SU‐5416 hypoxia 		Arotinolol (0.25 mg/kg/d)
Bisoprolol (10 mg/kg/d)
Carvedilol (15 mg/kg/d) 		Arotinolol (0.04 mg/kg/d)
Bisoprolol (1.6 mg/kg/d)
Carvedilol (2.4 mg/kg/d) 		Arotinolol: NA,
Bisoprolol: 10 mg
Carvedilol: 100 mg
Chloroquine Inhibitor of lysosomal degradation 1. Increased BMPR2 signaling via reduction in lysosomal degradation
2. Reduction in PASMC proliferation 		1. Blunted PV remodeling
2. Reduced RVH 		MCT 50 mg/kg/d 8.1 mg/kg/d 2.3 mg/kg
Colchicine Anti‐inflammatory and normalization of JPH2 levels via microtubule depolymerization 1. Reduction in PASMC proliferation
2. Restoration of structure and function of T‐tubules in RV cardiomyocytes 		1. Reduced PV remodeling
2. Reduced RVH
3. Improved RV function
4. Enhanced exercise capacity 		MCT 1.0 mg/kg/d for 5 d
0.5 mg/kg 3 times/wk 		0.16 mg/kg for 5 d
0.08 mg/kg 3 times/wk 		2.4 mg
DHEA Inhibits STAT3 which reduces NFATC2 and survivn and increases BMPR2 1. Reduction in PASMC proliferation
2. Increased PASMC apoptosis
3. Increased BMPR2 signaling 		1. Reduced PV remodeling
2. Reduced RVH
3. Improved RV function
4. Enhanced exercise capacity 		MCT,
SU‐5416 hypoxia 		10 mg/kg/d
30 mg/kg every other day
1% in food 		1.6 mg/kg/d
4.8 mg/kg every other day
0.16% in food 		100 mg
Dichloroacetate Counteract Warburg metabolic effect via PDK inhibition 1. Improved glucose oxidation
2. Reduced PASMC proliferation
3. Increased PASMC apoptosis
4. Increased potassium channel levels
5. Depolarization of mitochondria 		1. Reduced PV remodeling
2. Improved RV function
3. Enhanced RV contractility
4. Reduced RVH
5. Increased exercise capacity
6. Improved survival 		Hypoxic rats
MCT
SU‐5416
FHR
PAB rats 		70–80 mg/kg/d
0.75 g/L drinking water 		11.3–12.9 mg/kg/d
0.12 g/L of drinking water 		25 mg/kg
Metformin Inhibitor of MAPK activation, inhibitor of aromatase transcription, augments AMP activation 1. Reduced PASMC proliferation
2. Reduced PASMC contractility
3. Reduced RV lipid deposition 		1. Reduced PV remodeling
2. Reduced RVH 		Hypoxic rats
MCT
SU‐5416 hypoxia
BMPR2 R899X 		100 mg/kg/d
25 g/kg of high‐fat chow 		16.1 mg/kg /d
4.0 g/kg chow 		2550 mg
Nab‐rapamycin Inhibitor of mTORC1 and mTORC2 1. Reduced PASMC proliferation
2. Increased PASMC apoptosis 		1. Reduced PV remodeling (dose dependent)
2. Reduced RVH (dose dependent) 		MCT
Hypoxic mice 		Nab‐rapamycin not used in preclinical study Nab‐rapamycin not used in preclinical study 100 mg/m2
Olaparib Inhibitor of PARP1 1. Reduced PASMC proliferation
2. Increased PASMC apoptosis 		1. Reduced PV remodeling
2. Reduced RVH 		MCT
SU‐5416 		6 mg/kg/d 0.97 mg/kg/d 800 mg
Paclitaxel FOXO1 Activator 1. Reduced PASMC proliferation
2. Increased BMPR2 signaling
3. Increased PASMC apoptosis 		1. Reduced PV remodeling
2. Reduced RVH
3. Improved RV function 		SU‐5416 Hypoxia
MCT 		5–7 mg/kg/wk
1 mg/kg/wk aerosolized 		0.8–1.1 mg/kg/wk
0.16 mg/kg/wk aerosolized 		225 mg/m2 every 3 to 4 wks
Ranolazine Reduction of FAO and enhancement of glucose oxidation (by activating Randle cycle) 1. Reduced Glut1 and HK1 mRNA levels
2. Increased RV glucose oxidation
3. Increased ATP production
4. Decreased FAO 		1. Reduced RVH
2. Improved RV function
3. Decreased RV fibrosis
4. Reduced risk of arrhythmias
5. Increased exercise capacity 		PAB rats
MCT 		20 mg/d
0.25–0.5% in chow 		3.2 mg/d
0.04–0.08% in chow 		2000 mg
Rituximabb Anti‐inflammatory via blocking of CD20 1. Reduced IL6, HIF‐1α, and VEGF
2. Decreased PASMC proliferation 		1. Reduced PV remodeling
2. Reduced RVH 		Ovalbumin immunization plus SU‐5416 rats Rituximab not used in preclinical study Rituximab not used inpreclinical study 1000 mg every 2 wk
Rosiglitazone/
pioglitazone 		PPAR‐γ activators 1. Increased adiponectin levels
2. Reduced NOX4 levels
3. Reduced PASMC proliferation
4. Improved mitochondrial organization
5. Induced FAO genes
6. Improved FAO efficacy in cardiomyocytes 		1. Reduced PV remodeling
2. Reduced RVH
3. Improved RV function 		ApoE knockout mice
Hypoxic rats
Hypoxic mice
SU‐5416 rats 		Rosiglitazone (8–10 mg/kg/d)
Pioglitazone (20 mg/kg/d) 		Rosiglitazone (1.3–1.6 mg/kg/d)
Pioglitazone (3.2 mg/kg/d) 		Rosiglitazone: 8 mg
Pioglitazone: 45 mg
Tacrolimus Calcineurin inhibitor 1. Sequestered FK‐binding protein 2 from BMPR1 receptors
2. Increased BMPR2 signaling
3. Improved endothelial function
4. Reduced PASMC proliferation 		1. Reduced PV remodeling
2. Reduced RVH 		BMRP2 endothelial knockout mice
MCT
SU‐5416 hypoxia 		0.05 mg/kg/d 0.008 mg/kg/d 0.6 mg/kg
Tocilizumabb Inhibit inflammatory cytokine IL6 1. Reduced STAT3 activation
2. Induced PASMC apoptosis 		1. Reduced PV remodeling
2. Reduced RVH 		MCT
SU‐5416 hypoxia 		Tocilizumab not used in preclinical study Tocilizumab not used in preclinical study 800 mg every 4 wk
Trimetazidine Reduce FAO and enhance glucose oxidation (by activating Randle cycle) 1. Reduced Glut1 and HK1 mRNA levels
2. Increased RV glucose oxidation
3. Increased ATP production
4. Decreased FAO 		1. Reduced RVH
2. Improved RV function
3. Improved exercise capacity 		PAB rats 0.7 g/L of drinking water 0.11 g/L of drinking water 70 mg
TNF‐α inhibitor Anti‐inflammatory via blocking of TNF‐α signaling 1. Increased BMPR2 signaling
2. Decreased NOTCH2 expression
3. Reduced PASMC proliferation 		1. Reduced PV remodeling
2. Reduced RVH 		MCT
SU‐5416 		Etanercept: 2.5 mg/kg twice weekly 0.4 mg/kg twice weekly Etanercept: 100 mg twice weekly
Verteporfin Inhibitor of YAP‐induced glutaminolysis 1. Decreased lysyl oxidase activity
2. Reduced glutaminase activity
3. Reduced pulmonary arteriolar stiffness
4. Decreased PASMC proliferation 		1. Reduced PV remodeling
2. Reduced RVH 		MCT 25 mg/kg/d 4.0 mg/kg/d 6 mg/m2 every 3 mo

