Drug-Induced Pulmonary Arterial Hypertension: Mechanisms and Clinical Management

Identifying new drugs associated with pulmonary arterial hypertension: A WHO pharmacovigilance database disproportionality analysis

“…3,4 Increased mitochondrial ROS production. 3,5 Src kinase inhibition (vasoconstriction and vascular remodelling) 3 Bosutinib May increase mitochondrial ROS production 6 Frequently used after dasatinib 4 Ruxolitinib Paradoxical increase in STAT3 activity (inducing proliferation and anti-apoptosis of pulmonary arterial smooth muscle cells) 7 Used in myelofibrosis (known cause of PAH) JAK2 inhibition reduces proliferation of pulmonary arterial endothelial cells 8 Ponatinib Src kinase inhibition 9 Frequently used after dasatinib 24 Everolimus Inhibition of mTOR pathway has antiangiogenic effect through downregulation of the expression of VEGF-A/VEGFR-2 and VEGF-C/VEGFR-3 25 has been used as treatment 26 Leflunomide Inhibition of the src pathway, inhibition of COX-2 and dose-dependent toxicity against pulmonary endothelial cells 27 Understanding the mechanisms of iatrogenic PAH not only is important for exposed patients but also makes it possible to study how certain environmental factors can precipitate the onset of the disease in susceptible individuals. 6,18 While the exact mechanisms underlying the onset or aggravation of PAH are largely unknown, there is evidence that most of the known and newly identified drugs in this study may participate in the key cellular mechanisms leading to pulmonary vascular remodelling in PAH.…”

“…3 To date, various compounds have been associated with the onset of PAH including 1 protein kinase inhibitor dasatinib , some amphetamine ‐like appetite suppressants (aminorex, fenfluramine , dexfenfluramine , benfluorex), which have been withdrawn from the market primarily for this reason, and recreational drugs ( methamphetamine ). 1 , 4 …”

“…Furthermore, numerous case reports have suggested the onset or aggravation of PAH with other drugs and hypothesized a causative link 4–7 . However, given the scarcity of this pathology and the potential long latency period between drug intake and PAH onset, identifying iatrogenic aetiologies is challenging.…”

“…3 To date, various compounds have been associated with the onset of PAH including 1 protein kinase inhibitor dasatinib, some amphetaminelike appetite suppressants (aminorex, fenfluramine, dexfenfluramine, benfluorex), which have been withdrawn from the market primarily for this reason, and recreational drugs (methamphetamine). 1,4 Furthermore, numerous case reports have suggested the onset or aggravation of PAH with other drugs and hypothesized a causative link. [4][5][6][7] However, given the scarcity of this pathology and the potential long latency period between drug intake and PAH onset, identifying iatrogenic aetiologies is challenging.…”

“…1,4 Furthermore, numerous case reports have suggested the onset or aggravation of PAH with other drugs and hypothesized a causative link. [4][5][6][7] However, given the scarcity of this pathology and the potential long latency period between drug intake and PAH onset, identifying iatrogenic aetiologies is challenging. In this context, mining large pharmacovigilance databases constituted from spontaneously reported cases of suspected adverse drug reactions (ADRs) may be an interesting way to identify drugs possibly linked to PAH.…”