what s in the pah
play

Whats in the PAH Nitric Oxide Pathway Pathway Pathway - PowerPoint PPT Presentation

May 03, 2023 •103 likes •190 views

4/21/2018 Approved Therapies for PAH Endothelin Prostacyclin Whats in the PAH Nitric Oxide Pathway Pathway Pathway Endothelial cells Endothelial cells Therapeutic Pipelines? Pre-proendothelin Proendothelin Arachidonic acid

  1. 4/21/2018 Approved Therapies for PAH Endothelin Prostacyclin What’s in the PAH Nitric Oxide Pathway Pathway Pathway Endothelial cells Endothelial cells Therapeutic Pipelines? Pre-proendothelin Proendothelin Arachidonic acid Prostaglandin I 2 L-arginine L-citrulline Endothelin-1 Prostacyclin (prostaglandin I 2 ) Endothelin Endothelin receptor A Dunbar Ivy, MD receptor B Nitric Oxide Prostacyclin cAMP Exogenous derivatives nitric oxide Vasodilation Endothelin- cGMP sGC stimulator and antiproliferation receptor Vasoconstriction Phosphodiesterase and proliferation antagonists type 5 Vasodilation and antiproliferation Phosphodiesterase Smooth muscle cells type 5 inhibitor Smooth muscle cells Adapted from Humbert M et al. N Engl J Med . 2004;351:1425-1436. Approved Therapies for PAH Outline Endothelin Prostacyclin Nitric Oxide Pathway Pathway Pathway • Cancer / Metabolic agents: Dichloroacetate Endothelial cells Endothelial cells Pre-proendothelin Proendothelin Arachidonic acid Prostaglandin I 2 • Anti-estrogen: Anastrazole / Tamoxifen • Enhance BMPR2 Signaling: FK 506 L-arginine L-citrulline Endothelin-1 Prostacyclin (prostaglandin I 2 ) • Iron therapy Endothelin Endothelin receptor A receptor B Nitric Oxide • Tocilizumab: IL-6 Receptor Antagonist Prostacyclin cAMP Exogenous derivatives nitric oxide Vasodilation • Elastase Inhibitors Endothelin- cGMP sGC stimulator and antiproliferation receptor Vasoconstriction Phosphodiesterase and proliferation antagonists type 5 • Epigenetics Vasodilation Ralinepag Selective IP Agonist and antiproliferation Phosphodiesterase • DNA Damage Smooth muscle cells type 5 inhibitor Smooth muscle cells Adapted from Humbert M et al. N Engl J Med . 2004;351:1425-1436. 1

  2. 4/21/2018 Cancer traits by pulmonary vascular Comparison of Glycolysis Between cells during PAH progression Normal Tissue and Proliferated Tissue 95% 5% Boucherat, et al. Pulm Circ 2017 Jun; 7(2): 285–299 Richard Feinman Clinical Trial DCA Dichloroacetate Blocks PDK N=20 Ryan, Archer. Circulation. 2015;131:1691-1702 Michelakis et al., Sci. Transl. Med. 9, eaao4583 (2017) 2

  3. 4/21/2018 Estrogen Paradox Estrogen Paradox • Female IPAH preponderance (1.5-4:1 Female:Male) • BMPR2 gene expression reduced in females likely • Female IPAH patients survive longer through estrogen receptor alpha binding to BMPR2 • Female BMPR2 carriers more likely to develop PAH promoter (Austin, Biol Sex Differences, 2012) • 20% of carriers develop PAH • Females metabolizing estrogen to 16-oestrogens • 43% female vs 14% male but not 2- or 4- oestrogens more likely to develop • Pregnancy induced PAH PAH (Austin, ERJ 2009) • Estrogen levels higher in males and females with PAH Signaling by Estrogens Aromatase Inhibition: Anastrozole in PAH (AIPH) • Anastrozole Phase II Trial (PI: Kawut; NHLBI) • Reduce extragonadal estrogen production • Anastrazole blocks conversion of androgens to estrogens • Randomized, double-blind, placebo-controlled • 3 months Adapted from: Lahm Crit Care Med 2008 • PAH patients on background therapy • Males & Postmenopausal females Rapid Nongenomic Effects 1. Vasodilation • Anastrozole 1 mg (n=12) daily vs. Placebo (n=6) • Increase eNOS • • Primary Outcomes: Increase PGI 2 2. Promote angiogenesis • Change Estradiol (E2) Genomic Effects 3. Modify injury response • TAPSE Alter gene expression  Increase proliferative  Increase migration Kawut, et al AJRCCM 2017; 195(3):360-368 Adapted from Lahm et al Crit Care Med 2008 3

