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      Novel Mechanisms Targeted by Drug Trials in Pulmonary Arterial Hypertension.

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          Abstract

          Pulmonary arterial hypertension (PAH) is a rare disease associated with abnormally elevated pulmonary pressures and right heart failure resulting in high morbidity and mortality. Although the prognosis for patients with PAH has improved with the introduction of pulmonary vasodilators, disease progression remains a major problem. Given that available therapies are inadequate for preventing small-vessel loss and obstruction, there is active interest in identifying drugs capable of targeting angiogenesis and mechanisms involved in the regulation of cell growth and fibrosis. Among the mechanisms linked to PAH pathogenesis, preclinical studies have identified promising compounds that are currently being tested in clinical trials. These drugs target seven of the major mechanisms associated with PAH pathogenesis: bone morphogenetic protein signaling, tyrosine kinase receptors, estrogen metabolism, extracellular matrix, angiogenesis, epigenetics, and serotonin metabolism. In this review, we discuss the preclinical studies that led to prioritization of these mechanisms, and discuss completed and ongoing phase 2/3 trials using novel interventions such as sotatercept, anastrozole, rodatristat ethyl, tyrosine kinase inhibitors, and endothelial progenitor cells, among others. We anticipate that the next generation of compounds will build on the success of the current standard of care and improve clinical outcomes and quality of life for patients with PAH.

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          Author and article information

          Journal
          Chest
          Chest
          Elsevier BV
          1931-3543
          0012-3692
          April 2022
          : 161
          : 4
          Affiliations
          [1 ] Division of Pulmonary, Allergy, and Critical Care Medicine, Stanford University, Stanford, CA.
          [2 ] Division of Pulmonary, Allergy, and Critical Care Medicine, Wall Center for Cardiopulmonary Research, Stanford University, Stanford, CA.
          [3 ] Division of Pulmonary, Allergy, and Critical Care Medicine, Wall Center for Cardiopulmonary Research, Stanford University, Stanford, CA. Electronic address: vdejesus@stanford.edu.
          Article
          S0012-3692(21)04093-9
          10.1016/j.chest.2021.10.010
          9005865
          34655569
          24c3970f-d280-4067-a7dd-9db4e1e23cab
          History

          clinical trials,therapeutics,pulmonary hypertension,pathogenesis

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