ApoE indicates apolipoprotein E; Bcl‐2, B cell lymphoma 2; BMPR, bone morphogenic protein receptor; BRD‐4, bromodomain‐containing protein 4; ECM, extracellular matrix; FOXO1, forkhead box protein O1; FHR, Fawn hooded rat; Glut1, glucose transporter 1; HIF‐1α, hypoxia‐inducible factor 1α; HK1, hexokinase 1; JPH2, junctophilin 2; IL, interleukin; MAPK, mitogen‐activated protein kinase; MCT, monocrotaline; mTORC, mammalian target of rapamycin complex; NA, not available; NFATC2, nuclear factor of activated T cells 2; NOTCH2, notch 2; PAB, Pulmonary artery banded; PAH, pulmonary arterial hypertension; Parp‐1, poly(ADP‐ribose) polymerase 1; PASMC, pulmonary artery smooth muscle cell; PCOOH, phosphatidylcholine hydroperoxide; PPAR‐γ, peroxisome proliferator‐activator γ; PV, pulmonary vasculature; RV, right ventricular; RVH, right ventricular hypertrophy; SERCA2a, sarco/endoplasmic reticulum Ca2+‐ATPase; STAT3, signal transducer and activator of transcription 3; SU‐5416, Sugen‐5416; VEGF, vascular endothelial growth factor; YAP, Yes‐associated protein.

a

Indicates human dose was calculated via differences in body surface area.96

b

Indicates a molecule with similar mechanism of action was used in preclinical studies.