  4. 4/21/2018 AIPH Result: Safe & Tolerated Tamoxifen: Block Estrogen Signaling E2 Levels 6MWTD Change Tamoxifen Therapy to Treat Pulmonary Arterial Hypertension (T 3 PAH) 24 week, double-blind, randomized placebo-controlled proof of concept trial of tamoxifen in 24 pulmonary arterial hypertension (PAH) patients. • 12 tamoxifen • 12 placebo NIH P01 HL 108800 (Loyd) ** Kawut (PI), Ventetuolo and colleagues recently funded by NHLBI for AIPH2 ** Kawut, et al AJRCCM 2017; 195(3):360-368 FK506 in Human PAH Augment BMPR2 signaling • BMPR2 most common genetic mutation in PAH • BMPR2 signaling diminished in most forms of PAH • High throughput screening of 3600 drugs - FK 506 (Tacrolimus) identified as potent BMPR2 activator • Experimental evidence of reversal of endothelial <2 ng/ml 2-3 ng/ml dysfunction 3-5 ng/ml • Early clinical evidence of improvement Spiekerkoetter, J Clin Invest 2013 Spiekerkoetter, European Respiratory Journal 2017 50: 1602449 Spiekerkoetter, AJRCCM 2015 4

  5. 4/21/2018 FK506 in Human PAH Secondary Changes: FK 506 Spiekerkoetter, European Respiratory Journal 2017 50: 1602449 Spiekerkoetter, European Respiratory Journal 2017 50: 1602449 Exercise in iron Deficient IPAH Tocilizumab: IL-6 Receptor Antagonist Patients Before / After Iron • Inflammation and autoimmunity • Tocilizumab used in rheumatoid arthritis • Tocilizumab reversed PAH in MCTD and Lupus • TRANSFORM-UK • Group 1 PAH • IV Q month for 6 months • CoPrimary: Safety and PVR • Secondary: 6MWTD, NTproBNP, QOL, FC N=15 Ruiter, G, et al. Pulm Circ 2015 Sep;5(3):466-72 Hernandez-Sanchez, Pulmonary Circulation 2017; 8(1) 1–8 5

  6. 4/21/2018 Elafin increase Caveolin-1 induced Elafin: Elastase Inhibitor BMPR2 signaling Rabinovitch, Pulmonary Circulation 2017; 8(1) 1–8 Nickel, Am J Respir Crit Care Med Vol 191, Iss 11, pp 1273–1286 Epigenetics and PH Epigenetics and PH Valproic Acid HDAC Inhibitor Pullamsetti, Pulm Circ 2016 Dec; 6(4): 448–464 Pullamsetti, Pulm Circ 2016 Dec; 6(4): 448–464 6

  7. 4/21/2018 Epigenetics and PH DNA Damage and PH DMD: premature stop codon into the dystrophin mRNA Ataluren increases 6MWTD in DMD PAH: Increased BMPR2 signaling? Pullamsetti, Pulm Circ 2016 Dec; 6(4): 448–464 Ranchoux, et al. Int. J. Mol. Sci. 2016, 17, 990; doi:10.3390/ijms17060990 Pathogenesis of PAH Boucherat, et al. Pulm Circ 2017 Jun; 7(2): 285–299 7

Recommend

More recommend